Synthesis of tetrahydropyridines from Morita-Baylis-Hillman acetates of α,β-unsaturated aldehydes via an intramolecular 1,6-conjugate addition

Full text of DOI:10.1002/bkcs.10610

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DOI: 10.1002/bkcs.10610
BULLETIN OF THE
S. Y. Kim et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Tetrahydropyridines from Morita–Baylis–Hillman
Acetates of α,β-Unsaturated Aldehydes Via an Intramolecular
1,6-Conjugate Addition
*
Su Yeon Kim, Ko Hoon Kim, Hye Ran Moon, and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757,
Korea. *E-mail: kimjn@chonnam.ac.kr
Received August 13, 2015, Accepted September 7, 2015, Published online December 17, 2015
Keywords: Tetrahydropyridines, Intramolecular 1,6-conjugate addition, Morita–Baylis–Hillman adducts,
Double bond isomerization
Tetrahydropyridine-3-carboxylicacid derivatives haveshown
many interesting biological activities.1,2 The syntheses of
tetrahydropyridine-3-carboxylic acids have been carried out
by phosphine-catalyzed ring-forming reactions between
allenoates and imines,2a–d ring-closing metathesis (RCM)
reaction of homoallylic amine derivatives,2e chemical trans-
formations of Morita–Baylis–Hillman (MBH) adducts,2f–i
and intramolecular 1,6-conjugate addition of 2,4-
dienylamines.2j
MBH adducts have been used for the synthesis of many
interesting cyclic compounds.3–5 Recently the MBH adducts
ofα,β-unsaturatedaldehydes havebeenstudiedextensivelyby
us4 and other groups.5 During our recent studies using the
MBH adducts of cinnamaldehydes,4 we reasoned out that
introduction of a primary amine such as benzylamine at the
primary position of MBH acetate 1a could provide methyl
tetrahydropyridine-3-carboxylate 2a, as shown in Scheme 1.
The SN20 reaction between 1a and benzylamine would
afford 1:1 adduct I,6 and the following intramolecular 1,6-
conjugate addition2j,7 would provide 1,2,5,6-tetrahydropyri-
dine-3-carboxylate 2a.
unreactive 1:1 adduct I-Z and 1:2 adduct IV,8 as also shown
in Scheme 1. Thus, we decided to carry out the synthesis of
2a without separation of I-E. The cyclization of crude I to
2a did not proceed at room temperature even after a long time
(20 h). After some trials, we found that 2a could be formed in a
reasonable yield (52%) under the influence of K2CO3
in refluxing CH3CN for 20 h. The cyclization was less effec-
tive in the absence of K2CO3 even under refluxing CH3CN
condition.9 The role of K2CO3 is unclear at this stage; how-
ever, similar observation for the requirement of base in conju-
gate addition reactions was reported.10
Encouraged by the successful synthesis of 2a, the reactions
with some representative MBH acetates of α,β-unsaturated
aldehydes 1a–e were examined, and the results are summar-
ized in Table 1. The reactions of 1a with p-methoxybenzyla-
mine, 2-phenethylamine, 3-phenyl-1-propylamine, and
n-octylamine afforded 2b–2e in moderate yields (48–58%).
The reaction of MBH acetate of crotonaldehyde 1b and ben-
zylamine provided 2f in good yield (68%). The reaction of
1b and 1-phenethylamine afforded 2g in a similar yield
(63%) as an inseparable diastereomeric mixture (3:1).
At the outset of our experiment, the reaction of 1a and ben-
zylamine (4.0 equiv) was examined in CH3CN.6 The corre-
sponding 1:1 adduct I (E-isomer) was formed as a major
product at room temperature in short time (1 h); however,
the separation of I-E in pure form was somewhat difficult
due to the formation of many side products including
The reaction of 4-methyl derivative 1c and benzylamine
afforded double bond-isomerized product 2h in good yield
(79%) instead of generally expected product 2h0. As shown
in Scheme 2, a double bond isomerization of initially formed
product 2h did not occur presumably due to stabilizing hyper-
conjugation effect of the methyl group. Similar observation
Z
COOMe
1. BnNH2 (4.0 equiv), CH3CN, rt, 1 h
2. K2CO3 (2.0 equiv), CH3CN, reflux, 20 h
OAc
Ph
NHBn
COOMe
I (Z, 1:1 adduct)
COOMe
Ph
Ph
N
Bn
1a
2a (52%)
COOMe
BnNH2
- AcOH
Ph
Ph
OH
OMe
O
H
s-cis
E
N Bn
E
COOMe
COOMe
K2CO3
OMe
Ph
s-trans
HN
Bn
Ph
N
Ph
N
Ph HN
COOMe
II
III
Bn
Bn
IV (1:2 adduct)
Bn
I (E, 1:1 adduct)
Scheme 1. Synthesis of tetrahydropyridine 2a.
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Table 1. Synthesis of tetrahydropyridines.a
amines: benzylamine
1a: R = Ph, R1 = H, EWG = COOMe
p-methoxybenzylamine
2-phenethylamine
3-phenyl-1-propylamine
n-octylamine
1-phenethylamine
aniline
OAc
1b: R = Me, R1 = H, EWG = COOMe
1c: R = Ph, R1 = Me, EWG = COOMe
1d: R = Ph, R1 = H, EWG = COOEt
1e: R = Ph, R1 = H, EWG = COMe
EWG
R
R1
1a-e
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
Ph
N
Ph
Ph
N
Ph
N
Me
Ph
N
Ph
N
Ph
N
CH2CH2Ph
2c (48%)
CH2(CH2)2Ph
CH2(CH2)6CH3
Bn
Bn
PMB
2b (53%)b
COOMe
2a (52%)
2d (58%)
2f (68%)
2e (50%)
COOMe
Me
Ph
Me
Ph
COOMe
COOEt
COMe
COOMe
N
N
N
Ph
N
N
Me
N
Bn
PMB
Bn
Bn
Ph
Me
2g (63%)c
Ph
2h (79%)d
2i (65%)b,e
2l (0%)
2j (51%)
2k (31%)
a
Conditions: (i) MBH acetate (0.5 mmol), amine (2.0 mmol), CH3CN, room temperature, 1 h; (ii) K2CO3 (1.0 mmol), reflux, 20 h.
PMB, p-methoxybenzyl.
Inseparable diastereomeric mixture (3:1).
Each stereoisomer was separated in pure forms (47%/32%).
Each stereoisomer was separated in pure forms (34%/31%).
b
c
d
e
OAc
Me
Ph
COOMe
Me
Ph
COOMe
COOMe
Table 1
COOMe
Pd/C, MeOH, rt, 3 h
H2 balloon
Ph
N
N
2a
Ph
N
Me
1c
Bn
2h'
Bn
2h
Bn
3 (54%)
Me
COOMe
COOMe
NHBn
Scheme 3. Double bond isomerization of 2a.
Ph
Ph HN
Bn
s-cis
Me
1,6-conjugate addition to 2l was ineffective under the reaction
conditions.
s-trans
V
Scheme 2. Selective formation of 2h.
The synthesis of N-unsubstituted derivative with ammonia
source, such as NH4OH or NH4OAc, was unsuccessful due to
the formation of 1:2 and 1:3 adducts.8c,13 Thus, we examined
N-debenzylation of 2a under the typical hydrogenolysis con-
ditions, as shown in Scheme 3. Interestingly, a double bond
isomerization to 1,4,5,6-tetrahydropyridine derivative 3 was
observed unexpectedly.14,15
In summary, various tetrahydropyridine-3-carboxylates
were synthesized from MBH acetates of α,β-unsaturated alde-
hydes via SN20 type introduction of primary alkylamines and
the following intramolecular 1,6-conjugate addition reaction.
was also reported by Ramage and co-workers.2j In addition,
the yield of 2h was higher than other entries presumably
due to favorable s-cis conformation of the 1:1 adduct V, as
shown in Scheme 2. It is interesting to note that the synthesis
of 2h could also be carried out even at room temperature with-
out the assistance of K2CO3 in a similar yield (76%) after 20 h.
Each stereoisomer (cis/trans) was separated in pure forms
(47%/32%); however, the stereochemistry was not con-
firmed.11 The reaction of 1c and p-methoxybenzylamine
afforded 2i in good yield (65%).
Experimental
The reaction of ethyl ester 1d and benzylamine gave 2j in
moderate yield (51%). However, the reaction of acetyl deriv-
ative 1e and benzylamine afforded 2k in low yield (31%) due
to unwanted formation of the corresponding 1:2 adduct in a
larger amount. The 1:2 adduct was formed in appreciable
quantity during the synthesis of 1:1 adduct, even though ben-
zylamine was used in large excess (4.0 equiv).12 The reaction
of 1a and aniline failed to produce 2l. Although the corre-
sponding 1:1 adduct was formed, a subsequent intramolecular
Typical Procedure for the Synthesis of 2a. To a stirred solu-
tion of benzylamine (214 mg, 2.0 mmol) in CH3CN (1.0 mL)
was added a solution of 1a (130 mg, 0.5 mmol, 0.5 mL of
CH3CN), and the reaction mixture was stirred for
1 h. K2CO3 (138 mg, 1.0 mmol) was added, and the reaction
mixture was heated to reflux for 20 h. After the usual aqueous
extractive workup and column chromatographic purification
process (hexanes/EtOAc, 20:1), 2a was obtained as a pale
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yellow solid, 80 mg (52%). Other compounds were synthe-
sized similarly, and the selected spectroscopic data of 2a,
2b, 2h (major), 2h (minor), and 3 are as follows.
NMR (CDCl3, 75 MHz) δ 16.21, 28.76, 50.64, 57.45,
57.66, 95.12, 126.37, 127.34, 127.41, 127.76, 128.58,
128.73, 137.02, 141.48, 146.52, 168.88; ESIMS m/z
308 [M+H]+. Anal. Calcd for C20H21NO2: C, 78.15; H,
6.89; N, 4.56. Found: C, 78.44; H, 7.03; N, 4.61.
Methyl 1-benzyl-6-phenyl-1,2,5,6-tetrahydropyridiꢀne-
3-carboxylate (2a): 52%; pale yellow solid, mp 88–90 C;
IR (KBr) 1715, 1436, 1258 cm−1; 1H NMR (CDCl3,
300 MHz) δ 2.56–2.64 (m, 2H), 3.00–3.12 (m, 1H), 3.11 (d,
J = 13.5 Hz, 1H), 3.47–3.57 (m, 1H), 3.62 (t, J = 6.6 Hz,
1H), 3.71 (s, 3H), 3.77 (d, J = 13.5 Hz, 1H), 7.07–7.12 (m,
1H), 7.19–7.43 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ
34.63, 50.04, 51.50, 58.56, 62.08, 126.85, 127.43, 127.78,
128.22, 128.56, 128.63, 128.74, 137.27, 138.92, 142.27,
166.21; ESIMS m/z 308 [M+H]+. Anal. Calcd for
C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C,
78.34; H, 6.97; N, 4.31.
Acknowledgments. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Educa-
tion, Science and Technology (2014R1A1A2053606). Spec-
troscopic data were obtained from the Korea Basic Science
Institute, Gwangju branch.
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
Methyl 1-(4-methoxybenzyl)-6-phenyl-1,2,5,6-tetrahy-
dropyridine-3-carboxylate (2b): 53%; pale yellow oil; IR
(film) 1714, 1511, 1258 cm−1; 1H NMR (CDCl3, 300 MHz)
δ 2.54–2.62 (m, 2H), 2.97–3.09 (m, 1H), 3.05 (d, J = 12.9
Hz, 1H), 3.43–3.54 (m, 1H), 3.58 (t, J = 6.3 Hz, 1H), 3.69
(d, J = 12.9 Hz, 1H), 3.71 (s, 3H), 3.79 (s, 3H), 6.83 (d, J =
8.4 Hz, 2H), 7.05–7.10 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H),
7.24–7.31 (m, 1H), 7.32–7.42 (m, 4H); 13C NMR (CDCl3,
75 MHz) δ 34.68, 49.85, 51.53, 55.21, 57.94, 62.04,
113.63, 127.42, 127.81, 128.63, 128.78, 129.76, 130.81,
137.29, 142.34, 158.58, 166.27; ESIMS m/z 338 [M+H]+.
Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15.
Found: C, 74.49; H, 6.82; N, 4.03.
References
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1
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300 MHz) δ 1.45 (s, 3H), 2.54–2.64 (m, 1H), 3.09–3.20 (m,
2H), 3.27 (d, J = 13.5 Hz, 1H), 3.65 (d, J = 13.5 Hz, 1H),
3.66 (s, 3H), 3.84 (s, 1H), 5.71 (s, 1H), 7.17–7.41 (m, 10H);
13C NMR (CDCl3, 75 MHz) δ 21.32, 41.09, 47.96, 51.68,
58.12, 69.06, 118.51, 126.84, 127.33, 127.97, 128.19,
128.60, 129.39, 137.61, 139.12, 141.00, 173.93; ESIMS
m/z 322 [M+H]+. Anal. Calcd for C21H23NO2: C, 78.47; H,
7.21; N, 4.36. Found: C, 78.76; H, 7.50; N, 4.23.
Methyl
1-benzyl-5-methyl-6-phenyl-1,2,3,6-tetrahy-
dropyridine-3-carboxylate (2h, minor): 32%; pale yellow
1
oil; IR (film) 1739, 1453, 1171 cm−1; H NMR (CDCl3,
300 MHz) δ 1.40 (s, 3H), 2.48 (t, J = 10.5 Hz, 1H), 3.14
(dd, J = 11.4 and 5.1 Hz, 1H), 3.19 (d, J = 13.5 Hz, 1H),
3.34–3.48 (m, 1H), 3.66 (s, 3H), 3.71 (d, J = 13.5 Hz, 1H),
3.81 (s, 1H), 5.71 (s, 1H), 7.14–7.44 (m, 10H); 13C NMR
(CDCl3, 75 MHz) δ 21.25, 42.12, 48.88, 51.79, 58.46,
69.61, 118.93, 126.82, 127.41, 128.10, 128.24, 128.58,
129.17, 137.43, 139.10, 141.70, 173.53; ESIMS m/z
322 [M+H]+.
Methyl 1-benzyl-6-phenyl-1,4,5,6-tetrahydropyridine-
3-carboxylate (3): 54%; colorless oil; IR (film) 1681, 1620,
1296, 1152 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.88–2.06
(m, 3H), 2.32–2.50 (m, 1H), 3.74 (s, 3H), 4.20 (d, J = 15.3
Hz, 1H), 4.28 (t, J = 3.9 Hz, 1H), 4.43 (d, J = 15.3 Hz, 1H),
7.12–7.24 (m, 4H), 7.26–7.42 (m, 6H), 7.82 (s, 1H); 13C
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however, a significant NOE increment of the proton at
C5-position (−CHCOOMe) was not observed for both isomers
by irradiation of the proton at C2-position (−CHPh). Thus the
cis/trans stereochemistry could not be confirmed by NOE exper-
iment (see, Supporting Information).
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Bull. Korean Chem. Soc. 2016, Vol. 37, 95–98
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