Synthesis of cyclohexa-1,3-dienamines by Formal [3+3] cycloaddition

Article abstract of DOI:10.1055/S-0032-1316987

Formal [3+3] cycloadditions of β-carboxymethylenamino esters with acrolein derivatives give a range of cyclohexa-2,6-dicarboxymethyl-1,3- dienamines that are potential acceptordonor-acceptor systems. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0032-1316987

LETTER
▌2349
lSetyternthesis of Cyclohexa-1,3-dienamines by Formal [3+3] Cycloaddition
Synthesis of Cyclohexa-1,3-dienamines
Valérie Toum, Gérard Lhommet, Luc Dechoux*
Université Pierre et Marie Curie Paris 6, Institut Parisien de Chimie Moléculaire, UMR CNRS 7201, 4 place Jussieu, case courrier 43,
75005 Paris, France
Fax +33(1)44275079; E-mail: luc.dechoux@upmc.fr
Received: 05.06.2012; Accepted after revision: 01.07.2012
one of the major problems associated with these syntheses
is the β-elimination of HCN that occurs during the reac-
tion, leading to the formation of aromatic products.3c Here
we wish to present our results concerning the synthesis of
analogues of 4; cyclohexa-2,6-dicarboxymethyl-1,3-dien-
amines.
Abstract: Formal [3+3] cycloadditions of β-carboxymethylen-
amino esters with acrolein derivatives give a range of cyclohexa-
2,6-dicarboxymethyl-1,3-dienamines that are potential acceptor–
donor–acceptor systems.
Key words: multicomponent reactions, cyclohexa-1,3-dienamines,
[3+3] cycloaddition, donor–acceptor systems
NH2
R2
NC
R1
CN
CN
R3
CN
In a continuation of our investigations on the reactions of
stabilized β-carboxymethyl enamines,1 we were interest-
ed in their reaction with acrolein derivatives. It has been
shown that primary and secondary enamines 1, stabilized
by a carbonyl group, react with electrophilic olefins2 such
as acrylic and acrolein derivatives to furnish, respectively,
δ-lactams 2 and dihydropyridines 3, through an intra-
molecular N-addition process (Scheme 1).
+
R3CHO
+
2
O
R1
CN
R2
4
Scheme 2
The
starting
β-carboxymethylenamino
esters
(R2 = CH2CO2Me) 1 were synthesized by condensation of
dimethyl acetonedicarboxylate with a range of primary
amines 5. This reaction allowed the formation of Z- and E-
enaminoesters 1 with the Z-diastereoisomers as major
compounds (Scheme 3). We observed that the chemical
shift of the NH proton for the major Z-stereoisomers was
found downfield (δ = 8.5–9 ppm) from those of the E-ste-
reoisomers (δ = 5–5.5 ppm). It is noteworthy that the two
diastereoisomers are in equilibrium, the E-isomer being
the kinetic product and the Z-isomer the thermodynamic
R1O2C
CO2R1
R2
CO2R1
R2
O
Cl
O
H
R2
O
N
R3
N
R3
HN
R3
2
1
3
Scheme 1
However, in the reaction starting from β-carboxy-
methylenamino esters (R′ = CH2CO2Me) with acrolein
derivatives, we have observed the occurrence of both C-
and N-annulation (Table 1). Herein, we would like to re-
port the results of this study, which allow the construction
of useful multifunctional molecules, cyclohexa-1,3-dien-
amines 7, via a formal [3+3] cycloaddition. In almost all
cases the reported syntheses of 2,6-substituted cyclohexa-
1,3-dienamines involve the preparation of 2,6-tricarbo-
nitrile compounds 4, which were prepared by a one-pot
multi-component cyclization process involving a ketone,
an aldehyde, and usually two equivalents of malononitrile
(Scheme 2).3
1
product. An examination of the H NMR spectra of iso-
mers 1a in CDCl3 and in CD2Cl2 showed that after five
minutes the E-isomer predominates (Z/E = 10:90). After
10 minutes the ratio decreased (Z/E = 38:62) and after 25
minutes the ratio was inverted (Z/E = 61:39). After three
hours the equilibrium was reached in solution
(Z/E = 80:20). Moreover, we noted that in solvents such
as DMSO-d6, in which intermolecular hydrogen bonds
compete with intramolecular hydrogen bonds, the equilib-
rium was reached after five minutes, with the E-isomer re-
maining as the major isomer (Z/E = 19:81).
MeO2C
MeO2C
Compounds 4 belong to typical acceptor–donor–acceptor
systems (A-D-A), which form the basis for artificial
photosynthetic systems4 and materials presenting semi-
conducting or nonlinear optical properties.5 As a result,
numerous publications report their syntheses.3 However,
NH2
MeOH, r.t., 12 h
HN
CO2Me
+
O
R
Ph
R
Ph
5
CO2Me
1a (R = H)
1b (R = Me)
Scheme 3
SYNLETT 2012, 23, 2349–2352
Advanced online publication: 14.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316987; Art ID: ST-2012-D0478-L
© Georg Thieme Verlag Stuttgart · New York

2350
V. Toum et al.
LETTER
The crude mixtures of Z- and E-enaminoesters 1 (ratio be acidic, compound 8a is not stable and may be trans-
after equilibration in CH2Cl2: Z/E for 1a 80:20; Z/E for formed into compound 7a. Therefore, we followed the
1b 87:13) were used in the cyclization using acrolein de- conversion of 8a into 1,3-dienamine 7a by 1H NMR anal-
rivatives as the electrophilic olefin.6
ysis in CDCl3 using benzoic acid as catalyst. As expected,
after one week, we observed complete conversion.
The first reaction was performed by adding one equivalent
of acrolein 6a (R2 = R3 = H) to β-enaminoester 1a Thus, by slightly modifying the procedure (addition of a
(R1 = H) in dichloromethane. The reaction mixture was catalytic amount of benzoic acid to the reaction mixture;
stirred for 24 hours at room temperature and classical Table 1, entry 4) the yield of compound 7a reached 49%.
workup furnished a mixture of two products: the cyclo- When using more acidic reagent such as APTS, only trac-
hexa-1,3-dienamine 7a and 2-hydroxytetrahydropyridine es of product 7a were observed in the crude reaction mix-
8a.7 After chromatography on silica gel, the expected ture (data not shown).
cyclohexa-1,3-dienamine 7a was isolated in 39% yield
Substrate 1b (R1 = Me) gave the desired cyclohexa-1,3-
(Table 1, entry 1). Only small amounts of product 8a
dienamine 7b in low yield as a 50:50 mixture of diastereo-
(3% yield) were obtained, suggesting a degradation of this
isomers (Table 1, entry 5). This result indicates that no
asymmetric induction occurred.
compound on silica gel.
To optimize the reaction for the formation of cyclohexa-
1,3-dienamine 7a, various reaction conditions were inves-
tigated; the results are listed in Table 1 (entries 1–4). It
would be interesting to test the reaction on both pure dia-
stereoisomers Z and E but, unfortunately, the two isomers
are in fast equilibrium (see above).
We observed, by using electrophilic olefins such as meth-
acrolein (Table 1, entry 6), crotonaldehyde (entry 7), or
trans cinnamaldehyde (entry 8), the formation of the ex-
pected amino cyclohexadienes 7c–e in moderate to good
yields. The best yield and good diastereoselectivity in fa-
vor of the trans isomer was reached starting from croton-
Solvents such as CH2Cl2, THF and pentane were tested aldehyde (entry 7). In the case of cinnamaldehyde, only
and found to have a significant effect on the reaction out- the trans isomer was observed and isolated. The stereo-
come (Table 1, entries 1–3). In methanol a complex mix- chemical assignment of the two cyclohexadienes 7d and
ture of unidentified products was observed (data not 7e (entries 7 and 8) was inferred by 1H NMR spectroscopy
1
shown). In CH2Cl2 and THF we observed by H NMR (NOE experiments). For Table 1, entries 5–8, owing to the
analysis of the crude product, a mixture of compounds 7a complexity of the 1H NMR spectra of the crude mixtures
and 8a in favor of dienamine 7a (Table 1, entries 1 and 2). (several diastereoisomers could be formed) and due to the
In less polar solvent such as pentane (entry 3), tetrahydro- small quantities formed and the instability of compounds
pyridine 8a was found to be the major product. Unfortu- 8 on silica gel, compounds 8b–e could not be unambigu-
nately, this latter product could only be purified in trace ously identified and therefore no ratio was given for these
amounts. We believe that on silica gel, which is known to entries.
Table 1 Optimization of the Reaction Conditions
R3
R3
MeO2C
R3
R2
R2
additive
solvent
CO2Me
CO2Me
MeO2C
R2
CHO
+
+
HN
R1
HO
N
HN
R1
CO2Me
Ph
CO2Me
R1
Ph
Ph
1
6
7
8
Entry
R1
R2
R3
Additive (0.1 equiv) Solvent
Ratioa 7/8
Yield of 7 (%)b
d.r. of 7c
1
2
3
4
5
6
7
8
H
H
H
–
CH2Cl2
THF
54:46
66:34
30:70
74:26
–
7a
–
39
–
H
H
H
–
–
H
H
H
–
pentane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
–
H
H
H
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
7a
7b
7c
7d
7e
49
20
35
69
31
–
Me
H
H
H
50:50
–
Me
H
H
–
H
Me
Ph
–
89:11
>95:5
H
H
–
a Ratio 7/8 determined by 1H NMR analysis of the crude reaction mixture.
b Overall yield (two steps from 5).
c Diastereoisomeric ratio determined by 1H NMR analysis of the reaction mixture.
Synlett 2012, 23, 2349–2352
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Cyclohexa-1,3-dienamines
2351
R3
+
R3
R3
R3
MeO2C
HN
R2
O
R2
MeO2C
HN
R2
O
MeO2C
MeO2C
R2
O
MeO2C
HN
OH
NH
R1
R1
CO2Me
R1
CO2Me
PhCO2H
PhCO2
PhCO2H
R1
CO2Me
1
9
10'
10
R3
R3
R3
R3
MeO2C
HN
R2
MeO2C
R2
R2
MeO2C
HN
R2
MeO2C
MeO2C
HN
R1
OH
CO2Me
OH
CO2Me
N
OH
R1
CO2Me
R1
PhCO2
R1
7
12
11
8
Scheme 4
1992, 57, 5319. (d) Paulvannan, K.; Stille, J. R. Tetrahedron
Lett. 1993, 34, 6673. (e) Paulvannan, K.; Stille, J. R.
Tetrahedron Lett. 1993, 34, 8197. (f) Paulvannan, K.; Stille,
J. R. J. Org. Chem. 1994, 59, 1613. (g) Wagman, A. S.;
Wang, L.; Nuss, J. N. J. Org. Chem. 2000, 65, 9103.
(h) Agami, C.; Dechoux, L.; Ménard, C.; Hebbe, S. J. Org.
Chem. 2002, 67, 7573; and references cited therein.
(3) For recent papers concerning the synthesis of 2,6,6-
tricyanocyclohexa-1,3-dienamines, see: (a) Dyachenko, V.
D.; Rusanov, E. B. Russ. J. Org. Chem. 2006, 42, 1374.
(b) Wang, X. S.; Zhang, M. M.; Li, Q.; Yao, C. S.; Tu, S. J.
Tetrahedron 2007, 63, 5265. (c) Yan, C. G.; Song, X. K.;
Wang, Q. F.; Sun, J.; Siemeling, U.; Bruhn, C. Chem.
Commun. 2008, 1440. (d) Liu, X. G.; Shi, M. Eur. J. Org.
Chem. 2008, 6168. (e) Wang, X. S.; Wu, J. R.; Zhou, J.; Tu,
S. J. J. Comb. Chem. 2009, 11, 1011. (f) Babu, T. H.; Joseph,
A.; Muralidharan, D.; Paramasivan, T. P. Tetrahedron Lett.
2010, 51, 994. (g) Wang, J.; Li, Q.; Qi, C.; Liu, Y.; Ge, Z.;
Li, R. Org. Biomol. Chem. 2010, 8, 4240. (h) Wang, X. S.;
Zhou, J.; Yang, K.; Zhang, M. M. Synth. Commun. 2010,
1065.
A proposed mechanism for this formal [3+3] cycloaddi-
tion is presented in Scheme 4. This mechanism involves,
in the first step, a Michael addition of enamine 1 to the un-
saturated aldehyde. The resulting iminium 9 gives, by pro-
ton exchange, enamines 10 or 10′. Intramolecular C-
addition of 10 leads to iminium 11, which, after proton ex-
change, equilibrates to 1-aminocyclohexene 12. Water
elimination leads to the expected aminocyclohexadiene 7.
Compounds 8 should arise from cyclization of the regio-
isomer 10′ by intramolecular N-addition. We saw that the
acid-catalyzed opening of compound 8a in CDCl3 led to
product 7a (see above). This result indicates that it should
be possible to reverse the reaction of N-cyclization, thus
giving access to the more stable conjugated systems 7.
We have developed a simple method for the synthesis of
polysubstituted cyclohexa-1,3-dienamines by a formal
[3+3] cycloaddition.8 Moderate to good yields over the
two steps, the use of simple starting materials, and the fact
that the reaction can be carried out under mild conditions,
are advantages of this method. Moreover, we have pre-
sented the first synthesis of analogues of tricyanocyclo-
hexa-1,3-dienamines that are new one-donor poly-
acceptors systems.
(4) For a review, see: Kurreck, H.; Huber, M. Angew. Chem. Int.
Ed. Engl. 1995, 34, 849.
(5) For a review, see: Long, N. J. Angew. Chem. Int. Ed. Engl.
1995, 34, 21.
(6) In all experiments we obtained about 120% of the expected
weight.
(7) For recent publications concerning the synthesis of 2-
hydroxytetrahydropyridines, see: (a) Ohba, M.; Natsutani, I.
Tetrahedron 2007, 63, 12689. (b) Shen, L.; Cao, S.; Wu, J.;
Li, H.; Zhang, J.; Wu, M.; Qian, X. Tetrahedron Lett. 2010,
51, 4866. (c) Kumar, R.; Kumar, D.; Prasad, A. K. Synth.
Commun. 2011, 41, 2640. (d) Sun, J.; Wu, Q.; Xia, E. Y.;
Yan, C. G. Eur. J. Org. Chem. 2011, 2981.
(8) Typical Procedure: To a solution of dimethyl 3-benzyl-
aminopent-2-enedioate (0.43 g, 1.6 mmol) in CH2Cl2 (7 mL)
at 0 °C, was added aldehyde (0.11 mL, 1.6 mmol) and
benzoic acid (0.020 g, 0.16 mmol) and the reaction mixture
was stirred for 24 h. The mixture was poured into a solution
of NaHCO3, extracted with CH2Cl2, dried over anhydrous
MgSO4, and evaporated. The residue was purified by silica
gel column chromatography to afford the cyclohexa-1,3-
dienamine.
Acknowledgment
We wish to thank CNRS, UPMC for funding. FR2769 is acknow-
ledged for technical assistance. V.T. thanks the ‘Ministère de l’Edu-
cation Nationale, de l’Enseignement Supérieur et de la Recherche’
for fellowship and thanks to Prof. Serge Thorimbert for helpful
discussions.
References and Notes
(1) (a) Alladoum, J.; Dechoux, L. Tetrahedron Lett. 2005, 46,
8203. (b) Toum, V.; Kadouri-Puchot, C.; Hamon, L.;
Lhommet, G.; Mouries-Mansuy, V.; Vanucci-Bacqué, C.;
Dechoux, L. Synthesis 2011, 2781.
(2) (a) Hickmott, P. W.; Sheppard, G. J. Chem. Soc. C 1971,
1358. (b) Hickmott, P. W.; Sheppard, G. J. Chem. Soc. C
1971, 2112. (c) Paulvannan, K.; Stille, J. R. J. Org. Chem.
Dimethyl 2-Benzylamino-cyclohexa-1,5-diene-1,3-
dicarboxylate (7a). IR (NaCl): 3348, 1735, 1655, 1595,
1436, 1224, 697 cm–1. 1H NMR (250 MHz, CDCl3): δ = 2.25
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2349–2352

2352
V. Toum et al.
LETTER
(ddt, J = 2.9, 6.9, 16.8 Hz, 1 H, CHH), 2.65 (ddd, J = 1.4,
6.3, 16.8 Hz, 1 H, CHH), 3.47 (dd, J = 1.4, 6.9 Hz, 1 H,
CH2CH), 3.57 (s, 3 H, CH3), 3.67 (s, 3 H, CH3), 4.45 (m,
2 H, HNCH2), 5.23 (ddd, J = 2.9, 6.3, 9.4 Hz, 1 H, CH), 6.44
(dd, J = 2.9, 9.4 Hz, 1 H, CH), 7.20–7.43 (m, 5 H, PhH),
9.71 (m, 1 H, NH). 13C NMR (62.5 MHz, CDCl3): δ = 25.3,
40.0, 46.5, 50.2, 52.4, 92.9, 110.8, 124.5, 126.8, 127.5,
128.8, 137.7, 157.1, 168.8, 170.9. HRMS: m/z [M + Na]+
calcd for C17H19NO4: 324.1212; found: 324.1206.
52.6, 93.2, 118.3, 121.2, 126.9, 127.6, 128.9, 138.1, 155.5,
169.0, 171.3. HRMS: m/z [M + Na]+ calcd for C18H21NO4:
338.1368; found: 338.1363.
Dimethyl 2-Benzylamino-4-methyl-cyclohexa-1,5-diene-
1,3-dicarboxylate (7d): IR (NaCl): 3389, 1731, 1659, 1601,
1437, 1215, 668 cm–1. 1H NMR (250 MHz, CDCl3): δ = 0.83
(d, J = 7.2 Hz, 3 H, CH3), 2.74–2.86 (m, 1 H, CHCH3), 3.33
(s, 1 H, CHCO2Me), 3.60 (s, 3 H, CO2CH3), 3.68 (s, 3 H,
CO2CH3), 4.37–4.56 (m, 2 H, CH2Ph), 5.23 (dd, J = 5.6,
9.8 Hz, 1 H, CH), 6.37 (d, J = 9.8 Hz, 1 H, CH), 7.20–7.36
(m, 5 H, PhH), 9.73–9.84 (m, 1 H, NH). 13C NMR (62.5
MHz, CDCl3): δ = 17.8, 30.9, 46.3, 46.9, 50.5, 52.4, 92.1,
116.8, 122.1, 126.9, 127.5, 128.7, 138.5, 155.5, 168.8,
170.7. HRMS: m/z [M + Na]+ calcd for C18H21NO4:
338.1368; found: 338.1363.
Dimethyl 2-Benzylamino-4-phenyl-cyclohexa-1,5-diene-
1,3-dicarboxylate (7e): IR (NaCl): 3363, 1736, 1656, 1597,
1494, 1451, 1227, 699 cm–1. 1H NMR (250 MHz, CDCl3): δ
= 3.56–3.59 (m, 1 H, CHCO2Me), 3.62 (s, 3 H, CH3), 3.66
(s, 3 H, CH3), 3.99 (d, J = 6.2 Hz, 1 H, CHPh), 4.19–4.37
(m, 2 H, CH2Ph), 5.32 (ddd, J = 0.6, 6.1, 9.7 Hz, 1 H,
CH=CH), 6.64 (d, J = 9.7 Hz, 1 H, CH=CH), 6.76–7.17 (m,
10 H, PhH), 9.61–9.66 (m, 1 H, NH). 13C NMR (62.5 MHz,
CDCl3): δ = 41.4, 46.3, 48.4, 50.8, 53.0, 92.9, 113.6, 125.2,
126.5, 127.1, 127.3, 127.7, 128.7, 137.7, 140.1, 155.4,
168.9, 170.6. HRMS: m/z [M + Na]+ calcd for C23H23NO4:
400.1525; found: 400.1519.
Dimethyl 2-[(1R)-Phenylethylamino]cyclohexa-1,5-
diene-1,3-dicarboxylate (7b); Diastereoisomer 1: IR
(NaCl): 3367, 1736, 1655, 1592, 1449, 1241, 756, 700 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.53 (d, J = 6.7 Hz, 3 H,
CH3), 1.96–2.08 (m, 1 H, CHH), 2.38–2.64 (m, 1 H, CHH),
3.24 (dd, J = 1.4, 6.8 Hz, 1 H, CH2CH), 3.69 (s, 3 H, CH3),
3.71 (s, 3 H, CH3), 4.61–4.76 (m, 1 H, PhCH), 5.12–5.23 (m,
1 H, CH=CH), 6.42 (ddd, J = 3.1, 4.4, 9.7 Hz, 1 H,
CH=CH), 7.21–7.33 (m, 5 H, PhH), 9.70 (d, J = 7.0 Hz, 1 H,
NH). 13C NMR (62.5 MHz, CDCl3): δ = 25.0, 26.4, 40.7,
50.7, 52.7, 53.1, 92.9, 110.4, 124.9, 126.1, 127.3, 128.7,
144.2, 156.7, 169.1, 171.2.
Diastereoisomer 2: 1H NMR (250 MHz, CDCl3): δ = 1.53
(d, J = 6.7 Hz, 3 H, CH3), 2.38–2.64 (m, 2 H, CH2), 3.12 (s,
3 H, CH3), 3.70 (s, 3 H, CH3), 3.55 (dd, J = 1.8, 7.0 Hz, 1 H,
CH2CH), 4.61–4.76 (m, 1 H, PhCH), 5.12–5.23 (m, 1 H,
CH=CH), 6.42 (ddd, J = 3.1, 4.4, 9.7 Hz, 1 H, CH=CH),
7.21–7.33 (m, 5 H, PhH), 9.85 (d, J = 7.0 Hz, 1 H, NH). 13
C
NMR (62.5 MHz, CDCl3): δ = 25.2, 26.4, 40.2, 52.0, 52.8,
53.1, 93.2, 111.3, 124.5, 125.4, 127.4, 129.1, 144.1, 156.7,
169.1, 170.8. HRMS: m/z [M + Na]+ calcd for C18H21NO4:
338.1368; found: 338.1363
Methyl 1-Benzyl-6-hydroxy-2-methoxycarbonylmethyl-
1,4,5,6-tetrahydro-pyridine-3-carboxylate (8a): 1H NMR
(250 MHz, CDCl3): δ = 1.68–1.87 (m, 1 H, OHHCCHH),
1.96–2.10 (m, 1 H, HOHCCHH), 2.33–2.47 (m, 1 H, CHH),
2.67–2.77 (m, 1 H, CHH), 3.58 (d, J = 17.4 Hz, 1 H,
CHHCO2Me), 3.66 (s, 3 H, CH3), 3.68 (s, 3 H, CH3), 4.28 (d,
J = 17.4 Hz, 1 H, CHHCO2Me), 4.60 (q, J = 17.8 Hz, 2 H,
PhCH2), 4.80 (m, 1 H, CHOH), 7.13–7.37 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): δ = 17.4, 27.6, 35.4, 50.9,
52.4, 52.1, 80.1, 98.7, 125.9, 127.3, 129.1, 138.2, 148.2,
168.7, 171.3. HRMS: m/z [M + Na]+ calcd for C17H21NO5:
342.1317; found: 342.1312.
Methyl 2-Benzylamino-5-methyl-cyclohexa-1,5-diene-
1,3-dicarboxylate (7c): IR (NaCl): 3385, 1733, 1654, 1592,
1436, 1215, 757, 668 cm–1. 1H NMR (250 MHz, CDCl3): δ
= 1.79 (s, 3 H, CH3), 2.29–2.52 (m, 2 H, CH2), 3.75 (dd,
J = 1.9, 6.4 Hz, 1 H, CHCO2Me), 3.68 (s, 3 H, CH3), 3.73 (s,
3 H, CO2CH3), 4.46–4.64 (m, 2 H, CH2Ph), 6.20 (s, 1 H,
CH), 7.13–7.38 (m, 5 H, PhH), 9.51–9.60 (m, 1 H, NH). 13
NMR (62.5 MHz, CDCl3): δ = 22.6, 30.3, 40.7, 46.7, 50.7,
C
Synlett 2012, 23, 2349–2352
© Georg Thieme Verlag Stuttgart · New York