阅读说明：本技术 由α-烯胺酮制备杂环骨架的方法 (Method for producing heterocyclic skeletons from alpha-enaminones ) 是由 D·茨韦里科赫弗斯基 于 2018-03-21 设计创作，主要内容包括：<Image he="320" wi="700" file="DDA0002241082710000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明提供由式(I)的α-烯胺酮构建单元制备各种杂环骨架的方法。(The present invention provides methods for preparing various heterocyclic scaffolds from α -enaminone building blocks of formula (I).)

1. A process for preparing a heterocyclic compound comprising the steps of:

Wherein

X is halogen;

is a single or double bond;

R1-R4 are each independently selected from H, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, C5-C12 aryl, C5-C12 heteroaryl; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; or

R3 and R4 together with the atoms to which they are attached form a 5-to 15-membered saturated, unsaturated, or aromatic ring;

l is a leaving group;

n is an integer from 1 to 10;

And wherein

2. The method according to claim 1, wherein

Wherein R2 is H and n is greater than 1.

3. The method according to claim 1, wherein

Wherein R2 is linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, optionally substituted as defined above, and n is greater than 1.

4. The method according to claim 1, wherein

Wherein R2 is C5-C12 aryl, C5-C12 heteroaryl; which is optionally substituted as above, and n is greater than 1.

5. the method according to claim 1, wherein

Wherein R2 is a linear or branched C1-C15 alkyl group, a linear or branched C2-C15 alkenyl group, a linear or branched C2-C15 alkynyl group, a C5-C12 aryl group, a C5-C12 heteroaryl group; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; and n is 1.

6. The method according to claim 1, wherein

Wherein

X is halogen;

Is a single or double bond;

R1-R4 are each independently selected from H, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, C5-C12 aryl, C5-C12 heteroaryl; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; or

R3 and R4 together with the atoms to which they are attached form a 5-to 15-membered saturated, unsaturated, or aromatic ring;

L is a leaving group;

n is an integer from 1 to 10;

And wherein

7. a method according to claim 6, wherein

Wherein R2 is H and n is greater than 1.

8. A method according to claim 6, wherein

Wherein R2 is linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, optionally substituted as defined above, and n is greater than 1.

9. A method according to claim 6, wherein

Wherein R2 is C5-C12 aryl, C5-C12 heteroaryl; which is optionally substituted as above, and n is greater than 1.

10. a method according to claim 6, wherein

Wherein R2 is a linear or branched C1-C15 alkyl group, a linear or branched C2-C15 alkenyl group, a linear or branched C2-C15 alkynyl group, a C5-C12 aryl group, a C5-C12 heteroaryl group; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; and n is 1.

11. A compound having the following general formula (XX):

Wherein

X is halogen;

R1-R4 are each independently selected from H, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, C5-C12 aryl, C5-C12 heteroaryl; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; provided that at least one of R1-R4 is different from H;

Or R3 and R4 together with the atoms to which they are attached form a 5-to 15-membered saturated, unsaturated, or aromatic ring;

n is an integer of 1 to 10.

12. the compound according to claim 11, wherein at least two of R1-R4 are different from H.

13. The compound according to claim 11, wherein at least three of R1-R4 are different from H.

14. A compound having the following general formula (XXI):

Wherein

X is halogen;

R1 and R2 are each independently selected from H, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, C5-C12 aryl, C5-C12 heteroaryl; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl;

n is an integer of 1 to 10.

15. the compound according to claim 14, wherein at least one of R1-R2 is different from H.

Technical Field

The present invention provides versatile methods for preparing various heterocyclic scaffolds from alpha-enaminone building blocks.

background

References considered relevant to the background of the presently disclosed subject matter are listed below:

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Background

Enaminones are of increasing interest, particularly cyclic β -enaminones, which are known to be important intermediates and have proven to be versatile building blocks for the synthesis of various heterocyclic and natural products. The N-and β -positions are the most reactive positions. Beta-enaminones, used as ambiphilic agents, are suitable platforms for the construction of heterocyclic compounds such as pyridine, pyrimidine, indolizidine, quinolizidine and pyrrole derivatives, which are common motifs in alkaloid structures. A-enaminones are less well understood, apparently because they are not generally directly available from the corresponding diketones. Alpha-ketone derivatives behave chemically differently than beta-enaminones. They can be reacted as enamines (nucleophiles) as well as α, β -unsaturated ketones (electrophiles). Although there are many strategies available that utilize β -enaminones as building blocks, the methods of preparing heterocycles using α -ketoenamines are limited and often require harsh, functional intolerant conditions.

Double electronic state of a-enaminones (electronic atteude)

Of the various biochemical compounds, oxazine, azaspirone, quinoline, quinolinone, and quinazolinol structures are often observed as backbone moieties. These structures have been identified as building blocks for a number of alkaloids as well as other distinct and often remotely related (remotelized) families of metabolites. Unfortunately, the access to large numbers of these target molecules and their structural analogs is unknown or hindered by multi-step synthesis. An in-depth analysis of the core of this introduction suggests that the α -enaminone backbone of type 1 (scheme 1) has the potential to serve as an operable, collective (collective) key unit for their construction through controlled intramolecular cyclization.

Scheme 1

The inventors of the present application for the first time linked a simple and single enaminone core to such diverse heterocyclic structures and developed a new streamlined synthetic approach that enables rapid and collective construction of multiple targets using a single common precursor. The inventors have found that the reactivity of α, β -enaminones is driven by their "dual electronic state", which provides an unexplored, stable α -enaminone synthesis unit with a chemical behavior that is quite different from other known α -or β -counterparts, and reveal the particular functionality of these building blocks. The synthesis of several important classes of heterocycles by controlled cyclization of readily available alpha-enaminones, a common key precursor, is demonstrated herein.

Summary of The Invention

The present invention provides a process for preparing a heterocyclic compound comprising the steps of:

Wherein

X is halogen;

Is a single or double bond;

R1-R4 are each independently selected from H, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, C5-C12 aryl, C5-C12 heteroaryl; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; or

R3 and R4 together with the atoms to which they are attached form a 5-to 15-membered saturated, unsaturated, or aromatic ring;

L is a leaving group;

n is an integer from 1 to 10;

And wherein

In some embodiments, the methods of the invention comprise the steps of:

Wherein R2 is H and n is greater than 1.

In other embodiments, the methods of the present invention comprise the steps of:

wherein R2 is linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, optionally substituted as defined above, and n is greater than 1.

In other embodiments, the methods of the present invention comprise the steps of:

Wherein R2 is C5-C12 aryl, C5-C12 heteroaryl; which is optionally substituted as above, and n is greater than 1.

In a further embodiment, the method of the invention comprises the steps of:

Wherein R2 is a linear or branched C1-C15 alkyl group, a linear or branched C2-C15 alkenyl group, a linear or branched C2-C15 alkynyl group, a C5-C12 aryl group, a C5-C12 heteroaryl group; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; and n is 1.

In another embodiment, the method of the invention comprises the steps of:

Wherein

X is halogen;

Is a single or double bond;

R1-R4 are each independently selected from H, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, C5-C12 aryl, C5-C12 heteroaryl; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; or

R3 and R4 together with the atoms to which they are attached form a 5-to 15-membered saturated, unsaturated, or aromatic ring;

l is a leaving group;

n is an integer from 1 to 10;

And wherein

In some embodiments, the methods of the invention are:

Wherein R2 is H and n is greater than 1.

In other embodiments, the method of the invention is:

Wherein R2 is linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, optionally substituted as defined above, and n is greater than 1.

In another embodiment thereof, the method of the present invention comprises the steps of:

Wherein R2 is C5-C12 aryl, C5-C12 heteroaryl; which is optionally substituted as above, and n is greater than 1.

in other embodiments, the methods of the present invention comprise the steps of:

Wherein R2 is a linear or branched C1-C15 alkyl group, a linear or branched C2-C15 alkenyl group, a linear or branched C2-C15 alkynyl group, a C5-C12 aryl group, a C5-C12 heteroaryl group; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; and n is 1.

In some embodiments, L is H.

the present invention also provides compounds having the following general formula (XX):

Wherein

X is halogen;

R1-R4 are each independently selected from H, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, C5-C12 aryl, C5-C12 heteroaryl; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl; provided that at least one of R1-R4 is different from H;

or R3 and R4 together with the atoms to which they are attached form a 5-to 15-membered saturated, unsaturated, or aromatic ring;

n is an integer from 1 to 10;

In some embodiments, at least two of R1-R4 are different from H. In other embodiments, at least three of R1-R4 are different from H.

In another aspect, the present invention provides a compound having the following general formula (XXI):

Wherein

X is halogen;

R1 and R2 are each independently selected from H, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, C5-C12 aryl, C5-C12 heteroaryl; each of which is optionally substituted with at least one OH, amine, amide, halogen, linear or branched C1-C15 alkyl, linear or branched C2-C15 alkenyl, linear or branched C2-C15 alkynyl, -O (C1-C8 alkyl), -OC (═ O) (C1-C8 alkyl), -C (═ O) (C1-C8 alkyl), -C (═ O) O (C1-C8 alkyl), C5-C12 aryl, C5-C12 heteroaryl, C3-C12 cycloalkyl, C3-C12 heterocycloalkyl;

n is an integer of 1 to 10.

In some embodiments, at least one of R1-R2 is different from H.

Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, any such defined trailing element is an element that is connected to the parent moiety. For example, the complex group alkylamido represents an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl represents an alkoxy group attached to the parent molecule through an alkyl group.

As used herein, the term "acyl" refers to a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any other group in which the atom attached to the carbonyl group is carbon. "acetyl" refers to the group-C (═ O) CH 3. "alkylcarbonyl" or "alkanoyl" refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, but are not limited to, methylcarbonyl or ethylcarbonyl. Examples of acyl groups include, but are not limited to, formyl, alkanoyl, or aroyl.

The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. (C2-C6) alkenyl has 2 to 6 carbon atoms.

As used herein, the term "alkoxy" refers to an alkyl ether group, wherein the term alkyl is defined below. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or n-pentoxy.

As used herein, the term "alkyl" refers to a straight or branched chain alkyl group containing from 1 to 20 carbon atoms. (C1-C10) alkyl has 1 to 10 carbon atoms, (C1-C6) alkyl has 1 to 6 carbon atoms, (C1-C4) alkyl has 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl (isopentyl), neopentyl, isopentyl (iso-amyl), hexyl, heptyl, octyl, or nonyl.

As used herein, the term "alkylene" refers to an alkyl group attached at two positions, i.e., an alkanediyl group. Examples include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, or nonylene. Thus, the term "alkylene" may for example refer to a straight or branched chain alkylene group having 1 to 6 carbon atoms.

The term "alkylamino" as used herein, means an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono-or di-alkylated, and the groups formed include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-ethylmethylamino, N-diethylamino, N-propylamino, and N, N-methylpropylamino.

as used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. (C2-C6) alkynyl has 2 to 6 carbon atoms. (C2-C4) alkynyl has 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, or hexyn-2-yl.

As used herein, the terms "amido" and "carbamoyl" refer to an amino group, as described below, attached to the parent molecular moiety through a carbonyl group (e.g., -C (═ O) NRR '), and vice versa (-n (R) C (═ O) R'). "amido" and "carbamoyl" encompass "C-amido", "N-amido" and "amido" as defined herein. R and R' are as defined herein.

The term "C-amido", as used herein, refers to a-C (═ O) NRR 'group having R and R' as defined herein.

As used herein, the term "amino" refers to-NRR ', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, carbocyclyl, and heterocyclyl. In addition, R and R' may be combined to form a heterocyclic group.

As used herein, the term "aryl" refers to a carbocyclic aromatic system containing one ring or two or three rings fused together in which all of the ring atoms are carbon. The term "aryl" includes, but is not limited to, groups such as phenyl, naphthyl, or anthracenyl.

The term "arylalkoxy" or "arylalkoxy" as used herein, refers to an aryl group attached to the parent molecular moiety through an alkoxy group. Examples of arylalkoxy groups include, but are not limited to, benzyloxy or phenethyloxy.

The term "arylalkyl" or "aralkyl" as used herein, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

The term "aryloxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an oxy (-O-).

The term "carbamate" as used herein refers to an O-carbamoyl or N-carbamoyl group as defined herein.

As used herein, the term "carbonyl" includes formyl-C (═ O) H, alone, and in combination, a-C (═ O) -group.

As used herein, the term "carboxy" or "carboxy" refers to — C (═ O) OH or the corresponding "carboxylate" anion, as in carboxylate salts. "O-carboxy" refers to an RC (═ O) O-group, where R is as defined herein. "C-carboxy" refers to the group — C (═ O) OR, where R is as defined herein.

As used herein, the term "cyano" refers to — CN.

As used herein, the term "carbocyclyl" refers to a saturated or partially saturated monocyclic or fused bicyclic or tricyclic group in which the ring atoms of the ring system are all carbon, and in which each ring moiety contains from 3 to 12 carbon atom ring members. "carbocyclyl" encompasses benzo-fused carbocyclyl ring systems. One carbocyclic group has 5 to 7 carbon atoms. Examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2, 3-dihydro-1H-indenyl, or adamantyl.

The term "cycloalkyl" as used herein refers to a saturated monocyclic, bicyclic or tricyclic group in which the ring atoms of the ring system are all carbon, and in which each ring portion contains from 3 to 12 carbon atom ring members. One cycloalkyl group has 5 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

The term "cycloalkenyl" as used herein, refers to a partially saturated monocyclic, bicyclic, or tricyclic group in which the ring atoms of the ring system are all carbon, and in which each cyclic portion contains ring members of 3 to 12 carbon atoms. One of the alkenyl groups has 5 to 7 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

The term "cycloalkyl" as used herein refers to an aryl, heterocyclyl or carbocyclyl group as defined herein.

as used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "haloalkoxy," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2-fluoroethoxy, or 3-chloropropoxy.

as used herein, the term "haloalkyl" refers to an alkyl group having the meaning as defined above, wherein one or more hydrogens are replaced with a halogen. Specifically included are monohaloalkyl, dihaloalkyl or polyhaloalkyl groups. For example, the monohaloalkyl group may have an iodine, bromine, chlorine or fluorine atom therein. The dihalo-or polyhaloalkyl groups may have two or more of the same halogen atoms or a combination of different halogen groups. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, or dichloropropyl.

As used herein, the term "heteroalkyl" refers to a straight or branched alkyl chain wherein one, two, or three carbons forming the alkyl chain are each substituted with a heteroatom independently selected from O, N and S, and wherein one or more nitrogen and/or sulfur heteroatoms (if present) may optionally be oxidized and one or more nitrogen heteroatoms (if present) may optionally be quaternized. One or more of the heteroatoms O, N and S may be, for example, located at an internal position of the heteroalkyl group, i.e., the heteroalkyl group may be bonded to the remainder of the molecule through a carbon atom. Up to two heteroatoms may be consecutive, such as-CH 2-NH-OCH 3. Thus, another example of a "heteroalkyl" group is a straight or branched chain alkyl group, wherein two consecutive carbon atoms are substituted with heteroatoms S and N, respectively, and the sulfur heteroatom is further oxidized to yield a group such as-S (═ O)2-NH2, -S (═ O)2-NH (alkyl) or-S (═ O)2-N (alkyl).

As used herein, the term "heteroalkylene" refers to a heteroalkyl group attached at two positions. Examples include, but are not limited to, -CH2OCH2-, -CH2SCH 2-and-CH 2NHCH2-, -CH 2S-or-CH 2NHCH (CH3) CH 2-. Thus, the term "heteroalkylene" may, for example, refer to a straight or branched chain alkylene group (i.e., a straight or branched chain alkanediyl group) having 1 to 6 carbon atoms, wherein 1,2 (if present), or 3 (if present) of the carbon atoms are each substituted with a heteroatom independently selected from O, N or S. It will be understood that the presence of a hydrogen atom will depend on the valency of the heteroatom replacing each carbon atom. For example, if a carbon atom in a-CH 2-group is substituted with O or S, the resulting group would be-O-or-S-, respectively, and when a carbon atom is substituted with N, the resulting group would be-N (H) -. Similarly, if the central carbon atom in-CH 2-CH (-CH3) -CH 2-is substituted by N, the resulting group would be-CH 2-N (-CH3) -CH 2-. Examples of "heteroalkylene" groups are straight or branched chain alkylene groups in which two consecutive carbon atoms are substituted by heteroatoms S and N, respectively, and the sulfur heteroatom is further oxidized to yield a group such as-S (═ O)2-N (h) -or-S (═ O)2-N (alkyl) -. Thus, the groups-S (═ O)2-N (h) -and-S (═ O)2-N (alkyl) - (e.g., -S (═ O)2-N (C1-C6 alkyl) -) are exemplary "heteroalkylene groups.

the term "heteroaryl" as used herein refers to a 3 to 7 membered unsaturated monocyclic or fused monocyclic, bicyclic or tricyclic ring system, wherein the rings are aromatic and at least one ring contains at least one atom selected from O, S and N. One heteroaryl group has 5 to 7 carbon atoms. Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl (benzothiophenyl), benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridyl.

As used herein, the term "heterocyclyl" or "heterocycle" each refers to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocycle radical containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur atom may be oxidized (e.g., -N ═ O, -S (═ O) -or-S (═ O)2 "). In addition, 1,2 or 3 carbon atoms of the heterocyclyl group may be optionally oxidized (e.g., to give oxo or ═ O). One heterocyclyl group has 1 to 4 heteroatoms as ring members. Another heterocyclyl group has 1 to 2 heteroatoms as ring members. One heterocyclyl group has 3 to 8 ring members in each ring. Yet another heterocyclyl group has 3 to 7 ring members in each ring. Likewise, another heterocyclyl group has 5 to 6 ring members in each ring. "Heterocyclyl" is intended to encompass heterocyclyl groups fused to carbocyclyl or benzo ring systems. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino (piperidino), morpholino (morpholino), thiomorpholino (thiomorpholino), thioxanyl (thioxanthyl), piperazinyl, homopiperazinyl, azetidinyl (azetidinyl), oxetanyl (oxolanyl), thietanyl (thietanyl), homopiperidinyl, oxepanyl (oxacycloheptyl), thietanyl (thienyl), oxaazepinyl (oxazepinyl), diazepinyl (diazepinyl), thieazepinyl (thiazepinyl), 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolyl, pyrazolinyl, Dithianyl, dithiocyclopentyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolylimidazolinyl or imidazolidinyl. Examples of heteroaryl groups that are heterocyclyl groups include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridyl.

As used herein, the term "heterocycloalkyl" refers to a heterocyclic group that is not fully saturated, e.g., one or more ring systems of the heterocycloalkyl group is not aromatic. Examples of heterocycloalkyl groups include piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl.

as used herein, the term "hydroxy" as used herein refers to-OH.

as used herein, the term "hydroxyalkyl" as used herein, means a hydroxy group attached to the parent molecular moiety through an alkyl group.

as used herein, the term "nitro" refers to — NO 2.

as used herein, the terms "sulfonate," "sulfonic acid," and "sulfonic acid-based" refer to the-SO 3H group and its anion, as sulfonic acid is used to form salts.

The term "thioalkyl" as used herein refers to-S-.

the term "sulfinyl", as used herein, refers to-S (═ O) (R) -, where R is as defined herein.

the term "sulfonyl" as used herein refers to-S (═ O)2R, where R is as defined herein.

The term "sulfonamide" as used herein refers to an N-sulfonamide or S-sulfonamide group, as defined herein.

The term "N-sulfonamido" as used herein refers to an RS (═ O)2N (R ') -group having R and R' as defined herein. Exemplary non-limiting N-sulfonamide groups are-NHSO 2CH3, -NHSO2CH2CH3, -NHSO2 (phenyl), or-NHSO 2 (isopropyl).

The term "S-sulfonamide" as used herein refers to the-S (═ O)2NRR 'group having R and R' as defined herein.

As used herein, the term "urea" refers to the group-n (R) C (═ O) n (R), where R and R' are as defined herein.

asymmetric centers are present in the compounds disclosed herein. These centers are designated with the symbol "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. It is to be understood that the present invention encompasses all stereochemically isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as the d-and l-isomers and mixtures thereof. Individual stereoisomers of a compound may be prepared synthetically from commercially available starting materials containing chiral centers or by preparation of mixtures of enantiomeric products followed by separation (e.g. conversion to a mixture of diastereomers), followed by separation or recrystallization, chromatographic techniques, direct separation of the enantiomers on chiral chromatographic columns or any other suitable method known in the art. Starting compounds having a particular stereochemistry may be commercially available or may be prepared and resolved by techniques known in the art. In addition, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis (cis), trans (trans), cis (syn), trans (anti), heterolateral (E) and ipsilateral (Z) isomers, as well as suitable mixtures thereof. In addition, the compounds may exist as tautomers; the present invention provides all tautomers. In addition, the compounds disclosed herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to unsolvated forms.

As used herein, the term "optically active" refers to the ability of a compound to rotate plane polarized light. In the context of the present invention, the term refers to a mixture of enantiomers that is not a racemic mixture; that is, not a 50:50 mixture of the (+) enantiomer and the corresponding (-) enantiomer.

Detailed Description

A simple type 2 building block (Table 1; R1 ═ Et; see SI) was prepared and selected as a model precursor. Alpha-enaminone 4 is obtained by reaction of 2 with 1, 3-dibromopropane in the presence of K3PO4 (first equivalent of base). Surprisingly, an unexpected direct cyclization was observed. Alkylation of 2 with dibromopropane during preparation 4 resulted in the isolation of the stable bicyclic quinolinone system 3, rather than the expected isolation of the alpha-enaminones. It is assumed that subsequent rapid cyclization of 4 yields compound 3 as a proprietary single product. It is speculated that resonance driven by ketene is suppressed as the dominant enamine-type behavior establishes a balance between 5 and 4.

table 1. fast constitution of quinolinones: 1, 4-addition

Conditional evaluation of R1 ═ Et (compound 7)

Substrate Range d)

a) GC yield: 0.2mmol scale. b) All attempts to increase the conversion by increasing the temperature or by prolonging the reaction time lead to decomposition of the starting materials. c) The decrease in mass balance is due to degradation of the starting precursor during the reaction. d) Separation yield: 0.5mmol scale.

Subsequent nucleophilic attack results in an advantageous 6-membered ring 6. In the presence of a second equivalent of base, deprotonation of 6 occurs to yield product 3. No hydrolysis of 6 was detected and only 3 was observed, indicating that very rapid deprotonation may occur. This deprotonation enables the formation of thermodynamically favored products while retaining their α, β -unsaturation functionality. An effective system for the desired conversion comprises a combination of 2 with 10 equivalents of 1, 3-dibromopropane, 0.5 equivalents of TBAB and 2 equivalents of K3PO 4in toluene at 100 ℃ (table 1, entry 10). A control experiment was performed demonstrating that cyclization did not occur in the absence of base. Additional experiments were performed with various α -enaminone precursors with different R1 groups (table 1) under optimized cyclization conditions. Proprietary 1, 4-selectivities were detected, resulting in the formation of quinolinone backbones 7-10. [12]

The unexpected cyclization caused our attention when precursor 11(R2 ≠ H) was subjected to 1, 2-dibromoethane (table 2). During the preparation of α -enaminone 13, rapid cyclization leads to the unexpected separation of stable oxazin-12 (general structure). Surprisingly, 13 produced two different results (i.e., 12 a-methylene-oxazine or 12 b-benzoxazine) depending on the nature of the R2 substituent. The best system for forming the C-O bond involves combining 11 with 2 equivalents of 1, 2-dibromoethane, 0.2 equivalents of TBAB and 2 equivalents of base at 100 ℃. Table 2 lists the conditions for evaluation of alpha-enaminones incorporating an aliphatic R2 group (using DIEA as the optimal base; entry 6). The same set of variables was then applied to the starting material bearing aromatic R2 residues. For this setting, K2CO3 was determined to be the optimal base. It is believed that deprotonation of 13 is established in the presence of a base (two variants are possible depending on the R2 substituent; scheme 2). Subsequent nucleophilic attack by the transiently driven oxygen of the enone further leads to a more favorable 6-membered ring backbone with a conjugated double bond system (i.e., 12a) or a fully arylated oxazine (i.e., 12 b). Table 2 shows representative examples of methylene-and benzoxazines synthesized by C — O bond formation. For this transformation, compounds with various R1-and R2-substituted cores of type 11 (see section SI) were prepared and conditions optimized. The exclusive E-selectivity observed for the cyclized products 16-19 must also be mentioned. NMR analysis confirmed the key stereochemical assignment of the bicyclic target (see SI). [13]

As shown in Table 2, the isolated yields of compounds 20-21 were significantly lower than the isolated yields of 16-19. The apparent difference between the two groups is due to the nature of their R2 residues. As suggested in the table, aromatic R2 (in the presence of a base) is capable of forming a stable resonance form (23) of starting precursor 22, which significantly slows the alkylation step towards alpha-enaminone 24. We were able to recover large amounts of unreacted starting material confirming this result. In contrast, compounds incorporating an aliphatic R2 group are not converted to resonance form and are most likely subjected to the desired alkylation to yield bicyclic products.

TABLE 2 cyclization of alpha-enaminones formed by C-O bond: synthesis of methylene-and benzoxazines.

R1 ═ Ph, R2 ═ Et (compound 17)

a) GC yield 0.2mmol scale; separation yield: 0.5mmol Scale

Effect of resonance contribution on alkylation Rate

The aromatic R2 enables the formation of a stable resonance form that significantly slows down the alkylation step

There are suitable routes to quinolinones and oxazines, and the following experiments are directed to other cyclization reactions. The reaction range was extended to synthesize more challenging heterocycles using the same precursor (11) as starting material (table 3A). An interesting result was observed when 11(R2 ≠ H) was acted upon by 1, 3-dibromopropane instead of 1, 2-dibromoethane (as in the conversion discussed earlier). In contrast to α -enaminones 4 (table 1) and 13 (table 2), enaminones of type 27 are stable (for various R1 and R2). Another unexpectedly new cyclization reaction was detected after exposing enaminone 27 to basic conditions (an optimized reaction scheme is provided in entry 12 in table 4). 1, 3-addition was observed and azaspirone was formed (Table 3B). Derivatives of 27 were then synthesized and further subjected to optimized cyclization conditions to yield products 32-39 (tables 3C and 3D). Interestingly, in both intermediates (28 and 30; Table 3B), deprotonation occurred predominantly at 28, regardless of the nature of the R2 group (aliphatic CH2R or aromatic). Endo-terminated cyclization (29) was always observed as the major product of the conversion. It is speculated that the formation of 31 is inhibited (secondary outcome) due to steric hindrance within the R-group and alkyl bromide chain (30; Table 3B). Enaminones 27a (with the combined Me group R2) were prepared and subjected to optimized cyclization conditions (table 3E). The ratio of endo and exo products is reversed, with the predominant product being exo 40b, further reinforcing our core hypothesis. In addition, the influence of temperature on the selectivity (1, 3-addition) of the reaction was investigated. Thus, enaminone 27a (R1 and R2 are Et groups; scheme 2) is subjected to cyclization conditions at a lower temperature of 50 ℃ using NaOt-Bu as a base. [14] A similar ratio of products 36a and 36b was detected (67: 18). Despite the lack of selectivity, the successful construction of azaspirones by 1, 3-cyclization of enaminones is remarkable. All pairs of exo and endo products were successfully isolated, providing access to two conceptually different heterocycles. It should also be mentioned that a proprietary E-selectivity is observed for all exo-terminated products 35b, 36b, 37b, 38b and 39 b. NMR analysis confirmed the critical stereochemical distribution. [13]

TABLE 4 evaluation of the conditions for 1, 3-addition

R1 ═ Ph, R2 ═ Et (compound 17)

a) GC yield 0.2mmol scale

Scheme 2. Effect of temperature on Selectivity

To complete the delineation, the inventors performed additional cyclization reactions to study the 1, 2-addition of the final α -enaminone system. The protocol designed for the free-radical cyclization reaction of a typical enone was followed. [15] This attempt was made using the Smi2/HMPA system. [16] Here, α -enaminones of type 41 (see SI for preparation) were subjected to free radical cyclization conditions to provide bicyclic quinazolinols 42 or quinolines 43, but both gave low yields (table 5). Both conversions were confirmed to proceed with the desired termination despite the detection of reduction and other by-products in the reaction mixture (quinoline if R2 ═ aromatic). Although our goal was to enhance the results of this conversion by varying the temperature, solvent, concentration, amount of SmI2 or HMPA change, and order of addition of reagents, our efforts were not successful. Nevertheless, the free radical reaction of 41 gives the desired product. To our knowledge, these results represent the first example of intramolecular cyclization of quinolinols and quinolines from simple enaminones. In these less effective cyclization reactions, 4 equivalents of Sm reagent, 10 equivalents of HMPA and 10 equivalents of t-butanol are required to form 42 and 43. Despite the above disadvantages, the successful construction of the reported heterocycles by this type of transformation is unprecedented and unique.

Table 5 free radical 1, 2-cyclization: quinoline and quinalditol are directly obtained.

Isolation of elimination and reduction products in all reactions

The present inventors have reported the unprecedented reactivity of α, β -unsaturated enaminones driven by their "dual electron states", have introduced new, stable α -enaminone synthons, and have discovered that these building blocks are unusual and new in functionality. Readily available alpha-enaminone precursors readily undergo cyclization under basic conditions to give a wide range of heterocycles, such as azaspirones, quinolinones, quinolines, quinolinols, and oxazines. The precise design of the starting materials enables specific and selective functionalization of the unsaturated backbone, enabling the preparation of a wide variety of products.

Experimental part

General purpose

All reagents were purchased commercially and used without further purification unless otherwise indicated. The solvent used in the reaction is distilled over a suitable drying agent before use.

The reaction was monitored by Thin Layer Chromatography (TLC) on silica gel 60F254 aluminium plate (Merck) and/or by gas chromatography-mass spectrometry (GCMS). Visualization of the compounds on TLC was achieved by irradiation with uv light at 254nm, iodine or vanillin staining. GCMS analysis was performed by an Agilent 7820A gas chromatograph using an Agilent HP-5MS capillary column (30m,0.25mm,0.25 μm membrane) equipped with an Agilent 5975' quaternary mass selectivity detector.

column chromatography was performed using silica gel 60 (particle size 0.040-0.063mm) available from Sigma-Aldrich or basic activated alumina 90 (particle size 0.063-0.200mm) available from Merck.

NMR spectra of protons and carbon were recorded on a Varian Mercury 300MHz or Varian Mercury 500MHz spectrometer in deuterated solvents. Proton chemical shifts (CDCl3, δ 7.26ppm) are reported in ppm (δ) relative to tetramethylsilane and solvent resonance used as internal standard. 13C chemical shifts (CDCl3, δ 77.0ppm) are reported in ppm (δ) from tetramethylsilane and solvent resonance used as internal standard. The data are reported as follows: chemical migration, multiplicities (s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, m ═ multiplet), integration and coupling constants (Hz). High resolution mass spectra were determined on Thermo Scientific LTQ Orbitrap XL (FTMS).

Infrared spectra (IR) were recorded on a Thermo Fischer Scientific NICOLET iS10 spectrometer.

Diastereomer ratios were calculated from GCMS analysis of the crude reaction mixture, unless otherwise indicated.

2. General procedure a: synthesis of quinolinone (1, 4-addition)

To a flame-dried 15.0mL reaction tube flushed with nitrogen and equipped with a magnetic stir bar and a rubber septum was added iminoketone (1.0 equiv.) in dry toluene (0.1M), K3PO4(2.0 equiv.), dibromopropane (10.0 equiv.), TBAB (0.5 equiv.), and molecular sieve (500mg, 1.0mmol) at room temperature. The reaction mixture was refluxed at 100 ℃ for 16 hours. The mixture was then concentrated in vacuo and the crude mixture was purified by flash chromatography to give the desired product.

2.93-2.87(M,2H),2.72-2.63(M,2H),2.46-2.35(M,2H),2.27(t, J ═ 6.2Hz,2H),2.11(t, J ═ 6.6Hz,2H),1.89(p, J ═ 6.3Hz,2H),1.71-1.52(M,4H),0.85(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 196.20,141.09,139.17,54.61,47.59,39.29,31.10,29.74,22.51,21.96,18.54,11.49.. IR (neat sample (neat) 2930,2868,2824,1671,1603,1184cm-1.HRMS (M/z) C12H19 nonana ([ M + Na ] +) calculated value: 216.1359; 216.1356, measured value.

1H NMR (300MHz, CDCl3): δ 3.82(t, J ═ 6.7Hz,2H),3.00-2.93(M,2H),2.87(t, J ═ 6.7Hz,2H),2.44-2.36(M,2H),2.26(t, J ═ 6.2Hz,2H),2.11(t, J ═ 6.6Hz,2H),1.89(p, J ═ 6.3Hz,2H),1.67(p, J ═ 6.3Hz,2H),0.87(s,9H),0.05(s,6H), 13C NMR (75MHz, CDCl3): δ 196.23,140.74,138.84,62.87,54.83,49.31,39.21,31.04,29.62,25.94,22.49,18.90, — 5.33: (IR: pure Na 3917 cm) (+) pure Na 3917M (rt/ml) (+) calculated value; 322.2019, measured value.

δ 2.95-2.86(M,2H),2.56(d, J ═ 7.3Hz,2H),2.40(t, J ═ 7.4Hz,2H),2.27(t, J ═ 6.2Hz,2H),2.12(t, J ═ 6.6Hz,2H),2.02-1.84(M,3H),1.73-161(M,2H),0.93(d, J ═ 6.7Hz,6H), 13C NMR (75MHz, CDCl3): δ 196.14,141.47,138.70,59.80,47.64,39.54,31.23,29.82,27.69,22.44,20.63,18.31.IR (neat sample): 2951,2866,2822,1671,1602,1435,1184,1121,978cm-1.HRMS (M/z) C13H21NO ([ M + Na ] +) calculated value 230.1515); 230.1519, measured value.

CDCl3, calculated as δ 7.48-7.43(M,2H),7.34-7.19(M,3H),3.93(s,2H),2.80-2.76(M,2H),2.50-2.44(M,2H),2.31(t, J ═ 6.2Hz,2H),2.12(t, J ═ 6.5Hz,2H),1.95(p, J ═ 6.3Hz,2H),1.67-1.57(M,2H).13C NMR (75MHz, CDCl3): δ 196.13,140.72,140.52,139.79,129.05,128.10,126.88,55.71,46.54,39.44,31.15,29.85,22.51,17.83.. IR (neat sample) 2943,2928,2864,1661,1611,1161,946,746,702cm-1.HRMS (M/z) C16H19NO ([ M + H ] +); 242.1538, measured value.

3. General procedure B: synthesis of oxazines (C-O formation)

To a flame-dried 15mL reaction tube equipped with a magnetic stir bar and a rubber septum connected to a nitrogen source, α -iminoketone (1.0 equiv.), base (2.0 equiv.), TBAB (0.2 equiv.), dibromoethane (2.0 equiv.) were mixed in anhydrous THF (0.5M) at room temperature. The reaction mixture was refluxed at 100 ℃ for 16 hours. The mixture was then concentrated in vacuo and the crude mixture was purified by flash chromatography to give the desired product.

δ 5.48(q, J ═ 7.1Hz,1H),3.97-3.90(M,2H),2.94(t, J ═ 4.3Hz,2H),2.56-2.47(M,2H),2.22(q, J ═ 6.6Hz,4H),1.62-1.74(M,5H),1.54(H, J ═ 7.4Hz,2H),0.88(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 140.03,132.48,122.04,112.02,59.48,54.99,45.68,27.93,25.28,22.43,21.78,13.21,11.49.IR (pure sample 2958,2929,2869,1624,1455,1353,1143,700cm-1.HRMS (M/z) C13H21NO ([ M + 208.1696H ] +) calculated value; 208.1690, measured value.

1H NMR (300MHz, CDCl3): δ 7.43(d, J ═ 7.6Hz,2H),7.35(t, J ═ 7.4Hz,2H),7.31-7.23(M,1H),5.70(q, J ═ 7.2Hz,1H),3.99-3.95(M,2H),3.93(s,2H),2.90(t, J ═ 4.4Hz,2H),2.30(q, J ═ 6.7Hz,4H),1.77(q, J ═ 6.4Hz,2H),1.69(d, J ═ 6.9Hz,3H), 13C NMR (75 MHz), CDCl3, 140.97,139.40,132.24,128.44,127.81,126.86,121.35,112.00,59.44, δ 56.40,45.75,27.98,25.35,22.49, 13.30: [ 1.2H ]: pure 3917M ([ calculated value: 17M + 17M); 256.1693, measured value.

CDCl3): δ 5.54(q, J ═ 7.2Hz,1H),3.96(t, J ═ 4.4Hz,2H),3.76(t, J ═ 6.3Hz,2H),3.03(t, J ═ 4.4Hz,2H),2.73(t, J ═ 6.4Hz,2H),2.23(q, J ═ 6.2Hz,4H),1.63-1.75(M,5H),0.90(s,9H),0.07(s,6H), 13C NMR (75MHz, CDCl3): δ 2, 62.63,59.67,55.15,47.12,27.93,25.94,25.27,22.39,18.33,13.21, -5.35. (pure IR 3: (678), 670h, 7733, ([ 26-3H) calculated as # 8633, 3.35: [ 75H ], (+ 3.3H, 3M, 3H ] (+) M, 3H); 324.2354, measured value.

19. 1H NMR (300MHz, CDCl3): δ 7.27-7.22(M,1H),6.99-6.91(M,2H),5.77(q, J ═ 7.1Hz,1H),4.01(s,2H),3.95(t, J ═ 4.4Hz,2H),3.00-2.92(M,2H),2.36-2.23(M,4H),1.82-1.67(M,5H), 13C NMR (75MHz, CDCl3): δ 143.73,141.06,132.01,126.52,124.84,124.58,120.87,112.27,59.56,51.79,45.68,27.89,25.30,22.40,13.30.IR (neat sample): 2955,2928,2858,1455,1246,1094,830,771cm-1.HRMS (M/z) C15H19 ([ M + H ] +) NOS calculated value: 262.1260; 262.1251, measured value.

7.57-7.52(M,2H),7.41(dd, J ═ 8.2,6.6Hz,2H),7.36-7.31(M,1H),6.98-6.86(M,2H),6.82(dd, J ═ 7.1,2.0Hz,1H),4.13(t, J ═ 4.4Hz,2H),3.17(t, J ═ 4.5Hz,2H),2.54-2.46(M,2H),1.26-1.07(M,1H),0.47(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 147.71,141.07,136.01,134.23,129.09,128.13,126.69,123.59,121.90,116.37,60.33,57.75,45.65,20.70,11.09.IR (pure sample): 2964,2860,1580,1461,1433,1240,1006,871,775,702cm-1. ms (M/z) (. 19H) (+) 3619M, 3619H); 276.1360, measured value.

CDCl3 calculated δ 7.50-7.45(M,2H),7.38-7.33(M,2H),6.96-6.83(M,2H),6.74(dd, J ═ 7.2,1.9Hz,1H),4.10(t, J ═ 4.5Hz,2H),3.14(t, J ═ 4.5Hz,2H),2.50-2.42(M,2H),1.23-1.10(M,2H),0.49(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 139.42,132.50,130.40,128.27,123.36,122.13,116.69,60.21,57.71,45.40,20.69,11.14.. IR (pure sample): 2964,2930,2860,1580,1461,1433,1240,1134,1006,871,763,702cm-1.HRMS (M/z) C17H18ClNO ([ M + 288.1150 ]; 288.1152, measured value.

4. General procedure C: synthesis of azaspirodecanones (1,3 addition)

Hz,1H),2.56-2.57(M,2H),2.56-2.36(M,4H),1.88-1.77(M,3H),1.69-1.39(M,2H),0.84(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3), δ 213.43,143.13,140.98,130.28,129.26,127.38,126.86,73.08,51.17,50.33,39.51,34.37,24.38,22.62,22.50,12.08.IR (pure sample) calculated as 2958,2931,2871,2846,1704,1486,1174,1089,1015,822cm-1 HRMS (M/z) C18H22ClNO ([ M + H ] +) 304.1463; 304.1467, measured value.

1.90-1.69(M,3H),1.66-1.49(M,2H),1.33-1.47(M,1H),0.83(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): delta 213.06,142.08,139.32,132.80,130.66,130.55,127.51,72.95,51.10,50.32,39.45,34.43,24.31,22.59,22.48,12.09.IR (pure sample): 2957,2930,2846,1704,1442,1174,1075,759,698cm-1.HRMS (M/z) C18H23NO ([ M + H ] +) calculated: 270.18524; 270.18506, measured value.

34: 10-phenyl-1- (thien-2-ylmethyl) -1-azaspiro [4.5] dec-9-en-6-one general procedure C was used. Alpha-enaminone (3) (202mg, 0.5mmol) prepared according to general procedure F and Cs2CO3(326mg, 1.0mmol) were mixed at room temperature in anhydrous MeCN (0.5 mL). The reaction mixture was refluxed at 100 ℃ for 20 hours. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 5/95% ether/hexanes) to give 34 as a yellow oil in 75% yield (122 mg). 1H NMR (300MHz, CDCl3): δ 7.62-7.54(M,2H),7.40-7.28(M,3H),7.16(d, J ═ 5.1,1.3Hz,1H),6.93-6.86(M,1H),6.81(d, J ═ 3.4Hz,1H),6.20(t, J ═ 4.3Hz,1H),4.05-3.86(M,2H),3.10-2.99(M,1H),2.89(q, J ═ 8.0Hz,1H),2.80-2.68(M,1H),2.60-2.46(M,3H),2.14-2.01(M,1H),2.01-1.78(M,2H),1.77-1.56(M,1H), 13H (M,3H),2.14-2.01(M,1H), 2.01-1H), 2.78 (M,2H), 1.77-1H) (M, 13H), 13(M, 3H), 27M, 3H), 19M, 3619M, 20M, 3H, 3M, 3619M, 3H, 3619M, 20M, 3; 346.1236, measured value.

35a (inner type) and 35b (outer type): general operation C is applied. Alpha-enaminone (4) (178mg, 0.5mmol) prepared according to general procedure F and NaOMe (54mg, 1.0mmol) were mixed in anhydrous MeCN (0.5mL) at room temperature. The reaction mixture was refluxed at 100 ℃ for 1 hour. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 5/95% ether/hexanes) to give 54% 35a and 5% 35b (65 mg and 7mg, respectively).

36a (inner type) and 36b (outer type): general operation C is applied. α -enaminone (5) (151mg, 0.5mmol) prepared according to general procedure F and NaOMe (54mg, 1.0mmol) were mixed in anhydrous MeCN (0.5mL) at room temperature. The reaction mixture was refluxed at 100 ℃ for 1 hour. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 5/95% ether/hexanes) to give 71% 36a and 16% 36b as a pale yellow oil (78 mg and 18mg, respectively).

37a (inside type) and 37b (outside type): general operation C is applied. Alpha-enaminone (6) (175mg, 0.5mmol) prepared according to general procedure F and NaOMe (54mg, 1.0mmol) were mixed in anhydrous MeCN (0.5mL) at room temperature. The reaction mixture was refluxed at 100 ℃ for 1 hour. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 5/95% ether/hexanes) to give 63% 37a and 15% 37b (85 mg and 20mg, respectively).

38a (inner type) and 38b (outer type): general operation C is applied. α -enaminone (7) (209mg, 0.5mmol) prepared according to general procedure F and NaOMe (54mg, 1.0mmol) were mixed in anhydrous MeCN (0.5mL) at room temperature. The reaction mixture was refluxed at 100 ℃ for 1 hour. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 5/95% ether/hexanes) to give 60% 38a and 3% 38b as a pale yellow oil (101 mg and 5mg, respectively).

360.2329, respectively; 360.2327, measured value.

40a (inner type) and 40b (outer type): general operation C is applied. Alpha-enaminone (8) (144mg, 0.5mmol) prepared according to general procedure F and NaOMe (54mg, 1.0mmol) were mixed in anhydrous MeCN (0.5mL) at room temperature. The reaction mixture was refluxed at 100 ℃ for 1 hour. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 5/95% ether/hexanes) to give 17% 40a and 46% 40b as a pale yellow oil (18 mg and 48mg, respectively).

cm-1 HRMS (M/z) C13H21NO ([ M + H ] +) calculated 208.1696; 208.1696, measured value.

5. general operation D: synthesis of quinoline and Quinolinol (1, 2-addition)

In a flame-dried 100mL reaction flask, flushed with nitrogen and equipped with a magnetic stir bar and rubber septum, a solution of SmI2 (0.1M, 4.0 equiv.) in THF was added dropwise (1mL/min) at 0 deg.C to a solution of α -enaminone (1.0 equiv., 0.5mmol), HMPA (10.0 equiv., 5.0mmol) and t-BuOH (10.0 equiv., 5.0mmol) in anhydrous THF (0.05M). The reaction mixture was then stirred at room temperature under an inert atmosphere for 1 hour and quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography to give the desired product.

The crude product was purified by chromatography (silica gel, 10/90% EtOAc in hexanes) to give 44 as a mixture of 2 diastereomers as a yellow liquid in 43% yield (58 mg). 1H NMR (300MHz, CDCl3): δ 7.42-7.29(m,4H),7.28-7.21(m,1H),4.39(d, J ═ 14.5Hz,1H),3.83(d, J ═ 14.3Hz,1H),2.79-2.90(m,1H),2.60(t, J ═ 12.8,2.9Hz,1H),2.28(q, J ═ 7.5Hz,2H),2.17-2.02(m,2H),2.01-1.79(m,2H),1.79-1.71(m,1H),1.59-1.70(m,2H),1.56-1.38(m,2H),1.29-1.14(m,1H),0.99(t, J ═ 7.6Hz,3H), 13C (3 MHz, 78 MHz), 3.75 NMR): δ 142.41,140.98,130.13,128.28,128.08,126.70,69.37,60.26,48.13,39.37,39.33,29.28,24.84,18.39,18.07,12.79.IR (pure sample): 2930,2872,1710,1459,942,734,697cm-1 HRMS (M/z) C18H25NONa ([ M + Na ] +) Calcd: 294.1828, respectively; 294.1824, measured value.

Dried, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (basic alumina, 5/95% EtOAc/hexanes) to give 45 as a mixture of 2 diastereomers as a yellow liquid in 37% yield (41 mg). 1H NMR (300MHz, CDCl3): mixture of diastereomers: δ 3.09-2.92(m,2H),2.70-2.58(m,2H),2.16-2.06(m,3H),2.04-1.95(m,2H),1.86-1.71(m,2H),1.61-1.53(m,2H),1.52-1.38(m,4H),1.34-1.24(m,2H),0.95(t, J ═ 7.6Hz,3H),0.87(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): the major diastereomer: δ 142.78,127.72,69.31,58.40,49.22,39.66,38.90,29.50,25.13,22.97,19.59,18.68,12.97,11.63, minor diastereomer, characteristic signal: δ 79.90,57.91,53.66,42.41,34.71,34.05,23.57,20.99,19.44,18.98,12.12,6.71.IR (pure sample): 3486,2956,2925,2870,1709,1670,1457,1376,1088cm-1 HRMS (M/z) C14H25NO ([ M + H ] +) Calcd: 224.2009, respectively; 224.2014, measured value.

Purification was carried out to give 46 as a yellow oil in a yield of 30% (48 mg). 1H NMR (300MHz, CDCl3): δ 7.42-7.32(M,2H),7.25(d, J ═ 8.4Hz,2H),7.15-7.01(M,1H),6.67-6.53(M,1H),6.47(d, J ═ 7.5,1.2Hz,1H),3.39-3.17(M,4H),2.57(t, J ═ 6.3Hz,2H),1.84(p, J ═ 6.5Hz,1H),1.67(H, J ═ 7.4Hz,2H),0.97(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 145.98,145.52,140.93,132.44,130.51,128.02,126.58,119.47,116.92,109.89,53.71,49.41,26.64,22.19,19.54,11.60,1.04, 1. 2951,2925,2870,1714,1582,1484,1459,1199,1085,1017,831,774,719H. (M + 20 cm) pure hrz/M + 20M; 286.1365, measured value.

6. General operation E: preparation of alpha-imino ketones

Napier et al: 1A solution of epoxide precursor 2(1.0 equiv.) and amine (1.5 equiv.) in a 3:1 mixture of methanol to water was refluxed for 4 hours. After cooling, the solvent was removed, and the residue was diluted with saturated aqueous brine, extracted with EtOAc, dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography to give the desired product.

And concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 10/90% EtOAc/hexanes) to give the desired product in 63% yield (865mg) as a yellow liquid. 1H NMR (300MHz, CDCl3): δ 5.32(t, J ═ 4.7Hz,1H),4.15-3.90(M,1H),2.71(t, J ═ 7.0Hz,2H),2.42-2.32(M,2H),2.28(q, J ═ 5.6Hz,2H),1.50(H, J ═ 7.3Hz,2H),0.87(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 195.71,140.61,110.56,44.93,37.87,24.47,23.48,22.08,11.69.IR (neat sample): 3399,2958,2931,2872,1671,1626,1488,1167,867cm-1.HRMS (M/z) C9H15NO ([ M + H ] +) calculated value: 154.1226; 154.1228, measured value.

and (5) concentrating. The crude product was purified by flash chromatography (silica gel, 20/80% EtOAc/hexanes) to give the desired product in 44% yield (1.1g) as a yellow liquid. 1H NMR (300MHz, CDCl3): δ 5.43(t, J ═ 4.7Hz,1H),4.44(s,1H),3.73(t, J ═ 5.5Hz,2H),2.92(t, J ═ 5.5Hz,2H),2.49-2.38(M,2H),2.33(q, J ═ 5.6Hz,2H),1.91(p, J ═ 6.1Hz,2H),0.86(s,9H),0.02(s,6H).13C NMR (75MHz, CDCl3): δ 195.63,145.98,140.64,111.26,61.29,45.14,37.92,25.86,24.50,23.46,18.26, -5.39.IR (pure sample 2928,2856,1675,1629,1472,1629,1472,1252,1101,830,775cm-1.HRMS (M/z) C14H 27H + 389 5M + 64H ] +) calculated values; 270.1887, measured value.

The product was purified to give the desired product in 74% yield (1.1g) as a light brown liquid. 1H NMR (300MHz, CDCl3): δ 5.35(t, J ═ 4.7Hz,1H),4.15(s,1H),2.64-2.55(M,2H),2.46-2.37(M,2H),2.32(q, J ═ 5.6Hz,2H),1.89(p, J ═ 6.1Hz,2H),1.81-1.72(M,1H),0.89(d, J ═ 6.7,6H), 13C NMR (75MHz, CDCl3): δ 195.83,140.68,110.49,51.09,37.92,27.60,24.50,23.48,20.59.IR (neat sample): 3403,2953,2868,2827,1671,1626,1488,1333,1201,1167,1126,866cm-1.HRMS (M/z) C10H17NO ([ M + H ] +) calculated value: 168.1383; 168.1388, measured value.

The crude product was purified to give the desired product as a pale green solid (melting point 56-59 ℃) in 32% yield (1.02 g). 1H NMR (300MHz, CDCl3): δ 7.20-7.36(M,5H),5.42(t, J ═ 4.7Hz,1H),4.60(s,1H),4.08(d, J ═ 4.3Hz,2H),2.59-2.41(M,2H),2.33(q, J ═ 5.6Hz,2H),1.94(p, J ═ 6.3Hz,2H), 13C NMR (75MHz, CDCl3): δ 195.83,140.35,139.00,128.50,127.38,127.08,111.76,47.55,37.91,24.48,23.47.IR (neat sample): 3407,2928,1659,1619,1488,1361,1208,742,700cm-1.HRMS (M/z) C13H15NO ([ M + H ] +) calculated value: 202.1226; 202.1224, measured value.

Dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 10/90% EtOAc/hexanes) to give the desired product in 48% yield (880mg) as a yellow liquid. 1H NMR (300MHz, CDCl3): δ 3.69(s,1H),2.64(t, J ═ 7.1Hz,2H),2.38-2.15(M,6H),1.87-1.69(M,2H),1.39(q, J ═ 7.3Hz,2H),1.01(t, J ═ 7.6Hz,3H),0.82(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 196.63,143.41,139.51,51.27,37.09,28.93,26.19,23.56,22.11,11.59,11.48.IR (neat sample): 3337,2960,2874,1662,1625,1486,1168cm-1.HRMS (M/z) C11H19NO ([ M + H ] +) calculated value: 182.1539; 182.1539, measured value.

EtOAc/hexanes) to give the desired product in 58% yield (1.99g) as a yellow liquid. 1H NMR (300MHz, CDCl3): δ 7.30(d, J ═ 4.3Hz,4H),7.27-7.19(M,1H),4.14(s,1H),3.95(s,2H),2.29-2.45(M,7H),1.96-1.76(M,2H),1.11(t, J ═ 7.5Hz,3H), 13C NMR (75MHz, CDCl3): δ 196.96,140.98,138.80,128.91,128.10,128.03,127.09,48.34,37.20,32.04,23.02,22.34,11.28.IR (pure sample 2965,2935,2875,1660,1624,1453,1184,1161,734,697cm-1.HRMS (M/z) C15H19NO ([ M + H ] +) calculated value: 252.1364; 252.1357, measured value.

taken, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 1:1 DCM/hexane) to give the desired product as a yellow oil in 41% yield (1.17 g). 1H NMR (300MHz, CDCl3): δ 3.68(t, J ═ 5.6Hz,2H),2.91(t, J ═ 5.6Hz,2H),2.48-2.24(M,6H),1.91(q, J ═ 6.3Hz,2H),1.10(t, J ═ 7.5Hz,3H),0.91(d, J ═ 2.2Hz,9H),0.06(d, J ═ 2.1Hz,6H), 13C NMR (75MHz, CDCl3): δ 196.41,143.40,139.35,62.49,51.01,37.35,29.10,26.16,25.89,22.20,18.28,11.70, -5.36.IR (pure sample 2952,2928,2856,1666,1627,1462,1253,1103,830,774cm-1.HRMS (M/z) C16H 462 ([ 31H + 298.2197H ]); 298.2196, measured value.

the aqueous solution was diluted, extracted with EtOAc, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 60/40% DCM/hexane) to give the desired product in 48% yield (1.13g) as a yellow liquid. 1H NMR (300MHz, CDCl3): δ 7.15(dd, J ═ 4.9,1.5Hz,1H),6.97-6.80(M,2H),4.18(s,1H),4.12(s,2H),2.39(q, J ═ 7.0Hz,6H),1.87(p, J ═ 6.3Hz,2H),1.11(t, J ═ 7.6Hz,3H), 13C NMR (75MHz, CDCl3): δ 196.45,145.79,143.37,138.63,126.58,124.86,124.34,47.72,37.18,29.00,26.27,22.07,11.63.IR (pure sample): 3319,2930,2872,1656,1619,1464,1160,697cm-1.HRMS (M/z) C13H17NOS ([ M + Na ] +) calculated value: 258.0923; 258.0923, measured value.

(M,1H),4.27(s,1H),2.67(t, J ═ 6.0Hz,2H),2.58-2.46(M,2H),2.32(t, J ═ 7.0Hz,2H),2.03(q, J ═ 6.4Hz,2H),1.27(H, J ═ 7.2Hz,2H),0.69(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 196.96,140.97,138.80,128.89,128.12,128.04,127.10,48.34,37.20,32.04,23.02,22.34,11.31.IR (neat sample): 3341,2956,2920,2859,1660,1468,1328,1187,1128,765,670cm-1.HRMS (M/z) C15H19NO ([ M + H ] +) calculated value: 230.1538; 230.1539, measured value.

7.33-7.25(M,2H),4.28(s,1H),2.64(t, J ═ 6.0Hz,2H),2.57-2.44(M,2H),2.32(t, J ═ 6.9Hz,2H),2.01(p, J ═ 6.4Hz,2H),1.28(H, J ═ 7.1Hz,2H),0.71(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 196.76,139.35,139.10,132.58,129.50,128.26,126.75,48.54,37.06,31.69,23.05,22.16,11.32.IR (neat sample): 3351,2956,2927,2873,1662,1608,1488,1191,1091,1016,217,691cm-1.HRMS (M/z) C15H18ClNO ([ M + Na ] +) calculated value: 286.0969; 286.0981, measured value.

Yield of 80% (1.2g) gave 2- (cyclopropylamino) cyclohex-2-en-1-one as a yellow liquid. 1H NMR (300MHz, CDCl3): δ 5.83(t, J ═ 4.7Hz,1H),4.46(s,1H),2.46-2.32(M,4H),2.12-2.03(M,1H),1.92(p, J ═ 6.2Hz,2H),0.61-0.52(M,2H),0.40-0.31(M,2H), 13C NMR (75MHz, CDCl3): δ 195.83,140.97,113.19,37.86,24.54,24.27,23.52,6.53.IR (pure sample): 3394,2940,2839,1672,1630,1481,1379cm-1.HRMS (M/z) C9H13NO ([ M + H ] +) calculated value: 152.1070; 152.1070, measured value.

7. general operation F: synthesis of stable alpha-enaminones

To a stirred solution of the amine (1.0 eq) in THF (1M) was added anhydrous K2CO3(2 eq) at room temperature, followed by dibromopropane (10.0 eq) according to Sinha et al 3, and the resulting mixture was refluxed for 16 hours. The crude mixture was then filtered and concentrated in vacuo and purified by flash chromatography to give the desired product.

3.11(t, J ═ 6.6Hz,2H),2.80(t, J ═ 6.7Hz,2H),2.61-2.73(M,4H),2.51(t,2H),2.04(p, J ═ 6.5Hz,2H),1.72(p, J ═ 6.7Hz,2H),1.35-1.14(M,2H),0.72(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 199.29,151.65,142.34,139.11,133.49,129.10,128.12,55.47,51.27,39.63,32.69,32.06,31.84,22.39,21.75,11.60.IR (neat sample): 2956,2930,2869,1670,1489,1091,1016,823,699cm-1.HRMS (M/z) C18H23 clno ([ M + Na ] +) calculated value: 408.0524); 408.0523, measured value.

J6.6 Hz,2H),2.69(td, J6.8, 6.1,3.9Hz,4H),2.50(dd, J7.5, 5.9Hz,2H),2.08-1.98(M,2H),1.69(p, J6.6 Hz,2H),1.30-1.23(M,2H),0.71(t, J7.3 Hz,3H), 13C NMR (75MHz, CDCl3): δ 199.51,153.62,142.02,140.75,127.88,127.59,55.66,51.18,39.69,32.97,32.21,31.95,22.49,21.76,11.61.IR (neat sample): 2955,2927,2869,1667,1449,1180,1116,753,697cm-1.HRMS (M/z) C18H24 no ([ M + Na ] +) calculated value: 372.0933; 372.0931, measured value.

CDCl3 δ 7.43-7.29(m,3H),7.22-7.12(m,3H),6.90-6.82(m,1H),6.81-6.76(m,1H),4.24(s,2H),2.90(t, J ═ 6.9Hz,2H),2.79(t, J ═ 6.5Hz,2H),2.71(t, J ═ 6.0Hz,2H),2.59-2.51(m,2H),2.06(p, J ═ 6.2Hz,2H),1.64(p, J ═ 6.8Hz,3H), 13C NMR (75MHz, CDCl3) δ 199.27,155.96,143.19,141.11,140.27,128.14,127.93,127.47,126.15,124.95,53.01,50.10,39.66,33.20,32.05,31.86,22.41, 2951,2926,2850,1662,1610,1211,755,698cm (pure sample): 1-2951,2926,2850,1662,1610,1211,755,698 cm.

MHz, CDCl3, (. delta.7.17 (dd, J ═ 5.1,1.3Hz,1H),6.85-6.91(M,1H),6.91-6.80(M,1H),4.19(s,2H),3.35(t, J ═ 6.9Hz,2H),3.01(t, J ═ 7.0Hz,2H),2.51(q, J ═ 9.5,8.6Hz,2H),2.36(dt, J ═ 8.9,6.4Hz,4H),1.86(dp, J ═ 13.9,6.7Hz,4H),0.97(t, J ═ 7.6Hz,3H), 13C NMR (75MHz, CDCl3): delta.29, 53.63,51.27,39.63, 32.81, 2.31, 19: [ 19.11.26M ] (M, 18M) ((M, 18M) (+), 18M, 11M, M; 378.0495, measured value.

Delta 3.39(t, J ═ 6.8Hz,2H),2.94(t, J ═ 6.9Hz,2H),2.79-2.67(M,2H),2.49(q, J ═ 7.6Hz,2H),2.29-2.40(M,4H),1.85(dp, J ═ 13.6,6.5Hz,4H),1.28(dq, J ═ 15.4,7.7Hz,2H),1.01(t, J ═ 7.6Hz,3H),0.80(t, J ═ 7.3Hz,3H), 13C NMR (75MHz, CDCl3): delta 198.37,162.82,141.08,56.40,52.25,39.79,32.62,32.09,2, 26.19,22.44,22.41,11.95, 11.11H, (brt, 11.11H): pure hrz/18M 3979 (rt/ml); 302.1113, measured value.

δ 7.36-7.13(M,5H),4.00(s,2H),3.35(t, J ═ 6.9Hz,2H),3.01(t, J ═ 7.0Hz,2H),2.32-2.45(M,4H),2.27(t, J ═ 6.1Hz,2H),1.92-1.77(M,4H),0.85(t, J ═ 7.6Hz,3H), 13C NMR (75MHz, CDCl3): δ 198.50,163.57,140.47,139.93,129.12,128.01,126.77,58.64,51.81,39.73,32.46,31.81,29.19,26.22,22.31,11.66.IR (neat sample): 2959,2935,2863,1664,1610,1453,1130,728,699cm-1.HRMS (M/z) C18H24 no ([ M + Na ] +) calculated value: 372.0934; 372.0940, measured value.

(300MHz, CDCl3): δ 3.52(t, J ═ 6.4Hz,2H),3.45(t, J ═ 6.7Hz,2H),2.96(dt, J ═ 19.0,6.6Hz,4H),2.54(q, J ═ 7.7Hz,2H),2.38(t, J ═ 6.4Hz,4H),1.88(dp, J ═ 13.7,6.6Hz,4H),1.04(t, J ═ 7.6Hz,3H),0.87(s,9H),0.03(s,6H).13C NMR (75MHz, CDCl3): δ 198.14,162.96,141.38,62.27,56.84,52.64,39.68,32.77,32.07,29.22,26.13,25.92, 22.40: [ 29.19: 19M ], (-3619M) M + 19M (br 3619M); 252.1357, measured value.

The enaminoketones of (a). 1H NMR (300MHz, CDCl3): δ 3.42(t, J ═ 6.8Hz,2H),2.97(t, J ═ 6.8Hz,2H),2.76(t, J ═ 7.6Hz,2H),2.44-2.34(M,4H),1.99(s,3H),1.92-179(M,4H),1.30(H, J ═ 7.8Hz,2H),0.81(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3 δ 198.11,157.72,141.68,56.19,52.02,39.76,32.46,32.37,32.19,22.29,22.21,20.51,11.84.IR (neat sample): 2930,2869,1667,1429,1252,1219,1121cm-1.HRMS (M/z) C13H22 Na + 310.0777M + Na (+); 310.0776, measured value.

8. General operation G:

Alpha-enaminone (1.0 equiv.) and NaI (5.0 equiv.) were dissolved in acetone (0.5M). The solution was stirred at room temperature for 3 hours. The suspension was filtered and the filtrate was concentrated in vacuo. The crude mixture was purified by flash chromatography to give the desired product. 4

7.1Hz,2H),2.97(t, J ═ 7.0Hz,2H),2.39(dt, J ═ 16.5,7.3Hz,4H),2.28(t, J ═ 6.1Hz,2H),1.93-1.72(M,4H),0.86(t, J ═ 7.7Hz,3H), 13C NMR δ 198.49,163.55,140.50,139.94,129.14,128.03,126.79,58.71,53.82,39.74,33.31,29.20,26.24,22.33,11.72,4.55.IR (neat sample): 2935,2863,1664,1453,1193,1131,728,699cm-1.HRMS (M/z) C18H24INO ([ M + Na ] +) calculated value 420.0795; 420.0794, measured value.

Hz,2H),2.73(t, J ═ 8.7,6.7Hz,2H),2.49(q, J ═ 7.6Hz,2H),2.38-2.30(M,4H),1.93-1.75(M,4H),1.28(H, J ═ 7.8Hz,2H),1.01(t, J ═ 7.6Hz,3H),0.79(t, J ═ 7.3Hz,3H), 13C NMR (75MHz, CDCl3), δ 198.36,162.76,141.11,56.50,54.29,39.78,33.43,29.24,26.20,22.46,22.42,12.00,11.80,4.99.IR (pure sample 2956,2932,2870,1667,1456,1200,1172,1115cm-1.HRMS (M/z) C14H24 ona ([ M + inna ] +) calculated value of 372.0794: 372.0794; 372.0795, measured value.

7.29-7.22(M,2H),2.90(t, J ═ 6.8Hz,2H),2.78-2.63(M,5H),2.55-2.49(M,2H),2.05(p, J ═ 6.3Hz,2H),1.70(p, J ═ 6.8Hz,2H),1.37-1.21(M,3H),0.73(t, J ═ 7.4Hz,3H), 13C NMR (75MHz, CDCl3): δ 199.30,151.34,142.39,139.11,133.50,129.10,128.16,55.49,53.33,39.63,32.67,22.39,21.80,11.61,5.14.IR (neat sample): 2955,2929,2666,1670,1489,1201,1090,822,731cm-1.HRMS (M/z) C61H23 no ([ M + Na ] +) calculated value 454.0405; 454.0407, measured value.

dimerization of alpha-enaminone precursors: to obtain carbazole dione

2X-ray crystal structure

9-propyl-3, 4,5,6,7, 9-hexahydro-1H-carbazole-1, 8- (2H) -dione

2- (propylamino) cyclohex-2-en-1-one 1(0.9g, 5.9mmol, 1 eq.) and Cs2CO3(0.59g, 1.8mmol, 2 eq.) were combined in 10.0mL of anhydrous methanol. The mixture was then refluxed at 80 ℃ for 24 hours. After cooling, the solvent was removed, and the residue was diluted with saturated aqueous brine, extracted with EtOAc, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 10% ether/hexane) to give 2 as colorless crystals in 30% yield (220 mg). 1H NMR (300MHz, chloroform-d) δ 4.76-4.64(m,1H),2.63(t, J ═ 6.1Hz,2H),2.59-2.48(m,2H),2.07(H, J ═ 6.3,5.8Hz,2H),1.77-1.58(m,1H),0.88(t, J ═ 7.4Hz,1H), 13C NMR (75MHz, cd 3) δ 191.41,131.56,129.79,47.97,40.44,24.72,24.25,21.77, 10.89.

Direct synthesis of dibenzoazepines from alpha-enaminones

the starting enaminone 1(70mg, 0.2mmol, 1 equiv.) and K2CO3(80mg, 0.6mmol, 3 equiv.) are mixed in 0.5mL anhydrous THF. The mixture was then refluxed at 80 ℃ for 18 hours. After cooling, the solvent was removed and the residue was purified by flash chromatography (silica gel, 10% ether/hexane) to give 2.1H NMR (300MHz, chloroform-d) δ 8.15(d, J ═ 10.9Hz,1H),7.94(s,1H),7.40(d, J ═ 8.4Hz,1H),5.71(s,1H),5.27(s,1H),4.20(s,2H),2.70(t, J ═ 6.2Hz,2H),2.63-2.56(m,2H),2.51-2.44(m,2H),1.99(p, J ═ 6.4Hz,2H),1.55(H, J ═ 7.4Hz,2H),0.80(t, J ═ 7.4Hz,3H).