Synthesis of substituted nortrop-2-enes and 3-vinylpyridin-2-ones via reaction of 1,2,3,4,5,6,7-heptamethoxycarbonylcycloheptatriene with primary amines

Article abstract of DOI:10.1016/j.tetlet.2009.07.114

The mode of reaction of the 1,2,3,4,5,6,7-heptamethoxycarbonylcycloheptatriene with primary amines depends on the reaction conditions and leads to selective formation of N-substituted (heptamethoxycarbonyl)nortrop-2-enes and/or 3-vinylpyridin-2-ones beari

Full text of DOI:10.1016/j.tetlet.2009.07.114

Tetrahedron Letters 50 (2009) 5605–5608
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Synthesis of substituted nortrop-2-enes and 3-vinylpyridin-2-ones via
reaction of 1,2,3,4,5,6,7-heptamethoxycarbonylcycloheptatriene with
primary amines
*
Yury V. Tomilov , Dmitry N. Platonov, Galina P. Okonnishnikova
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
The mode of reaction of the 1,2,3,4,5,6,7-heptamethoxycarbonylcycloheptatriene with primary amines
depends on the reaction conditions and leads to selective formation of N-substituted (heptamethoxycar-
bonyl)nortrop-2-enes and/or 3-vinylpyridin-2-ones bearing six ester groups. The influence of the solvent
on the selectivity of the formation of nortropenes and pyridinones was studied.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 June 2009
Revised 6 July 2009
Accepted 17 July 2009
Available online 24 July 2009
Keywords:
Cycloheptatrieneheptacarboxylate
Michael addition
Intramolecular cyclization
Tropene derivatives
Pyridinones
Previously we have shown1 that the reaction of methyl diazo-
acetate with dimethyl dibromosuccinate in pyridine gives cyclo-
heptatriene-1,2,3,4,5,6,7-heptacarboxylic acid heptamethyl ester
(1) as the product of a cascade reaction. This compound contains
several electron-deficient double bonds which enable the Michael
addition of amines, and seven ester groups which implies the prob-
ability of partial amidation. There are many examples of the addi-
tion of various amines to fumaric and maleic acid esters to give
biologically active compounds.2–5 The known reaction of ammonia
or primary amines with ethyl cyclohepta-1,3,5-trienecarboxylate
proceeds via sequential double Michael addition of an amine mol-
ecule to the two double bonds of the heptatriene system and leads
to the formation of ethyl 8-azabicyclo[3.2.1]oct-2-ene-2-carboxyl-
ate (nortrop-2-ene-2-carboxylate).6 The ability of cycloheptatriene
amino derivatives to undergo intramolecular cyclization was also
used for the synthesis of 10,11-dihydro-5H-dibenzo[a,d]cyclohep-
ten-5,10-imine derivatives7–9 which exhibit anticonvulsant and
neuroprotective activities. We were encouraged by the present lit-
erature to investigate the reactions of primary amines with cyclo-
heptatriene 1.
reaction was very sensitive toward the nature of the solvent and
changing the reaction conditions allowed control of the ratio of
the products to a significant extent (Table 1). The nortropene deriv-
atives 3 are formed exclusively as single stereoisomers, and the
substituted 3-vinylpyridinones 4 are formed as a mixture of
E- and Z-isomers, the ratios of which are determined by the amine
and are only influenced weakly by the nature of the solvent
(Table 1). The 1H and 13C NMR spectra of compounds 3 exhibit
seven ester group signals and only two alkene carbon resonances
at 133–135 ppm.11 The NMR spectra of the isomeric propenylpy-
ridinones 4 show six ester group resonances and a characteristic
CH2-group signal represented by two doublets with a geminal
spin–spin coupling constant of about 17 Hz. These protons were
observed in the range 3.8–4.2 ppm for the E-isomers, and
3.2–3.5 ppm for the Z-isomers.12
Investigating the influence of the reaction conditions on the
regioselectivity revealed that less polar solvents (e.g., xylene and
chloroform) increased the yield of the bicyclic compounds 3, which
is most obvious in the case of benzylamine 2a. In contrast, polar
solvents significantly increased the yields of pyridinones 4; using
methanol as the solvent gave pyridinones 4a–d almost quantita-
tively with all the primary amines. Almost complete separation
of the E- and Z-isomers of the benzyl derivative of pyridinone 4a
was achieved by column chromatography using silica gel. In other
cases, pyridinones 4b–d were isolated as mixtures significantly en-
riched with either the E- or Z-isomer. In the 1H NMR spectra of
these compounds, the protons of the CH2-group are not equivalent.
It was found that the reaction of cycloheptatriene 1 with the
primary amines 2a–d proceeded under mild conditions (20 °C,
24 h) leading to the formation of heterocyclic compounds 3a–d
and/or 4a–d in overall yields greater than 90% (Scheme 1).10 The
* Corresponding author. Tel./fax: +7 499 135 6390.
E-mail address: tom@ioc.ac.ru (Y.V. Tomilov).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.114

5606
Y. V. Tomilov et al. / Tetrahedron Letters 50 (2009) 5605–5608
E
E
E
E
E
E
E
E
E
E
E
E
N
E
+
RNH2
+
E
E
E
E
E
N
R
4a—d
O
R
2a—d
E
E
1
3a—d
E = CO2Me
Scheme 1. Conditions: 1:2 = 1:1.5, 20 °C, 20–24 h, solvent (see Table 1).
compounds 3 and 4. The tropene structure of 3 (similar to that
formed in the reaction of ammonia or primary amines with ethyl
cyclohepta-1,3,5-trienecarboxylate6) results from addition of the
amine to the double bond of the cycloheptatriene such that both
sp3 carbon atoms are adjacent to each other. Further reaction in-
volves an intramolecular Michael addition of the amine fragment
to one of the remaining double bonds of the seven-membered ring
(Scheme 2). Here the regio- and stereoselectivity are due to the
most favorable spatial orientation of the ester groups during the
formation of the unsaturated bicyclic framework. We have ob-
served similar stereoselectivities in the formation of a bicy-
clo[3.2.0]hept-2-ene on reduction of the cycloheptatriene 1 with
sodium borohydride.13
In polar solvents, specifically in methanol, the starting triene 1 ap-
pearstoundergoinitialdeprotonationbytheamine,whichisinagree-
ment with its proceeding transformation into the stable
hepta(methoxycarbonyl)cycloheptatrienyl anion,1 and further reac-
tion involves addition of the amine to the double bond not participat-
ing in the negative charge delocalization within the seven-membered
ring.14 The resulting anion, which may also be formed by deprotona-
tion of the initially formed amine adduct, see Scheme 2, undergoes
ring-opening with simultaneous formation of the pyridinone ring
and the isomeric trisubstituted propenyl fragment (Scheme 2).
Table 1
Yields of compounds 3 and 4 on varying the solvent
Amine
R
Solvent
Yield 3a (%)
Yield 4a (%)
E/Z ratio
b
2a
Bn
CHCl3
95
—
b
CH3OH
p-xylene
CH3OH
p-xylene
CHCl3
—
96
45
91
21
46
77
96
46
93
2.7:1
2.2:1
2.4:1
1.4:1
1.6:1
1.4:1
1.7:1
1.9:1
1:9:1
2b
2c
BnCH2
50
b
—
c-C3H5
73
47
17
THF
b
CH3OH
p-xylene
CH3OH
—
2d
EtO(CH2)2
45
b
—
a
Yields are for isolated (chromatographed or crystallized) materials (>96% purity
by 1H NMR).
b
This compound was not observed by 1H NMR.
The splitting of the geminal protons can be explained by the pyrid-
inone ring and the exocyclic double bond being orthogonal to each
other with hindered rotation about the aryl-vinyl single bond.
The different structures of the products and strong dependency
of the regioselectivity on the solvent polarity seem to be evidence
for the existence of different mechanisms for the formation of
E
E
E
E
NHR
E
E
E
E
E
N
E
H
E
E
E
E
R
H
3
i
—H +
E
E
E
E
E
E
E
E
E
E
RNH2
ii
E
E
E
RHN
E
E
E
E
E
E
E
E
E
E
1
CO2Me
E
E
E
E
E
E
H+
R N
O
R N
O
E
E
+
E
E
E
NHR
E
E
E
E
E
E-4
Z-4
E = CO2Me; R = Bn, BnCH2, cyclo-C3H5, EtOCH2CH2
Scheme 2. Michael addition of amines to 1. (i) in non-polar solvents; (ii) in polar solvents with prior ionization of 1.

Y. V. Tomilov et al. / Tetrahedron Letters 50 (2009) 5605–5608
5607
OMe
O
1
O
E
O
E
3
9
HO
N
O
E
1
+
HOCH2CH2NH2
N
E
4
8
E
E
2´
7
2e
O
1´
E
E
E
E
E = CO2Me
5
6
Scheme 3. Conditions: 1:2e = 1:1.5, 20 °C, 20–24 h, solvent: CH2Cl2 or CH3OH.
9. Karady, S.; Corley, E. G.; Abramson, N. L.; Amato, J. S.; Weinstock, L. M.
A somewhat different outcome was observed in the reaction of
cycloheptatriene 1 with 2-aminoethanol. In this case, the reaction
gave the corresponding 3-vinylpyridin-2-one exclusively, regard-
less of the solvent. However, the reaction did not stop here, and
the product 5 underwent further cyclization into the lactone 6,15
which was easily isolated from the reaction mixture by crystalliza-
tion in a yield of 77% as the E-isomer only (Scheme 3). The struc-
tural assignment of compound 6 was strongly supported by
1H–1H HMBC, and 1H–13C HMQC NMR experiments.
It should be noted that the reaction of the cycloheptatriene 1
with amines is strongly influenced by the nature of the amine used.
In particular, the reaction with primary amines is only possible un-
der the mild conditions described, while the presence of bulky sub-
stituents on the amine prevents addition to the sterically hindered
double bonds of the substituted cycloheptatriene. Thus, for exam-
ple, no reaction occurs between 1 and dimethylamine, aniline, or
tert-butylamine.
The compounds obtained are of interest as building blocks for
the synthesis of analogs of various natural products, in particular
of the tropane derivatives used in the synthesis of natural photo-
chrome analogs16 and also of a number of biologically active com-
pounds including narcotic drug antagonists.17 Pyridin-2-ones are
widely used as central fragments in the synthesis of various alka-
loids.18 Despite the great variety of synthetic methods for pyri-
din-2-ones, the development of new synthetic routes leading to
pyridinone fragments is still important.
Tetrahedron 1991, 47, 757.
10. General method for compounds
3 and 4: To a stirred solution of cyclohe
ptatrieneheptacarboxylate 1 (1 mmol) in solvent (7 ml) (see Table 1) amine 2
(1.5 mmol) in the same solvent (0.5 ml) was added and the reaction mixture was
stirred at 20 °C for 24 h. The solvent was removed in vacuo and the residue was
crystallized or purified by column chromatography on silica gel using benzene–
AcOEt, 2:1 as eluent.
11. Heptamethyl 8-benzyl-8-azabicyclo[3.2.1]oct-2-ene-1,2,3,4,5,6,7-heptacarboxylate
3a: Colorless crystalline solid, mp 152–153 °C; 1H NMR (300 MHz, CDCl3): 3.01,
3.62, 3.69, 3.70, 3.73, 3.78 and 3.80 (all s, 7 ꢀ 3H, 7 OCH3); 3.68 and 3.89 (both d,
J = 15.6, 2 ꢀ 1H, CH2); 4.44 (s, 1H, H(6)); 4.45 (s, 2H, H(4) and H(7)); 7.17–7.34 (m,
5H, C6H5). 13C NMR (75.5 MHz, CDCl3): 46.38 (C(6)); 48.83 (C(7)); 48.89 (CH2);
52.47,52.48,52.69,52.75,52.78,52.82and52.89(7OCH3);56.48(C(4));71.99and
72.16 (C(1) and C(5)); 127.14 (Cp); 127.99 and 128.19 (2Co and 2Cm); 133.69 and
133.90 (C(2) and C(3)); 137.15 (Cipso); 165.90, 166.43, 167.12, 168.61, 168.88,
169.71 and 170.80 (7 COO). IR (KBr): m .
2956, 1725–1748 (COO), 1626, 1436 cmꢁ1
EI-MS, m/z: (%) 605 (M+, 2), 546 (M+ꢁCO2CH3, 3), 392 (5), 336(5), 305 (5), 248(30),
237(5), 121(10), 105(5), 91(CH2Ph+, 100).Anal.CalcdforC28H31NO14:C, 55.54;H,
5.12; N, 2.31. Found: C, 55.59; H, 4.96; N, 2.35.
Trans
(6,7)-8-(2-Ethoxyethyl)-1,2,3,4,5,6,7-heptamethoxycarbonyl-8-azabicyclo
[3.2.1]oct-2-ene 3d: 1H NMR (300 MHz, CDCl3): d 1.13 (t, J = 7.0 Hz, 3H, CH3),
2.83(m, 2H, CH2N), 3.14and2.28(bothddd, 2J = 9.8 Hz, 3J = 6.7 and 7.2 Hz, 2 ꢀ 1H,
CH2O), 3.38 (m, 2H, OCH2), 3.66, 3.70, 3.74, 3.75 and 3.81 (all s, 3 + 3 + 9 + 3 + 3H,
7OCH3),4.28(d,J = 9.2 Hz,1H,H(6)),4.40(d, J = 9.2 Hz, 1H, H(7)),4.45(s,1H,H(4));
13C NMR(75.5 MHz, CDCl3):d15.11(CH3), 44.77(CH2N), 46.19 (C(4)), 48.68 (C(6)),
52.40, 52.58, 52.64, 52.74, 52.79, 52.83 and 53.16 (7OCH3), 56.48 (C(7)), 66.53 and
69.15 (CH2OCH2), 71.91 (C(5)), 73.05 (C(1)), 133.85 (C(3)), 134.61 (C(2)), 165.73,
166.58, 167.87, 168.54, 168.64, 169.65 and 170.67 (7COO). IR mmax (NaCl) 1728–
1742(COO),1636,1437 cmꢁ1;EI-MS,m/z:528(M+–CO2CH3, 14), 318 (8),113(12),
73 (28), 59 (97), 45 (100). Anal. Calcd for C25H33NO15: C, 51.11; H, 5.66; N, 2.38.
Found: C, 50.91; H, 5.52; N, 2.19.
12. 1-Benzyl-(3-[(1,2,3-trimethoxycarbonyl)prop-1-enyl]-4,5,6-trimethoxycarbonylpyridi
n-2-one (4a): Colorless oil; IR (KBr):
m 3020, 2956, 1728–1747 (COO), 1664 (C@O),
1436. EI-MS, m/z: 573 (M+, 2), 514 (M+ꢁCO2CH3, 4), 392 (6), 121 (12), 105 (3), 91
(CH2Ph+, 100). Anal. Calcd forC27H27NO13 C, 56.54;H, 4.71; N, 2.44. Found:C, 56.74;
H, 4.77; N, 2.41. E-isomer 1H NMR (300 MHz, CDCl3): 3.61, 3.70, 3.72, 3.74, 3.76 and
3.81 (all s,6 ꢀ 3H,6OCH3), 3.80 and 4.15 (both d, J = 17.0, 2 ꢀ 1H,CH2),5.24and5.35
(both d, J = 15.1, 2 ꢀ 1H, CH2Ph), 7.18–7.37 (m, 5H, C6H5); 13C NMR (75.5 MHz,
CDCl3): 35.64 (CH2), 49.70 (CH2Ph), 52.19, 52.78, 52.89, 52.90, 52.95 and 53.40
(6OCH3), 106.19(C(5)), 127.35(2Co), 127.98(Cp), 128.61(2Cm), 128.89(C(3)), 133.85
Acknowledgments
This work was financially supported by the Presidium of the
Russian Academy of Sciences (Program for Basic Research ‘Elabora-
tion of Methods for the Synthesis of Chemical Substances and Cre-
ation of New Materials’, Subprogram ‘Development of
Methodology of Organic Synthesis and Creation of Compounds
with Valuable Applied Properties’) and the Federal Agency for Sci-
ence and Innovations (the Russian Federation President Grant NSh-
3237.2008.3).
´
´
(@C(1)), 135.01 (Ci), 139.06 (@C(2)), 139.55 (C(4)), 144.82 (C(6)), 159.84 (C(2)),
162.39, 163.26, 164.95, 165.11 and 166.10 (5COO), 169.85 (CH2COO); Z-isomer: 1
H
NMR(300 MHz, CDCl3): 3.24 and 3.39 (bothd, J = 17.0, 2 ꢀ 1H, CH2), 3.64, 3.72, 3.74,
3.77, 3.82 and 3.83 (all s, 6 ꢀ 3H, 6OCH3), 5.23 and 5.32 (both d, J = 15.0, 2 ꢀ 1H,
CH2Ph), 7.14–7.36 (m, 5H, C6H5); 13C NMR (75.5 MHz, CDCl3): 37.78 (CH2), 49.87
(CH2Ph), 52.26, 52.72, 52.85, 53.08, 53.23 and 53.53 (6OCH3), 106.11 (C(5)), 124.49
(C(3)), 127.53 (2Co), 128.20 (Cp), 128.69 (2Cm), 130.64 (C(10)), 134.63 (Ci), 139.76
(C(20)), 142.51 and 145.93 (C(4) and C(6)), 159.26 (C(2)), 162.01, 162.95, 164.65,
165.00 and 167.53 (5COO), 168.82 (CH2COO).
Supplementary data
1-(2-Ethoxyethyl)-(3-[(1,2,3-trimethoxycarbonyl)prop-1-enyl]-4,5,6-trimethoxycar
bonylpy ridin-2-one (4d): Colorless oil; IR mmax (NaCl) 1724–1744 (COO), 1668
(C@O), 1597(C@C)cmꢁ1;EI-MS:555(M+,2),524(M+ꢁOCH3, 4),496(M+ꢁCO2CH3,
24), 392 (20), 360 (17), 73 (94), 59 (95), 45 (100). Anal. Calcd for C24H29NO14: C,
51.89; H, 5.26; N, 2.52. Found: C, 51.64; H, 5.08; N, 2.38. E-isomer 1H NMR (600
MHz, CDCl3): d 1.15 (t, J = 7.0 Hz, 3H, CH3), 3.46 (q, J = 7.0, 2H, CH2O), 3.62 (m, 2H,
OCH2), 3.63, 3.70, 3.77, 3.79, 3.81 and 3.95 (all s, 6 ꢀ 3H, 6OCH3), 3.81 and 4.10
(both d, 2J = 17.0 Hz, 2 ꢀ 1H, CH2), 4.17 and 4.26 (both br.dt, 2J = 13.6 Hz,
3J = 6.7 Hz, 2 ꢀ 1H, CH2N); 13C NMR (151 MHz, CDCl3) d 14.92 (CH3), 35.59
(CH2), 47.01 (CH2N), 52.06, 52.61, 52.76, 52.81, 53.06, and 53.53 (6OCH3), 66.64
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.114.
References and notes
1. Tomilov, Yu. V.; Platonov, D. N.; Salikov, R. F.; Okonnishnikova, G. P.
Tetrahedron 2008, 64, 10201.
2. Stadler, P. A.; Hofmann, A. Helv. Chim. Acta 1962, 45, 2005.
3. Kampe, K.-D. Justus Liebigs Ann. 1974, 593.
4. Abelman, M. M.; Fisher, K. J.; Doerffler, E.; Edwards, P. J. Tetrahedron Lett. 2003,
44, 1823.
5. Pfau, M. Bull. Soc. Chim. Fr. 1967, 1117.
6. Grundmann, Ch.; Ottmann, G. Justus Liebigs Ann. 1957, 605, 24.
7. Lamanec, T. R.; Bender, D. R.; DeMarco, A. M.; Karady, S.; Reamer, R. A.;
Weinstock, L. M. J. Org. Chem. 1988, 53, 1768.
´
´
and 66.87(CH2OCH2),106.64(C(5)),128.49(C(3)),133.86(@C(1)), 138.97(@C(2)),
139.15 (C(4)), 145.90 (C(6)), 159.58 (C(2)), 162.31, 163.56, 164.90, 165.02 and
166.02 (5COO), 169.76 (CH2COO); Z-isomer 1H NMR (600 MHz, CDCl3): d 1.14 (t,
J = 7.0 Hz, 3H, CH3), 3.23and3.33(bothd, 2J = 17.0 Hz, 2 ꢀ 1H, CH2),3.44(q,J = 7.0,
2H, CH2O), 3.64 (m, 2H, OCH2), 3.66, 3.70, 3.71, 3.78, 3.81 and 3.95 (all s, 6 ꢀ 3H,
6OCH3), 4.21(m, 2H, CH2N); 13C NMR (151 MHz, CDCl3) d 14.88 (CH3), 37.57(CH2),
47.23 (CH2N), 52.14, 52.57, 52.70, 52.76, 52.95, and 53.65 (6OCH3), 66.63 and
´
´
66.83 (CH2OCH2), 106.55 (C(5)), 124.09 (C(3)), 130.89 (@C(1)), 139.22 (@C(2)),
8. Siganek, E.; Read, J. M., Jr.; Calabrese, J. C. J. Org. Chem. 1995, 60, 5795.
142.42 (C(4)), 144.75 (C(6)), 158.96 (C(2)), 161.97, 163.32, 164.80, 164.97 and

5608
Y. V. Tomilov et al. / Tetrahedron Letters 50 (2009) 5605–5608
´
167.40 (5COO), 168.79 (CH2COO). The structural assignment was strongly
65.48 (OCH2), 118.17 (C(9)), 130.42 (@C(1)), 134.71 and 135.32 (C(7) and C(8)),
supported by 1H–1H HMBC and 1H–13C HMQC NMR experiments.
13. Platonov, D. N.; Okonnishnikova, G. P.; Salikov, R. F.; Tomilov, Yu. V. Russ. Chem.
Bull., Int. Ed., 2009, 58, in press.
136.88 (@C(2)), 138.10 (C(10)), 157.10 and 158.00 (C(1) and C(6)), 163.98, 164.69,
´
165.33, 165.88, 169.94 (5COO). IR (KBr): m3012, 2956, 1720–1742, 1656, 1440. EI-MS,
m/z: 495 (M+, 3), 464 (3), 436 (48), 59 (100). Anal. Calcd for C21H21NO13 C, 50.92; H,
4.27; N, 2.83. Found: C, 50.79; H, 4.22; N, 2.71.
14. See the X-ray data for hepta(methoxycarbonyl)cycloheptatrienyl potassium in
Ref. 1.
16. Baasov, T.; Sheves, M. J. Am. Chem. Soc. 1985, 107, 7524.
17. Clarke, R. L.; Gambino, A. J.; Pierson, A. K.; Daum, S. J. J. Med. Chem. 1978, 21,
1235.
18. Tieckelmann, H.. In Pyridine and its Derivatives; Abramovitch, R. A., Ed.;
Interscience: NY, 1974; Vol. 14,. Part 3, Ch. 12 Chen, H.-W.; Hsu, R.-T.; Chang,
M.-Y.; Chang, N.-C. Org. Lett. 2006, 8, 3033; Tsai, T.-H.; Chung, W.-H.; Chang, J.-
K.; Hsu, R.-T.; Chang, N.-C. Tetrahedron 2007, 63, 9825.
15. Dimethyl 1,6-dioxo-7-[1,2,3-tris(methoxycarbonyl)propen-1-yl]-1,3,4,6-tetrahydropyri
do[2,1-c][1,4]oxazine-8,9-dicarboxylate 6: colorless crystals, mp 203–205 °C (EtOAc).
1H NMR (300 MHz, CDCl3): 3.64, 3.72, 3.73, 3.80 and 3.87 (all s, 5 ꢀ 3H, OCH3), 3.88
and 4.18 (both d, 2 ꢀ 1H, CH2, 2J = 16.9), 4.11 and 4.47 (both dt, 2 ꢀ 1H, NCH2,
2J = 15.4, 3J = 6.1 and 4.2), 4.67 (dd, 2 H, OCH2, 3J = 6.1 and 4.2); 13C NMR (75.5 MHz,
CDCl3): 35.39 (CH2), 40.41 (NCH2), 52.25, 52.94, 53.02, 53.34 and 53.57 (5 OCH3),