Cascade cyclizations via N,4-didehydro-2-(phenylamino)pyridine biradicals/zwitterions generated from enyne-carbodiimides

Article abstract of DOI:10.1021/jo020760n

Thermolysis of the enyne - carbodiimides 7 having the central carbon - carbon double bond incorporated as part of the cyclopentene ring favors the formation of the corresponding N,4-didehydro-2-(phenylamino)pyridine intermediates, either as the σ,π-biradicals 8 or as the zwitterions 8′, for subsequent synthetic elaborations. By placing appropriate substituents at the acetylenic terminus, a variety of the intramolecular decay routes are available for the initially formed σ,π-biradicals/zwitterions, leading to the 5,6-dihydrobenzo[c][1,8]naphthyridine 21, the 1,2,3,4-tetrahydro[1,8]naphthyridine 24 and related compounds 25 and 26, the 5,6-dihydrobenz[f]isoquinoline 28, and the benzofuro[3,2-c]pyridine 30. Surprisingly, the use of the dimethylamino group of the 2-(dimethylamino)phenyl substituent to capture the carbocationic center in the zwitterion 8e′ furnished the 5H-pyrido[4,3-b]indole 32 in only 14% yield. The majority of the products were the 1H-pyrrolo[2,3-b]quinolines 34 and 35, isolated in 48 and 7% yields, respectively. However, it was possible to redirect the reaction toward 32 by conducting thermolysis of the enyne - carbodiimide 7e in the presence of 5 equiv of dimethylphenylsilyl chloride. Under this reaction condition, the 2-pyridone imine 37 was isolated in 86% yield, which on exposure to silica gel was converted to 32 in essentially quantitative yield. Thermolysis of the enyne - carbodiimide 42 having a methoxymethyl substituent at the acetylenic terminus led to the formation of 46′ as a pyridine analogue of orthoquinone methide imine. An intramolecular hetero-Diels - Alder reaction of 46′ then furnished the tetrahydro[1,8]naphthyridino[2,1-c][1,4]benzoxazine 47.

Full text of DOI:10.1021/jo020760n

Ca sca d e Cycliza tion s via N,4-Did eh yd r o-2-(p h en yla m in o)p yr id in e
Bir a d ica ls/Zw itter ion s Gen er a ted fr om En yn e-Ca r bod iim id es
Hongbin Li, J effrey L. Petersen,† and Kung K. Wang*
Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506-6045
kwang@wvu.edu
Received December 20, 2002
Thermolysis of the enyne-carbodiimides 7 having the central carbon-carbon double bond
incorporated as part of the cyclopentene ring favors the formation of the corresponding N,4-
didehydro-2-(phenylamino)pyridine intermediates, either as the σ,π-biradicals 8 or as the zwitterions
8′, for subsequent synthetic elaborations. By placing appropriate substituents at the acetylenic
terminus, a variety of the intramolecular decay routes are available for the initially formed σ,π-
biradicals/zwitterions, leading to the 5,6-dihydrobenzo[c][1,8]naphthyridine 21, the 1,2,3,4-tetrahydro-
[1,8]naphthyridine 24 and related compounds 25 and 26, the 5,6-dihydrobenz[f]isoquinoline 28,
and the benzofuro[3,2-c]pyridine 30. Surprisingly, the use of the dimethylamino group of the
2-(dimethylamino)phenyl substituent to capture the carbocationic center in the zwitterion 8e′
furnished the 5H-pyrido[4,3-b]indole 32 in only 14% yield. The majority of the products were the
1H-pyrrolo[2,3-b]quinolines 34 and 35, isolated in 48 and 7% yields, respectively. However, it was
possible to redirect the reaction toward 32 by conducting thermolysis of the enyne-carbodiimide
7e in the presence of 5 equiv of dimethylphenylsilyl chloride. Under this reaction condition, the
2-pyridone imine 37 was isolated in 86% yield, which on exposure to silica gel was converted to 32
in essentially quantitative yield. Thermolysis of the enyne-carbodiimide 42 having a methoxymethyl
substituent at the acetylenic terminus led to the formation of 46′ as a pyridine analogue of ortho-
quinone methide imine. An intramolecular hetero-Diels-Alder reaction of 46′ then furnished the
tetrahydro[1,8]naphthyridino[2,1-c][1,4]benzoxazine 47.
In tr od u ction
cleaving studies suggest a two-step biradical pathway.
Unlike 1a , thermolysis of the benzannulated enyne-
carbodiimides 1b-f having a substituent at the alkynyl
terminus produced the indoloquinolines 6b-f exclusively.
In addition to providing easy access to indoloquinolines,
this pathway was also adopted for the synthesis of 6H-
indolo[2,3-b][1,6]naphthyridines and related compounds4
as the aza analogues of the naturally occurring ellipticine
alkaloids. Ellipticine and many of its derivatives have
been found to exhibit potent antitumor activities.5
Thermolysis of the benzannulated enyne-carbodiim-
ides provides easy access to the corresponding heteroaro-
matic biradicals for subsequent synthetic elaborations.1
Specifically, when 1a was subjected to heating in γ-ter-
pinene at 138 °C for 14 h, 2-(phenylamino)quinoline (3a )
was produced as the major product along with a minor
amount of the indoloquinoline 6a (Scheme 1). Apparently,
N,4-didehydro-2-(phenylamino)quinoline (2a ) was formed
preferentially, which behaved as a σ,π-biradical to ab-
stract hydrogen atoms from γ-terpinene to produce 3a .
An alternative pathway involving the formation of the
formal Diels-Alder adduct 5a followed by tautomeriza-
tion led to 6a . The transformation from 1 to 5 could
proceed either through a two-step biradical mechanism
via 4 followed by an intramolecular radical-radical
coupling or through a concerted Diels-Alder reaction. In
the analogous enyne-allene2 and enyne-ketenimine3
systems, the kinetic, mechanistic, theoretical, and DNA-
Compared with the analogous enyne-allene,2,6 enyne-
ketene,7 and enyne-ketenimine3 systems, the thermally
induced cyclization reaction of enyne-carbodiimide ap-
(2) (a) Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett.
1995, 36, 4975-4978. (b) Schmittel, M.; Strittmatter, M.; Kiau, S.
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Chem., Int. Ed. 1998, 37, 1960-1963. (f) Schreiner, P. R.; Prall, M. J .
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Schmittel, M.; Steffen, J .-P.; Angel, M. A. W.; Engels, B.; Lennartz,
C.; Hanrath, M. Angew. Chem., Int. Ed. 1998, 37, 1562-1564.
(4) (a) Zhang, Q.; Shi, C.; Zhang, H.-R.; Wang, K. K. J . Org. Chem.
2000, 65, 7977-7983. (b) Lu, X.; Petersen, J . L.; Wang, K. K. J . Org.
Chem. 2002, 67, 5412-5415. (c) Lu, X.; Petersen, J . L.; Wang, K. K. J .
Org. Chem. 2002, 67, 7797-7801.
* To whom correspondence should be addressed. Phone: (304) 293-
3068, ext 6441. Fax: (304) 293-4904..
† To whom correspondence concerning the X-ray structures should
be addressed. Phone: (304) 293-3435, ext 6423. Fax: (304) 293-4904.
E-mail: jpeterse@wvu.edu.
(1) (a) Shi, C.; Zhang, Q.; Wang, K. K. J . Org. Chem. 1999, 64, 925-
932. (b) Schmittel, M.; Steffen, J .-P.; Engels, B.; Lennartz, C.; Hanrath,
M. Angew. Chem., Int. Ed. 1998, 37, 2371-2373. For a photochemically
induced reaction, see: (c) Schmittel, M.; Rodr´ıguez, D.; Steffen, J .-P.
Angew. Chem., Int. Ed. 2000, 39, 2152-2155. (d) Alajar´ın, M.; Molina,
P.; Vidal, A. J . Nat. Prod. 1997, 60, 747-748.
10.1021/jo020760n CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/07/2003
5512
J . Org. Chem. 2003, 68, 5512-5518

Cascade Cyclizations
SCHEME 1
SCHEME 2
nus. A success could provide many opportunities to
exploit the chemical reactivities of these reactive biradical
intermediates.
We have explored the strategy of using the enyne-
carbodiimides 7 having the central carbon-carbon double
bond incorporated as part of the cyclopentene ring to
produce the σ,π-biradicals 8 (Scheme 2). It was antici-
pated that cyclization to form the σ,π-biradicals 9 would
be disfavored because of emergence of ring strain in the
resulting bicyclic ring system. The effect of ring strain
in dictating the biradical-forming pathway was observed
previously in the analogous enyne-allene system.8 We
now report our findings of thermolysis of 7 to generate
the corresponding N,4-didehydro-2-(phenylamino)pyri-
dine intermediates, either as the σ,π-biradicals 8 or as
the zwitterions 8′, for subsequent synthetic elaborations.
Derivatives of several interesting heteroaromatic com-
pounds such as 5,6-dihydrobenzo[c][1,8]naphthyridine,9
benzofuro[3,2-c]pyridine,10 5H-pyrido[4,3-b]indole,11 and
1H-pyrrolo[2,3-b]quinoline12 were synthesized.
pears to have a greater propensity to proceed toward the
Diels-Alder route. We are interested in exploring the
possibility of redirecting the cyclization reaction toward
the pathway leading to 2 and related biradicals even for
the systems having a substituent at the alkynyl termi-
Resu lts a n d Discu ssion
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1257-1259.
The synthetic sequence outlined in Scheme 3 provides
an efficient route to a variety of the enyne-carbodiimides
7. The commercially available ethyl 2-oxocyclopentane-
carboxylate (10) was converted to the triflate 11 as
reported previously.13 The Pd-catalyzed cross-coupling
reaction14 between 11 and the terminal alkynes 12 then
produced 13. Saponification followed by treatment of the
carboxylic acids 14 with diphenyl phosphorazidate (DP-
PA)15 then afforded the isocyanates 15. Condensation
between 15 and aniline gave the urea derivatives 16,
which on treatment with dibromotriphenylphosphorane16
furnished the enyne-carbodiimides 7 (Table 1).
(8) (a) Schmittel, M.; Steffen, J .-P.; Auer, D.; Maywald, M. Tetra-
hedron Lett. 1997, 38, 6177-6180. (b) Liu, B.; Wang, K. K.; Petersen,
J . L. J . Org. Chem. 1996, 61, 8503-8507. (c) Wang, K. K.; Zhang, H.-
R., Petersen, J . L. J . Org. Chem. 1999, 64, 1650-1656. (d) Schmittel,
M.; Steffen, J .-P.; Maywald, M.; Engels, B.; Helten, H.; Musch, P. J .
Chem. Soc., Perkin Trans. 2 2001, 1331-1339.
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Trans. 1 1999, 1505-1510. (b) Molina, A.; Vaquero, J . J .; Garcia-Navio,
J . L.; Alvarez-Builla, J .; de Pascual-Teresa, B.; Gago, F.; Rodrigo, M.
M.; Ballesteros, M. J . Org. Chem. 1996, 61, 5587-5599.
(12) Murugesan, M.; Soundararajan, N.; Ramasamy, K.; Shan-
mugam, P. Synthesis 1979, 352-354.
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(b) Crisp, G. T.; Meyer, A. G. J . Org. Chem. 1992, 57, 6972-6975.
(14) (a) Nakatani, K.; Isoe, S.; Maekawa, S.; Saito, I. Tetrahedron
Lett. 1994, 35, 605-608. (b) Nakatani, K.; Adachi, K.; Tanabe, K.; Saito,
I. J . Am. Chem. Soc. 1999, 121, 8221-8228.
(7) (a) Moore, H. W.; Yerxa, B. R. Chemtracts 1992, 273-313. (b)
Foland, L. D.; Karlsson, J . O.; Perri, S. T.; Schwabe, R.; Xu, S. L.; Patil,
S.; Moore, H. W. J . Am. Chem. Soc. 1989, 111, 975-989. (c) Chow, K.;
Nguyen, N. V.; Moore, H. W. J . Org. Chem. 1990, 55, 3876-3880. (d)
Tarli, A.; Wang, K. K. J . Org. Chem. 1997, 62, 8841-8847. (e) Musch,
P. W.; Remenyi, C.; Helten, H.; Engels, B. J . Am. Chem. Soc. 2002,
124, 1823-1828.
J . Org. Chem, Vol. 68, No. 14, 2003 5513

Li et al.
SCHEME 3
SCHEME 4
no)pyridine σ,π-biradical 8a as anticipated. A subsequent
1,5-hydrogen shift produced the π,π-biradical 20, which
could also be written as an ortho-quinodimethane deriva-
tive depicted in 20′. Rotation around the central carbon-
carbon bond followed by an intramolecular radical-
radical coupling, or an electrocyclic reaction if the resulting
biradical is also regarded as an ortho-quinodimethane
derivative, then afforded 21. This cascade sequence is
reminiscent of those of several examples of the enyne-
allene8b and enyne-ketene7c,d systems reported earlier.
In the case of 19, the cycloaromatization reaction requires
heating at a substantially higher temperature (180 °C
under refluxing 1,2-dichlorobenzene) to produce 22 in
36% yield (eq 3).
TABLE 1. Syn th esis of 13-16 a n d th e
En yn e-Ca r bod iim id es 7
13,
14,
15,
16,
7,
yield yield yield yield yield
entry
R
(%)
(%)
(%)
(%)
(%)
a
b
c
d
e
f
2-methylphenyl
propyl
2-phenylethyl
2-methoxyphenyl
2-(dimethylamino)phenyl 91
methoxymethyl 91
90
91
98
92
96
89
92
92
85
80
91
87
86
84
87
68
85
72
72
69
76
85
65
72
82
50
The use of the aza-Wittig reaction between the isocy-
anate 15a and the iminophosphorane 17,17 derived from
aniline and dibromotriphenylphosphorane, to form 7a
gave only 20% yield (eq 1). Attempts to improve the yield
of the reaction by conducting the aza-Wittig reaction at
-78 °C were unsuccessful. Interestingly, the reaction at
-78 °C between 15a and the iminophosphorane 18,18
derived from benzyl azide and triphenylphosphine, was
very efficient in producing the enyne-carbodiimide 19
in 86% isolated yield (eq 2).
When 7b was subjected to thermolysis, 24 (35%) was
isolated along with 25 (28%) and 26 (12%) (Scheme 5).
As observed previously in an enyne-ketene system,7d
cycloaromatization of 7b generated the σ,π-biradical 8b,
which underwent a 1,5-hydrogen shift to furnish 23. An
intramolecular radical-radical coupling then afforded 24.
In addition, 23 could also undergo a second intramolecu-
lar 1,5-hydrogen shift to produce 25 or could abstract
hydrogen atoms from elsewhere to give 26.
SCHEME 5
Thermolysis of 7a under refluxing chlorobenzene at
132 °C produced the 5,6-dihydrobenzo[c][1,8]naphthyridine
21 in 56% yield (Scheme 4). Apparently, cycloaromati-
zation of 7a generated the N,4-didehydro-2-(phenylami-
(15) (a) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30,
2151-2157. (b) Shioiri, T.; Ninomiya, K.; Yamada, S.-i. J . Am. Chem.
Soc. 1972, 94, 6203-6205. (c) Rigby, J . H.; Balasubramanian, N. J .
Org. Chem. 1989, 54, 224-228.
(16) (a) Palomo, C.; Mestres, R. Synthesis 1981, 373-374. (b)
Bestmann, H. J .; Lienert, J .; Mott, L. J ustus Liebigs Ann. Chem. 1968,
718, 24-32.
The aryl radical center of the σ,π-biradical 8c, gener-
ated from 7c, was captured by the carbon-carbon double
bond of the phenyl substituent in a 6-endo radical
cyclization reaction to give 27 (Scheme 6). A subsequent
tautomerization then produced 28 in 73% yield.
(17) Horner, L.; Oediger, H. J ustus Liebigs Ann. Chem. 1959, 627,
142-162.
(18) (a) Aubert, T.; Farnier, M.; Guilard, R. Tetrahedron 1991, 47,
53-60. (b) Aubert, T.; Farnier, M.; Hanquet, B.; Guilard, R. Synth.
Commun. 1987, 17, 1831-1837.
5514 J . Org. Chem., Vol. 68, No. 14, 2003

Cascade Cyclizations
SCHEME 6
SCHEME 8
SCHEME 7
The transformation from 7d to the benzofuro[3,2-c]-
pyridine 30 can be best accounted for by regarding the
initially formed σ,π-biradical 8d as the zwitterion 8d ′
(Scheme 7). The carbocationic center of 8d ′ was then
captured by the lone-pair electrons on the oxygen atom
to give the oxonium ion in 29, which was converted to
30 perhaps during workup and purification by column
chromatography. The structure of 30 was unequivocally
established by the X-ray structure analysis. The dual
chemical property of the cycloaromatized intermediate
as the σ,π-biradical 8d and as the zwitterion 8d ′ re-
sembles that of the biradical/zwitterion intermediate
derived from the Moore cyclization reaction of the enyne-
ketene system.7,19
The use of the dimethylamino group to capture the
carbocationic center in 8e′ was also successful, leading
to the formation of the 5H-pyrido[4,3-b]indole 32 (Scheme
8). Surprisingly, 32 was produced only as a minor product
in 14% yield. The 1H-pyrrolo[2,3-b]quinoline 34 and the
methylated derivative 35, both derived via the Diels-
Alder route through 33, combine to give a total of 55%
yield. The extra methyl group in 35 could come from 31.
The structures of 32 and 34 were unequivocally estab-
lished by the X-ray structure analysis. The reason for
such a switch is not clear at the present time. Perhaps
the 2-(dimethylamino)phenyl group is too sterically de-
manding, making the generation of 8e′ less favorable. In
the enyne-allene system, the presence of a sterically
demanding group such as the tert-butyl group or the
trimethylsilyl group at the alkynyl terminus causes the
cyclization reaction to adopt the Diels-Alder route.6h,i
In several cases of the enyne-ketene system, it was
reported that the efficiency of the zwitterion pathway
could be greatly enhanced by conducting thermolysis in
the presence of trimethylsilyl chloride.19 Indeed, it was
gratifying to observe that when 7e was heated in the
presence of 1.2 equiv of dimethylphenylsilyl chloride, 32
was produced as the major product in 70% isolated yield
after purification by column chromatography along with
only 14% of 34. With 5 equiv of dimethylphenylsilyl
chloride, 34 was not detected, and only 32 was isolated
in 84% yield. This dramatic change in favor of 32 is
presumably due to silylation of the amide anion in 31 to
form 36, preventing 31 from reverting back to 7e and
eventually producing 34 and 35. However, other path-
ways including an initial silylation of one of the nitrogen
atoms of the carbodiimide moiety in 7e to promote a
cationic reaction mechanism leading to a silylated adduct
such as 36 could not be completely ruled out.
Although it was initially assumed that the putative
intermediate 36 or the corresponding demethylated ad-
(19) Moore, H. W.; Chow, K.; Nguyen, N. V. J . Org. Chem. 1987,
52, 2530-2537.
J . Org. Chem, Vol. 68, No. 14, 2003 5515

Li et al.
SCHEME 10
duct would be converted directly to 32 during workup,
we were surprised to observe that its tautomer, the
2-pyridone imine 37, precipitated out of the chloroben-
zene solution as a yellow solid in 86% yield when the
solution was allowed to cool to room temperature after
thermolysis. It is worth noting that the (E)- configuration
was assigned to the carbon-nitrogen double bond in 37
in order to account for the observation of an upfield-
shifted aromatic 1H NMR signal at δ 6.43 (doublet). Such
an assignment would allow the magnetic ring current of
the phenyl substituent on the nitrogen to shield the
neighboring aromatic hydrogen, causing its 1H NMR
signal to shift upfield to δ 6.43. On exposure to silica gel,
37 was converted to 32 in essentially quantitative yield.
It was reported that in equilibrium, the parent 2-ami-
nopyridine predominates over the tautomeric isomer
2-pyridone imine.20 Therefore, it was quite unexpected
that 37 was produced in excellent yield. This serendipi-
tous discovery could provide a unique pathway for easy
access to a variety of highly labile 2-pyridone imines.
While it is difficult to exclude the possibility of hy-
drolysis of 36 and/or the corresponding demethylated
adduct to form 37 due to the presence of trace amount of
water during the period when the reaction mixture was
allowed to cool to room temperature, it is hard to imagine
that such a condition would not also induce the trans-
formation of 37 to 32. Hydrogen chloride would be
generated from reaction between water and the excess
dimethylphenylsilyl chloride, creating an acidic condition
that should also convert 37 to 32, as observed when 37
was passed through a silica gel column. One possible
alternative is for the putative intermediate 36 to undergo
a retro-ene reaction through a chairlike transition state
as depicted in 38 (Scheme 9) to afford 37 directly during
thermolysis with concomitant formation of 2-phenyl-2-
silapropene (39). It was reported that such a retro-ene
reaction took place with allyltrimethylsilane to produce
propene and transient 2-methyl-2-silapropene, albeit at
a much higher temperature (600 °C).21 Clearly, additional
studies will be needed to determine the exact reaction
pathway and at what stage methyl chloride was elimi-
nated from 36.
It was anticipated that 44, derived from 42 via a 1,5-
hydrogen shift of the initially formed σ,π-biradical 43,
would have the propensity to lose a molecule of formal-
dehyde to form 46, which could also be regarded as a
pyridine analogue of ortho-quinone methide imine de-
picted in 46′. It is worth noting that a similar fragmenta-
tion process was observed in several cases of the birad-
icals derived from enyne-ketenes.7b,d The isolation of 47
suggests that 46′ was indeed produced and then captured
in an intramolecular hetero-Diels-Alder reaction. How-
ever, unlike the enyne-ketene system, the fragmentation
process of 44 is relatively slow compared to the intramo-
lecular radical-radical coupling pathway. As a result, 45
was produced predominantly.
Con clu sion s
Thermolysis of the enyne-carbodiimides 7 provides
easy access to the σ,π-biradicals 8, which also behave as
the zwitterions 8′ under certain reaction conditions. The
presence of two reactive centers in 8/8′ affords many
opportunities for intramolecular decay, leading to a
variety of heteroaromatic compounds. The reaction se-
quence outlined in Scheme 10 represents a novel pathway
SCHEME 9
(20) (a) Elguero, J .; Marzin, C.; Katritzky, A. R.; Linda, P. In
Advances in Heterocyclic Chemistry; Katritzky, A. R., Boulton, A. J .,
Eds.; Academic Press: New York, 1976; Suppl. 1, pp 153, 206. (b)
Pietrzycki, W.; Sepioł, J .; Tomasik, P.; Brzo´zka, Ł. Bull. Soc. Chim.
Belg. 1993, 102, 709-717. (c) Alkorta, I.; Elguero, J . J . Org. Chem.
2002, 67, 1515-1519.
(21) (a) Barton, T. J .; Burns, S. A.; Davidson, I. M. T.; Ijadi-
Maghsoodi, S.; Wood, I. T. J . Am. Chem. Soc. 1984, 106, 6367-6372.
(b) Dubac, J .; Laporterie, A. Chem. Rev. 1987, 87, 319-334.
(22) (a) Abbas, A. A.; Elwahy, A. H. M. Synthesis 2001, 1331-1336.
(b) Tiffany, B. D. J . Am. Chem. Soc. 1948, 70, 592-594.
The enyne-carbodiimide 42 was likewise synthesized
by condensation of the isocyanate 15f with the aniline
4022 followed by treatment of the resulting urea deriva-
tive 41 with dibromotriphenylphosphorane (Scheme 10).
5516 J . Org. Chem., Vol. 68, No. 14, 2003

Cascade Cyclizations
benzene was added a solution of 0.83 mL of triethylamine (6.0
mmol) and 1.514 g of DPPA (5.5 mmol) in 5 mL of benzene.
After 6 h of stirring at room temperature, the reaction mixture
was then washed with brine and water, dried over sodium
sulfate, and concentrated. Purification of the residue by flash
column chromatography (silica gel/5% diethyl ether in hexanes,
Rf ) 0.72) afforded 1.117 g of 15a (5.00 mmol, 91% yield) as a
pale yellow solid: mp 63-65 °C; IR 2254, 2159, 757 cm-1; 1H
NMR δ 7.48 (1 H, d, J ) 7.3 Hz), 7.27-7.11 (3 H, m), 2.62 (2
H, tt, J ) 7.3, 2.4 Hz), 2.52 (2 H, tt, J ) 7.3, 2.4 Hz), 2.48 (3
H, s), 2.00 (2 H, quintet, J ) 7.6 Hz); 13C NMR δ 139.9, 136.6,
131.7, 129.4, 128.3, 127.4, 125.5, 122.7, 115.1, 96.3, 87.3, 34.6,
33.9, 21.0, 20.6; MS m/z 223 (M+), 194, 167.
N-[2-[(2-Met h ylp h en yl)et h yn yl]-1-cyclop en t en yl]-N′-
p h en ylu r ea (16a ). The following procedure is representative
for the preparation of the ureas 16 from the isocyanates 15. A
solution of 0.250 g of 15a (1.12 mmol) and 0.115 g of aniline
(1.23 mmol) in 5 mL of methylene chloride was stirred at room
temperature for 8 h before 5 mL of hexanes was added.
Filtration afforded 0.302 g of 16a (0.954 mmol, 85% yield) as
to the pyridine analogues of ortho-quinone methide imine
for the hetero-Diels-Alder reactions.
Exp er im en ta l Section
All reactions were conducted in oven-dried (120 °C) glass-
ware under a nitrogen atmosphere. Triethylamine, aniline, and
benzene were distilled over CaH2 prior to use. 1-Pentyne,
methyl propargyl ether, 4-phenyl-1-butyne, (trimethylsilyl)-
acetylene, Pd(PPh3)2Cl2, copper(I) iodide, N,N-diisopropylethyl-
amine, sodium hydride, trifluoromethanesulfonic anhydride,
diphenyl phosphorazidate (DPPA), dibromotriphenylphospho-
rane, sodium azide, triphenylphosphine, benzyl chloride, ethyl
2-oxocyclopetanecarboxylate (10), dimethylphenylsilyl chloride,
N,N-dimethylformamide (DMF), chlorobenzene (anhydrous),
1,2-dichlorobenzene (anhydrous), 2-iodotoluene, 2-iodoanisole,
and 2-iodoaniline were purchased from chemical suppliers and
were used as received. (2-Methylphenyl)acetylene (12a ) and
2-ethynylanisole (12d ) were prepared from 2-iodotoluene and
2-iodoanisole, respectively, using the procedure described for
12e. Ethyl 2-[[(trifluoromethyl)sulfonyl]oxy]-1-cyclopentene-
1-carboxylate (11),13 2-aminophenyl allyl ether (40),22 N,N-
dimethyl-2-iodoaniline,23 N-(triphenylphosphoranylidene)-
benzenamine (17),17 and N-(triphenylphosphoranylidene)-
benzenemethanamine (18)18 were prepared according to the
a white solid: mp 198-199 °C; IR (KBr) 3302, 2187, 1644 cm-1
;
1H NMR δ (DMSO-d6) 9.34 (1 H, s), 8.35 (1 H, s), 7.57 (1 H, d,
J ) 6.9 Hz), 7.50 (2 H, d, J ) 7.9 Hz), 7.38-7.27 (5 H, m),
7.05 (1 H, t, J ) 7.2 Hz), 3.09 (2 H, t, J ) 7.2 Hz), 2.53 (2 H,
t, J ) 7.4 Hz), 1.98 (2 H, quintet, J ) 7.3 Hz); 13C NMR δ
(DMSO-d6) 151.3, 146.4, 139.4, 139.0, 131.3, 129.5, 128.8,
128.1, 125.8, 123.1, 122.0, 118.1, 96.6, 94.0, 89.1, 32.8, 32.4,
21.6, 20.5.
1
reported procedures. Melting points are uncorrected. H (270
MHz) and 13C (67.9 MHz) NMR spectra were recorded in CDCl3
using CHCl3 (1H δ 7.26) and CDCl3 (13C δ 77.00) as internal
standards unless otherwise indicated.
N-[2-[(2-Met h ylp h en yl)et h yn yl]-1-cyclop en t en yl]-N′-
p h en ylca r bod iim id e (7a ). The following procedure is rep-
resentative for the preparation of the carbodiimides 7 from
the ureas 16. To a solution of 0.241 g of dibromotriphenylphos-
phorane (0.57 mmol) and 0.115 g of triethylamine (1.14 mmol)
in 10 mL of methylene chloride was added a suspension of
0.090 g of the urea 16a (0.285 mmol) in 5 mL of methylene
chloride over a period of 45 min. After 1 h of stirring at room
temperature, the solvent was removed, and the residue was
taken up with diethyl ether. The diethyl ether solution was
concentrated, and the residue was purified by flash column
chromatography (silica gel/5% diethyl ether in hexanes, Rf )
0.53) to afford 0.072 g of 7a (0.241 mmol, 85% yield) as a yellow
liquid: IR (neat) 2130, 1628, 1593 cm-1; 1H NMR δ 7.31-7.23
(3 H, m), 7.18-7.03 (6 H, m), 2.68-2.57 (4 H, m), 2.43 (3 H,
s), 2.02 (2 H, quintet, J ) 7.5 Hz); 13C NMR δ 141.9, 139.9,
138.4, 134.9, 131.7, 129.3, 129.2, 128.1, 125.4, 125.3, 124.1,
123.0, 113.4, 95.8, 88.2, 34.8, 34.6, 21.2, 20.7.
Eth yl 2-[(2-Meth ylp h en yl)eth yn yl]-1-cyclop en ten eca r -
boxyla te (13a ). The following procedure is representative for
the preparation of the esters 13. To a mixture of the enol
triflate 11 (4.324 g, 15.0 mmol), N,N-diisopropylethylamine
(2.6 mL, 15.0 mmol), Pd(PPh3)2Cl2 (0.316 g, 0.45 mmol), and
copper(I) iodide (0.143 g, 0.75 mmol) in 30 mL of DMF was
added slowly a solution of (2-methylphenyl)acetylene (1.742
g, 15.0 mmol) in 5 mL of DMF. After 2 h of stirring at room
temperature, 50 mL of a saturated aqueous ammonium
chloride solution and 50 mL of diethyl ether were added. The
organic layer was separated, and the aqueous layer was back-
extracted with diethyl ether. The combined organic layers were
washed with brine and water, dried over sodium sulfate, and
concentrated. Purification of the residue by flash column
chromatography (silica gel/5% diethyl ether in hexanes, Rf )
0.33) afforded 3.459 g of 13a (13.6 mmol, 90% yield) as a yellow
1
liquid: IR (neat) 2197, 1700, 757 cm-1; H NMR δ 7.47 (1 H,
d, J ) 7.5 Hz), 7.24-7.11 (3 H, m), 4.27 (2 H, q, J ) 7.1 Hz),
2.76 (4 H, t, J ) 7.7 Hz), 2.50 (3 H, s), 1.96 (2 H, quintet, J )
7.7 Hz), 1.32 (3 H, t, J ) 7.1 Hz); 13C NMR δ 164.5, 140.5,
137.4, 134.2, 132.1, 129.3, 128.7, 125.4, 122.7, 98.6, 89.4, 60.1,
39.4, 33.3, 22.1, 20.5, 14.3; MS m/z 254 (M+), 239, 225, 208.
2-[(2-Met h ylp h en yl)et h yn yl]-1-cyclop en t en eca r b ox-
ylic Acid (14a ). The following procedure is representative for
the hydrolysis of the carboxylic esters 13 to the carboxylic acids
14. A solution of 4.274 g of the ester 13a (16.80 mmol) in 10
mL of THF and 60 mL of a 1 M aqueous sodium hydroxide
solution was heated at 70 °C for 16 h. The reaction mixture
was cooled in an ice-water bath and acidified with a dilute
HCl solution. Filtration afforded 3.634 g of 14a (16.06 mmol,
96% yield) as a white solid: mp 142-143 °C; IR (KBr) 3300-
N-[2-[(2-Met h ylp h en yl)et h yn yl]-1-cyclop en t en yl]-N′-
(p h en ylm eth yl)ca r bod iim id e (19). To a solution of 0.492 g
of N-(triphenylphosphoranylidene)benzylamine (18, 1.34 mmol)
in 20 mL of methylene chloride at -78 °C was added slowly a
solution of 0.276 g of 15a (1.24 mmol) in 5 mL of methylene
chloride. After the reaction mixture was allowed to warm to
room temperature, the solvent was removed in vacuo, and the
residue was purified by flash column chromatography (silica
gel/5% diethyl ether in hexanes, Rf ) 0.30) to afford 0.332 g of
19 (1.06 mmol, 86% yield) as a yellow liquid: IR (neat) 2124,
1
1626, 756 cm-1; H NMR δ 7.41 (1 H, d, J ) 7.5 Hz), 7.37-
7.28 (5 H, m), 7.18 (2 H, d, J ) 3.8 Hz), 7.14-7.07 (1 H, m),
4.50 (2 H, s), 2.58 (2 H, tt, J ) 7.3, 2.2 Hz), 2.44 (3 H, s), 2.42
(2 H, tt, J ) 8.1, 2.0 Hz), 1.94 (2 H, quintet, J ) 7.5 Hz); 13C
NMR δ 143.8, 139.9, 137.6, 137.2, 131.6, 129.3, 128.6, 128.0,
127.7, 127.3, 125.4, 123.3, 111.3, 95.0, 88.6, 50.6, 34.6, 34.5,
21.1, 20.8.
1
2500 (br), 2198, 1655, 759 cm-1; H NMR δ 12.15 (1 H, s br),
7.49 (1 H, d, J ) 7.2 Hz), 7.28-7.12 (3 H, m), 2.81 (4 H, t, J )
7.4 Hz), 2.48 (3 H, s), 2.01 (2 H, quintet, J ) 7.6 Hz); 13C NMR
δ 169.9, 141.0, 137.5, 136.8, 132.3, 129.5, 129.0, 125.5, 122.5,
100.5, 89.2, 39.6, 33.0, 22.2, 20.5; MS m/z 226 (M+), 208, 197.
1-[(2-Isocya n a t o-1-cyclop en t en yl)et h yn yl]-2-m et h yl-
ben zen e (15a ). The following procedure is representative for
the preparation of the isocyanates 15 from the acids 14. To a
solution of 1.253 g of 14a (5.5 mmol) in 40 mL of anhydrous
5,8,9,10-Tetr a h yd r o-6-p h en yl-6H-ben zo[f]cyclop en ta -
[b][1,8]n a p h th yr id in e (21). A solution of 0.072 g of 7a (0.241
mmol) in 5 mL of chlorobenzene was heated under reflux for
10 h. The solvent was then removed in vacuo. Purification of
the residue by flash column chromatography (silica gel/20%
diethyl ether in hexanes, Rf ) 0.30) afforded 0.040 g of 21
(0.0134 mmol, 56% yield) as a yellow solid: IR 1593, 1417 cm-1
;
1H NMR δ 7.85 (1 H, s), 7.72 (1 H, d, J ) 7.5 Hz), 7.39-7.33
(5 H, m), 7.25 (1 H, td, J ) 7.3, 1.1 Hz), 7.15 (1 H, d, J ) 7.3
(23) Bunnett, J . F.; Mitchel, E.; Galli, C. Tetrahedron 1985, 41,
4119-4132.
J . Org. Chem, Vol. 68, No. 14, 2003 5517

Li et al.
Hz), 7.12-7.06 (1 H, m), 4.91 (2 H, s), 2.91 (2 H, t, J ) 7.5
Hz), 2.85 (2 H, t, J ) 7.7 Hz), 2.09 (2 H, quintet, J ) 7.5 Hz);
13C NMR δ 163.9, 153.9, 145.2, 132.1, 131.4, 128.9, 128.4,
127.7, 127.4, 127.2, 125.6, 123.0, 122.2, 116.2, 52.7, 34.4, 30.2,
23.3; MS m/z 298 (M+), 297.
2,3,6,7-Tetr a h yd r o-N-p h en yl-1H-ben zo[f]cyclop en t[c]-
isoqu in olin -5-a m in e (28). The same procedure was repeated
as described for 21 except that 0.132 g of 7c (0.422 mmol) was
used to afford 0.097 g of 28 (0.309 mmol, 73% yield) as a yellow
solid: mp 83-85 °C; IR 3370, 1601, 1578 cm-1; 1H NMR δ 7.73
(1 H, dd, J ) 6.2, 2.3 Hz), 7.38-7.21 (5 H, m), 7.16-7.12 (2 H,
m), 6.91 (1 H, tt, J ) 7.2, 1.2 Hz), 6.24 (1 H, s), 3.23 (2 H, t, J
) 7.1 Hz), 3.00 (2 H, t, J ) 7.5 Hz), 2.82-2.77 (2 H, m), 2.63-
2.58 (2 H, m), 2.14 (2 H, quintet, J ) 7.4 Hz); 13C NMR δ 162.9,
151.3, 142.7, 140.2, 139.0, 133.4, 128.8, 128.4, 127.8, 127.0,
126.4, 126.2, 120.7, 117.8, 117.5, 34.2, 32.6, 28.9, 24.0, 23.4;
MS m/z 312 (M+), 311.
2,3-Dih yd r o-N-p h en yl-1H-ben zofu r o[2,3-d ]cyclop en ta -
[b]p yr id in -5-a m in e (30). The same procedure was repeated
as described for 21 except that 0.127 g of 7d (0.40 mmol) was
used to afford 0.052 g of 30 (0.172 mmol, 43% yield) as brown
crystals: mp 174-175 °C; IR 3431, 1642, 1600 cm-1; 1H NMR
δ 7.59 (1 H, d, J ) 8.1 Hz), 7.51-7.45 (3 H, m), 7.41 (1 H, td,
J ) 7.8, 1.4 Hz), 7.35-7.27 (3 H, m), 7.02 (1 H, t, J ) 7.3 Hz),
6.77 (1 H, s), 3.17 (2 H, t, J ) 7.4 Hz), 3.10 (2 H, t, J ) 7.9
Hz), 2.26 (2 H, quintet, J ) 7.5 Hz); 13C NMR δ 163.5, 159.8,
155.2, 149.9, 141.0, 129.1, 126.0, 123.3, 122.1, 121.9, 121.0,
118.7, 112.9, 111.4, 105.9, 34.9, 27.1, 23.2; MS m/z 300 (M+),
299. The structure of 30 was established by X-ray structure
analysis.
column chromatography (silica gel) to afford 0.075 g of 32 (0.24
mmol, 70%) and 0.016 g of 34 (0.049 mmol, 14%).
2-P yr id on e Im in e 37. A solution of 0.0722 g of 7e (0.22
mmol) and 0.188 g of dimethylphenylsilyl chloride (1.1 mmol)
in 8 mL of chlorobenzene was heated under reflux at 132 °C
for 3 h. A yellow solid appeared as the reaction mixture was
allowed to cool to room temperature. Suction filtration gave
0.0593 g of 37 (0.189 mmol, 86%) as a yellow solid: mp 268-
270 °C dec without melting; IR (KBr) 3418, 1634, 756 cm-1
;
1H NMR δ 10.02 (1 H, s), 7.43 (2 H, d, J ) 3.8 Hz), 7.25 (2 H,
t, J ) 7.5 Hz), 7.14 (1 H, t, J ) 7.4 Hz), 7.05-6.94 (3 H, m),
6.43 (1 H, d, J ) 8.1 Hz), 4.09 (3 H, s), 3.46 (2 H, t, J ) 7.3
Hz), 3.32 (2 H, t, J ) 7.8 Hz), 2.40 (2 H, quintet, J ) 7.6 Hz);
13C NMR δ 149.1, 146.4, 146.3, 140.6, 138.7, 129.4, 126.5,
124.9, 124.7, 122.0, 121.5, 120.5, 112.8, 109.2, 105.0, 31.3, 30.7,
29.8, 23.1; MS m/z 313 (M+), 312.
To a solution of 8.2 mg of 37 in 4 mL of methylene chloride
was added a small amount of silica gel. After 5 h, silica gel
was removed by filtration, and the filtrate was pumped to
dryness in vacuo to give 8.0 mg of 32 (98%). The 1H NMR
spectrum indicates that the product was essentially pure
without the need for further purification.
1,2,4,6,7,8-H e xa h yd r o-1-[2-(2-p r op e n yloxy)p h e n yl]-
cyclop en t a [1′,2′:5,6]p yr id o[2,3-d ][1,3]oxa zin e (45) a n d
6a ,7,8,10,11,12-H exa h yd r o-6H -cyclop en t a [1′,2′:6,7][1,8]-
n a p h th yr id in o[2,1-c][1,4]ben zoxa zin e (47). A solution of
0.086 g of 42 (0.278 mmol) in 10 mL of chlorobenzene was
heated under reflux for 8 h. The solvent was then removed in
vacuo. The residue was purified by flash column chromatog-
raphy to afford 0.042 g of 45 (0.136 mmol, 49% yield) as a light
yellow oil and 0.023 g of 47 (0.083 mmol, 30% yield) as a pale
yellow oil. Com p ou n d 45: IR 1608, 1573, 1425 cm-1; 1H NMR
δ 7.19 (1 H, dd, J ) 8.2, 1.5 Hz), 7.16-7.09 (1 H, m), 7.08 (1
H, s), 6.96-6.90 (2 H, m), 5.93 (1 H, ddt, J ) 17.2, 10.5, 5.3
Hz), 5.29 (1 H, dq, J ) 17.3, 1.6 Hz), 5.17 (1 H, dq, J ) 10.6,
1.4 Hz), 5.06 (2 H, s), 4.91 (2 H, s), 4.52 (2 H, dt, J ) 5.0, 1.6
Hz), 2.82 (2 H, t, J ) 7.3 Hz), 2.80 (2 H, t, J ) 7.5 Hz), 2.03 (2
H, quintet, J ) 7.5 Hz); 13C NMR δ 162.7, 153.4, 152.3, 134.2,
133.3, 128.9, 128.2, 127.7, 126.0, 121.1, 116.8, 115.0, 113.9,
81.8, 69.1, 67.7, 34.2, 30.0, 23.2; MS m/z 308 (M+), 293, 277.
1,2,3,10-Tet r a h yd r o-10-m et h yl-N-p h en ylcyclop en t a -
[1′,2′:5,6]p yr id o[4,3-b]in d ol-5-a m in e (32), 2-(1,2,3,4-Tetr a -
h yd r ocyclop en t a [1′,2′:4,5]p yr r olo[2,3-b]q u in olin -10-yl)-
N,N-dim eth ylben zen am in e (34), an d 2-(1,2,3,4-Tetr ah ydr o-
4-m et h ylcyclop en t a [1′,2′:4,5]p yr r olo[2,3-b]q u in olin -10-
yl)-N,N-d im eth ylben zen a m in e (35). The same procedure
was repeated as described for 21 except that 0.073 g of 7e (0.22
mmol) was used to afford 0.010 g of 32 (0.03 mmol, 14% yield)
as a brown solid, 0.035 g of 34 (0.107 mmol, 48%) as brown
crystals, and 0.005 g of 35 (0.015 mmol, 7%) as a brown solid.
Compound 32: mp 177-178 °C; IR 3460, 1601, 1574 cm-1; 1H
NMR δ 7.78 (1 H, d, J ) 7.7 Hz), 7.55 (2 H, d, J ) 7.7 Hz),
7.48-7.39 (2 H, m), 7.34-7.23 (3 H, m), 6.97 (1 H, t, J ) 7.3
Hz), 6.87 (1 H, s br), 4.01 (3 H, s), 3.41 (2 H, t, J ) 7.3 Hz),
3.09 (2 H, t, J ) 7.7 Hz), 2.26 (2 H, quintet, J ) 7.5 Hz); 13C
NMR δ 159.5, 149.6, 144.6, 141.4, 140.3, 129.0, 124.6, 121.5,
121.2, 120.8, 120.3, 118.6, 110.7, 108.6, 104.5, 34.1, 30.8, 29.5,
23.1; MS m/z 313 (M+), 312. Com p ou n d 34: mp 260-261 °C
1
Com p ou n d 47: IR 1571, 1494, 1420 cm-1; H NMR δ 7.98-
7.91 (1 H, m), 7.16 (1 H, s), 6.90-6.82 (3 H, m), 4.44 (1 H, dd,
J ) 10.2, 1.9 Hz), 3.95 (1 H, t, J ) 9.8 Hz), 3.87-3.76 (1 H,
m), 2.92 (2 H, t, J ) 7.2 Hz), 2.82 (2 H, t, J ) 7.3 Hz), 2.72 (2
H, tt, J ) 15.2, 3.9 Hz), 2.28-2.19 (1 H, m), 2.08 (2 H, quintet,
J ) 7.5 Hz), 1.46 (1 H, qd, J ) 12.3, 4.8 Hz); 13C NMR δ 161.2,
151.1, 145.9, 132.3, 128.2, 127.7, 122.2, 121.2, 120.0, 118.8,
116.9, 70.3, 53.3, 34.2, 30.1, 26.3, 25.1, 23.3; MS m/z 278 (M+),
277.
1
dec; IR 3149, 758, 732 cm-1; H NMR δ 11.8 (1 H, s br), 8.11
(1 H, d, J ) 8.2 Hz), 7.82 (1 H, dd, J ) 8.5, 1.4 Hz), 7.62 (1 H,
ddd, J ) 8.5, 6.9, 1.5 Hz), 7.43 (1 H, ddd, J ) 8.4, 7.2, 1.7 Hz),
7.33 (1 H, ddd, J ) 8.3, 6.9, 1.1 Hz), 7.22 (1 H, dd, J ) 7.4, 1.7
Hz), 7.14 (1 H, d, J ) 8.2 Hz), 7.05 (1 H, td, J ) 7.3, 1.0 Hz),
3.14-3.07 (2 H, m), 2.49-2.37 (10 H, m); 13C NMR δ 154.6,
152.4, 148.7, 143.2, 138.2, 132.9, 128.9, 128.4, 127.1, 126.6,
126.4, 122.9, 122.6, 120.1, 119.1, 117.1, 43.2, 27.6, 26.8, 25.4;
MS m/z 327 (M+), 312, 298. Com p ou n d 35: mp 130-131 °C;
IR 1594, 1446, 758 cm-1; 1H NMR δ 8.15 (1 H, d, J ) 8.5 Hz),
7.77 (1 H, dd, J ) 8.5, 1.2 Hz), 7.58 (1 H, ddd, J ) 8.4, 6.8, 1.4
Hz), 7.40 (1 H, ddd, J ) 8.4, 7.2, 1.7 Hz), 7.29 (1 H, ddd, J )
8.5, 7.0, 1.2 Hz), 7.18 (1 H, dd, J ) 7.5, 1.8 Hz), 7.12 (1 H, d,
J ) 7.5 Hz), 7.02 (1 H, td, J ) 7.4, 1.1 Hz), 3.90 (3 H, m),
2.98-2.91 (2 H, m), 2.44-2.33 (4 H, m), 2.41 (6 H, s); 13C NMR
δ 153.4, 152.4, 150.7, 144.0, 137.6, 132.9, 128.74, 128.68, 127.6,
126.7, 126.4, 122.8, 122.4, 120.1, 118.3, 117.0, 115.0, 43.1, 29.6,
27.0, 25.65, 25.61; MS m/z 341 (M+), 326, 312. The structures
of 32 and 34 were established by X-ray structure analysis.
A solution of 7e (0.112 g, 0.342 mmol) and dimethylphenyl-
silyl chloride (0.070 g, 0.41 mmol) in 10 mL of chlorobenzene
was heated under reflux at 132 °C for 3 h. After the reaction
mixture was allowed to cool to room temperature, the solvent
was removed in vacuo. The residue was purified by flash
Ack n ow led gm en t. The financial support of the
National Science Foundation (CHE-9618676) to K.K.W.
is gratefully acknowledged. J .L.P. acknowledges the
support (CHE-9120098) provided by the Chemical In-
strumentation Program of the National Science Foun-
dation for the acquisition of a Siemens P4 X-ray
diffractometer in the Department of Chemistry at West
Virginia University.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for N,N-dimethyl-2-[(trimeth-
ylsilyl)ethynyl]aniline, 7b-e, 12e, 13b-f, 14b-f, 15b-f, 16b-
e, 24-26, 41, and 42; 1H and 13C NMR spectra for N,N-
dimethyl-2-[(trimethylsilyl)ethynyl]aniline, 7a -e, 12e, 13a -
f, 14a -f, 15a -f, 16a -e, 19, 21, 22, 24-26, 28, 30, 32, 34, 35,
37, 41, 42, 45, and 47; and ORTEP drawings and tables of
crystallographic data for the X-ray diffraction analyses of 30,
32, and 34. This material is available free of charge via the
Internet at http://pubs.acs.org.
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