Aryl Radical Endo Cyclization of Enamidines. Selective Preparation of Trans and Cis Fused Octahydrobenzo[f]quinolines

Article abstract of DOI:10.1021/jo971158d

Aryl radicals from N-protected 6-[2-(2-halophenyl)ethyl]-1,2,3,4-tetrahydropyridines and 6-[3-(2-halophenyl)propyl]-1,2,3,4-tetrahydropyridines undergo intramolecular cyclization onto the enamide/ enamidine double bond by 6-endo and 7-endo closure, respectively. In the 6-endo cyclization the trans/cis ratio of the formed N-protected octahydrobenzo[f]quinoline can be controlled, and selective synthesis of either the trans or the cis isomer can be achieved with triphenyltin hydride and tris(trimethylsilyl)silicon hydride, respectively. In the 7-endo cyclization to N-protected octahydro-1H-benzo[3,4]cyclohepta[1,2-b]pyridine, the trans fused isomer predominates, although the selectivity is low. The oxidized cyclization products, with a restored enamide/enamidine double bond, are formed at low concentrations of tris(trimethylsilyl)silicon hydride.

Full text of DOI:10.1021/jo971158d

84
J . Org. Chem. 1998, 63, 84-91
Ar yl Ra d ica l En d o Cycliza tion of En a m id in es. Selective
P r ep a r a tion of Tr a n s a n d Cis F u sed Octa h yd r oben zo[f]qu in olin es
Lena Ripa and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University,
Box 574, SE-751 23 Uppsala, Sweden
Received J une 25, 1997X
Aryl radicals from N-protected 6-[2-(2-halophenyl)ethyl]-1,2,3,4-tetrahydropyridines and 6-[3-(2-
halophenyl)propyl]-1,2,3,4-tetrahydropyridines undergo intramolecular cyclization onto the enamide/
enamidine double bond by 6-endo and 7-endo closure, respectively. In the 6-endo cyclization the
trans/cis ratio of the formed N-protected octahydrobenzo[f]quinoline can be controlled, and selective
synthesis of either the trans or the cis isomer can be achieved with triphenyltin hydride and tris-
(trimethylsilyl)silicon hydride, respectively. In the 7-endo cyclization to N-protected octahydro-
1H-benzo[3,4]cyclohepta[1,2-b]pyridine, the trans fused isomer predominates, although the selec-
tivity is low. The oxidized cyclization products, with a restored enamide/enamidine double bond,
are formed at low concentrations of tris(trimethylsilyl)silicon hydride.
In tr od u ction
Radical cyclization of 5-hexenyl and 6-heptenyl radicals
occurs normally with a preference for exo cyclization.1
Functional groups that allow the intermediate radical to
be stabilized frequently alter the exo/endo cyclization
ratio. Several examples of 5-hexenyl and 6-heptenyl type
radical cyclizations onto an enamide or enamine double
bond where the regioselectivity of the cyclization is
influenced not only by the nitrogen atom but also by a
second stabilizing group have been reported.2 Rigby3 and
Schults4 have conducted selective 6-endo and 7-endo
cyclizations of aryl radicals onto hydroindole and hydro-
quinoline enamide systems. To our knowledge, all
reported alkyl and aryl radical cyclizations onto cyclic
enamides and enamines result in the formation of
heterocycles comprising the nitrogen atom in the new
ring formed (type I, Figure 1).
We herein report a radical endo cyclization where a
carbocycle is created (type II) and demonstrate that for
the 6-endo cyclization proper selection of reaction condi-
tions allows the isolation in fair yields of either (a) the
trans fused product, (b) the cis fused product, or (c) the
oxidatively cyclized product. The Heck reaction using the
same precursors has been shown to provide the exo
cyclized products exclusively.5
F igu r e 1.
was conducted in toluene at -20 °C with triphenyltin
hydride and with triethylborane as initiator [condition
A: [R3MH]0 ) 0.03 M (1.5 equiv), Et3B6 (1.0 equiv)]. The
amidine 5a was further converted to the secondary amine
(2) For examples where the nitrogen and the second radical stabiliz-
ing group cooperate, see: (a) Colombo, L.; Di Giacomo, M.; Papeo, G.;
Carugo, O.; Scolastico, C.; Manzoni, L. Tetrahedron Lett. 1994, 35,
4031-4034. (b) Colombo, L.; Di Giacomo, M.; Scolastico, C.; Manzoni,
L.; Belvisi, L.; Molteni, V. Tetrahedron Lett. 1995, 36, 625-628. (c)
Fang, J .-M.; Chang, H.-T.; Lin, C.-C. J . Chem. Soc. Chem. Commun.
1988, 1385-1388. (d) Fidalgo, J .; Castedo, L.; Dom´ınguez, D. Tetra-
hedron Lett. 1993, 34, 7317-7318. (e) Pigeon, P.; Decroix, B. Tetra-
hedron Lett. 1996, 37, 7707-7710. (f) Rigby, J . H.; Qabar, M. J . Am.
Chem. Soc. 1991, 113, 8975-8976. (g) Rigby, J . H.; Qabar, M. N. J .
Org. Chem. 1993, 58, 4473-4475. (h) Rodr´ıgues, G.; Cid, M. M.; Saa´,
C.; Castedo, L.; Dom´ınguez, D. J . Org. Chem. 1996, 61, 2780-2782.
(i) Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1990, 31, 1151-
1156. (j) Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Tetrahedron
Lett. 1990, 31, 2315-2318. (k) Yang, C.-C.; Fang, J .-M. J . Chem. Soc.,
Perkin Trans. 1 1995, 879-887. For examples of cyclizations where
the directing effect of the nitrogen and the second stabilizing group
counteracts, see ref 2b and the following: (l) Beckwith, A. L. J .;
Westwood, S. W. Tetrahedron 1989, 45, 5269-5282. (m) Beckwith, A.
L. J .; J oseph, S. P.; Mayadunne, R. T. A. J . Org. Chem. 1993, 58, 4198-
4199. (n) Cladingboel, D. E.; Parsons, P. J . J . Chem. Soc. Chem.
Commun. 1990, 1543-1544. (o) Ishibashi, H.; Kawanami, H.; Iriyama,
H.; Ikeda, M. Tetrahedron Lett. 1995, 36, 6733-6734. (p) Ishibashi,
H.; Kawanami, H.; Ikeda, M. J . Chem. Soc., Perkin Trans. 1 1997,
817-821. (q) Lee, E.; Li, K. S.; Lim, J . Tetrahedron Lett. 1996, 37,
1445-1446. (r) Parker, K. A.; Fokas, D. J . Org. Chem. 1994, 59, 3927-
3932. (s) O¨ zlu¨, Y.; Cladingboel, D. E.; Parsons, P. J . Tetrahedron 1994,
50, 2183-2206. See also: (t) Glover, S. A.; Warkentin, J . J . Org. Chem.
1993, 58, 2115-2121. (u) Okano, T.; Sakaida, T.; Eguchi, S. J . Org.
Chem. 1996, 61, 8826-8830.
Resu lts
6-En d o Cycliza tion s. The results are summarized
in Schemes 1 and 2 and in Table 1. In a preparative
experiment the trans fused product 5a was isolated in
61% yield from the aryl iodide 1 (Scheme 1). The reaction
X Abstract published in Advance ACS Abstracts, December 15, 1997.
(1) For selected general reviews and books, see: (a) Curran, D. P.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Lonon, 1991; Vol. 4; pp 779-831. (b) Curran, D. P.;
Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH:
Weinheim, 1996. (c) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J .;
Thoma, G.; Kulicke, K. J .; Trach, F. Org. React. 1996, 48, 301-856.
(d) J asperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91,
1237-1286. (e) Motherwell, M. B., Crich, D. In Best Synthetic Methods,
Free Radical Chain Reactions in Organic Synthesis, Academic Press:
London, 1991.
(3) Rigby, J . H.; Mateo, M. E. Tetrahedron 1996, 52, 10569-10582.
(4) (a) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J . Am. Chem.
Soc. 1993, 115, 7904-7905. (b) Schultz, A. G.; Guzzo, P. R.; Nowak,
D. M. J . Org. Chem. 1995, 60, 8044-8050. (c) Schultz, A. G.; Holoboski,
M. A.; Smyth, M. S. J . Am. Chem. Soc. 1996, 118, 6210-6219.
(5) (a) Ripa, L.; Hallberg, A. J . Org. Chem. 1996, 61, 7147-7155.
(b) Ripa, L.; Hallberg, A. J . Org. Chem. 1997, 62, 595-602.
S0022-3263(97)01158-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

Aryl Radical Endo Cyclization of Enamidines
J . Org. Chem., Vol. 63, No. 1, 1998 85
Ta ble 1. P r od u ct Distr ibu tion in Ra d ica l Cycliza tion Rea ction s of 1-4
ratio of cyclized productsb
trans/cis endo/exo red/ox
cyclization
products
dehalogenate
product
cyclization
dehalogenation % yield
entry
R
R3MH
conda temp, °C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
1
1
1
1
1
2a
2a
2a
2b
2b
2b
3
4a
4a
4a
4b
TBF Ph3SnH
Ph3SnH
Ac
A
A
B
D
D
B
B
C
B
B
C
D
B
B
Cg
B
-20
20
85
85
85
85
85
85
100
85
85
100
85
85
85
5a +7a
12:1
6:1
5:1
3:1
1:2
3.8:1
2.3:1
2.4:1
1:5.5
3:1
84d
76d
85d
74d
81d
77d
85d
74d
77d
76e
39e
31e
59e
5a +7a
Ph3SnH
Ph3SnH
TMS3SiH
Bu3SnH
5a +7a
5a +7a
5a +7a +11a
5a +7a
5a +7a +9a
5a +7a +9a
5a +7a +11a
5b+7b+9b
5b+7b+9b
5b+7b+11b
12a
1:15
TBF Ph3SnH
Bu3SnH
TMS3SiH
CHO Ph3SnH
Bu3SnH
49:1
99:1
12:1
5:1
24:1
32:1
9:1
1:5
TMS3SiH
TBF TMS3SiH
TBF Bu3SnH
Ph3SnH
TMS3SiH
CHO Bu3SnH
6a +8a
6a +8a
6a +8a +12a
6b+8b
2:1f
2:1f
4:1f
1:1
13a
13a
13a
13b
3:1
2:1
9:1
1.2:1
99d
82d
81d
56e
100
85
6.5:1
a
Conditions: A ) [R3MH]0 ) 0.03 M (1.5 equiv), Et3B (1.0 equiv); B ) [R3MH]0 ) 0.03 M (1.5 equiv), AIBN (0.1 equiv); C ) [R3MH]0
b
) 0.2 M (2.0 equiv), AIBN (0.3 equiv); D ) [R3MH]0 ) 0.004 (1.2 equiv), AIBN (1.0 equiv). Reactions were run overnight; see ref 41. The
isomer ratio was determined by GLC-MS, and the response factors for the isomers were assumed to be identical. When nothing is denoted,
the amount was below the detection limit. c Toluene was used as solvent. Isolated combined yield after acid/base extraction. e Isolated
d
combined yield after chromatography. f The 6a /8a ratio was determined by GLC-MS after hydrazinolysis to the secondary amines 16
g
and 17. One equivalent of AIBN was used.
Sch em e 1
Sch em e 2
temperature (cf. entries 1-3). Reactions at the same
temperature (85 °C) revealed that triethylborane, as
(6) Triethylborane is known to initiate radical reactions at low
temperatures: (a) Nozaki, K.; Oshima, K.; Utimoto, K. J . Am. Chem.
Soc. 1987, 109, 2547-2549. (b) Miura, K.; Ichinose, Y.; Nozaki, K.;
Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. J pn. 1989, 62,
143-147. See also: (c) Brown, H. C.; Midland, M. M. Angew. Chem.,
Int. Ed. Engl. 1972, 11, 692-700.
14 by hydrazinolysis in 65% yield. An inferior trans/cis
ratio was encountered after increasing the reaction

86 J . Org. Chem., Vol. 63, No. 1, 1998
Ripa and Hallberg
compared to azobisisobutyronitrile (AIBN), as initiator
provided a better trans/cis ratio (cf. entries 3 and 4). The
corresponding aryl bromide 2a was not suitable as a
precursor for the trans product 5a since 2a remained
intact at the low temperatures required for fair trans/
cis selectivity.7 With AIBN as initiator [condition B: [R3-
MH]0 ) 0.03 M (1.5 equiv), AIBN (0.1 equiv)] at 85 °C
the aryl bromide 2a , as compared to the aryl iodide 1,
tended to provide more of the cis compound, with a minor
amount of the spiro compound 9a also formed (cf. entries
4 and 7). Substitution of triphenyltin hydride for tribu-
tyltin hydride (entry 8) or an alteration of the hydride
concentration (0.15 or 0.06 M) had no significant effect
on the product ratio. Cyclization of the aryl bromide 2b
(enamide instead of enamidine) employing triphenyltin
hydride (condition B) resulted in a similar outcome as
with the aryl bromide 2a (entry 10). However, a com-
bination of 2b and tributyltin hydride delivered a higher
trans/cis ratio (9:1), although the isolated yield was low
(entry 11).
The cis fused amidine 7a could be prepared in 46%
yield, after chromatography, by cyclization of 2a in the
presence of tris(trimethylsilyl)silicon hydride8 [condition
C: [R3MH]0 ) 0.2 M (2.0 equiv), AIBN (0.3 equiv)] at 100
°C. Subsequent hydrazinolysis of 7a gave the secondary
amine 15 in 79% yield (Scheme 1). The silicon hydride
provided a reversed trans/cis ratio with the cis product
predominant. In all experiments performed with tris-
(trimethylsilyl)silicon hydride, a varying amount of the
oxidized9 product 11a was obtained, but the formation
of this product could be suppressed by using a high
concentration2d of the silicon hydride (entry 9). A similar
product distribution with preference for the cis fused
isomer was obtained after cyclization of the enamide 2b
in the presence of tris(trimethylsilyl)silicon hydride,
although the yield was low in this case (entry 12).10
The preparation of the amidine 11a was accomplished
by refluxing the aryl iodide 1 in the presence of a low
concentration of tris(trimethylsilyl)silicon hydride [condi-
tion D: [R3MH]0 ) 0.004 M (1.2 equiv), AIBN (1.0 equiv)]
and 1 equiv of AIBN. A 67% yield of 11a was isolated
(Scheme 1 and entry 5). No consumption of the starting
material was observed in the absence of silicon hydride,
and a catalytic amount of tris(trimethylsilyl)silicon hy-
dride (0.1 equiv) caused decomposition of the starting
material as deduced from GC-MS. Attempts to improve
the yield by either employing a smaller amount of AIBN
or by adding tris(trimethylsilyl)silicon hydride and AIBN
slowly with a syringe pump met with no success. Fur-
thermore, substitution of the tris(trimethylsilyl)silicon
hydride for tributyltin hydride, under otherwise identical
conditions, led exclusively to the formation of the trans
and cis fused products (cf. entries 5 and 6). The aryl
bromide 2a was not prone to react under the conditions
where the corresponding aryl iodide 1 reacted smoothly.
isolated as a mixture of 6a and 8a together with the
dehalogenated uncyclized product 13a in a quantitative
yield (Scheme 2). Subsequent hydrazinolysis provided
the trans and cis fused secondary amines, 16 and 17,
which were isolated in 29% and 14% yield, respectively.
Attempts to minimize the dehalogenation by slow addi-
tion of tributyltin hydride and AIBN resulted in only
minor improvements and with lower yields. A more
prevailed dehalogenation was observed with triphenyltin
hydride as compared to tributyltin hydride (entry 15),
and a combination of triethylborane and aryl iodide 3
(condition A) led to an incomplete conversion and a more
predominant formation of 13a . Tris(trimethylsilyl)silicon
hydride as radical chain carrier (condition C) suppressed
the formation of 13a but led to formation of the oxidized
product 12a in a low yield (entry 16). Cyclization of the
enamide 4b under condition B delivered an inferior
cyclization/dehalogenation ratio (cf. entries 14 and 17).
Cyclization of enamidine 3 in the presence of tris-
(trimethylsilyl)silicon hydride at low concentration (con-
dition D) proceeded smoothly and the enamidine 12a was
isolated in 59% yield (Scheme 2 and entry 13).
Attem p ted 5-En d o Cycliza tion s. Attempts to cy-
clize the aryl iodide 21 in a disfavored 5-endo11 mode,
with tributyltin hydride (condition B), led only to the
dehalogenated starting material.12 Lowering the tribut-
yltin hydride concentration by a syringe pump technique
or employing tris(trimethylsilyl)silicon hydride resulted
in incomplete conversion and no cyclized products.13
Deter m in a tion of th e Rela tive Con figu r a tion .
The stereochemical assignments of the trans and cis
1
fused cyclization products are based on H and 13C NMR
analysis in CDCl3 and in CD3OD. The cis-octahydroben-
zo[f]quinoline system is reported to exist in two inter-
convertible conformations,14 both of which have the
angular proton H-4a in a syn-relationship with respect
to the nitrogen lone pair. The rigid trans-octahydroben-
zo[f]quinoline system conversely has the angular proton
H-4a in an anti position with respect to the nitrogen lone
pair. This results in deshielding of the H-4a proton in
compound 15 as compared to the H-4a proton in 14, due
to the shielding effect of the nitrogen lone pair.15 To
confirm the stereochemical assignments, compounds 14
and 15 were converted to their N-benzylated deriva-
(11) For examples of disfavored 5-endo cyclization onto enamides
by carbamoylmethyl radicals, see: (a) Goodall, K.; Parsons, A. F. J .
Chem. Soc., Perkin Trans. 1 1994, 3257-3259. (b) Ishibashi, H.;
Nakamura, N.; Sato, T.; Takeuchi, M.; Ikeda, M. Tetrahedron Lett.
1991, 32, 1725-1728. (c) Ishibashi, H.; Fuke, Y.; Yamashita, T.; Ikeda,
M. Tetrahedron: Asymmetry 1996, 7, 2531-2538. (d) Sato, T.; Machi-
gashira, N.; Ishibashi, H.; Ikeda, M. Heterocycles 1992, 33, 139-142.
(e) Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi, H.; Ikeda,
M. J . Chem. Soc., Perkin Trans. 1 1992, 2399-2407. (f) Sato, T.; Chono,
N.; Ishibashi, H.; Ikeda, M. J . Chem. Soc., Perkin Trans. 1 1995, 1115-
1120. See also ref 4b.
(12) Spectroscopic data was consistent with data described else-
where: Meyers, A. I.; Edwards, P. D.; Bailey, T. R.; J agdmann, G. E.
J . J . Org. Chem. 1985, 50, 1019-1026.
(13) Ikeda and co-workers have shown that the cyclization does not
occur unless a carbonyl group is incorporated in the new ring formed;
see refs 11b and 11d.
(14) (a) Cannon, J . G.; Hatheway, G. J .; Long, J . P.; Sharabi, F. M.
J . Med. Chem. 1976, 19, 987-993. (b) Cannon, J . G.; Suarez-Gutierrez,
C.; Lee, T.; Long, J . P.; Costall, B.; Fortune, D. H.; Naylor, R. J . J .
Med. Chem. 1979, 22, 341-347. (c) Cannon, J . G. Adv. Biosci. 1979,
20 (Peipher. Dopaminergic Recept.), 87-94.
(15) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine. Structure, Prepa-
ration, Reactivity, and Synthetic Applications of Piperidine and its
Derivatives; Studies in Organic Chemistry 43; Elsevier: Amsterdam,
1991.
7-En d o Cycliza tion s. Cyclization of 4a under the
conditions A, B, or C furnished either no or low trans/cis
selectivity (entries 14-16). With tributyltin hydride
under condition B the 7-endo cyclized product was
(7) Even at 85 °C the starting material remained intact. See also
ref 6b.
(8) Chatgilialoglu, C. Acc. Chem. Res 1992, 25, 188-194.
(9) Bowman, R. W.; Heaney, H.; J ordan, B. M. Tetrahedron 1991,
47, 10119-10128. See also refs 2d and 3.
(10) The structure of compound 11b was confirmed by comparison
(GC-MS) with a hydrolyzed (KOH, MeOH/H2O) sample of 11a .

Aryl Radical Endo Cyclization of Enamidines
J . Org. Chem., Vol. 63, No. 1, 1998 87
Sch em e 3
F igu r e 2.
consecutive exo cyclization and neophyl rearrangement.20
The ratio of endo/exo cyclization was not affected by the
hydride concentration, suggesting that the former process
is operating.21 The trans fused product 5a should be
obtained after an axial hydrogen abstraction by the
postcyclization radical22 (Figure 2) which is anticipated
to be slightly pyramidalized.23 The unpaired electron
involved in forming the new bond and the electron pair
at the nitrogen atom remain in one plane so that a
stabilizing interaction can occur. An axial attack at the
stabilized radical is favored,24 and a â-face selective
abstraction of hydrogen from the tin hydrides proceeds.
However, with the bulkier silicon hydride an approach
from the axial direction seems less attractive due to 1,3-
steric repulsions, as deduced from an analysis of molec-
ular models. The barrier to inversion is low and an
equatorial attack by the silicon hydride at the less
hindered R-face appears more favorable,25 eventually
leading to the cis fused product 7a .
tives.16 The N-benzyl methylene protons of the trans
isomer gave rise to a pair of doublets, while the corre-
sponding protons in the cis isomer appeared as a sin-
glet.17
For the trans- and cis-octahydro-1H-benzo[3,4]cyclo-
hepta[1,2-b]pyridine system, molecular mechanics cal-
culations18 revealed one low-energy conformation (within
2.6 kcal/mol) for the cis fused ring system 17 having the
H-4a proton in a syn relationship to the nitrogen lone
pair and five low-energy conformations (within 4.2 kcal/
mol) for the trans fused 16 all having the H-4a proton
anti with respect to the nitrogen lone pair. This is
consistent with the observation that the H-4a proton in
compound 16 resonates at a higher field than the
corresponding proton in 17.
Syn th esis of P r ecu r sor s. Compounds 1 and 3 were
prepared as described earlier.5a In an analogous reaction
sequence, the amidines 2a , 4a , and 21 were prepared by
lithiation and alkylation19 of N-(N′-tert-butylformim-
idoyl)-1,2,3,4-tetrahydropyridine12 with the corresponding
2-halophenyl alkyl halides in 48%, 72%, and 58% yield,
respectively (Scheme 3). Subsequent hydrolysis5b of the
enamidines 2a and 4a afforded the enamides 2b and 4b
in 65% and 75% yield, respectively.
With the more flexible seven-membered cyclic system,
although the selectivities are low, all hydride reagents
preferentially attack at the â-face. This preference
should be attributed to stereoelectronic factors, but no
simple explanation is apparent to us, which explains the
relatively low trans/cis selectivity encountered.26 The
large amount of dehalogenated product in the cyclization
of 4a , as compared to cyclization of 2, also at low hydride
concentrations, originates mainly from a competing in-
tramolecular 1,5-hydride shift, delivering a stabilized
allylic radical.27 An experiment with tributyltin deu-
teride clearly demonstrated that the 1,5-hydride shift was
the dominating reduction mechanism.
Discu ssion
The R-nitrogen radical is derived either from a direct
endo cyclization of the aryl radical or alternatively from
(20) The latter process has recently been discussed as a possible
mechanism for endo cyclization of aryl radicals onto enamides; see ref
2p.
(21) (a) Abeywickrema, A. N.; Beckwith, A. L. J .; Gerba, S. J . Org.
Chem. 1987, 52, 4072-4078. (b) Parker, K. A.; Spero, D. M.; Inman,
K. C. Tetrahedron Lett. 1986, 27, 2833-2836.
(22) The R-nitrogen radical may be sufficiently persistent to relax,
prior to hydrogen abstraction, to the configurationally more stable
chair-chair structure with the aryl group in equatorial position; see
ref 2g for an example.
(23) Structural studies of R-aminoalkyl radicals give contradictory
results, see: Renaud, P.; Giraud, L. Synthesis 1996, 913-926.
(24) (a) Crich, D.; Lim, L. B. L. J . Chem. Soc., Perkin Trans. 1 1991,
2205-2208. (b) Giese, B. Angew. Chem., Int. Ed. Engl. 1989, 28, 969-
1146. (c) Korth, H.-G.; Sustmann, R.; Giese, B.; Ru¨ckert, B.; Gro¨ninger,
K. S. Chem. Ber. 1990, 123, 1891-1898. (d) Renaud, P. Helv. Chim.
Acta 1991, 74, 1305-1313.
(25) The trans/cis ratio for the reduction of the bridgehead octahy-
dronaphthalene radical is reported to depend on the size of the
hydrogen atom donor, giving more cis fused product with bulkier
hydrogen donors. Beckwith, A. L. J .; Gream, G. E.; Struble, D. L. Aust.
J . Chem. 1972, 25, 1081-1105.
(26) Compare with: (a) Ghosh, A. K.; Ghosh, K.; Pal, S.; Ghatak,
U. R. J . Chem. Soc. Chem. Commun. 1993, 809-811, 1176. (b) Pal, S.;
Mukhopadhyaya, J . K.; Ghatak, U. R. J . Org. Chem. 1994, 59, 2687-
2694.
(16) The secondary amines were stirrred with K2CO3 (2.6 equiv) and
benzyl bromide (1.0 equiv) in acetonitrile under argon.
(17) (a) Cannon, J . G.; Koble-Suarez, C.; Long, J . P.; Ilhan, M.;
Bhatnagar, R. K. J . Pharm. Sci. 1985, 74, 672-675. (b) Cannon, J .
G.; Kirschbaum, K. S. Synthesis 1993, 1151-1154. (c) Walsh, D. A.;
Smissman, E. E. J . Org. Chem. 1974, 39, 3705-3708.
(18) The calculations of model compounds 16 an 17 were performed
using the MM2* force as implemented in the program Macromodel
version 5.5. (a) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson,
T. J . Am. Chem. Soc. 1990, 112, 6127-6129. The general born solvent
accessible surface area (GB/SA) method for CHCl3 developed by Still
was used in the calculations. (b) Mohamadi, F.; Richards, N. G. J .;
Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J . Comput. Chem. 1990, 11, 440-467.
The number of torsion angles allowed to vary simultaneously during
each Monte Carlo step ranged from one to four. Conformational
searches was conducted by use of the systematic unbound multiple
minimum search (SUMM) method in the batchmin program (command
SSPMC). (c) Goodman, J . M.; Still, W. C. J . Comput. Chem. 1991, 12,
1110-1117. 5000-step runs were performed, and those conformations
within 50 kJ /mol of the global minimum were kept.
(19) When 2-(2′-bromophenyl)ethyl iodide was used as alkylating
agent, the vinyllithium was treated with pentynylcopper prior to
alkylation to avoid competing elimination; see ref 5a.

88 J . Org. Chem., Vol. 63, No. 1, 1998
Ripa and Hallberg
described elsewhere,34 and only previously unreported data are
given here. 2-Iodobenzyl bromide 2032a was synthesized from
2-iodobenzyl alcohol (Aldrich) as described elsewhere.35 2-(2′-
Bromophenyl)ethyl mesylate36 is a known compounds, and only
previously unreported data are given here. N-(N′-tert-Butyl-
formimidoyl)-1,2,3,4-tetrahydropyridine was prepared as de-
scribed previously.5a,12 Pentynylcopper was prepared from
pentyne and CuI.37 All other reagents were obtained from
commercial sources and used as received.
To enforce oxidation, and to provide 11a and 12a , we
took advantage of the relatively slow hydrogen donor tris-
(trimethylsilyl)silicon hydride.28 At a low concentration
of this hydride, hydrogen transfer to the postcyclization
radical is inefficient and the concomitant oxidation by
either single electron transfer29 followed by proton loss
or â-hydrogen atom abstraction30 predominates.31
2-(2′-Br om oph en yl)eth yl Mesylate.36 2-(2′-Bromophenyl)-
ethanol32a,38 (47 g, 0.23 mol) and triethylamine (48 mL, 0.35
mol) were dissolved in CH2Cl2 (500 mL). Methanesulfonyl
chloride (20 mL, 0.26 mol) was added dropwise at 0 °C under
30 min, and the solution was stirred for 2 h at room temper-
ature. The solution was washed successively with ice-water
(2 × 250 mL), cold 5 N HCl (2 × 250 mL), saturated aqueous
NaHCO3 (2 × 250 mL), and brine (2 × 250 mL), dried (MgSO4),
and concentrated to yield 2-(2′-bromophenyl)ethyl mesylate (61
g, 93%): 1H NMR δ 7.57 (d, 1H), 7.29-7.24 (m, 2H), 7.17-
7.11 (m, 1H), 4.45 (t, J ) 6.9 Hz, 2H), 3.21 (t, J ) 6.9 Hz, 2H),
2.88 (s, 3H); 13C NMR δ 135.5, 133.0, 131.5, 128.9, 127.7, 124.4,
68.4, 37.2, 35.9; IR 1360, 1175 cm-1; MS [IP 70 eV; m/z (% rel
int)] 280 (M+ + 2, 1), 278 (M+, 1), 184 (100), 182 (100), 171
(37), 169 (37).
Con clu sion
We have demonstrated that intramolecular radical
arylations of cyclic enamidines and enamides can be
accomplished to give the endo cyclized products.
selective preparation of either the trans fused product,
the cis fused product, or the oxidized compound, the latter
with a restored double bond, can be achieved with the
enamidine in the 6-endo cyclization.
A
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 270 and 67.8 MHz, respectively (400 and 100 MHz for
compound 11a , 16, and 17). Spectra were recorded at ambient
temperature with CDCl3 as solvent (unless otherwize noted)
and tetramethylsilane as internal standard. Peak assign-
3-(2′-Br om op h en yl)p r op yl Mesyla te. 3-(2′-Bromophen-
yl)propyl mesylate was synthesized in 97% yield (14 g, 48
mmol) from 3-(2′-bromophenyl)propanol33,39 (11 g, 49 mmol)
as described above for the synthesis of 2-(2′-bromophenyl)ethyl
mesylate: 1H NMR δ 7.54 (d, 1H), 7.29-7.22 (m, 2H), 7.14-
7.03 (m, 1H), 4.27 (t, J ) 6.3 Hz, 2H), 3.03 (s, 3H), 2.88 (t, J
) 7.7 Hz, 2H), 2.14-2.06 (m, 2H); 13C NMR δ 139.6, 133.0,
130.6, 128.1, 127.6, 124.3, 69.0, 37.4, 32.1, 29.1; IR 1359, 1176
cm-1; MS [IP 70 eV; m/z (% rel int)] 294 (M+ + 2, 3), 292 (M+,
ments of the cyclized products were made by 13C-13C and H-
1
13C correlation experiments. Coupling constants are given as
absolute values. Low-resolution electron-impact MS spectra
were measured at an ionization potential of 70 eV. The mass
detector was interfaced with a gas chromatograph equipped
with a HP-1 (25 m × 0.2 mm) column. Isomers were assumed
to have the same response factors. Infrared spectra were
recorded on a FTIR spectrophotometer as solutions in CDCl3
unless otherwise noted. Elemental analyses were performed
by Mikro Kemi AB, Uppsala, Sweden, or by Analytische
Laboratorium, Prof. Dr. H. Malissa and G. Reuter GmbH,
Gummersbach, Germany. Melting points were determined in
open capillary tubes in a melting point microscope and are
uncorrected. Thin-layer chromatography (TLC) was carried
out on aluminum sheets precoated with silica gel 60 F254 (0.25
mm, Macherey-Nagel). Column chromatography was per-
formed on silica gel S (0.032-0.063 mm, Riedel-de Hae¨n) or
silica gel 60 (fine) (0.015-0.040 mm, E. Merck) and centrifugal
chromatography was carried out on a Harrison Research
Chromatotron (model 7924T) with silica gel 60 PF254 contain-
ing gypsum (E. Merck) as solid phase. Preparative thin-layer
chromatography was carried out on glass sheets precoated with
silica gel 60 F254 (2.0 mm, E. Merck).
3), 198 (57), 196 (57), 117 (100). Anal. Calcd for C10H13
BrO3S: C, 40.97; H, 4.47. Found: C, 41.3; H, 4.6.
-
2-(2′-Br om op h en yl)eth yl Iod id e (18).32 2-(2-Bromophen-
yl)ethyl mesylate36 (5.9 g, 20 mmol) was mixed with NaI (13
g, 85 mmol) in acetone (80 mL), and the mixture was refluxed
until TLC indicated full conversion of the starting material.
After 2 h water (200 mL) was added and the solution was
extracted with diethyl ether (3 × 100 mL). The combined
organic layers were washed with water (2 × 50 mL), dried
(MgSO4), and concentrated. The product was purified by
column chromatography (SiO2, pentane, Rf 0.44) to yield 18
(6.35 g, 99%) as a clear oil. Spectroscopic data were consistent
with data described elsewhere.32b 13C NMR δ 139.8, 133.0,
130.7, 128.6, 127.6, 124.0, 40.5, 3.2.
3-(2′-Br om op h en yl)p r op yl Iod id e (19). Compound 19
was synthesized from 3-(2′-bromophenyl)propyl mesylate (14
g, 48 mmol) as described above for the synthesis of 18. The
product was purified by column chromatography (SiO2, pen-
tane, Rf 0.39) to yield 19 (14 g, 87%). Spectroscopic data were
consistient with data described elsewere.33
N-(N′-ter t-Bu t ylfor m im id oyl)-6-[2-(2-b r om op h en yl)-
eth yl]-1,2,3,4-tetr a h yd r op yr id in e (2a ). To a solution of
N-(N′-tert-butylformimidoyl)-1,2,3,4-tetrahydropyridine5a,12 (5.5
g, 33 mmol) in 4:1 diethyl ether/THF (33 mL) was added slowly
t-BuLi (29 mL, 43 mmol, 1.5 M in hexane) at -78 °C under
argon. The yellow solution was stirred at -20 °C until a white
solid had precipitated (2 h). The reaction mixture was cooled
to -50 °C, pentynylcopper37 (6.0 g, 46 mmol) in THF (33 mL)
was added, and the reaction mixture was allowed to stir at
-20 °C for 1 h. The reaction mixture was cooled to -78 °C,
compound 18 (15 g, 49 mmol) was added, and the mixture was
Ma ter ia ls. Benzene was distilled from Na and degassed
with argon prior to use. Azobisisobutyronitrile (AIBN), tribut-
yltin hydride (Bu3SnH), triphenyltin hydride (Ph3SnH), tribu-
tyltin deuteride (Bu3SnD), and tris(trimethylsilyl)silicon hy-
dride (TMS3SiH) were used as received. Compounds 1832 and
1932b,33 were prepared according to a synthetic strategy
(27) Such
a 1,5-hydride shift occurs readily to an aryl radical
especially when a stabilized radical is formed. (a) Cohen, T.; McMullen,
C. H.; Smith, K. J . Am. Chem. Soc. 1968, 90, 6866-6867. (b) Snieckus,
V.; Cuevas, J .-C.; Sloan, C. P.; Liu, H.; Curran, D. P. J . Am. Chem.
Soc. 1990, 112, 896-898. See also refs 2l and 4b,c.
(28) Tris(trimethylsilyl)silicon hydride is about 13 times slower than
triphenyltin hydride at donating a hydrogen atom to an alkyl radical.
Newcomb, M. Tetrahedron 1993, 49, 1151-1176.
(29) Radicals located R to a nitrogen atom are sensitive to oxidation,
see: Curran, D. P. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Ed.; Pergamon: Oxford, 1991; Vol. 4; p 726.
(30) Bogen, S.; Malacria, M. J . Am. Chem. Soc. 1996, 118, 3992-
3993.
(31) Oxidation products has been observed in cyclization reactions
of enamides mediated with tributyltin hydride; see refs 2d and 3. A
pseudo SRN1 mechanism has been suggested for similar processes; see
ref 9.
(33) Beak, P.; Allen, D. J . J . Am. Chem. Soc. 1992, 114, 3420-3425.
(34) Ciulfolini, M. A.; Qi, H.-B.; Browne, M. E. J . Org. Chem. 1988,
53, 4149-4151.
(35) L′abbe´, G.; Leurs, S.; Sannen, I.; Dehaen, W. Tetrahedron 1993,
49, 4439-4446.
(36) Bickelhaupt, F.; Stach, K.; Thiel, M. Chem. Ber. 1965, 98, 685-
704.
(37) Stephens, R. D.; Castro, C. E. J . Org. Chem. 1963, 28, 3313-
3315.
(38) Gilman, H.; Marrs, O. L. J . Org. Chem. 1965, 30, 325-328.
(39) Beeby, M. H.; Mann, F. G. J . Chem. Soc. 1951, 411-415.
(32) (a) Beak, P.; Allen, D. J .; Lee, W. K. J . Am. Chem. Soc. 1990,
112, 1629-1630. (b) Wender, P. A.; White, A. W. J . Am. Chem. Soc.
1988, 110, 2218-2223.

Aryl Radical Endo Cyclization of Enamidines
J . Org. Chem., Vol. 63, No. 1, 1998 89
thereafter stirred at -20 °C overnight. The reaction mixture
was filtered, diluted with more diethyl ether, washed several
times with aqueous NH3 (until the aqueous layer no longer
was colored blue), and extracted with 3 N HCl (5 × 60 mL).
The combined acidic aqueous layers were extracted with CH2-
Cl2 (5 × 60 mL). The combined CH2Cl2 layers were washed
with 5% aqueous NaOH (2 × 60 mL) and brine (60 mL), dried
over K2CO3/Na2SO4 1:1, and concentrated to a yellow oil. The
crude product was filtered through a pad of SiO2 eluting with
10% triethylamine in pentane40 to yield 2a (5.6 g, 48%): 1H
NMR δ 7.94 (s, 1H), 7.53 (dd, 1H), 7.24-7.14 (m, 2H), 7.10-
7.04 (m, 1H), 4.59 (t, J ) 4.0 Hz, 1H), 3.67-3.63 (m, 2H), 2.94-
2.85 (m, 2H), 2.56 (app t, 2H), 2.05-1.96 (m, 2H), 1.80-1.69
(m, 2H), 1.22 (s, 9H); 13C NMR δ 145.4, 140.5, 137.7, 132.7,
130.6, 127.8, 127.4, 124.2, 103.1, 53.6, 41.9, 35.2, 33.3, 31.3,
22.5, 21.7; IR 1626 cm-1; MS [IP 70 eV; m/z (% rel int)] 350
8.51 (s, 1H), 7.53 (app d, 1H), 7.26-7.13 (m, 2H), 7.06 (m, 1H),
4.3 (t, J ) 3.5 Hz, 1H), 3.68-3.64 (m, 2H), 2.76 (app t, 2H),
2.44 (app t, 2H), 2.13-2.07 (m, 2H), 1.88-1.73 (m, 4H); 13C
NMR δ 159.9, 140.7, 135.4, 132.8, 130.2, 127.7, 127.4, 124.3,
108.8, 39.4, 35.4, 32.0, 27.4, 22.5, 21.4; IR 1647 cm-1; MS [IP
70 eV; m/z (% rel int)] 309 (M+ + 2, 13), 307 (M+, 13), 228 (8),
125 (53), 97 (100). Anal. Calcd for C15H18BrNO: C, 58.45; H,
5.89; N, 4.54. Found: C, 58.6; H, 6.0; N, 4.5.
N-F or m yl-6-[2-(2-br om op h en yl)eth yl]-1,2,3,4-tetr a h y-
d r op yr id in e (2b). Compound 2b was synthesized from 2a
(1.5 g, 4.2 mmol) as described above for the synthesis of 4b.
Purification by column chromatography (SiO2, pentane/EtOAc
1
3:1, Rf 0.24) gave 2b (0.80 g, 65%). The H NMR spectra show
the existence of two rotamers in an approximately 98:2 ratio.
Shift values are given only for the major isomer. 1H NMR δ
8.69 (s, 1H), 7.54 (app d, 1H), 7.27-7.11 (m, 3H), 4.89 (t, J )
3.8 Hz, 1H), 3.70-3.65 (m, 2H), 2.94 (app t, 2H), 2.66 (app t,
2H), 2.07-2.03 (m, 2H), 1.81-1.73 (m, 2H); 13C NMR δ 159.0,
139.8, 135.1, 132.8, 130.4, 128.0, 127.5, 124.1, 109.4, 39.4, 34.6,
32.7, 22.5, 21.3; IR 1650 cm-1; MS [IP 70 eV; m/z (% rel int)]
(M+ + 2, 17), 348 (M+, 17), 186 (100). Anal. Calcd for C18H25
-
BrN2: C, 61.89; H, 7.21; N, 8.02. Found: C, 61.8; H, 7.2; N,
8.0
N-(N′-ter t-Bu t ylfor m im id oyl)-6-[3-(2-b r om op h en yl)-
p r op yl]-1,2,3,4-tetr a h yd r op yr id in e (4a ). To a solution of
N-(N′-tert-butylformimidoyl)-1,2,3,4-tetrahydropyridine5a,12 (3.3
g, 20 mmol) in 4:1 diethyl ether/THF (40 mL) was added slowly
t-BuLi (19 mL, 26 mmol, 1.4 M in hexane) at -78 °C under
argon. The yellow solution was stirred at -20 °C until a white
solid had precipitated (2 h). The reaction mixture was cooled
to -78 °C, compound 19 (9.8 g, 30 mmol) was added, and the
reaction mixture was stirred at -20 °C overnight. The
reaction mixture was poured into 3 N HCl (150 mL), washed
with diethyl ether (3 × 50 mL), and extracted with CH2Cl2 (5
× 50 mL). The combined CH2Cl2 layers were washed with 1N
NaOH (2 × 40 mL), dried over K2CO3/Na2SO4 1:1, and
concentrated to a yellow oil. The crude product was filtered
through a pad of SiO2 eluting with 10% triethylamine in
pentane40 to yield 4a (5.3 g, 72%): 1H NMR δ 7.76 (s, 1H),
7.52 (dd, 1H), 7.23-7.18 (m, 2H), 7.08-7.02 (m, 1H), 4.62 (t,
J ) 4.0 Hz, 1H), 3.65-3.61 (m, 2H), 2.78-2.72 (m, 2H), 2.34
(t, J ) 7.6 Hz, 2H), 2.05-2.01 (m, 2H), 1.83-1.71 (m, 4H),
1.15 (s, 9H); 13C NMR δ 145.4, 141.2, 138.0, 132.8, 130.3, 127.6,
127.4, 124.4, 102.4, 53.6, 41.8, 35.6, 32.8, 31.2, 28.2, 22.5, 21.8.
IR 1625 cm-1; MS [IP 70 eV; m/z (% rel int)] 364 (M+ + 2, 11),
362 (M+, 11), 193 (100), 97 (97). Anal. Calcd for C19H27BrN2:
C, 62.81; H, 7.49; N, 7.71. Found: C, 63.1; H, 7.6; N, 7.6.
N-(N′-ter t-Bu tylfor m im idoyl)-6-[(2-iodoph en yl)m eth yl]-
1,2,3,4-tetr a h yd r op yr id in (21). Compound 21 was synthe-
sized from N-(N′-tert-butylformimidoyl)-1,2,3,4-tetrahydro-
pyridine5a,12 (0.78 g, 4.7 mmol) and 2-iodobenzylbromide (2.1
g, 7.0 mmol) as described above for the synthesis of 3a . The
crude product was filtered through a pad of SiO2 eluting with
10% triethylamine in pentane40 to yield 21 (1.1 g, 58%): 1H
NMR δ 7.83 (dd, 1H), 7.37 (s, 1H), 7.31-7.19 (m, 2H), 6.94-
6.88 (m, 1H), 4.69 (t, J ) 3.8 Hz, 1H), 3.72-3.63 (m,
AB-spectra, 2H), 2.18-2.12 (m, 2H), 1.89-1.81 (m, 2H), 0.95
(s, 9H); 13C NMR δ 146.3, 140.6, 139.3, 135.8, 128.8, 128.6,
128.3, 105.2, 100.7, 53.5, 45.2, 41.6, 39.6, 31.0, 22.7, 21.6. IR
1633 cm-1; MS [IP 70 eV; m/z (% rel int)] 382 (M+, 75), 179
(85), 172 (100). Anal. Calcd for C17H23IN2: C, 53.41; H, 6.06;
N, 7.32. Found: C, 53.8; H, 6.3; N, 6.9.
294 (3), 292 (3), 214 (100), 186 (54). Anal. Calcd for C14H16
BrNO: C, 57.16; H, 5.48; N, 4.76. Found: C, 57.1 H, 5.6; N,
4.6.
-
tr a n s- an d cis-4-For m yl-1,2,3,4,4a,5,6,10b-octah ydr oben -
zo[f]qu in olin e (5b a n d 7b). Compound 2b (0.20 g, 0.67
mmol) was dissolved in degassed benzene (33 mL), AIBN (33
mg, 0.2 mmol) and Bu3SnH (0.29 g, 1.0 mmol) were added,
and the solution was refluxed overnight.41 After cooling, the
solvent was evaporated and the residue was dissolved in
diethyl ether (15 mL) and stirred with 1 N KF (10 mL) for 2
h. The mixture was filtered and the aqueous layer was
extracted with diethyl ether (5 mL). The combined organic
layers were dried (K2CO3) and concentrated, and the resulting
oil was washed with isohexane (3 × 1 mL) to yield the crude
product. The mixture was filtered through a short pad of SiO2
and the cis and trans isomers were isolated with centrifugal
chromatography (EtOAc/isohexane 9:1) to yield 5b (46 mg,
32%) and 7b (4 mg, 3%). Compound 5b: 1H NMR δ 8.29 (s,
1H, CHO), 7.32-7.07 (m, 4H, Ar-H), 4.75-4.66 (m, 1H, H-3),
3.22 (ddd, J ) 12.3, 10.3, and 2.3 Hz, 1H, H-4a), 3.12-2.88
(m, 2H, H-6), 2.68-2.56 (m, 2H, H-1, H-10b), 2.54 (ddd, J )
12.9, 12.9, and 3.2, 1H, H-3), 2.42-2.31 (m, 1H, H-5), 2.16-
1.98 (m, 1H, H-5), 1.96-1.84 (m, 1H, H-2), 1.80-1.58 (m, 1H,
H-2), 1.55-1.36 (m, 1H, H-1); 13C NMR δ 158.5 (CHO), 137.3,
134.6 (C-6a, C-10a), 128.9, 126.5, 126.3, 126.0 (C-7, C-8, C-9,
C-10), 60.7 (C-4a), 44.6 (C-10b), 41.8 (C-3), 30.5 (C-1), 29.6 (C-
6), 25.8 (C-5), 25.6 (C-2); IR 1642 cm-1; MS [IP 70 eV; m/z (%
rel int)] 215 (M+, 58), 170 (62), 144 (89), 129 (100). Compound
1
7b: The H NMR spectra show the existence of two rotamers
in an approximately 1:1 ratio. 1H NMR δ 8.18 and 8.11 (s,
1H, CHO), 7.22-7.03 (m, 4H, Ar-H), 4.81 and 3.89 (ddd, J )
13.0, 5.2, and 3.5 Hz, 1H, H-4a), 4.42-4.31 and 3.52-3.41 (m,
1H, H-3), 3.26-3.13 and 2.79-2.66 (m, 1H, H-3), 3.11-2.79
(m, 3H, H-6, H-10b), 2.50-2.30 and 2.30-2.11 (m, 1H, H-5),
2.07-1.93 (m, 1H, H-1), 1.88-1.40 (m, 4H, H-1, H-2, H-5); 13
C
NMR δ 161.3 and 161.2 (CHO), 139.6, 139.5, 134.7, 134.2 (C-
6a, C-10a), 129.0, 128.8, 126.3, 126.2, 126.1, 125.9 (two pairs
of signals are overlapping) (C-7, C-8, C-9, C-10), 54.8, 47.6 (C-
4a), 42.4, 35.9 (C-3), 39.9, 38.3 (C-10b), 31.2, 31.1 (C-1), 29.0
(C-6), 26.4, 25.1 (C-2), 23.4, 21.4 (C-5); IR 1658 cm-1; MS [IP
70 eV; m/z (% rel int)] 215 (M+, 100), 170 (17), 144 (18), 129
(60). For comparison, compounds 5b and 7b were converted
(MeLi, THF, 0 °C)5b to 14 and 15, respectively.
N-F or m yl-6-[3-(2-br om op h en yl)p r op yl]-1,2,3,4-tetr a h y-
d r op yr id in e (4b). A solution of 4a (80 mg, 0.22 mmol) and
KOH (85 mg, 1.5 mmol) in MeOH (1.8 mL) and water (0.70
mL) was heated at 60 °C under argon until TLC indicated
complete consumption of the enamidine (3 h). Upon cooling,
the solvent was removed under reduced pressure and the
residue was dissolved in CH2Cl2 (3 mL). The organic layer
was washed with saturated aqueous NaHCO3 (3 × 1 mL) and
brine (2 mL), dried (K2CO3), and concentrated. Purification
by column chromatography [SiO2 (fine), pentane/EtOAc 3:1,
Rf 0.33] gave 4b (51 mg, 75%). The 1H NMR spectra show
the existence of two rotamers in an approximately 98:2 ratio.
Shift values are given only for the major isomer. 1H NMR δ
tr a n s- a n d cis-1-F or m yl-2,3,4,4a ,5,6,7,11b -oct a h yd r o-
1H-ben zo[3,4]cycloh epta[1,2-b]pyr idin e (6b an d 8b). Com-
pounds 6b and 8b was synthesized from 4b (0.15 g, 0.50
mmol), AIBN (24 mg, 0.15 mmol), and Bu3SnH (0.22 g, 0.75
mmol) in degassed benzene (25 mL) as described above for the
synthesis of 5b and 7b. The mixture was filtered through a
short pad of SiO2 and the cis and trans isomers were isolated
with centrifugal chromatography (EtOAc/isohexane 7:3) to
yield 6b (12 mg, 11%) and 8b (7 mg, 6%), together with a mixed
(40) The amidines were purified essentially according to a procedure
developed by Meyers; see ref 12.
(41) The reaction times were not optimized.

90 J . Org. Chem., Vol. 63, No. 1, 1998
Ripa and Hallberg
fraction of cis and trans isomers (20 mg) and the dehalogenated
starting material 13b (30 mg). The 1H NMR spectra show the
existence of two rotamers in an approximately 2:3 ratio for
6b and 1:1 ratio for 8b. Compound 6b: 1H NMR δ 8.02 and
7.99 (s, 1H, CHO), 7.24-7.07 (m, 4H, Ar-H), 4.25-4.12 (m,
0.4H, H-3), 3.93-3.80 and 3.22-3.09 (m, 1H, H-4a), 3.52-3.30
(m, 1.2H, H-3), 3.08-2.84 (m, 2.2H, H-3, H-7, H-11b), 2.82-
2.68 (m, 1.2H, H-7), 2.26-1.42 (m, 8H, H-1, H-2, H-5, H-6);
13C NMR δ 161.6 and 161.0 (CHO), 142.7, 142.2, 141.9, 141.8
(C-7a, C-11a), 129.0, 128.8, 126.6, 126.4, 126.3, 124.5, 124.3
(two peaks overlaps, C-8, C-9, C-10, C-11), 59.9 and 54.6 (C-
4a), 42.2 and 41.4 (C-11b), 37.9 and 32.5 (C-3), 37.3 and 34.9
(C-1),35.0 and 34.4 (C-7), 26.5 and 26.2 (C-5), 23.2 and 22.8
(C-2), 22.8 and 21.2 (C-6); IR 1668 cm-1; MS [IP 70 eV; m/z (%
rel int)] 229 (M+, 100), 184 (43), 143 (62), 129 (70), 115 (55).
Compound 8b: 1H NMR δ 8.13 and 8.02 (s, 1H, CHO), 7.26-
7.01 (m, 4H, Ar-H), 4.70 and 3.79 (ddd, J ) 12.6, 4.1 and 4.1
Hz, 1H, H-4a), 4.33 (m, 0.5H, H-3R) 3.44-3.38 (m, AB-spectra,
1H, H-3â, H-3R) 3.05-2.67 (m, 2.5H, H-3â, H-11b, H-7), 2.65-
2.46 (m, 0.5H, H-5), 2.42-2.18 (m, 1.5H), 2.14-1.95 (m, 1H),
1.94-1.76 (m, 2H), 1.75-1.40 (m, 4H); 13C NMR δ 160.8, 160.4
(CHO), 142.1 (br), 141.3, 141.0 (C-7a, C-11a), 131.6, 131.4,
130.4, 130.3, 127.0, 126.8, 126.6, 126.5 (C-8, C-9, C-10, C-11),
57.4, 50.1 (C-4a), 52.8, 51.1 (C-11b), 41.7, 35.2 (C-3), 36.7, 36.3
(C-7), 32.2, 30.1, 27.3, 26.7 (br), 25.91, 25.87, 25.8; IR 1656
cm-1; MS [IP 70 eV; m/z (% rel int)] 229 (M+, 100), 184 (28),
143 (52), 129 (60), 115 (45). For comparison compounds 6b
and 8b were converted (MeLi, THF, 0 °C)5b to 16 and 17,
respectively.
tr a n s-4-(N-ter t-Bu tylfor m im id oyl)-1,2,3,4,4a ,5,6,10b-oc-
ta h yd r oben zo[f]qu in olin e (5a ). Compound 1 (0.20 g, 0.50
mmol) and Ph3SnH (0.26 g, 0.70 mmol) were dissolved in
toluene (25 mL) and cooled to -20 °C, air was bubbled through
the solution for 2 min, Et3B (0.50 mL, 1 M in hexane, 0.50
mmol) was added, and the solution was stirred at -20 °C
overnight.41 The solvent was evaporated and the resulting
residue was partitioned between 3 N HCl (25 mL) and EtOAc
(15 mL) until all the white foam was dissolved. The aqueous
layer was washed with EtOAc (2 × 15 mL) and the combined
organic layers were extracted with 3 N HCl (15 mL). The
combined acidic aqueous layers were extracted with CH2Cl2
(4 × 20 mL) and the combined CH2Cl2 layers were washed
with 1 N NaOH (2 × 20 mL), dried (K2CO3), and concentrated
to yield the crude product (0.13 g). The crude product was
purified on preparative TLC (SiO2, 10% triethylamine in
isohexane,40 Rf 0.28) to yield 5a as an oil (83 mg, 61%): 1H
NMR δ 7.62 (s, 1H, NCHdN), 7.30-7.03 (m, 4H, Ar-H), 4.58-
4.46 (m, 1H, H-3), 3.07 (ddd, J ) 12.2, 10.3, and 2.5 Hz, 1H,
H-4a), 3.08-2.88 (m, 2H, H-6), 2.67-2.25 (m, 3H, H-1, H-3,
H-10b), 2.32-2.21 (m, 1H, H-5), 2.12-1.88 (m, 1H, H-5), 1.83-
1.67 (m, 2H, H-2), 1.52-1.32 (m, 1H, H-1) 1.17 (s, 9H, C(CH3)3);
13C NMR δ 146.4, (NdCH), 138.5, 135.2 (C-6a, C-10a), 128.7,
126.0 (3C's) (C-7, C-8, C-9, C-10), 61.7 (C-4a), 53.3 (C(CH3)3),
44.6 (C-3), 43.6 (C-10b), 31.3 (C(CH3)3), 30.9 (C-1), 29.9 (C-6),
26.4 (C-5), 24.5 (C-2); IR 1622 cm-1; MS [IP 70 eV; m/z (% rel
int)] 270 (M+, 100), 255 (58), 213 (54), 198 (22), 186 (36). Anal.
Calcd for C18H26N2: C, 79.95; H, 9.69; N, 10.36. Found: C,
79.8 H, 9.6; N, 10.2.
(33). Anal. Calcd for C18H26N2: C, 79.95; H, 9.69; N, 10.36.
Found: C, 79.8; H, 9.7; N, 10.3.
tr a n s-1,2,3,4,4a ,5,6,10b -Oct a h yd r ob en zo[f]q u in olin e
(14).17a Compound 5a (51 mg, 0.2 mmol) was mixed with
hydrazine monohydrate (76 mg, 1.5 mmol) and acetic acid (34
mg, 0.57 mmol) in EtOH (2.8 mL) and the mixture warmed at
60 °C until TLC indicated full conversion of the amidine. After
6 h the reaction mixture was allowed to cool, concentrated,
taken up in 1 N NaOH (5 mL), and extracted with CH2Cl2 (5
× 2 mL). The combined organic layers were dried (K2CO3)
and concentrated. The crude product was purified by column
chromatography (SiO2, 10% triethylamine in isohexane/EtOAc
1:1) to yield 14 as a white solid (23 mg, 65%), mp 88-89 °C.
For elemental analyses, the secondary amine was converted
to the HCl salt, mp 277-278 °C: 1H NMR (CD3OD) δ 7.25-
7.21 (m, 1H, Ar-H), 7.12-7.00 (m, 3H, Ar-H), 3.12-3.03 (m,
1H, H-3), 3.02 (m, 2H, H-6), 2.68 (ddd, J ) 12.2, 12.2 and 3.2
Hz, 1H, H-3), 2.59-2.48 (m, 1H, H-1), 2.47-2.33 (m, 2H, H-4a,
H-10b), 1.97-1.59 (m, 4H, H-2, H-5), 1.33-1.15 (m, 1H, H-1);
13C NMR (CD3OD) δ 140.4, 137.9 (C-6a, C-10a), 130.5, 127.73,
127.67, 127.1 (C-7, C-8, C-9, C-10), 61.2 (C-4a), 48.2 (C-3), 44.8-
(C-10b), 31.9 (C-5), 31.3 (C-1), 30.7 (C-6), 28.3 (C-2); MS [IP
70 eV; m/z (% rel int)] 187 (M+, 100), 186 (42). Anal. Calcd
for C13H17N‚HCl: C, 69.79; H, 8.11; N, 6.26. Found: C, 69.9;
H, 8.0; N, 6.2.
cis-1,2,3,4,4a,5,6,10b-Octah ydr oben zo[f]qu in olin e (15).17a
Compound 15 was synthesized from 7a (71 mg, 0.27 mmol)
as described above for the synthesis of 14. The crude product
was purified by column chromatography (SiO2, 10% triethyl-
amine in isohexane/EtOAc 1:1) to yield 15 as a white solid (40
mg, 79%), mp 66-68 °C. For elemental analyses the amine
was converted to the HCl salt, mp 262-263 °C: 1H NMR (CD3-
OD) δ 7.14-7.03 (m, 4H, Ar-H), 3.18 (ddd, J ) 10.1, 4.6 and
3.2 Hz, 1H, H-4a), 2.98-2.67 (m, 5H, H-3, H-6, H-10b), 2.30-
2.13 (m, 1H, H-5), 1.89-1.79 (m, 2H, H-1), 1.78-1.66 (m, 1H,
H-5), 1.64-1.52 (m, 2H, H-2); 13C NMR (CD3OD) δ 142.0, 137.4
(C-6a, C-10a), 130.6, 130.2, 127.73, 127.66 (C-7, C-8, C-9, C-10),
54.6 (C-4a), 43.0, 40.9 (C-3, C-10b), 31.7 (C-1), 30.1 (C-6), 27.0
(C-2), 26.0 (C-5); MS [IP 70 eV; m/z (% rel int)] 187 (M+, 100),
186 (41). Anal. Calcd for C13H17N‚HCl: C, 69.79; H, 8.11; N,
6.26. Found: C, 69.9; H, 8.0; N, 6.2.
tr a n s- a n d cis-2,3,4,4a ,5,6,7,11b-Octa h yd r o-1H-ben zo-
[3,4]cycloh ep ta [1,2-b]p yr id in e (16 and 17). Compound 4a
(0.36 g, 1.0 mmol) was dissolved in degassed benzene (50 mL),
AIBN (16.4 mg, 0.1 mmol) and Bu3SnH (0.44 g, 1.5 mmol) were
added, and the solution was refluxed overnight.41 After
cooling, the solvent was evaporated and the resulting residue
was partitioned between 3 N HCl (50 mL) and diethyl ether
(3 × 25 mL). The combined organic layers were extracted with
3 N HCl (25 mL) and the combined acidic aqueous layers were
thereafter extracted with CH2Cl2 (4 × 25 mL). The combined
CH2Cl2 layers were washed with 1 N NaOH (2 × 25 mL), dried
(K2CO3), and concentrated to yield the crude product (0.30 g),
as a mixture of 6a and 8a , and the dehalogenated starting
material 13a . The crude product was mixed with hydrazine
monohydrate (0.40 g, 8.0 mmol) and acetic acid (0.18 g, 3.0
mmol) in EtOH (11 mL) and warmed at 60 °C until TLC
indicated full conversion of the amidine. After 4 h the reaction
mixture was allowed to cool and concentrated. The resulting
residue was taken up in 3 N HCl (15 mL), washed with EtOAc
(2 × 5 mL), made basic with 1 N NaOH, and extracted with
CH2Cl2 (6 × 8 mL). The combined organic layers were dried
(K2CO3) and concentrated. The trans and cis isomers were
separated by column chromatography (SiO2, 10% triethyl-
amine in isohexane/EtOAc 1:1) to yield 16 (58 mg, 29%) and
17 (29 mg, 14%) as low-melting solids. Compound 16: For
elemental analyses the amine was converted to the HCl salt,
mp 241-242 °C: 1H NMR (CD3OD) δ 7.22-7.05 (m, 4H, Ar-
H), 3.17-3.08 (m, 1H, H-3), 3.09-3.01 (m, 1H, H-7), 2.82-
2.65 (m, 3H, H-3, H-7, H-11b), 2.41 (ddd, J ) 9.7, 4.8, and 4.8
Hz, 1H, H-4a), 2.11-1.83 (m, 4H, H-2, H-5, H-6), 1.77-1.54
(m, 3H, H-1, H-2, H-6), 1.50-1.41 (m, 1H, H-1); 13C NMR (CD3-
OD) δ 142.4, 142.3 (C-7a, C-11a), 129.9, 127.4 (2 C's), 125.8
(C-8, C-9, C-10, C-11), 61.4 (C-4a), 47.7 (C-3), 45.1 (C-11b),
34.6 (C-1), 33.8 (C-7), 30.3 (C-5), 27.5 (C-2), 22.5 (C-6); MS [IP
cis-4-(N-ter t-Bu t ylfor m im id oyl)-1,2,3,4,4a ,5,6,10b -oc-
ta h yd r oben zo[f]qu in olin e (7a ). Compound 2a (0.35 g, 1.0
mmol) was dissolved in degassed benzene (10 mL), AIBN (49
mg, 0.30 mmol) and TMS3SiH (0.50 g, 2.0 mmol) were added,
and the solution was heated in a sealed Pyrex tube at 100 °C
overnight.41 Workup as described for compound 5a and
purification on preparative TLC (SiO2, 10% triethylamine in
isohexane,40 Rf 0.42) gave 7a as an oil (0.13 g, 46%): 1H NMR
δ 7.40 (s, 1H, NCHdN), 7.24-7.06 (m, 4H, Ar-H), 3.92 (app
br d, 1H, H-4a), 3.81 (app br d, 1H, H-3), 3.05-2.78 (m, 4H,
H-3, H-6, H-10b), 2.30-2.14 (m, 1H, H-5), 2.06-1.85 (m, 1H,
H-1), 1.78-1.56 (m, 4H, H-1, H-2, H-5), 1.17 (s, 9H, C(CH3)3);
13C NMR δ 150.6, (NdCH), 140.7, 134.9 (C-6a, C-10a), 129.0,
128.6, 125.9, 125.7 (C-7, C-8, C-9, C-10), 54.6 (br, C-4a), 52.9
(C(CH3)3), 40.2 (C-3), 39.2 (C-10b), 31.4 (C-1), 31.3 (C(CH3)3),
29.2 (C-6), 25.4 (C-2), 21.6 (C-5); IR 1631 cm-1; MS [IP 70 eV;
m/z (% rel int)] 270 (M+, 100), 255 (49), 213 (61), 198 (57) 186

Aryl Radical Endo Cyclization of Enamidines
J . Org. Chem., Vol. 63, No. 1, 1998 91
70 eV; m/z (% rel int)] 201 (M+, 100), 186 (18), 158 (39). Anal.
Calcd for C14H19N‚HCl‚1/4H2O: C, 69.40; H, 8.53; N, 5.78.
Found: C, 69.6; H, 8.3; N, 5.8. Compound 17: For elemental
analyses the amine was converted to the HCl salt, mp 250-
252 °C: 1H NMR (CD3OD) δ 7.23 (app d, 1H, Ar-H), 7.16-
7.04 (m, 3H, Ar-H), 3.13 (ddd, J ) 11.3, 3.7 and 3.6 Hz, 1H,
H-4a), 3.16-3.05 (m, 2H, H-3, H-11b), 2.84 (ddd, J ) 14.8, 10.5,
and 3.0 Hz, 1H, H-7), 2.81-2.75 (m, 2H, H-3, H-7), 2.32-2.23
(m, 2H, H-1, H-5), 2.08-2.00 (m, 1H, H-6), 1.91-1.81 (m, 2H,
H-1, H-2) 1.79-1.71 (m, 1H, H-2), 1.69-1.52 (m, 1H, H-5),
1.50-1.42 (m, 1H, H-6); 13C NMR (CD3OD) δ 143.4, 143.2 (C-
7a, C-11a), 131.5, 131.0, 127.5, 127.4 (C-8, C-9, C-10, C-11),
56.4 (C-4a), 50.9 (br, C-11b), 41.1 (C-3), 36.7 (C-7), 31.9 (C-1),
27.7 (C-2), 27.1 (C-6), 26.7 (C-5); MS [IP 70 eV; m/z (% rel int)]
201 (M+, 100), 186 (17), 158 (36). Anal. Calcd for C14H19N‚-
HCl: C, 70.72; H, 8.48; N, 5.89. Found: C, 70.5; H, 8.3; N,
5.8.
4-(N-ter t-Bu tylfor m im id oyl)-1,2,3,4,5,6-h exa h yd r oben -
zo[f]qu in olin e (11a ). Compound 1 (120 mg, 0.30 mmol) was
dissolved in degassed benzene (90 mL), AIBN (49 mg, 0.3
mmol) and TMS3SiH (90 mg, 0.36 mmol) were added, and the
solution was refluxed overnight.39 Workup as described above
for the synthesis of 5a and filtration through a pad of SiO2
eluting with 10% triethylamine in isohexane40 gave 11a (54
mg, 67%). 1H NMR δ 8.02 (s, 1H, NCHdN), 7.20-7.17 (ddd,
1H, Ar-H), 7.13-7.06 (m, 2H, Ar-H), 7.04-6.98 (ddd, 1H,
Ar-H), 3.71 (m, 2H, H-3), 2.86 (app t, 2H, H-6), 2.58-2.52
(m, 2H, H-5), 2.47-2.41 (m, 2H, H-1), 2.00-1.93 (m, 2H, H-2),
1.21 (s, 9H, C(CH3)3); 13C NMR δ 144.5, (NdCH), 136.8, 135.8,
132.0, 109.2 (C-4a, C-6a, C-10a, C-10b), 126.5, 126.4, 124.1,
120.8 (C-7, C-8, C-9, C-10), 54.0 (C(CH3)3), 42.2 (C-3), 31.1
(C(CH3)3), 28.3 (C-6), 24.7 (C-5), 23.1 (C-1), 21.6 (C-2); IR 1614
cm-1; MS [IP 70 eV; m/z (% rel int)] 268 (M+, 26), 211 (10),
185 (100). Anal. Calcd for C18H24N2‚1/4H2O: C, 79.22; H, 9.05;
N, 10.26. Found: C, 79.4 H, 8.9; N, 10.0.
4-(N-ter t-Bu tylfor m im id oyl)-2,3,4,5,6,7-h exa h yd r o-1H-
ben zo[3,4]cycloh ep ta [1,2-b]p yr id in e (12a ). Compound 3
(120 mg, 0.30 mmol) was dissolved in degassed benzene (90
mL), AIBN (49 mg, 0.3 mmol) and TMS3SiH (90 mg, 0.36
mmol) were added, and the solution was refluxed overnight.41
Workup as described above for the synthesis of 5a and
filtration through a pad of SiO2 eluting with 10% triethylamine
in isohexane40 gave 12a (50 mg, 59%). 1H NMR δ 7.92 (s, 1H,
NCHdN), 7.29-7.07 (m, 4H, Ar-H), 3.79-3.73 (m, 2H, H-3),
2.60 (app t, 2H, H-7), 2.45 (app t, 2H, H-2), 2.23-2.07 (m, 4H,
H-5, H-6), 1.98-1.86 (m, 2H, H-1), 1.22 (s, 9H, C(CH3)3); 13C
NMR δ 145.5, (NdCH), 142.8, 139.8, 136.5, 113.0 (C-4a, C-7a,
C-11a, C-11b), 128.6, 126.4, 126.1, 125.5 (C-8, C-9, C-10, C-11),
53.8 (C(CH3)3), 42.4 (C-3), 33.8, 26.7 (C-5, C-6), 32.3 (C-7), 31.2
(C(CH3)3), 26.9 (C-2), 22.3 (C-1); IR 1615 cm-1; MS [IP 70 eV;
m/z (% rel int)] 282 (M+, 49), 199 (100). Anal. Calcd for
C19H26N2‚1/2H2O: C, 78.30; H, 9.34; N, 9.61. Found: C, 78.1;
H, 9.0; N, 9.6.
Ack n ow led gm en t. The authors are grateful to the
Swedish Natural Science Research Council for financial
support and to Dr Anders Karle´n for the molecular
mechanics calculations.
J O971158D