Exploring tertiary enamides as versatile synthons in organic synthesis

Article abstract of DOI:10.1039/c4cc10327k

Tertiary enamides have long been thought of as stable and marginally valuable enamine variants in synthesis. This notion has been challenged, however, in recent years. Enabling the regulation of the cross-conjugation system of the tertiary enamides has been successfully shown to enhance delocalization of the nitrogen lone-pair electrons into a carbon-carbon double, thereby reinvigorating the enaminic reactivity of the tertiary enamides. In this article, I summarize the recent advances in the exploration of the nucleophilic reactions of tertiary enamides and their applications in the synthesis of natural products and heterocyclic compounds of biological and pharmaceutical relevance, with a primary focus on our own work.

Full text of DOI:10.1039/c4cc10327k

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Exploring Tertiary Enamides as Versatile Synthons in Organic SynthDeOsiI:s10.1039/C4CC10327K
Mei-Xiang Wang
MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology,
Department of Chemistry, Tsinghua University, Beijing 100080, China
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin,
300072, China.
TOC:
Contrary to general notion, tertiary enamides are reactive and unique synthons for the
construction of diverse heterocycles of biological significance.
Abstract: Tertiary enamides had long been known as stable and marginally valuable
enamine variants in synthesis. The notion has been challenged however in recent
years. Enabled regulation of the cross conjugation system of tertiary enamides has

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been shown successfully to enhance delocalization of the nitrogen lone-pair electrons
into carbon-carbon double, reinvigorating the enaminic reactivity of tertiary enamides.
In this Feature article, I will summarize the recent advances in the exploration of
nucleophilic reactions of tertiary enamides and their applications in the synthesis of
natural products and heterocyclic compounds of biological and pharmaceutical
relevance, with a primary focus on our own work.
Introduction
Enamines are powerful synthetic intermediates and find wide applications in organic
synthesis owing to the Stork’s milestone works in 1950s.1,2 The importance of
enamine chemistry has been substantiated in recent years by asymmetric enamine
catalysis.3 When one of the N-alkyl groups of enamines is replaced by an
electron-withdrawing group such as an acyl, tertiary enamides are generated. Further
substitution of the other N-alkyl by hydrogen leads to the formation of secondary
enamides (Figure 1). In comparison to enamines, enamides exhibit much diminished
enaminic reactivity because the N-electron-withdrawing group alleviates the
delocalization of lone-pair electrons of the nitrogen atom into the carbon-carbon
double bond.4 The stability of enamides is well demonstrated by the occurrence of
stable enamide structures in natural products.5 The vast majority of synthetic
applications of enamides documented in literature are their asymmetric reduction
reactions. Indeed, enamides or dehydroamino acid derivatives are used as a testing
ground for the study of efficiency and enantioselectivity of catalytic asymmetric
hydrogenation of the carbon-carbon double bond.6
Figure 1. General structures of enamine, tertiary and secondary enamides.

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Secondary enamides have been shown recently to be reactive towards highly
electron-deficient unsaturated reactants.7-10 However, these reactions catalyzed by
either chiral Lewis acids or Brønsted acids proceed through the typical aza-ene
addition reaction pathways in which secondary enamides act actually as the aza-ene
components (C=C-N-H). No reactions take place when tertiary enamides are
employed instead of secondary enamides under the identical conditions. Only in the
case of interacting with powerful electrophiles such as oxonium,11 iminium12,13 and
acyl halides,12 do tertiary enamides display enaminic or nucleophilic reactivity.
Synthetic applications of tertiary enamides are therefore very limited.
The notion that tertiary enamides are stable, silenced enamines and marginally
valuable chemical entities has been challenged. Structural analysis reveals a cross
conjugation system within tertiary enamides. Conjugation of the lone-pair electrons of
nitrogen with the carbon-carbon double bond and with the carbon-oxygen double
bond would favor the charge-separated resonance forms A and B, respectively (Figure
2). We envisioned that the enabled regulation of the cross conjugation system by
means of electronic and steric effects of the substituents attached on the enamide
segment (C=C-N-CO) would enhance the delocalization of the lone-pair electrons of
nitrogen into the carbon-carbon double bond, reviving the nucleophilicity of tertiary
enamides. Changing the reaction conditions by varying the polarity of the reaction
media for instance would also tune the cross conjugation system to rejuvenate the
enaminic reactivity of tertiary enamides. In the past years we have endeavored to
explore the nucleophilic reactions and synthetic applications of stable tertiary
enamides. We have shown that tertiary enamides are unique shelf stable enamine
variants and versatile synthons in synthesis. This feature article will highlight recent
advances in the nucleophilic reactions of tertiary enamides and their applications in
the synthesis of N-heterocyclic compounds, with a primary focus on our own work.

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Figure 2. General structure of tertiary enamide and its resonance forms
Nucleophilic reaction with epoxides
Our research project on tertiary enamides embarked with the exploration of synthetic
applications of enantiomerically pure 2R,3S-2-arylglycidamides that were readily
prepared from biotransformations of racemic trans-2,3-epoxy-3-arylpropanenitriles
catalyzed by Rhodococcus erythropolis AJ270, a nitrile hydratase and amidase
containing microbial whole-cell catalyst.14 Our attention was initially drawn by the
epoxide-bearing tertiary enamide (+)-SB204900 3, an alkaloid isolated from a hexane
extract of Clausena lansium leaves.15 By means of CuI-catalyzed coupling reaction of
2S,3R-(+)- and 2R,3S-(-)-2-phenylglycidamides with (Z)-1-phenyl-2-bromoethene
followed by exclusive N-methylation, we established the first synthesis of both
antipodes of SB204900 and assigned the absolute configuration of the naturally
occurring enantiomer16 (Scheme 1). It was the study that stirred our curiosity about
other clausena alkaloids such as clausenamide, neoclausenamide, homoclausenamide,
and -clausenamide. The alkaloids were isolated from the hot water extract of leaves
of Rutaceae Clausena lansium, a type of fruit tree widely distributed in southern
China.17 In Chinese folk medicine, the leaves and fruits are used to treat asthma,
influenza, gastrointestinal disorders, viral hepatitis and dermatological diseases.18
Despite the unique structures and intriguing biological activities, we were surprised to
find out that the biosynthesis of diverse structures of clausena alkaloids had not been
elucidated and their syntheses had remained largely unexplored.19 Structural scrutiny
led us to propose the biosynthetic pathways hypothesizing SB204900 is the key
precursor to all other clausena alkaloids through different intramolecular cyclization
reactions. To our delight, SB204900 was transformed selectively into the desired
natural products following our hypothesis.20,21 As depicted in Scheme 1, for example,

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(+)-SB204900 3 underwent TFA-mediated 6-endo-tet enamine-epoxide cyclization in
refluxing ButOH to produce (-)-homoclausenamide 4 in 62% yield.20,21 In acetonitrile
at ambient temperature, 8-endo-arene-epoxide cyclization of (+)-SB204900 was
promoted upon the treatment with 2 equivalents of p-toluenesulfonic acid, affording a
good yield of (-)--clausenamide 5.19 However, the 5-endo-tet alkene-epoxide
cyclization reaction of (+)-SB204900 proceeded in a hot aqueous Na2CO3 solution to
form a mixture of neoclausenamide 6 and its 6-epimer 7 in a 3:7 ratio.20,21 The Jones
oxidation led to (+)-neoclausenamidone 8 which underwent epimerization under
kinetic conditions followed by reduction to furnish (-)-clausenamide 10.21
Scheme 1. Synthesis of (+)-SB204900 3 and its conversion to (-)-homoclausenamide
4, (-)--clausenamide 5, (-)-neoclausenamide 6, and (-)-clausenamide 10
The successful biomimetic synthesis of homoclausenamide 4 from SB204900
indicated convincingly that tertiary enamide 3 was capable of acting as an enamine 3’

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to undergo nucleophilic attack at the epoxide moiety. In addition, in a perfectly
predisposed conformational structure of 3 in acetonitrile, conjugation of the tertiary
enamide was probably extended to the benzene moiety to form a pseudo-dienamide
system 3”, facilitating arene-epoxide cyclization reaction to produce -calusenamide
5. Furthermore, in pure water, the tertiary enamide adopted most likely a
conformation in which the phenylvinyl moiety is perpendicular to the plane of the
conjugated carboxamide. The delocalization of the nitrogen lone pair electrons into
the carbon-carbon double bond is therefore prohibited. The ostensible tertiary
enamide behaved actually as an isolated styrene 3’’’. As a consequence, the
alkene-epoxide cyclization reaction was favored energetically. It is especially worth
addressing that the reaction pathways are strongly dependent upon the reaction
conditions, particularly the nature or the polarity of reaction solvent employed. In
other words, different conditions can alter or regulate conformational structures and
enhance the conjugational systems, rendering the tertiary enamide as an enamine, a
pseudo-dienamine or an alkene species (Scheme 1).
The enaminic reaction of tertiary enamides with epoxides was utilized in the
preparation of a number of 4,6-diaryl-3-hydroxy-3,4-dihydropyridin-2(1H)-ones,
isomers of homoclausenamide 4.22 We16 also successfully applied the strategy of
8-endo-tet arene-epoxide cyclization of tertiary enamide, accomplishing the first
synthesis of (-)-balasubramide (-)-16, an indole-fused eight-membered
lactam-containing alkaloid isolated from Clausena indica which grows in the central
montane rainforests in Sri Lanka23 (Scheme 2).

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Scheme 2. Synthesis of (-)-balasubramide 16
Nucleophilic reaction with carbonyls
Encouraged by the enaminic reaction of tertiary enamides with epoxides, we next
examined the intramolecular nucleophilic addition of tertiary enamides to ketones. As
we expected, tertiary enamides 17 underwent cyclization readily with the activated
ketone moieties in the presence of a Lewis acid catalyst. Interestingly, while zinc
salt-catalyzed reactions gave a mixture of 3-hydroxy-1H-pyrrol-2(3H)-ones 18 and
their 5-hydroxy-1H-pyrrol-2-(5H)-one isomers 19, FeCl3-catalyzed reactions afforded
exclusively 5-hydroxy-1H-pyrrol-2-(5H)-one products under various conditions. It
was evident that the 3-hydroxy group resulting from initial attack of enaminic carbon
at the ketonic carbonyl underwent spontaneous rearrangement to 5-position. As
summarized in Scheme 3, the FeCl3-catalyzed reaction was highly efficient and robust.
Irrespective of the nature of substituents, almost all tertiary enamides 17 were
transformed into 5-hydroxy-1H-pyrrol-2-(5H)-one derivatives 19 in nearly
quantitative yields.24 It is noteworthy that the resulting products resemble the structure
of naturally occurring oteromycin,25 a microbial metabolite acting as an antagonist of
endothelin receptor. Some 5-hydroxy-1H-pyrrol-2-(5H)-one analogs have been shown

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to possess interesting biological activities26 and to serve as intermediates in the
synthesis of natural products.27
Scheme 3. Synthesis of 5-hydroxy-1H-pyrrol-2-(5H)-one derivatives 19 by means of
intramolecular nucleophilic addition of tertiary enamides to ketones
Delineated in Scheme 4 is a most plausible reaction mechanism.24 The direct
enaminic reaction of a tertiary enamide to FeCl3-activated ketonic carbonyl generates
a cyclic iminium intermediate 21 which undergoes deprotonation to afford
3-hydroxy-3,5-diaryl-1H-pyrrol-2(3H)-one product 18. Dehydration of 18 leads to the
formation of 2-oxo-2H-pyrrolium intermediate 22 which is trapped by a water
molecule to furnish the formation of final 5-hydroxy-3,5-diaryl-1H-pyrrol-2(5H)-one
product 19. It should be addressed that the activation of the ketone carbonyl occurs
most likely in a mono-coordination fashion as 20. The chelation of the -oxo amide to
iron is not beneficial or responsible for the intramolecular enaminic reaction because
the rigid geometry of the chelation structure does not bring proximity of the enaminic
carbon to the ketone carbonyl carbon. The involvement of the 2-oxo-2H-pyrrolium
intermediate 22 was supported by the fact that an enantioenriched
(S)-1-benzyl-3-hydroxy-3,5-diphenyl-1H-pyrrol-2(3H)-one (S)-18a with ee of >99%

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was
converted
quantitatively
into
a
racemic
mixture
of
1-benzyl-5-hydroxy-3,5-diphenyl-1H-pyrrol-2(5H)-one 19a.
Scheme 4. A plausible reaction mechanism for FeCl3-catalyzed cyclization reaction of
tertiary enamides 17
In the presence of a catalytic amount (5 mol %) of Cr(III)(R,R-salen)Cl complex,
tertiary enamides 17 undergo enantioselective intramolecular nucleophilic addition to
ketones to produce (S)- or (R)-3-hydroxy-1H-pyrrol-2(3H)-one derivatives 1828
(Scheme 5). Other complexes between R,R-salen ligand and AlIII-Cl, FeIII-Cl, CoII-Cl
and MnIII-Cl do not catalyze the reaction. The use of Na2CO3 helps to inhibit
rearrangement of the hydroxy group from 3- to 5-position which is facilitated by an
acid, ensuring the high chemical yields of products 18. The asymmetric catalysis
shows remarkable enantioselectivity as high enantiomeric excess values (94% - 99%)
are obtained for almost all products 18. Only in the case of substrates that bear an
N-methyl or N-phenyl, do the reactions of 17k and 17l give products 18k and 18l with
89% ee and 88% ee, respectively. A fused tricyclic product 18n of high enantiopurity
(94% ee) is also synthesized in 92% yield from the tetralone-derived tertiary enamide
albeit a higher catalyst loading (20 mol %) and an elongated reaction time (144 h) are
required.

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Scheme 5. Catalytic asymmetric addition of tertiary enamides to ketones
The resulting unsaturated -lactam compounds that contain a hydroxylated
tetrasubstituted stereogenic carbon atom are valuable chiral intermediates. Their
synthetic applications have been demonstrated in the practical preparation of
(3S,5S)-3,5-diphenyl-3-pyrrolidinol,28 whose racemic form has been found to possess
various pharmacological properties.29 As illustrated in Scheme 6, catalytic
hydrogenation of 18i affords quantitatively product 23 as a single diastereomer. The
excellent diastereoselectivity results probably from both the directing effect of the
hydroxy group and the steric effect of the 3-phenyl group. Treatment of 23 with Ac2O
gives compound 24 with its absolution configuration being determined
unambiguously by X-ray crystallography. Deprotection of N-PMP by CAN and of
acetyl group by hydrolysis leads to the formation of product 26. Reduction of the
lactam by LiAlH4 furnishes the formation of (3S,5S)-3,5-diphenyl-3-pyrrolidinol 27.
The overall yield of this five-step synthesis of 27 from 18i is about 80%.

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Scheme 6. Synthesis of (3S,5S)-3,5-diphenyl-3-pyrrolidinol 27
Following the successful reaction with activated ketones, we30 tested
intramolecular addition of tertiary enamides to aldehydes in the presence of a chiral
Lewis acid catalyst. A number of metal-(R,R-salen) complexes were screened, and
they displayed either appallingly low activity or disappointing enantioselectivity. A
mixture of R-BINOL and Ti(OiPr)4 (2:1) (5 mol %) was found to be an efficient
catalytic system, promoting the transformation of reactants 28 into
o
o
(S)-1,2,3,4-tetrahydropyridin-4-ol derivatives 29 in DCM at -20 C - -35 C. The
catalytic asymmetric cyclization reaction shows a broad substrate scope (Scheme 7).
When N-benzoyl-substituted tertiary enamides 28a-h are used, all reactions give good
to excellent yields of 29 with ee values ranging from 91.4% to >99.5%. Notably, the
velocity of the reaction is governed by the nature of the N-electron-withdrawing group.
Replacement of an N-benzoyl by an N-benzyloxycarbonyl leads to slow
transformation of 28i at -30 oC with product 29i being isolated in only 69% in 42 h. A
o
higher temperature (-20 C) and an elongated time (50 h) are required to implement
the conversion of an N-acetyl-substituted substrate 28j into product 29j in 82% yield.
The reaction also allows the construction of an enantiopure bicyclic product 29k.

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O
N
OH
chiral cat.
chiral cat. (5 mol %)
CH2Cl2 (10 mM)
-20 - -35 oC
OH
Ar
Ar
N
OH
6 - 50 h
O
R
O
R
28
29
+ Ti(OiPr)4 (2: 1)
OH
OH
29a
29b
29c
29d
29e
, Ar = Ph, 89%, 92.8% ee
, Ar = 4-F-C6H4, 97%, 92.6% ee
, Ar = 4-Cl-C6H4, 92%, 97.6% ee
, Ar = 4-Br-C6H4, 99%, 97.6% ee
, Ar = 4-Me-C6H4, 77%, >99.5% ee
, Ar = 2-Cl-C6H4, 96%, >99.5% ee
Cl
N
Ar
N
Cl
29g
O
Ph
29f
O
Ph
, 97%, >99.5% ee
OH
OH
OH
OH
O
O
N
Ph
N
Ph
N
N
O
Ph
O
OBn
O
Me Ph
29k
, 82%, 88.6% ee (-20 C) , 66%, >99.5% ee
O
o
29h
, 94%, 91.4% ee
29i
29j
, 69%, 93.5% ee
Scheme 7. Catalytic asymmetric addition of tertiary enamides to aldehydes
It is interesting to note that the mechanism of asymmetric catalysis is not trivial.
Almost identical positive nonlinear effects are observed with different catalyst
concentrations. However, the higher the catalyst loading, the faster the transformation
of 28. These results exclude the monomeric (R)-BANOL-Ti(OiPr)4 as an active
1
species in catalysis. Detailed studies of H NMR spectroscopy and diffusion-ordered
spectroscopy along with computer simulation have revealed the involvement of
[(R)-bino-Ti(OiPr)2]3 as the most probable catalytic species albeit its structure awaits
further investigation.30,31
Nucleophilic reaction with imines
Tertiary enamides exhibit good enaminic reactivity in addition reactions to aromatic
imines under mild conditions. When aldehyde-containing tertiary enamides 28 are
treated with anilines 30 in DCM at room temperature, for example,
4-anilino-1,2,3,4-tetrahydropyridine derivatives are formed without the detection of
imine intermediates. This indicates convincingly that the speed of nucleophilic

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reaction of tertiary enamides to imine exceeds the velocity of condensation reaction
between aldehyde and anilines. As summarized in Scheme 8, reaction between 28 and
aromatic amines 30 affords products 32a-o in excellent yields. It is interesting to note
that the reaction rate varies dramatically depending on the nature of the substituent on
the anilines. It takes less than 0.5 h for electron-rich anilines to finish the cyclization
whereas the reaction of halogen-substituted anilines requires 1 to 8 h to go to
completion. In the case of 4-nitroaniline and 2-nitroaniline, good yields of products
32d and 32e are obtained in 3 and 7 days, respectively. It should be noted, however,
that the substituent effect influences only the first reaction step, viz. the formation of
imine from the condensation between aniline and aldehyde. The electron-deficient
anilines appear less reactive towards the aldehyde group. Once aromatic imines are
generated, they are attacked by the nucleophilic enamides, leading to the formation of
the six-membered heterocyclic ring products efficiently.32
Scheme 8. Nucleophilic addition of tertiary enamides to aromatic and aliphatic imines
In contrast to anilines, aliphatic amines react with tertiary enamides to form

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aliphatic imine intermediates 33 quantitatively. No nucleophilic reaction between
enamides and aliphatic imines occurs under the identical conditions. The clear-cut
difference in reactivity of tertiary enamides towards aromatic and aliphatic imines is
intriguing, reflecting the requirement of active imine components to react with tertiary
enamides. Catalyzed by a Brønsted acid such as p-toluenesulfonic acid,
intramolecular addition of tertiary enamides to aliphatic imines proceeds effectively to
produce 4-amino-1,2,3,4-tetrahydropyridine derivatives 34 in high yields32 (Scheme
8). The resulting products are analogs of 1-benzoyl-2-benzyl-4-aminopiperidine CGP
49823, an orally and centrally active non-peptide NK1 antagonist.33
Nucleophilic reaction with nitriliums
Isonitriles are unique divalent species and are able to undergo -addition reactions
with both electrophiles and nucleophiles at the same carbon atom. The reaction
proceeds initially with the addition of isonitriles to electrophiles such as aldehydes to
form nitrilium intermediates. The resulting nitrilium intermediates are highly reactive
and are readily intercepted by heteroatom nucleophiles.34 Based on the reactivity of
isonitriles, we designed a [5+1] cycloaddition reaction of N-formylmethyl-substituted
tertiary enamides to isonitriles to construct six-membered N-heterocycles. We were
pleased to discover that, promoted by Zn(OTf)2, N-formylmethyl-substituted tertiary
enamides 35 undergo reaction with isonitriles 36 and acyl chlorides 37 under aerobic
conditions to produce 2-substituted 4-acylamino-5-acyloxypyridines 38. The key
steps in this reaction cascade involve an unprecedented -addition of aldehyde and
enamide to isonitrile, facile aerobic oxidative aromatization followed by
intermolecular acyl transfer from pyridinium nitrogen to 5-hydroxy and acylation of
the 4-amino group by an external acyl chloride (Scheme 9). The reaction is very
general, accepting all types of tertiary enamides, isonitriles and acyl chlorides as
substrates to afford efficiently 2-substituted 4-acylamino-5-acyloxypyridines in good
to excellent yields.35 The resulting diversely substituted pyridines are very useful in
medicinal chemistry as their analogs have been shown to possess strong
acetylcholinesterase (AChE) inhibitory activity.36

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O
N
R3
COR4
R4COCl (37)
N
C
aerobic
Zn(OTf)2
4Å MS, rt
OCOR2
auto-oxidation
Et3N, rt
R1
+ R3 NC
36
5 - 48 h
R1
N
38
O
R2
35
R4COCl (37) Et3N, rt
Zn(OTf)2, 4Å MS, rt
R3
acylation
R3
R3
R1
N
R3
NH
N+
NH
C
N
O-
H
C
OH
C
OH
O2
C
OCOR2
R1
N
R1
N+
R1
N
R2
O
R2
R2
O
O
A
D
C
B
p-MeO-C6H4
COPh
p-MeO-C6H4
COPh
p-MeO-C6H4
COPh
N
N
N
N
N
N
OCOPh
OCOPh
OCOPh
R
38a, R = Ph, 10 h, 91%
38b, R = 4-F-C6H4, 7 h, 85%
38c, R = 4-Cl-C6H4, 8 h, 75%
38d, R = 3-Cl-C6H4, 7 h, 90%
38e, R = 2-Cl-C6H4, 7 h, 82%
38f, R = 4-Br-C6H4, 8 h, 91%
38g, R = 2,4-Cl2-C6H3, 10 h, 87%
38h, R = 4-NO2-C6H4, 16 h, 64%
38i, R = 4-Ph-C6H4, 8 h, 82%
38j, R = 4-Me-C6H4, 5 h, 84%
38k, R = 4-MeO-C6H4, 5 h, 77%
38m, 4 h, 70%
38l, 4 h, 60%
PhCO
Ph
R
38n, R = Ph, 18 h, 77%
38o, R = 4-Br-C6H4, 24 h, 44%
38p, R = Bn, 48 h, 70%
38q, R = n-Bu, 24 h, 60%
38r, R = c-Hex, 24 h, 41%
N
OCOPh
N
Scheme 9. Synthesis of polysubstituted pyridines from the reaction of
N-formylmethyl-substituted tertiary enamides with isonitriles and acyl chlorides
Since the cycloaddition reaction between N-formylmethyl-substituted tertiary
enamides and isonitriles forms initially intermediate B (Scheme 9), termination of
sequential reaction by reduction or hydrolysis of the imino moiety of presumed
intermediate B prior to its oxidative aromatization would furnish functionalized
1,2,3,4-tetrahydropyridines and 2,3-dihydropyridin-4(1H)-ones, respectively. As
depicted in Scheme 10, Zn(OTf)2-mediated reaction between isonitriles and
N-formylmethyl-substituted tertiary enamides followed by reduction with
Me4NBH(OAc)3
at
ambient
temperature
produces
1,6-disubstituted
trans-3-hydroxy-4-amino-1,2,3,4-tetrahydropyridines 39 in moderate to good yields.37

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The high stereoselectivity for preferential formation of trans-configured product
reflects most probably a powerful directing effect of the hydroxy group in the
reduction of the imine group of B with Me4NBH(OAc)3. Trapping of the intermediate
B by an acyl chloride followed by hydrolysis under acid conditions before
auto-oxidative aromatization leads to the formation of substituted
2,3-dihydropyridin-4(1H)-one products 4037 (Scheme 11). It is remarkable that the
cascade reactions between N-formylmethyl-substituted tertiary enamides and
isonitriles provide powerful and divergent synthetic routes to pyridine,
1,2,3,4-tetrahydropyridine and 2,3-dihydropyridin-4(1H)-one derivatives simply by
means of employing different terminating methods.
Scheme 10. Synthesis of trans-3-hydroxy-4-amino-1,2,3,4-tetrahydropyridine
derivatives.

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O
C
OMe
1. Zn(OTf)2, 4Å MS, rt
2. R4COCl (37), Et3N, rt, 5 min
OCOR3
O
N
R1
+
3. HCl (conc.) rt, 12 h
R1
N
O
R2
Ph
NC
O
R2
40
35
36a
O
C
40g, R = 2,4-Cl2-C6H3, 10 h, 84%
40h, R = 4-NO2-C6H4, 16 h, 70%
40i, R = 4-Ph-C6H4, 5 h, 80%
40j, R = 4-Me-C6H4, 5 h, 81%
40k, R = 4-MeO-C6H4, 5 h, 60%
40a, R = Ph, 10 h, 92%
O
40b, R = 4-F-C6H4, 7 h, 72%
40c, R = 4-Cl-C6H4, 8 h, 82%
40d, R = 3-Cl-C6H4, 7 h, 72%
40e, R = 2-Cl-C6H4, 7 h, 72%
40f, R = 4-Br-C6H4, 8 h, 82%
O
R
N
O
Ph
O
O
C
O
O
C
C
O
Ph
O
Ph
C
O
Me
O
Ph
O
O
O
O
N
N
Ph
N
Ph
N
O
Ph
O
Ph
O
Ph
O
R
40l, 4 h, 53%
40m, 4 h, 48%
40n, R = 4-Tolyl, 7 h, 82%
40o, R = Me, 5 h, 38%
40p, 10 h, 70%
Scheme 11. Synthesis of 2,3-dihydropyridin-4(1H)-one derivatives.
We then extended our study to the reaction of N-formylmethyl-substituted tertiary
enamides with isonitriles and amines, envisaging the formation of 3-aminopyridine,
3,4-diamino-1,2,3,4-tetrahydropyridine or 3-amino-2,3-dihydropyridin-4(1H)-one
derivatives. Surprisingly, the reaction does not form any of the designed products.
Instead, functionalized imidazolinium salts 42 are obtained in good yields.38 An
18O-labeling experiment reveals an intriguing reaction pathway which comprises the
formation and fragmentation of a bridged heterocyclic intermediate (Scheme 12). It is
noteworthy that the enamine unit does not participate in the reaction probably due to
its lower nucleophilicity in comparison to that of the nitrogen anion of intermediate F.
Because the tertiary enamide moiety remains intact in the reaction, synthesis is
successfully expanded to various N-formylmethyl-substituted tertiary amides. The
three component reaction of N-formylmethyl-substituted tertiary amides with amines
and isonitriles has now been developed into an efficient method for the expedient
synthesis of diverse polysubstituted imidazolinium salts.38

ChemComm
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OMe
NH2
O
N
Ar
Zn(OTf)2 (1 equiv)
CH3CN, rt, 1 - 2 h
N
+
+
+
Ar
O
R
N
O
R
TfO- Bn
R = Ph, Me
81 - 88%
NHC6H4-OMe-p
NC
36a
41
35
42
Zn(OTf)2
BnN
N
Bn
N
Bn
ZnOTf
N
Ar'
NAr'
N
C N Ar'
C
-OTf
O
O
N
O
N
R
R
R
Ar
Ar
Ar
F
G
E
Scheme 12. Synthesis of imidazolinium derivatives.
Difunctionalization of tertiary enamides
Nnucleophilic reactions of tertiary enamides with electrophiles initially form iminium
intermediates. In all aforementioned examples, the iminium intermediates undergo
spontaneously deprotonation to afford adducts or mono-functionalized products.
Since the resulting iminium intermediates are highly electrophilic, their interception
by nucleophilic reagents would generate difunctionalized products of tertiary
enamides. To explore the difunctionalization of tertiary enamides, we39 have studied
very recently the intermolecular reaction between tertiary enamides and
salicylaldehydes. Catalyzed by the complex between (R)-BINOL and Ti(OiPr)4, both
cyclic and acyclic tertiary enamides 43 are able to undergo cyclization with almost all
tested salicylaldehydes 44, affording diverse cis,trans-configured 4-chromanols 45
that contain three continuous stereogenic centers in good yields with excellent
diastereoselectivity and enantioselectivity. The reaction proceeds through tandem
enaminic addition of tertiary enamide to aldehyde followed by the intramolecular
trapping of the resulting iminium by the hydroxy group. Oxidation of the resulting
cis,trans-configured 4-chromanols yielded almost quantitatively chroman-4-one
derivatives which are converted diastereospecifically into cis,cis-configured

Page 19 of 24
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4-chromanols upon reduction with NaBH4. It should be noted that, as the members of
dihydrobenzopyran family, 4-chromanol and chroman-4-one derivatives occur as
natural and synthetic products with various biological activities.40 Perinadine A, a
complex alkaloid isolated recently from marine-derived fungus Penicillium citrinum,
for example, features a pyrrolidine-fused 4-chromanol core structure.41
O
OH
R"
N
(R)-BINOL:Ti(OPri)4:H2O
R2
R2
R"
N
[(2:1:2), 10 mol%]
H
R'
+
R'
OH
O
COR1
o-xylene, Ar, 40 oC
COR1
43
44
45
OH
OH
R
R
N
N
O
O
COPh
COPh
R
45j, R = Cl, 2 h, 90%, dr >20:1, 96.0% ee
45k, R = Br, 2 h, 89%, dr >20:1, 95.1% ee
OH
45a, R = H, 17 h, 98%, dr >20:1, 96.5% ee
45b, R = F, 2 h, 91%, dr >20:1, 97.9% ee
45c, R = Cl, 3 h, 86%, dr >20:1, 96.5% ee
45d, R = Br, 3 h, 94%, dr >20:1, 97.8% ee
45e, R = CN, 3 h, 91%, dr >20:1, 96.1% ee
45f, R = CO2Me, 5 h, 93%, dr >20:1, 97.0% ee
45g, R = Ph, 6 h, 99%, dr >20:1, 98.2% ee
45h, R = Me, 17 h, 92%, dr >20:1, 97.1% ee
45i, R = MeO, 6 h, 78%, dr >20:1, 95.9% ee
N
R
O
COPh
45l, R = Br, 6 h, 99%, dr 15:1, 95.3% ee
45m, R = OMe, 168 h, 39%, dr 9:1, 51.2% ee
OH
OH
OH
Br
O
O
N
O
N
N
O
O
R
COPh
COPh
O
45n, 24 h, 27%, dr >20:1
45o, 96 h, 77%, dr >20:1
45p, R = Cl, 4 h, 95%, dr >20:1, 99.2% ee
45q, R = MeO, 2 h, 95%, dr >20:1, 98.7% ee
81.9% ee
95.5% (95.8%) ee
OH
OH
OH
Br
Br
Br
N
O
Bn
O
N
O
N
R
COPh
COPh
O
45u, 24 h, 52%, dr 7:1
45t, 120 h, 65%
dr 11:1, 95.7% ee
45r, R = Me, 2 h, 69%, dr >20:1, 43.2% ee
45s, R = OBn, 1 h, 67%, dr > 20:1, 80.2% ee
99.1% ee
Scheme 13. Synthesis of 4-chromanols from catalytic asymmetric di-functionalization
of tertiary enamides with salicylaldehydes.
Conclusion and perspective

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We have shown that, contrary to general notion, tertiary enamides exhibit good
enaminc reactivity towards functional groups such as epoxides, carbonyls, imines and
nitriliums. Both intramolecular and intermolecular reactions of tertiary enamides
provide efficient methods for the synthesis of diverse heterocycles that are not readily
obtained by other means. Furthermore, reactions between tertiary enamides and
carbonyls catalyzed by chiral Lewis acids lead to the construction of functionalized
heterocyclic compounds of high enantiopurity.
Admittedly, the study of the reactions and applications of tertiary enamides is still
in its infancy. Reactivity and synthetic versatility of tertiary enamides await for
example
extensive
and
in-depth
exploration.
Asymmetric
catalytic
difunctionalizations of tertiary enamides through cascade reactions and
multicomponent reactions, which would produce molecules of complexity, are
particularly worth pursuing. Synthesis of natural products such as alkaloids using
tertiary enamides protocol is a challenging but very attractive goal. It is anticipated
that easy availability, tunable stability and versatile reactivity will render tertiary
enamides powerful and unique synthons in organic synthesis.
Acknowledgment
I would like to thank research students Luo Yang, Shuo Tong, Chuan-Hu Lei and Ling
He for their great contributions to the project of tertiary enamides in this laboratory. I
am very grateful to Prof. Jieping Zhu at EPFL, Switzerland, Prof. De-Xian Wang and
Prof. Zhi-Tang Huang at ICCAS, Beijing and Prof. Liang Zhao at Tsinghua University
for their collaborations. This project is supported by National Natural Science
Foundation of China (21320102002).
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