Structure and Thermal Isomerization of the Adducts Formed in the Reaction of Cyclohexyl Isocyanide with Dimethyl Acetylenedicarhoxylate

Article abstract of DOI:10.1021/jo981427f

Reaction of cyclohexyl isocyanide (Id) with dimethyl acetylenedicarboxylate (DMAD) gave a mixture of products such as the cyclopenta[6]pyridine derivatives 14 (28%) and 19 (1%), the azaspirononatriene derivative 13 (2%), and the azahicyclononatriene 16 (3

Full text of DOI:10.1021/jo981427f

J . Org. Chem. 1998, 63, 9801-9805
9801
Str u ctu r e a n d Th er m a l Isom er iza tion of th e Ad d u cts F or m ed in
th e Rea ction of Cycloh exyl Isocya n id e w ith Dim eth yl
Acetylen ed ica r boxyla te1
H. J unjappa,2a M. K. Saxena,2a D. Ramaiah,2b B. B. Loharay,2a N. P. Rath,2c and
M. V. George*,2a,b,d,e
Photochemistry Research Unit, Regional Research Laboratory (CSIR), Trivandrum 695 019, India,
Department of Chemistry, University of MissourisSt. Louis, Missouri 63121, Department of Chemistry,
Indian Institute of Technology, Kanpur 208 016, India, Radiation Laboratory, University of Notre Dame,
Notre Dame, Indiana 46556, and J awaharlal Nehru Centre for Advanced Scientific Research,
Bangalore 560 064, India
Received J uly 21, 1998
Reaction of cyclohexyl isocyanide (1d ) with dimethyl acetylenedicarboxylate (DMAD) gave a mixture
of products such as the cyclopenta[b]pyridine derivatives 14 (28%) and 19 (1%), the azaspironon-
atriene derivative 13 (2%), and the azabicyclononatriene 16 (3%). Interestingly, 14 on refluxing
in xylene for 3 h gave exclusively 13 (92%), whereas when the reaction was continued for 6 h, a
mixture of 13 (85%) and 19 (9%) was formed. In a separate reaction, when 13 was heated in a
sealed tube at 200 °C for 1 h, 19 was isolated in 63% yield. Activation energies for the thermal
isomerization of 14 to 13 and 13 to 19 have been found to be 19.4 and 16.7 kcal/mol, respectively.
Hydrogenation of 13 and 14 gave a mixture of the tetrahydro derivatives, 22 and 23, in each case.
The structures of 13, 14, 16, 19, 22, and 23 were established unambiguously through X-ray
crystallographic analysis.
In tr od u ction
co-workers13,14 have shown that complex mixtures of
products are formed from the reactions of aromatic
isocyanides such as 2,6-dimethylphenyl and 4-bromo-2,6-
dimethylphenyl isocyanides with DMAD (Scheme 1).
Some of these include the 2:1 adduct 3, the 3:1 adduct 5,
and the 2:3 adduct 4. Interestingly, the product 4 has
been found to be thermally sensitive and undergoes facile
isomerization to give 6.13 The reaction of aliphatic
isocyanides with various acetylenic substrates has been
reported by Winterfeldt and co-workers.6,7,15,16 Thus, for
example, the reaction of tert-butyl and cyclohexyl isocya-
nides (1c and 1d ) with DMAD at 0 °C gave a mixture of
1:2 adducts 7c and 7d , respectively, whereas the reaction
of tert-butyl isocyanide with DMAD at -20 °C gave an
interesting 2:3 adduct, the bicyclobutane derivative 8c
(Scheme 2). In addition, other products such as the 1:2
adducts were also isolated from this reaction.6,7,10 The
bicyclobutane derivative 8c formed in this reaction has
been found to undergo thermal isomerization to a pen-
talene derivative 9c (Scheme 2).15,16 Our interest in the
reaction of cyclohexyl isocyanide with DMAD dates back
to 1961, when in some preliminary studies an initially
formed 2:3 adduct 14 was isolated.17 Since then there
have been several reports dealing with the reaction of
In view of our general interest in the reaction of 1,3-
dipolar systems, we have examined the reaction of a
nucleophilic carbene such as cyclohexyl isocyanide with
dimethyl acetylenedicarboxylate (DMAD), a reaction in
which potential 1,3- and 1,5-dipolar intermediates could
be involved. Reactions of aliphatic and aromatic isocya-
nides with ketones3,4 and acetylenic compounds5-12 have
been investigated in detail. Thus, it has been reported8,9
that the reaction of several isocyanides with hexafluoro-
2-butyne gives interesting cyclopropene derivatives in
aprotic solvents, whereas when the reaction is carried
out in protic media such as methanol, two different 1:1:1
adducts (isocyanide:acetylene:alcohol), an unsaturated
imino ester and a ketenimine, are formed. Suzuki and
(1) (a) Dedicated to Professor Dr. Rolf Huisgen. (b) Document No.
RRLT-PRU-85 from the Regional Research Laboratory, Trivandrum,
and No. NDRL-4078 from the Notre Dame Radiation Laboratory.
(2) (a) Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India. (b) Photochemistry Research Unit, Regional
Research Laboratory (CSIR), Trivandrum 695019, India. (c) Depart-
ment of Chemistry, University of Missouri-St. Louis, MO 63121. (d)
Radiation Laboratory, University of Notre Dame, Notre Dame, IN
46556. (e) J awaharlal Nehru Centre for Advanced Scientific Research,
Bangalore 560 064, India.
(3) Middleton, W. J .; England, D. C.; Krespan, C. G. J . Org. Chem.
1967, 32, 948-950.
(4) Obata, N.; Takizawa, T. Tetrahedron Lett. 1969, 3403-3406.
(5) Takizawa, T.; Obata, N.; Suzuki, T.; Yanagida, T. Tetrahedron
Lett. 1969, 3407-3410.
(13) Suzuki, Y.; Obata, N.; Takizawa, T. Tetrahedron Lett. 1970,
2667-2670.
(6) Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1966, 5, 741.
(7) Winterfeldt, E.; Schumann, D.; Dillinger, H. J . Chem. Ber. 1969,
102, 1656-1664.
(14) Suzuki, Y.; Iitaka, Y. Bull. Chem. Soc. J pn. 1971, 44, 56-63.
(15) Dillinger, H. J .; Fengler, G.; Schumann, D.; Winterfeldt, E.
Tetrahedron 1974, 30, 2553-2559.
(8) Oakes, T. R.; David, H. G.; Nagel, F. J . J . Am. Chem. Soc. 1969,
91, 4761-4765.
(16) Dillinger, H. J .; Fengler, G.; Schumann, D.; Winterfeldt, E.
Tetrahedron 1974, 30, 2561-2564.
(9) Oakes, T. R.; Donovan, D. J . J . Org. Chem. 1973, 38, 1319-1325.
(10) J ohnson, F.; Gulbenkian, A. H.; Nasutavicus, W. A. Chem.
Commun. 1970, 608-609.
(17) Preliminary studies on the reaction of cyclohexyl isocyanide
with DMAD were carried out by one of the authors (M.V.G.) in
Professor Huisgen’s laboratory in Mu¨nchen. Subsequently these studies
were pursued at IIT, Kanpur, on Professor Huisgen’s suggestion. The
work on this project was interrupted several times and hence the delay
in summarizing the results.
(11) J autelat, M.; Ley, K. Synthesis 1970, 593-594.
(12) Saegusa, T.; Ito, Y.; Tomita, S.; Kinoshita, H.; Taka-Ishi, N.
Tetrahedron 1971, 27, 27-31.
10.1021/jo981427f CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

9802 J . Org. Chem., Vol. 63, No. 26, 1998
J unjappa et al.
Sch em e 1
action of 1d with DMAD (in a 2:3 ratio) in diethyl ether
at ca. 5-10 °C gave a mixture of the cyclopenta[b]-
pyridine derivatives 14 (28%) and 19 (1%), the aza-
spirononatriene 13 (2%), and the azabicyclononatriene
derivative 16 (3%) (Scheme 3). In contrast, when the
reaction was carried out with 1:2, 1:3, and 1:4 ratios of
isocyanide and DMAD under identical conditions, only
14 could be isolated, along with some unreacted DMAD,
in each case. Interestingly, when the adduct 14 was
heated for 3 h in xylene at ca. 130 °C, it underwent
isomerization to give 13 in quantitative yields, whereas
when 14 was refluxed for 6 h, a mixture of 13 (85%) and
another isomer 19 (9%) was formed. Similarly, com-
pound 13, on heating at ca. 200 °C for 1 h, gave 63% of
isomer 19.
Treatment of 14 with perchloric acid gave a perchlorate
salt, 17a (Scheme 3). The same salt was obtained on
treatment of 13 with perchloric acid, suggesting that 14
undergoes initial isomerization to 13, which then is
converted to 17a . Treatment of 13 with hydrobromic acid
likewise gave the hydrobromide 17b. The structure of
17b was confirmed through X-ray crystallographic analy-
sis by Gougoutas and Saenger,21 using a crystal provided
by us.
Hydrogenation of 14 in methanol using Raney nickel
catalyst gave a mixture of two tetrahydro derivatives, 22
(48%) and 23 (10%) (Scheme 4). Similarly, hydrogenation
of 13 in methanol, under analogous conditions, gave a
mixture of 22 (74%) and 23 (11%). The structures of the
different adducts, 14, 13, 16, 19, and the reduction
products 22 and 23 have been determined on the basis
of analytical results and spectral data. Further confir-
mation of these structures was derived through X-ray
crystallographic analysis.22
Sch em e 2
The formation of the 2:3 adducts 14, 13, 19 and 16 in
the reaction of cyclohexyl isocyanide with DMAD can be
rationalized in terms of the pathways shown in Scheme
3. Addition of cyclohexyl isocyanide to the triple bond of
DMAD, leading to the formation of the 1,3-dipolar
intermediate 10 is well documented in the litera-
ture.8,13-16,23 Subsequent reaction of 10 with DMAD could
give rise to a 1,5-dipolar intermediate 11, which in turn
could give rise to the iminocyclopentadiene derivative 15.
The reaction of 15 with the 1,3-dipolar intermediate 10
through a [4 + 6] cycloaddition pathway would result in
the formation of the cyclopenta[b]pyridine derivative 14,
which is the primary 2:3 adduct. Similar 2:3 adducts
have been reported in the reaction of 2,6-dimethylphenyl
isocyanide and 4-bromo-2,6-dimethylphenyl isocyanide
with DMAD.13 A bicyclic adduct such as 14 can undergo
facile rearrangements, leading to isomeric products.
Thus, the facile thermal isomerization of 14, involving a
1,5-sigmatropic shift, would lead to the azaspiro adduct
13, which in turn can undergo further 1,5-sigmatropic
shifts leading to the more stable adduct 19. The forma-
tion of 19 from 13 may be going through the intermediate
dihydropyrindine derivative 18 (Scheme 3). One could
also visualize the formation of 19, directly from 14
through several sequential 1,5-sigmatropic shifts.
isocyanides with DMAD,13-16 and other substrates.18,19
Some of these involve the formation of 1,3-dipolar species
as primary intermediates. The reactions of 1,3- and 1,4-
dipolar species with different dipolarophiles have been
extensively used in the synthesis of numerous hetero-
cycles.20 Herein we present the results of our studies
dealing with the reaction of cyclohexyl isocyanide with
DMAD, the isolation of different cycloadducts, and the
thermal isomerization of some of the adducts.
Resu lts a n d Discu ssion
1. Rea ction of Cycloh exyl Isocya n id e (1d ) w ith
Dim eth yl Acetylen ed ica r boxyla te (DMAD). The re-
(18) Ugi, I.; Domling, A.; Horl, W. Endeavour 1994, 18, 115. (b)
Keating, T. A.; Armstrong, R. W. J . Am. Chem. Soc. 1995, 117, 7842-
7848. (c) Keating, T. A.; Armstrong, R. W. J . Org. Chem. 1996, 61,
8935-8939.
(19) Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997, 38, 359-
362. (b) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Tetrahedron
Lett. 1997, 38, 2519-2520.
(20) Huisgen, R. In Topics in Heterocyclic Chemistry; Castle, R. N.,
Ed.; Wiley & Sons. Inc.: New York, 1969; pp 223-252. (b) 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.; Wiley & Sons Inc.: New
York, 1984; Vols 1 and 2.
The formation of 16, on the other hand, proceeds
through an altogether different route. The 1,5-dipolar
(21) Gougoutas, J . Z.; Saenger, W. J . Org. Chem. 1971, 36, 3632-
3633.
(22) Ramaiah, D.; J unjappa, H.; Saxena, M. K.; Rath, N. P.; George,
M. V. Acta Crystallogr. C, in press.

Cyclohexyl Isocyanide/Dimethyl Acetylenedicarboxylate Adducts
J . Org. Chem., Vol. 63, No. 26, 1998 9803
Sch em e 3
Ta ble 1. Ra te Con sta n ts a n d Th er m od yn a m ic Da ta of
th e Th er m a l Isom er iza tion of 14 to 13 a n d 13 to 19a
Sch em e 4
thermal
temp
(K)
rate constant,
Ea,
kcal/mol
isomerizationb
k, 10-4 s-1
∆S, eu
-25.6
14 to 13
358
368
378
413
423
428
0.84
1.74
3.71
1.10
1.76
2.22
19.4
16.7
13 to 19
-38.9
a
Average of more than two experiments. b The thermal isomer-
ization monitoring wavelengths (λmax) are 420 nm for 14 to 13 and
380 nm for 13 to 19.
from 13 upon Raney nickel treatment may proceed
through the initially formed intermediates, 20 and 21,
respectively (Scheme 4). Hydrogenation of the pyrroli-
dine ring of 13 would result in 20, which subsequently
isomerizes to 22. It has been possible to locate the
positions of all the hydrogen atoms through X-ray
analysis, and it is interesting to note that 22 exists as a
zwitterionic species with the two nitrogens bearing two
hydrogen atoms and the positive charge and the cyclo-
pentadiene ring having the negative charge. Hydrogena-
tion of the cyclopentadiene moiety, on the other hand,
may lead to 21, which can undergo further rearrange-
ment in the presence of Raney nickel to give 23.
intermediate 11 could react further with DMAD to give
the iminocycloheptatriene derivative 12. Further reac-
tion of the starting isocyanide 1d with 12 could give yet
another 2:3 adduct, 16.
2. Th er m a l Isom er iza tion of 14 to 13 a n d 13 to
19. The observed rate of isomerization followed first-
order kinetics uniformly with different concentrations of
14 at different temperatures in xylene. The progress of
the reaction was followed by the decrease in the extinc-
tion coefficient at λmax 420 nm (characteristic of compound
14) as a function of time at a given temperature. Plot of
log A versus time gave a straight line, and from the slope,
the rate of the reaction was calculated. Table 1 sum-
marizes the kinetic and thermodynamic parameters for
the thermal isomerization of 14 and 13.
Both 14 and 13, on treatment with Raney nickel in
methanol gave a mixture of 22 and 23, in each case,
although in different yields. It is assumed that both 22
and 23 are derived from the common precursor 13. In
the presence of Raney nickel, 14 isomerizes to 13 initially,
before it undergoes hydrogenation. This is substantiated
by the fact that there was a decrease in the absorption
at 420 nm, characteristic of 14 and a corresponding
increase in the absorption at 328 nm, characteristic of
13, when 14 was treated with Raney nickel alone,
without hydrogen.
The activation energy for this isomerization was found
to be 19.4 kcal mol-1, with a large negative entropy
The formation of the tetrahydro derivatives 22 and 23

9804 J . Org. Chem., Vol. 63, No. 26, 1998
J unjappa et al.
nol) 252 nm (ꢀ, 10000), 384 (25120), 440 (5100); 1H NMR
(CDCl3) δ 1.1-1.9 (18H, m), 2.75-2.95 (4H, m), 3.76 (3H, s),
3.77 (3H, s), 3.78 (6H, s), 3.80 (3H, s), 3.89 (3H, s); 13C NMR
(CDCl3) δ 24.31, 25.26, 25.80, 29.44, 33.44, 51.84, 52.05, 52.50,
53.58, 57.24, 65.99, 68.07, 107.79, 113.04, 120.52, 135.89,
141.53, 146.15, 157.70, 161.40, 163.82, 164.20, 164.77, 166.11;
mass spectrum m/e (relative intensity) 644 (M+, 14), 480 (48),
471 (74). Anal. Calcd for C32H40N2O12: C, 59.62; H, 6.25; N,
4.53. Found: C, 59.59; H, 6.27; N, 4.53.
Further elution of the column gave 385 mg (3%) of hexa-
methyl 8-cyclohexyl-9-(cyclohexylimino)-8-azabicyclo[5.2.0]-
nona-2,4,6-triene-1,2,3,4,5,6-hexacarboxylate (16), mp 183-
184 °C, after recrystallization from ethyl acetate: IR νmax (KBr)
1741, 1727, 1714 cm-1; UV λmax (methanol) 264 nm (ꢀ, 15850),
365 (9330); 1H NMR (CDCl3) δ 1.0-2.3 (20H, m), 3.3 (1H, m),
3.72 (3H, s), 3.74 (3H, s), 3.76 (3H, s), 3.81 (6H, s), 3.83 (3H,
s), 4.20 (1H, m); 13C NMR (CDCl3) δ 23.86, 24.25, 24.49, 25.44,
25.56, 29.14, 30.12, 33.82, 34.00, 51.70, 52.52, 52.62, 52.80,
53.40, 58.89, 59.05, 64.29, 95.31, 123.21, 128.04, 131.00,
133.80, 142.72, 159.10, 163.99, 164.62, 164.77, 164.98, 167.60;
mass spectrum m/e (relative intensity) 644 (M+, 43), 562 (66),
480 (10). Anal. Calcd for C32H40N2O12: C, 59.62; H, 6.25; N,
4.34. Found: C, 59.84; H, 6.40; N, 4.26.
change (-25 eu), which is typical of usual sigmatropic
rearrangements.
The kinetic studies on the thermal isomerization of
compound 13 to 19 were carried out in o-dichlorobenzene.
Measurement of λmax at 328 nm did not show gradual
decrease in the extinction coefficient but rather a gradual
increase in the extinction coefficient along with the
development of new peak at λmax 380 nm (characteristic
of compound 19). We have found that the plot of log A
at λmax 380 nm with time at a given temperature for the
initial period (35 min) of isomerization reaction gave a
straight line and the slope of which yielded the rate of
isomerization of 13 to 19 (Table 1). The activation energy
for this process was found to be 16.7 kcal mol-1 with a
large negative entropy change (-39 eu). This indicates
the fact that the isomerization of 13 to 19 is very facile,
even though involving several steps.
Exp er im en ta l Section
The equipment and procedures for melting point determi-
nation and spectral recordings are described in earlier pa-
pers.24 Solvents were purified by standard procedures before
use. Kinetic experiments were carried out in a constant-
temperature bath ((0.1 °C). Xylene and o-dichlorobenzene
used for kinetic measurements were purified and dried before
use.
Sta r tin g Ma ter ia ls. Cyclohexyl isocyanide (1d ), bp 56-
58 °C (11 mm),25 dimethyl acetylenedicarboxylate (2, DMAD),
bp 95-98 °C (19 mm),26 and Raney nickel catalyst27 were
prepared by reported procedures.
Finally, the column was eluted with a mixture (4:1) of
benzene and ethyl acetate to give 250 mg (2%) of hexamethyl
1-cyclohexyl-2-(cyclohexylimino)-1-azaspiro[4.4]nona-3,6,8-triene-
3,4,6,7,8,9-hexacarboxylate (13), mp 136-137 °C, after recrys-
tallization from methanol: IR νmax (KBr) 1755, 1740, 1725
1
cm-1; UV λmax (methanol) 242 nm (ꢀ, 15140), 365 (2570); H
NMR (CDCl3) δ 1.0-1.8 (18H, m), 1.95-2.17 (2H, m), 2.81-
3.01 (1H, m), 3.30 (1H, m), 3.70 (3H, s), 3.75 (6H, s), 3.90 (6H,
s), 3.91 (3H, s); 13C NMR (CDCl3) δ 24.31, 25.26, 25.62, 26.28,
28.63, 35.44, 52.23, 52.35, 52.71, 55.25, 57.78, 80.22, 136.07,
138.08, 140.90, 142.04, 148.12, 160.23, 161.10, 162.41, 165.13;
mass spectrum m/e (relative intensity) 644 (M+, 100), 553 (8).
Anal. Calcd for C32H40N2O12: C, 59.62; H, 6.25; N, 4.53.
Found: C, 59.59; H, 6.13; N, 4.45.
Rea ction of Cycloh exyl Isocya n id e (1d ) w ith Dim eth yl
Acetylen ed ica r boxyla te (DMAD). To a solution of 1d (4.36
g, 0.04 mol) in anhydrous diethyl ether (100 mL) at around
5-10 °C was added, in portions, an ethereal solution (100 mL)
of DMAD (12.18 g, 0.085 mol) over a period of 2 h with constant
stirring. After the addition was over, the reaction mixture was
allowed to stand at room temperature for 2 h, and then the
ether was distilled off on a water bath to give a sticky dark
red mass. It was cooled and triturated with ethanol (15 mL)
and kept in the refrigerator overnight to give 3.6 g (28%) of
hexamethyl 1-cyclohexyl-2-(cyclohexylimino)-1H-cyclopenta[b]-
pyridine-3,4,4a,5,6,7(2H)-hexacarboxylate (14), mp 156-157
°C, after recrystallization from ethanol: IR νmax (KBr) 1738,
1708 cm-1; UV λmax (methanol) 214 nm (ꢀ, 19050), 424 (10000);
1H NMR (CDCl3) δ 1.1-1.95 (20H, m), 2.41 (1H, m), 3.21 (1H,
m), 3.67 (3H, s), 3.69 (3H, s), 3.75 (3H, s), 3.77 (3H, s), 3.79
(3H, s), 3.93 (3H, s); 13C NMR (CDCl3) δ 23.73, 23.74, 25.35,
25.62, 26.25, 26.63, 28.60, 30.48, 32.81, 33.79, 51.64, 51.73,
52.32, 52.47, 53.72, 60.56, 65.03, 66.23, 106.89, 118.23, 127.98,
139.65, 142.36, 152.33, 160.56, 161.22, 161.76, 162.65, 164.14,
164.56, 165.10; mass spectrum, m/e (relative intensity) 644
(M+, 100), 585 (9), 374 (6). Anal. Calcd for C32H40N2012: C,
59.62; H, 6.25; N, 4.34. Found: C, 59.99; H, 6.27; N, 4.38.
The mother liquor, after removal of the solid, was chro-
matographed over alumina. Elution of the column with a
mixture (1:1) of benzene and petroleum ether gave 130 mg (1%)
of hexamethyl 1-cyclohexyl-2-(cyclohexylimino)-1,2-dihydro-
7H-cyclopenta[b]pyridine-3,4,5,6,7,7-hexacarboxylate (19), mp
197-198 °C: IR νmax (KBr) 1780, 1710 cm-1; UV λmax (metha-
The experiment was repeated using 1:2, 1:3, and 1:4 ratios
of isocyanide and DMAD, under identical conditions to give
9%, 15%, and 26%, respectively, of 14 as the only isolable
product, along with some amounts of the unreacted DMAD,
in each case.
Th er m a l Tr a n sfor m a tion of 14. A solution of 14 (1.29
g, 2.0 mmol) in dry xylene (25 mL) was refluxed for 3 h under
nitrogen atmosphere. The reaction mixture slowly turned
blood red. The solvent was removed under vacuum to give a
deep red viscous liquid, which was triturated with ethanol to
give 1.18 g (92%) of 13, mp 136-137 °C (mixture mp), after
recrystallization from ethanol.
In a separate run when the solution of 14 (3.22 g, 5.0 mmol)
in dry xylene (30 mL) was refluxed for 6 h under nitrogen
atmosphere, and workup of the reaction mixture as in the
earlier case gave 2.75 g (85%) of the red product 13, mp 136-
137 °C (mixture mp). The mother liquor, after removal of the
red solid, was concentrated and fractionally recrystallized from
methanol to give 300 mg (9%) of 19, mp 197-198 °C (mixture
mp).
Th er m a l Tr a n sfor m a tion of 13. A sample of 13 (322 mg,
0.5 mmol) was heated in an oil bath at ca. 200 °C for 1 h in
a sealed tube. The reaction mixture was dissolved in ethanol
and fractionally recrystallized to give 200 mg (63%) of 19, mp
198 °C (mixture mp).
Rea ction of 14 w ith P er ch lor ic Acid . To a warm
solution of 14 (322 mg, 0.5 mmol) in methanol (5 mL) was
added perchloric acid (1 mL) in portions, and the reaction
mixture was allowed to stand at room temperature for 6 h.
The reaction mixture became colorless. It was diluted with
cold water when a colorless solid precipitated out. The solid
product was filtered, washed with cold water, and recrystal-
lized from ethanol to give 320 mg (86%) of the perchlorate salt
of hexamethyl 1-cyclohexyl-2-(cyclohexylimino)-1-azaspiro[4.4]-
nona-3,6,8-triene-3,4,6,7,8,9-hexacarboxylate (17a ), mp 186-
188 °C: IR νmax (KBr) 3331, 1724 cm-1; UV λmax (methanol)
(23) (a) Winterfeldt, E.; Giesler, G. Chem. Ber. 1968, 101, 4022-
4031. (b) Kauer, J . C.; Simmons, H. E. J . Org. Chem. 1968, 33, 2720-
2726.
(24) (a) Ramaiah, D.; Muneer, M.; Gopidas, K. R.; Das, P. K.; Rath,
N. P.; George, M. V. J . Org. Chem. 1996, 61, 4240-4246. (b) Ramaiah,
D.; Ashok, K.; Barik, R. K.; Venugopal, D.; Rath, N. P.; Bhattacharyya,
K.; Das, P. K.; George, M. V. J . Org. Chem. 1992, 57, 6032-6037.
(25) Ugi, I.; Meyer, R. Chem. Ber. 1960, 93, 239-248.
(26) Huntress, E. H.; Lesslie, T. E.; Bornstein, J . Organic Syntheses;
Blatt, A. H., Ed.; J ohn Wiley & Sons: New York, 1963; Collect. Vol. 4,
pp 329-330.
1
245 nm (ꢀ, 28900), 295 (20420); H NMR (CDCl3) δ 1.6-2.15
(27) Vogel, A. I. A Text-Book of Practical Organic Chemistry; ELBS,
Longman Group Ltd.: London, 1984; pp 303-304.
(22H, m), 3.8 (3H, s), 3.9 (6H, s), 4.0 (6H, s), 4.1 (3H, s); 13C

Cyclohexyl Isocyanide/Dimethyl Acetylenedicarboxylate Adducts
J . Org. Chem., Vol. 63, No. 26, 1998 9805
NMR (CDCl3) δ 24.24, 24.86, 25.17, 25.57, 29.66, 32.67, 53.47,
53.81, 54.22, 55.87, 135.35, 136.15, 145.48, 159.43, 159.62,
161.44, 161.45. Anal. Calcd for C32H41N2O16Cl: C, 51.50; H,
5.78; N, 4.51. Found: C, 51.81; H, 5.76, N, 4.06.
Rea ction of 13 w ith P er ch lor ic Acid . To a solution of
13 (322 mg, 0.5 mmol) in methanol (5 mL) was added
perchloric acid (1 mL) in small portions. The reaction mixture
became colorless after 6 h. It was then diluted with cold water,
when a thick colorless solid precipitated. The product was
recrystallized from ethanol to give 330 mg (89%) of the same
perchlorate salt, 17a , mp 186-188 °C (mixture mp).
added Raney nickel catalyst (1.0 g), and the reaction mixture
was shaken in the presence of hydrogen at 70 psi for 24 h.
The catalyst was filtered and washed with an additional
amount of methanol (20 mL). The filterate was concentrated
under vacuum, and the products were chromatographed over
silica gel. Elution with a mixture (1:4) of ethyl acetate and
benzene gave 72 mg (11%) of 23, mp 193-194 °C (mixture mp),
after recrystallization from ethyl acetate.
Continued elution of the column with a mixture (1:1) of
benzene and ethyl acetate gave 478 mg (74%) of 22, mp 213-
214 °C (mixture mp), after recrystallization from ethyl acetate.
Kin etic Mea su r em en ts. A degassed solution of 14 in
xylene (4.3 × 10-5 M) was placed in a 250 mL flask, covered
with a septum, and maintained at the desired temperature.
Aliquots of this solution were removed at different time
intervals to glass vials, and the reaction, in each case, was
quenched by dipping it in ice-bath. The absorbance was
measured, and the change in absorbance with respect to time
was plotted to give a straight line. The value of the rate
constant was evaluated using standard equations, and it was
found that the reaction followed first-order kinetics. Measur-
ing the rate constants at three different temperatures and
plotting the values of log k versus 1/T gave a straight line.
The values of the activation energy (Ea) and entropy change
(∆S) were evaluated using standard equations.
Similarly, a degassed solution of 13 in o-dichlorobenzene
(4.5 × 10-5) was subjected to kinetics studies as in the earlier
case. The values for rate constants and Arrhenius parameters
for the conversion of 14 to 13 and 13 to 19 are presented in
Table 1.
X-r a y Str u ctu r e Deter m in a tion of 13, 14, 16, 19, 22, a n d
23. Crystals of 13, 14, 16, 19, 22, and 23 were subjected to
X-ray crystallographic analysis, employing a Siemens R3
automated four circle diffractometer. Data reduction and
structure solution were achieved by SHELXTL-PLUS struc-
ture solution package.28 Full details on the crystal and
molecular structures will be published elsewhere.22
Rea ction of 13 w ith Hyd r obr om ic Acid . To a solution
of 13 (644 mg, 1.0 mmol) in methanol (5 mL) was added
hydrobromic acid (2 mL), and the reaction mixture was allowed
to stand at room temperature for 12 h. It was then poured on
crushed ice. The solid product that precipitated out was
filtered, washed with cold water, and recrystallized from
methanol to give 720 mg (99%) of the hydrobromide salt of
hexamethyl 1-cyclohexyl-2-(cyclohexylimino)-1-azaspiro[4.4]-
nona-3,6,8-triene-3,4,6,7,8,9-hexacarboxylate (17b),18 mp 156-
157 °C: IR νmax (KBr) 1724, 1650 cm-1; UV λmax (methanol)
246 nm (ꢀ, 13490), 300 (5250). Anal. Calcd for C32H41N2O12
-
Br: C, 52.95; H, 5.56; N, 3.86. Found: C, 52.90; H, 5.74; N,
3.82.
Ca ta lytic Hyd r ogen a tion of 14 in Meth a n ol. To a
solution of 14 (515 mg, 0.8 mmol) in methanol (30 mL) was
added freshly prepared Raney nickel catalyst (1.0 g), and the
reaction mixture was shaken in hydrogen atmosphere at 80
psi for 32 h. The catalyst was filtered and washed with an
additional amount of methanol (20 mL). The filtrate was
concentrated under vacuum, and the resultant viscous mass
was chromatographed over silica gel. Elution with a mixture
(1:1) of benzene and petroleum ether gave 52 mg (10%) of
hexamethyl 1-cyclohexyl-2-(cyclohexylimino)-3aH-indole-3,-
3a,4,5,6,7-hexacarboxylate 23, mp 193-194 °C, after recrys-
tallization from methanol: IR νmax (KBr) 3320, 1740, 1700
1
cm-1; UV λmax (methanol) 260 nm (ꢀ, 36770), 352 (31940); H
NMR (CDCl3) δ 0.8-2.3 (20H, m), 2.6-3.1 (2H, s), 3.35 (1H,
d, J ) 9 Hz), 3.7 (3H, s), 3.8 (6H, s), 3.9 (7H, s), 4.0 (3H, s),
4.65 (1H, d, J ) 2 Hz), 4.71 (1H, s); 13C NMR (CDCl3) δ 24.15,
25.58, 26.00, 26.50, 26.75, 27.49, 27.64, 34.35, 41.62, 42.32,
43.41, 49.62, 51.70, 52.25, 52.48, 52.63, 52.81, 53.98, 54.39,
58.74, 59.39, 61.45, 90.32, 99.83, 149.40, 150.29, 167.64,
167.77, 169.63, 170.37, 170.73, 174.10; mass spectrum (chemi-
cal ionization) m/ s 649 (MH+, 100). Anal. Calcd for
Ack n ow led gm en t. The authors thank Professor Dr.
Rolf Huisgen for helpful discussions and Dr. Klaus
Herbig for partial experimental assistance. We (D.R.
and M.V.G.) thank the Council of Scientific and Indus-
trial Research, Government of India, the Regional
Research Laboratory (CSIR), Trivandrum, the Depart-
ment of Chemistry, Indian Institute of Technology,
Kanpur, India, (H.J ., M.K.S., B.B.L., and M.V.G.), the
University of Missouri-St. Louis (N.P.R.) and J awaha-
rlal Nehru Centre for Advanced Scientific Research,
Bangalore 560 012, India (M.V.G.), and the Office of
Basic Energy Sciences of the U. S. Department of
Energy (M.V.G. (in part)) for financial support of this
work.
C
32H44N2O12: C, 59.25; H, 6.79; N, 4.32. Found: C, 59.44; H,
6.42; N, 4.54.
Continued elution of the column with a mixture (1:4) of ethyl
acetate and benzene gave 248 mg (48%) of tetramethyl 5-[3-
(cyclohexylamino]-3-(cyclohexylimino)-1,2-bis(methoxycarbonyl)-
2-propenyl]-1,3-cyclopentadiene-1,2,3,4-tetracarboxylate (22),
mp 213-214 °C, after recrystallization from ethyl acetate: IR
νmax (KBr) 3410, 1750, 1730, 1715 cm-1; UV λmax (methanol)
1
227 nm (ꢀ, 17400), 301 (14500); H NMR (CDCl3) δ 0.71-2.2
(20H, m), 2.9-3.4 (2H, m), 3.55 (3H, s), 3.65 (3H, s), 3.70 (3H,
s), 3.72 (3H, s), 3.80 (3H, s), 3.87 (3H, s), 3.90-4.4 (1H, m),
5.4 (2H, q, J ) 12 Hz), 6.51 (1H, d, J ) 8 Hz, D2O-
exchangeable), 8.9 (1H, d, J ) 8 Hz, D2O-exchangeable); 13C
NMR (CDCl3) δ 24.31, 24.42, 24.67, 24.99, 29.29, 30.69, 33.21,
33.60, 42.28, 47.19, 50.71, 51.07, 51.55, 51.79, 52.35, 53.52,
54.76, 109.82, 113.89, 116.18, 123.34, 159.42, 166.74, 167.10,
168.56, 169.75, 170.66, 173.01; mass spectrum m/e (relative
intensity) 648 (M+, 4), 280 (39), 199 (52), 67 (100). Anal. Calcd
for C32H44N2O12: C, 59.20; H, 6.80; N, 4.32. Found: C, 59.40;
H, 6.70; N, 4.57.
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagrams
of structures and copies of 1H and 13C NMR spectra of
compounds 13, 14, 16, 19, 22, and 23, and a kinetics plot (22
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O981427F
Ca ta lytic Hyd r ogen a tion of 13 in Meth a n ol. To a
solution of 13 (644 mg, 1.0 mmol) in methanol (50 mL) was
(28) Sheldrick, G. M. Siemens Analytical X-ray Division, Madison,
WI, 1989.