Synthesis of 4-amino-1,2,3,4-tetrahydropyridine derivatives by intramolecular nucleophilic addition of tertiary enamides to in-situ generated imines

Article abstract of DOI:10.1016/j.tet.2012.05.108

The reactivity of stable tertiary enamides in nucleophilic addition reaction with various in-situ generated imines was explored. Under very mild conditions, formyl-bearing tertiary enamides reacted with both aromatic and aliphatic amines to form imine intermediates. In the absence or presence of p-toluenesulfonic acid as a catalyst, intramolecular nucleophilic addition of enamide to imine functionality proceeded effectively to produce diverse 4-amino-1,2,3,4-tetrahydropyridine derivatives in good to excellent yields.

Full text of DOI:10.1016/j.tet.2012.05.108

Tetrahedron 68 (2012) 6492e6497
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Tetrahedron
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Synthesis of 4-amino-1,2,3,4-tetrahydropyridine derivatives by intramolecular
nucleophilic addition of tertiary enamides to in-situ generated imines
,
,b,
Shuo Tong a, Xu Yang b, De-Xian Wang a, Liang Zhao b, Jieping Zhu b c, Mei-Xiang Wang a
*
a Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
b MOST Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China
c
ꢀ ꢀ
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 April 2012
Received in revised form 20 May 2012
Accepted 25 May 2012
Available online 1 June 2012
The reactivity of stable tertiary enamides in nucleophilic addition reaction with various in-situ generated
imines was explored. Under very mild conditions, formyl-bearing tertiary enamides reacted with both
aromatic and aliphatic amines to form imine intermediates. In the absence or presence of p-toluene-
sulfonic acid as a catalyst, intramolecular nucleophilic addition of enamide to imine functionality pro-
ceeded effectively to produce diverse 4-amino-1,2,3,4-tetrahydropyridine derivatives in good to excellent
yields.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
challenged recently after the discovery of intramolecular nucleo-
philic addition reaction of tertiary enamides to oxirane ring in the
4-Aminopiperidine derivatives have been shown to possess var-
ious biological activities and are of important values in drug discov-
ery and development.1e6 2-Substituted 4-aminopiperidine
derivatives such as 1-benzoyl-2-benzyl-4-aminopiperidine CGP
49823 is, for example, an orally and centrally active non-peptide NK1
antagonist.2 Most of the simple 4-aminopiperidine compounds are
obtained predominantly by means of reductive amination of piper-
idin-4-ones.1,4 Synthesis of 4-aminopiperidines containing other
substituents or functional groups on the N-heterocyclic ring gener-
ally requires multistep reactions.3,5e8 They suffer from either tedious
stepwise chemical manipulations or low overall chemical yields.
General and efficient methods are therefore highly desirable for the
synthesis of diverse and bioactive 4-aminopiperidine derivatives.
Enamides are enamine variants in which nitrogen is substituted
by an electron-withdrawing group such as benzoyl and acetyl (Fig.1).
Because of the electronic effect of electron-withdrawing groups, the
delocalization of nitrogen lone-pair electrons into carbonecarbon
double bond is decreased, leading to the alleviation of electron
density and therefore the nucleophilicity of enaminic carbon.9
Whereas secondary enamides, which bear an NeH moiety, are aza-
ene components that undergo aza-ene reactions with active elec-
trophiles,9,10 tertiary enamides have been known as stable and inert
species.9,11 The stability of enamides is also exemplified by their oc-
currences in natural products.12 The notion of tertiary enamides as
inert chemical entities toward electrophiles, however, has been
biomimetic synthesis of Clausena alkaloids and their analogs.13 The
nucleophilicity of tertiary enamides has more recently been exploi-
ted in chiral Lewis acid-catalyzed intramolecular addition reactions
to activated ketones14 and aldehydes15 to produce enantioenriched
five- and six-membered N-heterocyclic compounds that are func-
tionalized with a hydroxyl group in excellent yields with high
enantioselectivity. Moreover, oneuniquefeatureof tertiaryenamides
we perceived is the regulation of their reactivity by the nature of
substituents R and R0 (Fig. 1). Control of the electronic and steric ef-
fects of the N-substituents, for instance, would enhance or decrease
the conjugation of enamine segment, upper- or down-tuning
therefore the enaminic reactivity of enamides. Our continued effort
in the exploration of the chemistry of tertiary enamides,13e15 and the
interest in developing a new method for the synthesis of diverse 4-
aminopiperidine derivatives led us to study the intramolecular ad-
dition of tertiary enamides toward imines. To the best of our
knowledge, no reaction of stable tertiary enamides with imines has
been reported in literature.9 We report herein for the first time that
stable tertiary enamides show unexpectedly high nucleophilic re-
activity toward in-situ generated N-arylimines under very mild
conditions. The reaction of aldehyde-bearing tertiary enamides with
* Corresponding author. E-mail addresses: wangmx@mail.tsinghua.edu.cn,
mxwang@iccas.ac.cn (M.-X. Wang).
Fig. 1. Structure of enamine, and secondary and tertiary enamides.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.108

S. Tong et al. / Tetrahedron 68 (2012) 6492e6497
6493
both aromatic and aliphatic amines, which proceeded consecutively
through imine formation and intramolecular addition of enamide to
C]N bond, provided an efficient method for the construction of 4-
amino-1,2,3,4-tetrahydropyridine derivatives that are not readily
accessible by other means. Facile reduction of the resulting products
furnished substituted 4-aminopiperidine compounds.
Preparative reactions between tertiary enamides 1 and a wide
variety of aromatic amines 2 were then studied. The reaction under
mild conditions provided a general and high-yielding approach to 4-
arylamino-1,2,3,4-tetrahydropyridine derivatives 4. As summarized
inTable 1, enamide 1a reacted effectively with avarietyof substituted
anilines in dichloromethane at ambient temperature. Complete
Table 1
2. Results and discussion
Synthesis of 4-arylamino-1,2,3,4-tetrahydropyridine derivatives 4a
We initiated our study with examination of the reaction between
enamide 1a (R¼Ph) and aniline 2a (Ar¼C6H5) (Scheme 1). Using 1H
NMR spectroscopy to follow the reaction in CDCl3, we found that the
reaction took place very rapidly at room temperature. For example,
no proton signals corresponding to starting materials were observed
when equimolar reactants 1a and 2awere mixed in an NMR tube and
the spectrum was recorded immediately (see Supplementary data).
Surprisingly, no signals of imine intermediate 3a were observed ei-
ther. Instead, a complete and quantitative conversion to 4-anilino-
1,2,3,4-tetraheydropyridine product 4a was evidenced clearly by the
observation of an exclusive set of proton resonance peaks (see
Supplementary data). Toshedlightonthereactionprocess,especially
the substituent effect on the reaction rate, anilines bearing either an
electron-donating or an electron-withdrawing group were allowed
to react with 1a (Scheme 1). Monitored by 1H NMR spectral changes
again, it was found that electron-rich aniline p-methoxyaniline 2b
reacted as equally efficient as aniline 2a, while 4-nitroaniline 2c, an
electron-deficient aniline, underwent a slow reaction with enamide
1a. Quantitative formation of product 4b was effected within 5 min
from 2b, whereas 30 min were required for 2c to complete its con-
version to product 4c (see Supplementary data). The change of sub-
stitution pattern from para to ortho-position led to a very sluggish
transformation of 2-nitroaniline 2d, with 100% conversion to 4d
being achieved after its 3 days’ interaction with enamide 1a (Scheme
1) (see Supplementary data). It should be addressed that in all cases
no accumulation of imine intermediates 3aed was evidenced by 1H
NMR spectra. The outcomes indicated convincingly that addition of
tertiary enamides to an imine moiety proceeded much fast than the
formation of imine from the condensation reaction between alde-
hyde of 1a and anilines 2aed. In other words, the imine formation
reaction, which was strongly governed by both electronic and steric
effectsofasubstituentonaniline, wasaratelimitedstepintheoverall
reaction tandem. Regardless of the nature of imines 2aed that were
generated in-situ from aromatic amines, enamide 1a always exhibi-
ted excellent reactivity and underwent efficient intramolecular nu-
cleophilic addition reaction to arylimine to afford heterocyclic
products 4aed (Scheme 1).
Entry
1
Ar0
R
2
Ar
Ph 2a Ph
Ph 2b 4-MeOeC6H4 10 min 4b
Timeb
20 min 4a
4
Yieldc (%)
1
2
3
4
5
6
7
8
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1a 4-BrC6H4
1b Ph
85
91
100
84
87
99
99
96
95
89
88
86
81
94
84
Ph 2c 4-NO2eC6H4 72 h
Ph 2d 2-NO2eC6H4 7 d
4c
4d
Ph 2e 4-MeeC6H4
Ph 2f 4-FeC6H4
Ph 2g 4-CleC6H4
Ph 2h 4-BreC6H4
Ph 2i 2-BreC6H4
Ph 2j 3-BreC6H4
Ph 2k 1-Naph
Ph 2a Ph
10 min 4e
8 h
4 h
5 h
5 h
1 h
4f
4g
4h
4i
9
10
11
12
13
14
15
4j
30 min 4k
10 min 4l
1c 4-MeeC6H4 Ph 2a Ph
1d 4-CleC6H4
1e Ph
5 min
30 min 4n
1.5 h 4o
4m
Ph 2a Ph
Me 2a Ph
a
A mixture of 1 (1 mmol) and 2 (1 mmol) in dichloromethane (50 mL) was stirred
at room temperature.
b
Monitored by TLC.
Isolated yield.
c
conversion of reactants into desired product was observed in all
cases. Not surprisingly, however, the reaction velocity, which was
monitored by TLC and consistent with 1H NMR monitoring (vide
supra), varied dramatically based on the aromatic amines employed
because of their different reactivities in the rate-determining imine
formation reaction. For example, reaction of enamide 1a with aniline
2a, p-methoxyaniline 2b, p-toluidine 2e, and naphthalene-1-amine
2k went completion within 30 min (entries 1, 2, 5, and 11, Table 1).
The presence of an electron-attracting halogen substituent such as
fluoro, chloro, and bromo on aniline led to an elongated reaction
(entries 6e10, Table 1). Reaction became very slow when 4-
nitroaniline 2c was used. Due to the unfavorable electronic and ste-
ric effects in the initial step of imine formation, 2-nitroaniline 2d
appeared the least active in reaction (entry 4, Table 1). Nevertheless,
all reactions tested gave complete chemical conversion, and
pure 4-arylamino-1,2,3,4-tetrahydropyridine products 4aek were
obtained in 85e100% isolated yields (entries 1e11, Table 1). 4-
Arylamino-1,2,3,4-tetrahydropyridine products 4 bearing a differ-
ent aryl group at 6-position were conveniently synthesized from the
analogous reaction using enamides 1bed with variation of aromatic
substituent Ar0. This has been exemplified by the high-yielding syn-
thesis of products 4len from very efficient reaction between enam-
ides1bedandaniline2a(entries 11e14, Table 1). Analogousenamide
that contains an N-acetyl substituent instead of an N-benzoyl group
was able to undergo same condensation reaction and subsequent
cyclization with anilines. Listed in Table 1 is the example of the
synthesis of 1-acetyl-4-anilino-6-phenyl-1,2,3,4-tetrahydropyridine
4o from the reaction between 1e and 2a (entry 15, Table 1). Notice-
ably, the reaction of N-acetyl-substituted enamide 1e was slower
than that of N-benzoyl-substituted enamide 1a (entries 1 and 15,
Table 1). The higher nucleophilicity of enamide 1a is the reflection of
Scheme 1. Examination of reaction of enamide 1a with anilines 2aed by means of 1
H
NMR spectroscopy.

6494
S. Tong et al. / Tetrahedron 68 (2012) 6492e6497
stronger delocalization of nitrogen lone-pair electrons into carbon-
ecarbon double bond. It also suggests that benzoyl group is less
powerful than acetyl in pulling nitrogen lone-pair electrons in
enamides.
evaporation of the solvent from the solution in a mixture of pe-
troleum ether and ethyl acetate, and its X-ray molecular structure
was determined (Fig. 2).
Encouraged by the successful synthesis of 4-arylamino-1,2,3,4-
tetrahydropyridine derivatives from the reaction of tertiary
enamides 1aee with aromatic amines 2aek, we then turned our
attention to aliphatic amines (Scheme 2). Under the identical
conditions for the reaction with aromatic amines, the reaction of
enamide 1a with benzylamine 5a occurred rapidly. Surprisingly,
however, reaction stopped at the stage of imine formation. Intra-
molecular addition of enamide to alkylimine 6a did not proceed at
all under neutral conditions. This is most probably attributed to the
lower electrophilicity of alkylimine 6a than arylimine 2 and its easy
isomerization of the corresponding enamine. To promote the re-
action, Brønsted acid was employed to activate alkylimino group.
To our delight, in the presence of p-toluenesulfonic acid as a cata-
lyst, cyclization reaction proceeded smoothly at room temperature
to produce 4-benzylamino-1,2,3,4-tetrahydropyridine 7a in an al-
most quantitative yield (Scheme 2). Although the reaction rate
appeared low, Brønsted acid-catalyzed intramolecular addition of
tertiary enamides to aliphatic imines allowed introduction of
alkylamino groups, enriching the diversity of products. Scheme 2
shows, for example, the synthesis of 1,2,3,4-tetrahydropyridine
derivatives 7b and 7c that contain either an allylamino or a buty-
lamino group.
Fig. 2. X-ray molecular structure of 4c.
As the functionalized six-membered N-heterocyclic compounds,
resulting 4-amino-1,2,3,4-tetrahydropyridines are conceivably
useful intermediates in organic synthesis. Demonstrated in Scheme
3 is the preparation of 4-amino-2-phenylpiperidines, which are the
analogs of a potent NK1 antagonist CGP 49823.2 In the presence of
Pd/C as a catalyst, hydrogenation of 4l with a hydrogen balloon at
room temperature afforded almost quantitatively products 11a and
11b with roughly a ratio of 1:1 (Scheme 4).
Scheme 4. Catalytic hydrogenation of 4l.
Scheme 2. p-TsOH-catalyzed synthesis of 4-alkylamino-1,2,3,4-tetrahydropyridine
derivatives.
3. Conclusion
In conclusion, we have established a new and general method
for the synthesis of substituted 4-amino-1,2,3,4-tetrahydropyridine
compounds from the reaction of aldehyde-bearing tertiary enam-
ides with both aromatic and aliphatic amines under mild condi-
tions. The one-pot reaction process comprises the formation of
imines from condensation between aldehydes and amines followed
by intramolecular nucleophilic addition of tertiary enamides to
imines. The outcomes along with our previous discoveries show
convincingly that tertiary enamides are versatile and valuable nu-
cleophiles. The study of various enaminic reactions of tertiary
enamides in synthesis is being actively pursued in this laboratory
and the results will be reported in due course.
It should also be noted that the synthesis is not limited to 2-aryl-
substituted 4-amino-1,2,3,4-tetrahydropyridine derivatives. As
a demonstration, the synthesis of a fused N-heterocyclic compound
was illustrated in Scheme 3. In the presence of a catalytic amount of
p-toluenesulfonic acid, tertiary enamide 8 derived from cyclohex-
anone underwent consecutively condensation reaction with
diphenylmethanamine 9 and intramolecular enamideealdehyde
addition reaction to afford 1,2,3,4,5,6,7,8-octahydroquinoline de-
rivative 10 in 89% yield.
4. Experimental part
4.1. General procedure for the synthesis of 4-arylamino-6-
aryl-1,2,3,4-tetrahedropyridine derivatives 4
A mixture of enamides 1 (1 mmol) and aromatic amines 2
(1 mmol) in dry CH2Cl2 (50 mL) was stirred at ambient tempera-
ture. After reactants were consumed in a period of time (see Table
1), which was monitored by TLC, an aqueous NaHCO3 solution (5%,
50 mL) was added, and the resulting mixture was extracted by
CH2Cl2 (3ꢀ30 mL). The combined organic layer was washed with
brine (2ꢀ50 mL) and dried with anhydrous Na2SO4. After removal
of solvent, the residue was chromatographed on a silica gel column
Scheme 3. Synthesis of 4-alkylamino-1,2,3,4,5,6,7,8-octahydroquinoline 10.
Structures of heterocyclic products are established on the basis
of spectroscopic date and microanalyses. To put the structure be-
yond any ambiguity, a single crystal of 4c was cultivated by slow

S. Tong et al. / Tetrahedron 68 (2012) 6492e6497
6495
eluted with a mixture of petroleum ether and ethyl acetate (4:1) to
give pure 4.
(br s, 2H), 6.92 (t, J¼8.8 Hz, 2H), 6.64 (br s, 2H), 5.50 (br s, 1H),
4.19e4.21 (m, 2H), 3.63 (t, J¼10.4 Hz, 1H), 3.63 (br s, 1H, NH),
2.04e2.09 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 171.2, 142.4,
4.1.1. 1-Benzoyl-6-(4-bromophenyl)-4-(phenyl)amino-1,2,3,4-
142.3, 137.4, 135.8, 131.5, 131.2, 128.5, 128.3, 127.6, 121.8,
116.2, 116.0, 115.7, 114.7, 47.3, 44.1, 30.6; FT-ICRMS m/z (%) 450
(10) [M] þ, 452 (10), 342 (90), 340 (100). HRMS (FT-ICRMS) cal-
culated for C24H20BrFN2O: 450.0743, 452.0723. Found: 450.0737,
452.0717.
tetrahydropyridine 4a. Mp 185e187 ꢁC; IR (KBr) 3388, 1650, 1620,
1602 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 7.07e7.48 (m, 11H), 6.74 (t,
J¼6.0 Hz, 1H), 6.65 (d, J¼8.0 Hz, 2H), 5.51 (br s, 1H), 4.26 (d,
J¼3.7 Hz, 1H), 4.22 (br s, 1H), 3.86 (br s, 1H, NH), 3.61 (t, J¼9.2 Hz,
1H), 2.08 (br s, 2H); 13C NMR (100 MHz, CDCl3)
d 171.1, 146.0, 141.9,
137.4, 135.7, 131.3, 131.0, 129.5, 128.4, 128.2, 127.5, 121.6, 118.0, 116.2,
113.3, 46.2, 43.7, 30.8; GCeMS (EI) m/z (%) 432 (5) [M]þ, 434 (4), 342
(10), 340 (12), 235 (100), 233 (95), 105 (48). HRMS (EI) calculated
for C24H21BrN2O: 432.0837, 434.0817. Found: 432.0844, 434.0825.
4.1.7. 1-Benzoyl-6-(4-bromophenyl)-4-(4-chlorophenyl)amino-
1,2,3,4-tetrahydropyridine 4g. Mp 232e233 ꢁC; IR (KBr) 3387, 1648,
1617, 1597 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.27e7.48 (m, 7H),
7.14 (d, J¼8.4 Hz, 2H), 7.68 (d, J¼7.6 Hz, 2H), 6.57 (d, J¼9.2 Hz, 2H),
5.48 (br s, 1H), 4.21e4.22 (m, 2H), 3.82 (br s, 1H, NH), 3.60 (t,
J¼10.4 Hz, 1H), 2.04e2.10 (m, 2H); 13C NMR (100 MHz, CDCl3)
4.1.2. 1-Benzoyl-6-(4-bromophenyl)-4-(4-methoxyphenyl)amino-
1,2,3,4-tetrahydropyridine 4b. Mp 163e164 ꢁC; IR (KBr) 3383, 1647,
d 171.2, 144.7, 142.3, 137.4, 135.8, 131.5, 131.2, 129.4, 128.5, 128.3,
1617 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.25e7.46 (m, 7H), 7.07 (d,
127.6, 122.6, 121.9, 115.7, 114.4, 46.5, 43.9, 30.8; FT-ICRMS m/z (%)
466 (5) [M] þ, 468 (7), 391 (70), 342 (80), 340 (100). HRMS (FT-
ICRMS) calculated for C24H20BrClN2O: 466.0448, 468.0418. Found:
466.0444, 468.0411.
J¼8.0 Hz, 2H), 6.80 (d, J¼8.2 Hz, 2H), 6.62 (d, J¼8.2 Hz, 2H), 5.51 (s,
1H), 4.17e4.19 (m, 2H), 3.75 (s, 3H), 3.61 (dt, J¼11.4, 2.8 Hz, 2H),
1.98e2.12 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 171.1, 152.6, 141.7,
140.1, 137.5, 135.9, 131.3, 131.0, 128.4, 128.2, 127.5, 121.6, 116.6, 115.1,
115.0, 55.8, 47.4, 44.0, 30.9; GCeMS (CI) m/z (%) 462 (3) [M]þ, 464
(3), 105 (100), 340 (30), 342 (30). Anal. Calcd for C25H23BrN2O2: C,
64.80; H, 5.00; N, 6.05. Found: C, 64.51; H, 5.10; N, 5.85.
4.1.8. 1-Benzoyl-6-(4-bromophenyl)-4-(4-bromophenyl)amino-
1,2,3,4-tetrahydropyridine 4h. Mp 225e227 ꢁC; IR (KBr) 3388, 1648,
1619, 1590 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.47 (d, J¼6.4 Hz, 2H),
7.22e7.35 (m, 7H), 7.08 (d, J¼8.0 Hz, 2H), 6.54 (d, J¼8.4 Hz, 2H),
5.47 (br s, 1H), 4.21e4.22 (m, 2H), 3.89 (br s, 1H, NH), 3.60 (t,
J¼10.0 Hz, 1H), 2.04e2.09 (m, 2H); 13C NMR (100 MHz, CDCl3)
4.1.3. 1-Benzoyl-6-(4-bromophenyl)-4-(4-nitrophenyl)amino-
1,2,3,4-tetrahydropyridine 4c. Mp 194e196 ꢁC; IR (KBr) 3379, 1646,
1598, 1639 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
8.08 (d, J¼8.8 Hz,
d 171.2, 144.7, 142.3, 137.4, 135.8, 131.5, 131.2, 129.4, 128.5, 128.3,
2H), 7.47 (d, J¼6.8 Hz, 2H), 7.26e7.37 (m, 7H), 7.08 (d, J¼7.6 Hz, 2H),
6.58 (d, J¼9.2 Hz, 2H), 5.44 (d, J¼2.8 Hz, 1H), 4.75 (br s, 1H), 4.36 (br
s, 1H), 4.26 (d, J¼10.8 Hz, 1H), 3.62 (t, J¼10.4 Hz, 1H), 2.04e2.16 (m,
127.6, 122.6, 121.9, 115.7, 114.4, 46.5, 43.9, 30.8. GCeMS (CI) m/z (%)
510 (3) [M]þ, 512 (3), 340 (50), 432 (50), 105 (100). Anal. Calcd for
C24H20Br2N2O: C, 56.27; H, 3.94; N, 5.47. Found: C, 55.74; H, 3.92;
N, 5.29.
2H); 13C NMR (100 MHz, CDCl3)
d 171.2, 151.2, 143.2, 138.5, 137.0,
135.5, 131.5, 131.4, 128.4, 128.3, 127.5, 126.5, 122.1, 113.9, 111.5, 46.0,
43.7, 30.6; FT-ICRMS m/z (%) 467 (5) [M]þ, 469 (7), 342 (90), 340
(100). HRMS (FT-ICRMS) calculated for C24H20BrN3O3: 477.0688,
479.0668. Found: 477.0682, 479.0639. Slow evaporation of solvent
from the solution in a mixture petroleum ether and ethyl acetate
(4:1) gave X-ray quality single crystals of 4c.
4.1.9. 1-Benzoyl-6-(4-bromophenyl)-4-(2-bromophenyl)amino-
1,2,3,4-tetrahydropyridine 4i. Mp 208e209 ꢁC; IR (KBr) 3378, 1651,
1622, 1598 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.10e7.50 (m, 11H),
6.73 (d, J¼8.0 Hz, 1H), 6.60 (t, J¼7.2 Hz, 1H), 5.52 (d, J¼1.6 Hz, 1H),
4.45 (d, J¼7.2 Hz, 1H), 4.28 (br s, 1H), 4.23 (br s, 1H, NH), 3.60 (dt,
J¼10.0, 3.6 Hz, 1H), 2.04e2.06 (m, 2H); 13C NMR (100 MHz, CDCl3)
4.1.4. 1-Benzoyl-6-(4-bromophenyl)-4-(2-nitrophenyl)amino-
d 171.1, 142.9, 142.4, 137.2, 135.7, 132.8, 131.3, 131.1, 128.5, 128.4,
1,2,3,4-tetrahydropyridine 4d. Mp 86e88 ꢁC; IR (KBr) 3370, 1658,
128.2, 127.6, 121.8, 118.4, 115.3, 111.6, 110.2, 46.2, 44.0, 30.7; GCeMS
(CI) m/z (%) 510 (2) [M]þ, 512 (2), 340 (60), 342 (60), 105 (100). Anal.
Calcd for C24H20Br2N2O: C, 56.27; H, 3.94; N, 5.47. Found: C, 56.27;
H, 4.01; N, 5.31.
1614, 1570 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
8.21 (dd, J¼4.4,
1.6 Hz, 1H), 8.16 (d, J¼7.2 Hz, 1H), 7.25e7.50 (m, 7H), 7.11 (d,
J¼7.3 Hz, 2H), 6.95 (d, J¼8.7 Hz, 1H), 6.69e6.72 (t, J¼7.3 Hz, 1H),
5.51 (br s, 1H), 4.46 (br s, 1H), 4.25 (d, J¼11.0 Hz, 1H), 3.67 (dt, J¼7.6,
2.4 Hz, 1H), 2.08e2.20 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
171.3,
4.1.10. 1-Benzoyl-6-(4-bromophenyl)-4-(3-bromophenyl)amino-
143.5, 143.2, 137.1, 136.4, 135.6, 132.6, 131.5, 131.3, 128.6, 128.4, 127.7,
127.4, 122.2, 116.1, 113.9, 113.8, 45.6, 43.8, 30.9; FT-ICRMS m/z (%)
500.1 [MþNa]þ, 502.1. HRMS (FT-ICRMS) calculated for
C24H20BrN3O3Na: 500.0567, 502.0553. Found: 500.0586, 502.0565.
1,2,3,4-tetrahydropyridine 4j. Mp 134e136 ꢁC; IR (KBr) 3363, 1621,
1594 cmꢂ1
; d 7.28e7.46 (m, 7H),
1H NMR (400 MHz, CDCl3)
7.01e7.09 (m, 2H), 6.84 (d, J¼8.0 Hz, 1H), 6.78 (s, 1H), 6.55 (dd,
J¼5.8, 2.0 Hz, 1H), 5.46 (br s, 1H), 4.22 (br s, 2H), 3.91 (br s, 1H, NH),
3.59 (t, J¼10.4 Hz, 1H), 2.04e2.10 (m, 2H); 13C NMR (100 MHz,
4.1.5. 1-Benzoyl-6-(4-bromophenyl)-4-(4-methylphenyl)amino-
CDCl3) d 171.1, 147.3, 142.3, 137.2, 135.4, 131.4, 131.1, 130.7, 128.4,
1,2,3,4-tetrahydropyridine 4e. Mp 215e216 ꢁC; IR (KBr) 3384, 2913,
128.2, 127.5, 123.5, 121.8, 120.7, 115.6, 115.3, 111.9, 46.0, 43.7, 30.7;
GCeMS (CI) m/z (%) 510 (2) [M]þ, 512 (2), 340 (30), 432 (30), 105
(100). Anal. Calcd for C24H20Br2N2O: C, 56.27; H, 3.94; N, 5.47.
Found: C, 56.24; H, 3.98; N, 5.30.
1617 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 7.25e7.47 (m, 7H), 7.07 (d,
J¼6.0 Hz, 2H), 7.01 (d, J¼8.0 Hz, 2H), 6.58 (d, J¼7.8 Hz, 2H), 5.51 (br
s, 1H), 4.23 (br s, 1H), 4.23 (br s, 1H, NH), 3.69 (br s, 1H, NH), 3.60 (t,
J¼10.0 Hz, 1H), 2.25 (s, 3H), 2.04e2.06 (m, 2H); 13C NMR (100 MHz,
CDCl3)
d
171.1, 143.7, 141.7, 137.5, 135.9, 131.3, 131.0, 130.0, 128.4,
4.1.11. 1-Benzoyl-6-(4-bromophenyl)-4-(naphthalen-1-yl)amino-
128.2, 127.5, 127.4, 121.6, 116.5, 113.5, 46.6, 44.0, 30.9, 20.4; GCeMS
(CI) m/z (%) 446 (5) [M]þ, 340 (30), 342 (30), 105 (100). Anal. Calcd
for C25H23BrN2O: C, 67.12; H, 5.18; N, 6.26. Found: C, 67.22; H, 5.14;
N, 6.09.
1,2,3,4-tetrahydropyridine 4k. Mp 143e145 ꢁC; IR (KBr) 3360, 1616,
1579 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.80 (d, J¼7.2 Hz, 2H),
7.25e7.52 (m, 11H), 7.15 (br s, 2H), 6.71 (d, J¼7.2 Hz, 1H), 5.62 (br s,
1H), 4.46e4.50 (m, 2H), 4.26 (br s, 1H, NH), 3.66 (t, J¼10.0 Hz, 1H),
2.19 (br s, 2H); 13C NMR (100 MHz, CDCl3)
d 171.2, 142.3, 141.0,137.4,
4.1.6. 1-Benzoyl-6-(4-bromophenyl)-4-(4-fluorophenyl)amino-
1,2,3,4-tetrahydropyridine 4f. Mp 208e210 ꢁC; IR (KBr) 3386, 1648,
135.8, 134.5, 131.4, 131.1, 128.8, 128.4, 128.2, 127.5, 126.4, 125.9,
124.9, 123.5, 121.7, 119.8, 118.0, 116.0, 104.8, 46.2, 44.0, 30.6; GCeMS
(CI) m/z (%) 482 (2) [M]þ, 340 (30), 342 (30), 105 (100). Anal. Calcd
1618 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.29e7.47 (m, 7H), 7.09

6496
S. Tong et al. / Tetrahedron 68 (2012) 6492e6497
for C28H23BrN2O: C, 69.57; H, 4.80; N, 5.80. Found: C, 69.30; H, 4.67;
N, 5.65.
3.77 (dt, J¼9.2, 3.2 Hz, 1H), 3.47e3.51 (m, 1H), 1.95e2.04 (m, 2H);
13C NMR (100 MHz, CDCl3)
171.1, 140.9, 140.2, 137.8, 136.1, 131.3,
d
128.6, 128.5, 128.4, 128.2, 127.6, 127.3, 121.4, 118.4, 51.2, 50.4, 44.5,
31.0; FT-ICRMS m/z (%) 340 (10), 342 (10), 296 (100). Anal. Calcd for
C25H23BrN2O: C, 67.12; H, 5.18; N, 6.26. Found: C, 67.35; H, 5.31;
N, 6.03.
4.1.12. 1-Benzoyl-6-phenyl-4-(phenyl)amino-1, 2, 3, 4-
tetrahydropyridine 4l. Mp 198e200 ꢁC; IR (KBr) 3389, 1651, 1621,
1602 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.13e7.46 (m, 12H), 6.74
(t, J¼7.2 Hz, 1H), 6.66 (d, J¼8.0 Hz, 2H), 5.49 (br s, 1H), 4.26e4.29
(m, 1H), 4.26 (br s, 1H, NH), 3.85 (br s, 1H, NH), 3.57e3.64 (m,
4.2.2. 4-Allylamino-1-benzoyl-6-(4-bromophenyl)-1,2,3,4-
1H), 2.08 (br s, 2H); 13C NMR (100 MHz, CDCl3)
d
171.1, 146.0,
tetrahydropyridine 7b. Mp 84e86 ꢁC; IR (KBr) 3421, 1722, 1654,
141.9, 137.0, 133.5, 131.0, 129.5, 128.4, 128.2, 127.8, 127.2, 126.0,
118.0, 116.1, 113.2, 46.2, 43.9, 30.9; FT-ICRMS m/z (%) 354 (8)
[M]þ, 262 (100). HRMS (FT-ICRMS) calculated for C24H22N2O:
354.1732. Found: 354.1718.
1580; 1H NMR (400 MHz, CDCl3)
d 7.06e7.44 (m, 9H), 5.87e5.97 (m,
1H), 5.48 (br s, 1H), 5.18 (dd, J¼18.0, 12.0 Hz, 2H), 4.08 (br s,1H, NH),
3.76e3.78 (m, 1H), 3.47e3.50 (m, 1H), 3.36e3.38 (m, 2H), 1.91e2.08
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 171.1, 140.9, 137.8, 136.6, 131.3,
130.9, 128.4, 128.2, 128.0, 127.6, 121.4, 118.3, 116.5, 50.4, 49.7, 31.1,
29.8; FT-ICRMS m/z (%) 419 (10) [MþNa]þ, 421 (20), 340 (100), 342
(100). HRMS (FT-ICRMS) calculated for C21H21BrN2O: 419.0720.
Found: 419.0735.
4.1.13. 1-Benzoyl-6-(4-methylphenyl)-4-(phenyl)amino-1,2,3,4-
tetrahydropyridine 4m. Mp 193e194 ꢁC; IR (KBr) 3391, 1650, 1621,
1601 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.46 (d, J¼5.2 Hz, 2H),
7.18e7.29 (m, 5H), 7.09 (d, J¼6.0 Hz, 2H), 6.94 (d, J¼7.2 Hz, 2H), 6.75
(t, J¼7.2 Hz, 1H), 6.68 (d, J¼8.0 Hz, 2H), 5.47 (br s, 1H), 4.26e4.28
(m, 2H), 4.05 (br s, 1H, NH), 3.60 (dt, J¼11.0, 3.6 Hz, 1H), 2.22 (s, 3H),
4.2.3. 1-Benzoyl-6-(4-bromophenyl)-4-butylamino-1,2,3,4-
tetrahydropyridine 7c. Mp 118e120 ꢁC; IR (KBr) 3426, 1724, 1655,
2.09 (br s, 2H); 13C NMR (100 MHz, CDCl3)
d
171.2, 145.8, 143.0,
1580; 1H NMR (400 MHz, CDCl3)
d 7.04e7.43 (m, 9H), 5.48 (br s,1H),
137.6,136.2, 135.6,130.7,129.5, 128.9,128.4,128.0,125.8,118.1,114.7,
113.5, 46.5, 43.7, 30.9, 21.1; FT-ICRMS m/z (%) 368 (5) [M]þ, 276
(100). HRMS (FT-ICRMS) calculated for C25H24N2O: 368.1889.
Found: 368.1877.
4.06 (br s,1H, NH), 3.76e3.79 (m,1H), 3.49e3.50 (m,1H), 2.56e2.59
(m, 2H), 1.89e2.20 (m, 2H), 0.85 (t, J¼4.0 Hz, 3H), 0.49e0.52 (m,
2H), 0.11e0.15 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 171.1, 140.9,
137.8, 131.3, 130.9, 128.4, 128.2, 128.1, 127.5, 121.4, 118.2, 52.2, 51.0,
31.0, 29.8, 11.4, 3.7, 3.6; FT-ICRMS m/z (%) 412 (10) [M]þ, 414 (10),
340 (100), 342 (100). HRMS (FT-ICRMS) calculated for C21H21BrN2O:
412.1150, 414.1130. Found: 412.1140, 414.1147.
4.1.14. 1-Benzoyl-6-(4-chlorophenyl)-4-(phenyl)amino-1,2,3,4-
tetrahydropyridine 4n. Mp 171e173 ꢁC; IR (KBr) 3395, 1650, 1622,
1601 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.44 (d, J¼5.2 Hz, 2H),
7.10e7.24 (m, 9H), 6.74 (t, J¼7.6 Hz, 1H), 6.66 (d, J¼8.0 Hz, 2H), 5.49
4.3. Synthesis of 10
(br s, 1H), 4.27e4.29 (m, 2H), 3.91 (br s, 1H, NH), 3.59 (dt, J¼9.8,
3.6 Hz, 1H), 2.10 (br s, 2H); 13C NMR (100 MHz, CDCl3)
d
171.2, 146.2,
Following the same reaction procedure for the synthesis of 7,
reaction between 8 and 9 gave product 10: mp 144e146 ꢁC; IR
(KBr) 3331, 1662, 1636, 1600; 1H NMR (400 MHz, CDCl3)
143.0, 138.6, 136.4, 130.7, 129.6, 128.5, 128.3, 128.1, 127.9, 126.1,
118.0, 115.7, 113.3, 46.4, 43.5, 31.1; FT-ICRMS m/z (%) 388 (10) [M]þ,
307 (30), 296(100). HRMS (FT-ICRMS) calculated for C24H21ClN2O:
388.1342. Found: 388.1326.
d
7.16e7.54 (m, 15H), 4.96 (s, 1H), 3.60e3.71 (m, 1H), 3.52e3.58 (m,
1H), 3.01 (s, 1H), 2.69e2.74 (m, 1H), 2.25 (br s, 1H), 2.04e2.74 (m,
1H), 1.86e1.91 (m, 3H), 1.49e1.67 (m, 5H); 13C NMR (100 MHz,
4 .1.15 . 1 - A c e t yl - 6 - p h e n yl - 4 - ( p h e n yl ) a m i n o - 1, 2 , 3 , 4 -
CDCl3) d 170.1, 144.9, 143.6, 137.3, 134.7, 130.5, 128.63, 128.59, 128.4,
tetrahydropyridine 4o. Mp 94e95 ꢁC; IR (KBr) 3359, 1652, 1627,
128.2, 127.7, 127.33, 127.28, 127.2, 124.0, 64.4, 52.4, 44.8, 30.5,
29.3, 27.6, 23.4, 22.8; MS GCeMS (EI) m/z (%) 442 [M]þ (5), 105
(100), 77 (32). HRMS (EI) calculated for C29H30N2O: 422.2358.
Found: 422.2364.
1601 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.32e7.35 (m, 5H), 7.19 (t,
J¼8.0 Hz, 2H), 6.73 (t, J¼7.2 Hz, 1H), 6.64 (d, J¼8.0 Hz, 2H), 5.53 (d,
J¼3.2 Hz, 1H), 4.41 (br s, 1H), 4.18e4.21 (m, 1H), 3.85 (br s, 1H, NH),
3.36 (t, J¼10.4 Hz, 1H), 1.98e2.09 (m, 2H), 1.67 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d
171.1, 146.1, 142.3, 138.9, 129.5, 128.9, 128.5,
4.4. Procedure for catalytic hydrogenation of 4l
125.9, 117.9, 115.6, 113.3, 46.7, 40.8, 31.2, 25.2; FT-ICRMS m/z (%) 292
(10) [M]þ, 200 (100). HRMS (FT-ICRMS) calculated for C19H20N2O:
292.1576. Found: 292.1577.
In the presence of Pd/C catalyst (5%, 20 mg), 4l (142 mg,
0.4 mmol) in dry methanol (10 ml) was hydrogenated overnight at
room temperature using a hydrogen balloon to give, after silica gel
column chromatography eluted with a mixture of petroleum ether
and ethyl acetate (from 10:1 to 5:1), pure 11(49 mg, 45%) and
11(69 mg, 49%).
4.2. General procedure for the synthesis of 4-alkylamino-6-
aryl-1,2,3,4-tetrahedropyridine derivatives 7
A mixture of enamides 1a (1 mmol) and aliphatic amines 5aec
(1 mmol) in dry CH2Cl2 (50 mL) was stirred at ambient temperature
for 0.5 h. p-Toluenesulfonic acid (17.2 mg, 0.1 mmol) was added and
the resulting mixture was kept stirring for 24 h (5a), 48 h (5b) or
60 h (6c). An aqueous NaHCO3 solution (5%, 50 mL) was then added,
and the resulting mixture was extracted by CH2Cl2 (3ꢀ30 mL). The
combined organic layer was washed with brine (2ꢀ50 mL) and
dried with anhydrous Na2SO4. After removal of solvent, the residue
was chromatographed on a silica gel column eluted with ethyl ac-
etate to give pure 7aec.
4.4.1. 2,4-trans-1-Benzoyl-2-phenyl-4-(phenyl)aminopiperidine
11. Mp 166e167 ꢁC; IR (KBr) 3317, 1614, 1600, 1576; 1H NMR
(400 MHz, DMSO-d6)
d
7.31e7.45(m, 10H), 7.05 (t, 2H, J¼7.2 Hz),
6.52e6.53 (m, 3H), 5.64 (br s,1H), 5.12 (br s,1H), 4.04 (br s,1H), 3.38
(br s, 1H), 2.90e3.05 (m, 3H), 2.67e2.75(m, 1H), 1.95 (d, J¼12.0 Hz,
1H), 1.62e1.90 (m, 1H), 1.40e1.46 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 170.8, 148.2, 139.8, 137.1, 129.9, 129.44, 129.37, 129.0, 127.3,
126.8, 126.6, 116.6, 113.3, 54.0, 46.4, 35.4, 32.9; MS GCeMS (EI) m/z
(%) 356 (25) [M]þ, 77 (32) , 105 (100). HRMS (EI) calculated for
C24H24N2O: 356.1889. Found: 356.1894.
4.2.1. 1-Benzoyl-4-benzylamino-6-(4-bromophenyl)-1,2,3,4-
tetrahydropyridine 7a. Mp 90e92 ꢁC; IR (KBr) 3300, 1650, 1619,
4.4.2. 2,4-cis-1-Benzoyl-2-phenyl-4-(phenyl)amino-piperidine
1578; 1H NMR (400 MHz, CDCl3)
d
7.25e7.44 (m, 12H), 7.04 (br s,
11. Mp 162e163 ꢁC; IR (KBr) 3422, 1626, 1600; 1H NMR (400 MHz,
2H), 5.48 (br s, 1H), 4.07 (br s, 1H, NH), 3.90 (ABq, J¼13.2 Hz, 2H),
DMSO-d6)
d
7.22e7.42 (m,10H), 7.06 (t, 2H, J¼7.6 Hz), 6.48e6.57 (m,

S. Tong et al. / Tetrahedron 68 (2012) 6492e6497
6497
4. Manetti, D.; Martini, E.; Ghelardini, C.; Dei, S.; Galeotti, N.; Guandalini, L.;
Romanelli, M. N.; Scapecchi, S.; Teodori, E.; Bartolini, A.; Gualtieri, F. Bioorg.
Med. Chem. Lett. 2003, 13, 2303.
5. Lubbers, T.; Bohringer, M.; Gobbi, L.; Hennig, M.; Hunziker, D.; Kuhn, B.; Loffler,
B.; Mattei, P.; Narquizian, R.; Peters, J.-U.; Ruff, Y.; Wessel, H. P.; Wyss, P. Bioorg.
Med. Chem. Lett. 2007, 17, 2966.
3H), 5.31 (t, J¼6.0 Hz, 1H), 4.69 (br s, 1H), 3.86e3.88 (m, 1H), 3.75
(br s, 1H), 3.53 (dt, J¼13.6, 4.8 Hz, 1H), 2.30e2.36 (m, 1H), 2.09e2.19
(m, 2H), 1.59e1.62 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 171.1, 147.9,
€
€
€
142.9, 137.5, 129.8, 129.4, 128.9, 128.87, 128.84, 127.0, 125.9, 116.7,
113.4, 54.9, 46.3, 39.9, 35.0, 30.6; MS GCeMS (CI) m/z (%) 356 (50)
[M]þ, 77 (40), 105 (100). HRMS (EI) calculated for C24H24N2O:
356.1889. Found: 356.1893.
6. Benmehdi, H.; Lamouri, A.; Serradji, N.; Pallois, F.; Heymans, F. Eur. J. Org. Chem.
2008, 299.
ꢀ
7. Barluenga, J.; Mateos, C.; Aznar, F.; Valdes, C. Org. Lett. 2002, 4, 3667.
~
ꢀ
8. Badorrey, R.; Portana, E.; Díaz-de-Villegas, M. D.; Galvez, J. A. Org. Biomol. Chem.
2009, 7, 2912.
Acknowledgements
9. For reviews: (a) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455; (b) Gopalaiah,
K.; Kagan, H. B. Chem. Rev. 2011, 111, 4599.
10. (a) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292 and references
cited therein; (b) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed.
2006, 45, 2254; (c) Terada, M.; Machioka, K.; Sorimachi, K. J. Am. Chem. Soc.
2007, 129, 10336; (d) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J.
J. Am. Chem. Soc. 2009, 131, 4598; (e) Dagousset, G.; Zhu, J.; Masson, G. J. Am.
Chem. Soc. 2011, 133, 14804.
11. For examples of enaminic reactions of tertiary enamides with very strong
electrophiles: (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane,
S.-i.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697; (b) Eberson, L.;
Malmberg, M.; Nyberg, K. Acta Chem. Scand. 1984, 38, 391; (c) Meth-Cohn, O.;
Westwood, K. T. J. Chem. Soc., Perkin Trans. 1 1984, 1173; (d) Nilson, M. G.; Funk,
R. L. Org. Lett. 2006, 8, 3833.
We thank National Natural Science Foundation of China (Grant
no. 20820102034), Ministry of Science and Technology (Grant no.
2009CB724704), and Tsinghua University for financial support. The
support of K.C. Wong Education Foundation, Hong Kong to J.Z. is
also gratefully acknowledged.
Supplementary data
1H and 13C spectra of all products. Supplementary data associ-
ated with this article can be found in the online version, at
doi:10.1016/j.tet.2012.05.108.
12. For some examples, see: (a) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333 and
references cited therein; (b) Su, S.; Kakeya, H.; Osada, H.; Porco, J. A., Jr.
Tetrahedron 2003, 59, 8931; (c) Milner, P. H.; Costes, N. J.; Gilpin, M. L.; Spear,
S. R. J. Nat. Prod. 1996, 59, 400.
13. (a) Yang, L.; Zheng, Q.-Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Org. Lett.
2008, 10, 2461; (b) Yang, L.; Deng, G.; Wang, D.-X.; Huang, Z.-T.; Zhu, J.;
Wang, M.-X. Org. Lett. 2007, 9, 1387; (c) Yang, L.; Wang, D.-X.; Zheng, Q.-Y.;
Pan, J.; Huang, Z.-T.; Wang, M.-X. Org. Biomol. Chem. 2009, 7, 2628; (d)
Yang, L.; Tong, S.; Wang, D.-X.; Huang, Z.-T.; Zhu, J.; Wang, M.-X. Synlett
2010, 927.
14. (a) Yang, L.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Am. Chem. Soc. 2009, 131,
10390; (b) Yang, L.; Lei, C.-H.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Org. Lett.
2010, 12, 3918.
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