Novel 7- and 8-endo 2-indolylacyl radical cyclizations: Efficient construction of azepino-and azocinoindoles

Article abstract of DOI:10.1021/jo070322m

(Chemical Equation Presented) Regioselective 7- and 8-endo cyclizations of selenoester derived 2-indolylacyl radicals upon amino tethered alkenes have been used to synthesize azepino[3,2-b]- and azocino-[4,3-b]indoles, which are tricyclic subunits present

Full text of DOI:10.1021/jo070322m

efficiently assembled by cyclization of N-alkenyl substituted
2-indolylacyl radicals under reductive conditions.6,7 We went
on to consider extending the above annulation methodology to
the construction of higher homologues, in particular 7- and
8-membered azacycles that are fused to the 2,3-position of the
indole ring, which are subunits present in several indole
alkaloids8 such as mersicarpine9 or apparicine.10 In this context,
we wished to investigate if 2-indolylacyl radicals of general
formula I (6-heptenoyl radicals) and II (7-octenoyl radicals)
would undergo regioselective 7- and 8-endo cyclizations upon
amino tethered alkenes, which would ultimately lead to the target
tricyclic substructures (Scheme 1).
Novel 7- and 8-Endo 2-Indolylacyl Radical
Cyclizations: Efficient Construction of Azepino-
and Azocinoindoles†
M.-Llu¨ısa Bennasar,* Toma`s Roca, and Davinia Garc´ıa-D´ıaz
Laboratory of Organic Chemistry, Faculty of Pharmacy,
UniVersity of Barcelona, Barcelona 08028, Spain
bennasar@ub.edu
ReceiVed February 16, 2007
Neither radical process was evident a priori. It is well accepted
that the 6-exo ring closure of 6-heptenyl-type radicals is
generally preferred to the alternative 7-endo cyclization,11
although the latter can be competitive and, in some particular
substrates, preponderant.12 Acyl radicals13 exhibit an even higher
tendency to undergo 6-exo cyclizations,14,15 in particular those
intermediates that bear a phenyl group in the tether between
the radical and the acceptor,16 which are closely related to
indolylacyl derivatives I. More favorable to our purposes,
cyclizations of 7-octenyl-type radicals, when feasible, prefer-
entially take place through the 8-endo mode, and several elegant
examples, which mainly involve R-carbonyl radicals, have been
recently reported.17 However, the 8-endo cyclization of acyl
radicals13 is rare and is usually limited to conformationally
Regioselective 7- and 8-endo cyclizations of selenoester
derived 2-indolylacyl radicals upon amino tethered alkenes
have been used to synthesize azepino[3,2-b]- and azocino-
[4,3-b]indoles, which are tricyclic subunits present in the
indole alkaloids mersicarpine and apparicine, respectively.
Radical cyclizations are recognized as powerful tools in
organic synthesis,1 as is illustrated by numerous reports that
deal with the construction of 5- and 6-membered carbo- and
heterocyclic rings in the context of the synthesis of complex
molecules.1,2 In contrast with this intense activity, kinetically
less favorable cyclizations leading to 7- or 8-membered rings,
which can be found in the skeleton of many natural and synthetic
compounds, have been comparatively less studied.3
As part of a research program aimed at the synthesis of
bioactive indole compounds using selenoester derived 2-indolyl-
acyl radicals,4,5 we have previously reported that valuable 5-
and 6-membered indolo 1,2-fused carbocyclic ketones are
(6) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2004, 6, 759-
762.
(7) For the formation of a 6-membered 2,3-fused carbocyclic ring, see:
Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org. Chem. 2006, 71, 1746-
1749.
(8) (a) Sundberg, R. J. Indoles; Academic Press: New York, 1996. (b)
Joule, J. A. Science of Synthesis; Houben-Weyl, Methods of Molecular
Transformations; Georg Thieme Verlag: Stuttgart, 2000; Vol. 10, pp 361-
652. (c) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73-103 and
761-793.
(9) Kam, T.-S.; Subramaniam, G.; Lim, K.-H.; Choo, Y.-M. Tetrahedron
Lett. 2004, 45, 5995-5998.
(10) Joule, J. A. Indoles, The Monoterpenoid Indole Alkaloids; Saxton,
J. E. Ed.; Wiley: New York, 1983; Vol 25, pp 265-292.
(11) (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-
3941. (b) For a more recent study of 6-heptenyl radical cyclizations, see:
Bailey, W. F.; Longstaff, S. C. Org. Lett. 2001, 3, 2217-2219.
(12) For instance, see: (a) Justicia, J.; Oller-Lo´pez, J. L.; Campan˜a, A.
G.; Oltra, J. E.; Cuerva, J. M.; Bun˜uel, E.; Ca´rdenas, D. J. J. Am. Chem.
Soc. 2005, 127, 14911-14921. (b) Taniguchi, T.; Ishita, A.; Uchiyama,
M.; Tamura, O.; Muraoka, O.; Tanabe, G.; Ishibashi, H. J. Org. Chem.
2005, 70, 1922-1925.
(13) For a review on acyl radical chemistry, see: Chatgilialoglu, C.;
Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991-2069.
(14) For a study of the regioselectivity of 6-heptenoyl radical cyclizations
that depend on the substitution, see: (a) Crich, D.; Fortt, S. M. Tetrahedron
1989, 45, 6581-6598. (b) Crich, D.; Eustace, K. A.; Fortt, S. M.; Ritchie,
T. J. Tetrahedron 1990, 46, 2135-2148.
(15) For regioselective 7-endo cyclizations, see: (a) Batty, D.; Crich,
D. Tetrahedron Lett. 1992, 33, 875-878. (b) Ohtsuka, M.; Takekawa, Y.;
Shishido, K. Tetrahedron Lett. 1998, 39, 5803-5806.
† Dedicated to Professor Joan Bosch on the occasion of his 60th birthday.
* To whom correspondence should be addressed. Tel: 34 934 024 540, Fax:
34 934 024 539.
(1) For leading reviews, see (a) Renaud, P.; Sibi, M. P., Eds.; Radicals
in Organic Synthesis; Wiley-VCH: Weinheim, 2001. (b) Gansa¨uer, A., Ed.;
Topics Current Chemistry; Radicals in Synthesis I and II; Springer: Berlin;
2006; Vols. 263 and 264.
(2) For specific reviews on the synthesis of heterocycles by radical
cyclization, see (a) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem.
Soc,. Perkin Trans. 1 2002, 2747-2762. (b) Majumdar, K. C.; Basu, P.
K.; Chattopadhyay, S. K. Tetrahedron 2007, 63, 793-826, and previous
reviews in these series.
(3) For reviews on the use of radical cyclizations for the synthesis of
medium-sized rings, see: (a) Yet, L. Tetrahedron 1999, 55, 9349-9403.
(b) Srikrishna, A. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds; Wiley-VCH: Weinheim, 2001; Vol 2, pp 163-187.
(4) For intermolecular reactions of 2-indolylacyl radicals with alkenes,
see: (a) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. Org. Lett. 2001,
3, 1697-1700. (b) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. J. Org.
Chem. 2001, 66, 7547-7551.
(16) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429-1443.
(17) For instance, see: (a) Udding, J. A.; Giesselink, J. P. M.; Hiemstra,
H.; Speckamp, W. N. J. Org. Chem. 1994, 59, 6671-6682. (b) Lee, E.;
Yoon, C. H.; Lee, T. H.; Kim, S. Y.; Ha, T. J.; Sung, Y.-S.; Park, S.-H.;
Lee, S. J. Am. Chem. Soc. 1998, 120, 7469-7478. (c) Liu, L.; Chen, Q.;
Wu, Y. D.; Li, C. J. Org. Chem. 2005, 70, 1539-1544. (d) Lang, S.; Corr,
M.; Muir, N.; Khan, T. A.; Scho¨nebeck, F.; Murphy, J. A.; Payne, A. H.;
Williams, A. C. Tetrahedron Lett. 2005, 46, 4027-4030. (e) El Ka¨ım, L.;
Grimaud, L.; Miranda, L. D.; Vieu, E. Tetrahedron Lett. 2006, 47, 8259-
8261.
(5) For cyclizations of 2-indolylacyl radicals upon (hetero)aromatic rings,
see: (a) Bennasar, M.-L.; Roca, T.; Ferrando, F. Tetrahedron Lett. 2004,
45, 5605-5609. (b) Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org. Chem.
2005, 70, 9077-9080. (c) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org.
Lett. 2006, 8, 561-564.
10.1021/jo070322m CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/09/2007
4562
J. Org. Chem. 2007, 72, 4562-4565

SCHEME 1
SCHEME 3
from the direct hydrogen abstraction from the hydride or from
an eventual [1,5]-hydrogen atom transfer was observed.
More satisfactorily, the inclusion of a carbamate nitrogen
atom in the connecting chain enhanced the 7-endo regioselec-
tivity, although the formation of the six-membered ring still
predominated. Thus, the amino tethered selenoester 4a, upon
subjection to the above protocol, led to a 1.5:1 mixture of exo-
endo products, from which the desired azepino[3,2-b]indole 6
could be isolated in a significant 29% yield along with
pyridoindole 5 (45% yield).23 At this point, we explored the
possibility of increasing the amount of endo product by carrying
out the radical cyclization at lower hydride concentrations. Our
aim was to shift the equilibration of the initially formed cyclized
radicals A and B (Scheme 3, n ) 0, X ) NCO2Me, Y ) CH2)
in favor of the thermodynamically more stable endo radical B
through an intramolecular rearrangement that results in ring
expansion.24 Unfortunately, the exo-endo product ratio was not
significantly modified by the hydride concentration (0.07, 0.02,
or 0.005 M), so we assumed that such a rearrangement was not
included in the reaction pathway.
SCHEME 2. 6-Heptenoyl Radical Cyclizations
Finally, the 7-endo closure became the predominant route
when a temporary substituent, such as a bromine atom, was
introduced at the 6-exo position of the alkene acceptor.25,26
Treatment of selenoester 4b, which incorporated a 2-bromo-2-
propenyl instead of an allyl moiety, with n-Bu3SnH (2 M equiv)
led to a mixture of the same two products 5 and 6 but in a
different ratio (approximately 1:3). The excess hydride ensured
the final reductive removal of the bromine atom after the
cyclization step. In this manner, the tricyclic substructure of
mersicarpine (6) was isolated as the major product in a
synthetically acceptable 62% yield along with minor amounts
(19%) of 5.
Attention was then directed to 7-octenoyl radicals II (Scheme
1) with the final aim of achieving the azocino[4,3-b]indole
substructure of apparicine. The feasibility of the desired 8-endo
cyclization was tested using a range of precursor selenoesters,
bearing different five-atom chains (4-pentenyl, 3-butenylamino,
or allylaminomethyl) at the indole 3-position.22 In full ac-
cordance with our previous results using the regioisomeric
N-substituted radicals,6 no cyclization was observed when the
model selenoester 7 was treated with n-Bu3SnH-Et3B under
different conditions, and only aldehyde 8 could be isolated from
the reaction mixtures (60-80% yield, Scheme 4). Reduction
restricted substrates.18 Most of the reported examples deal with
7-exo cyclizations upon diversely substituted alkenes.16,19-21
To examine the behavior of 6-heptenoyl radicals I we focused
our attention on selenoesters 1 and 4 (Scheme 2), which were
prepared from the respective 3-substituted indole-2-carboxylic
esters.22 Consistent with the above precedents as well as with
our previous results using the regioisomeric N-(3-butenyl)-2-
indolylacyl radicals,6 treatment of the model selenoester 1 with
2 M equiv of n-Bu3SnH with Et3B as the initiator in benzene
(0.07 M) led to the 6-exo carbocyclic ketone 2 as the major
product (62% yield), although in this case the 7-endo product
3 could also be isolated from the reaction mixture (11% yield).
No evidence of radical reduction (i.e., formation of an aldehyde)
(18) (a) Crich, D.; Chen, C.; Hwang, J.-T.; Yuan, H.; Papadatos, A.;
Walter, R. I. J. Am. Chem. Soc. 1994, 116, 8937-8951. (b) De Boeck, B.;
Herbert, N.; Pattenden, G. Tetrahedron Lett. 1998, 39, 6971-6974.
(19) For 7-exo acyl radical cyclizations on electron-deficient alkenes,
see: (a) Evans, P. A.; Roseman, J. D.; Garber, L. T. J. Org. Chem. 1996,
61, 4880-4881. (b) Evans, P. A.; Manangan, T. J. Org. Chem. 2000, 65,
4523-4528. (c) Evans, P. A.; Manangan, T.; Rheingold, A. L. J. Am. Chem.
Soc. 2000, 122, 11009-11010. (d) Evans, P. A.; Raina, S.; Ahsan, K. Chem.
Commun. 2001, 2504-2505. (e) Quirante, J.; Vila, X.; Escolano, C.;
Bonjoch, J. J. Org. Chem. 2002, 67, 2323-2328.
(20) For a recent example of a 7-exo acyl radical cyclization on an
unactivated alkene, see: (a) Grant, S. W.; Zhu, K.; Zhang, Y.; Castle, S.
L. Org. Lett. 2006, 8, 1867-1870. For 7-exo acyl radical cyclizations on
enol ethers, see: (b) Inoue, M.; Ishihara, Y.; Yamashita, S.; Hirama, M.
Org. Lett. 2006, 8, 5801-5804 and 5805-5808.
(23) The same result was obtained using AIBN as the initiator in refluxing
benzene.
(24) For discussions, see: (a) Beckwith, A. L. J.; O’Shea, D. M.;
Westwood, S. W. J. Am. Chem. Soc. 1987, 110, 2565-2575. (b) Dowd,
P.; Zhang, W. Chem. ReV. 1993, 93, 2091-2115. (c) Chatgilialoglu, C.;
Ferreri, C.; Lucarini, M.; Venturini, A.; Zavitsas, A. A. Chem.sEur. J.
1997, 3, 376-387. See also ref 16.
(21) For 7-exo acyl radical cyclizations on carbon-nitrogen double bonds,
see: (a) Ryu, I.; Miyazato, H.; Kuriyama, H.; Matsu, K.; Tojino, M.;
Fukuyama, T.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2003, 125,
5632-5633. (b) Tojino, M.; Otsuka, N.; Fukuyama, T.; Matsubara, H.;
Schiesser, C. H.; Kuriyama, H.; Miyazato, H.; Minakata, S.; Komatsu, M.;
Ryu, I. Org. Biomol. Chem. 2003, 1, 4262-4267.
(25) For similar halogen-controlled 7-endo aryl,25a vinyl,25b or alkyl25c
radical cyclizations, see: (a) Kamimura, A.; Taguchi, Y. Tetrahedron Lett.
2004, 45, 2335-2337. (b) Padwa, A.; Rashatasakhon, P.; Ozdemir, A. D.;
Willis, J. J. Org. Chem. 2005, 70, 519-528. (c) Sharp, L. A.; Zard, S. Z.
Org. Lett. 2006, 8, 831-834.
(22) See the Supporting Information for the preparation of all radical
precursors.
(26) For halogen-controlled 7- and 8-endo amidyl radical cyclizations,
see: Hu, T.; Shen, M.; Chen, Q.; Li, C. Org. Lett. 2006, 8, 2647-2650.
J. Org. Chem, Vol. 72, No. 12, 2007 4563

TABLE 1. Cyclization of 5-Aza-7-octenoyl Radicalsa
SCHEME 4. Unsuccessful 7-Octenoyl Radical Cyclizations
SCHEME 5. Cyclization of 4-Aza-7-octenoyl Radicals
radical
entry precursor
concn endo:exo
endo:exo
aldehyde
(M)
ratio
yield (%)b
yield (%)b
1
2
3
4
14a
14a
14a
14b
0.02
0.14
0.005
0.005
3:1
1:1
7:1
4:1
15a (32), 16a (10) 17a (42)
15a (10), 16a (10) 17a (50)
15a (55), 16a (8)
17a (25)
15b (40), 16b (11) 17b (15)c
to 8 was also observed when the poorer hydrogen-atom donor
(Me3Si)3SiH was used as the radical mediator.
a Reaction conditions: n-Bu3SnH (2 M equiv), Et3B (2 M equiv), C6H6,
rt. b Isolated yields after column chromatography. c 5% Unreacted sele-
noester.
After the above unsuccessful result in the carbocyclic series,
we were pleased to find that the inclusion of a carbamate or
amide nitrogen atom in the chain enabled the cyclization to
proceed. Significantly, the regioselectivity of the ring closure
depended upon the position of the heteroatom, although the
8-endo route clearly predominated. When selenoester 11, a
precursor of 4-aza-7-octenoyl radicals, was subjected to the usual
reductive protocol (n-Bu3SnH, Et3B, 0.07 M) the azocino[3,2-
b]indole 12, which is a higher homologue of the mersicarpine
substructure 6, was isolated as the only cyclized product (38%)
along with minor amounts of aldehyde 13 (21%). Satisfactorily,
the premature reduction of the acyl radical could be minimized
(16%) by performing the cyclization in a more dilute solution
(0.02 M), to give access to 12 in a 54% yield (Scheme 5).
On the other hand, the cyclization of 5-aza-7-octenoyl radicals
that were derived from selenoesters 14 followed a different
course because it led to mixtures of 8-endo and 7-exo products
in ratios that were dependent on the hydride concentration. The
results are summarized in Table 1. As can be observed,
cyclization of N-acetyl selenoester 14a at a hydride concentration
of 0.02 M gave a 3:1 mixture of azocino[4,3-b]indole 15a and
azepino[4,3-b]indole 16a (entry 1). Nearly equimolecular
amounts (with respect to cyclized products) of the corresponding
aldehyde 17a were also obtained, which indicated that the
reduction of the acyl radical was a serious competitor in these
series. Significantly, the use of more concentrated solutions
(0.14 M, entry 2) not only resulted in a predictable major
reduction but also in an increase of the relative amounts of the
7-exo product 16a with respect to 15a. In contrast, the use of
highly diluted solutions (0.005 M, entry 3) led to a 7:1 mixture
of the endo-exo products, from which the tricyclic substructure
of apparicine 15a was isolated in a 55% yield. The analogous
tricyclic compound 15b could also be obtained as the major
product by applying this protocol to N-Boc selenoester 14b.
The above results clearly indicated that the rearrangement
between cyclized radicals A and B that are depicted in
Scheme 3 (n ) 1, X ) CH2, Y ) NAc or NBoc) was now
included in the reaction pathway and played a key role in the
enhancement of the 8-endo regioselectivity.
SCHEME 6. Synthesis of Azocino[4,3-b]indoles
the internal position either by a bromine atom26 or by a methyl
group (Scheme 6). Whereas both substituents sterically pre-
vented the competitive 7-exo attack, the halogen atom also
benefited the cyclization, probably by activation of the double
bond. Thus, the apparicine substructure 15a was cleanly obtained
(75% yield) from bromovinyl substituted selenoester 18, without
evidence of seven-membered ring formation or premature
reduction even when working at 0.02 M. Meanwhile, selenoester
19, which incorporated a (2-methyl-2-propenyl)amino moiety,
gave azocinoindole 20 in a lower yield (40%) along with minor
amounts of aldehyde 21 (11%).
Although not directly relevant to our targeted alkaloids, we
also examined the behavior of 7-octenoyl radicals that were
derived from selenoester 9 (Scheme 4) to see if a tetracyclic
system might be constructed after the radical addition to the
cyclic double bond. However, both 7-exo and 8-endo routes
were too slow for the radical chain to be productive, and only
aldehyde 9 was formed.
In conclusion, our study has shown that 7- and 8-endo
cyclizations of suitably substituted 2-indolylacyl radicals are
viable methods for the construction of 7- and 8-membered rings
fused to the 2,3-position of the heterocycle. The presence of a
substituted nitrogen atom in the tether is crucial for both the
enhancement of the endo regioselectivity and the feasibility of
Gratifyingly, the regioselectivity was completely switched to
the 8-endo mode when the alkene acceptor was substituted at
4564 J. Org. Chem., Vol. 72, No. 12, 2007

δ 1.94 and 2.16 (2 s, 3H, Me), 2.01 and 2.11 (2 m, 2H, H-4), 2.91
and 3.02 (2 m, 2H, H-5), [3.53 (t, J ) 6 Hz) and 3.79 (t, J ) 6
Hz), 2H, H-3], 3.86 and 4.05 (2 s, 3H, NMe), 4.92 and 5.13 (2 s,
2H, H-1), 7.20 (m, 1H, H-10), 7.40 (m, 2H, H-8,9), [7.61 (d, J )
8.1 Hz) and 7.82 (d, J ) 8.1 Hz), 1H, H-11]; 13C NMR (75.4 MHz,
HSQC and HMBC) δ 21.7 and 22.1 (Me), 24.6 and 26.5 (C-4),
31.7 and 32.7 (NMe), 41.0 and 42.2 (C-5), 42.1 and 45.8 (C-1),
45.5 and 46.7 (C-3), 110.2 and 110.5 (C-8), 117.8 and 118.4 (C-
11b), 119.3 and 121.0 (C-11), 120.7 and 120.8 (C-10), 124.9 (C-
11a), 125.5 and 126.5 (C-9), 133.4 and 134.1 (C-6a), 138.1 and
138.8 (C-6b), 169.9 and 171.0 (NCO), 194.2 and 198.1 (C-6);
HRMS [M + H]+ calcd for C16H19N2O2 271.1441, found 271.1447.
the ring closure. From the synthetic standpoint, the best yields
of azepinoindole 6 and azocinoindole 15a, related to the
alkaloids mersicarpine and apparicine, respectively, are obtained
by endo cyclizations that are controlled by vinylic halogen
substitution. The application of this work to the synthesis of
the natural products is currently underway in our laboratory.
Experimental Section
Representative Cyclization Procedure: 2-Acetyl-7-methyl-
1,2,3,4,5,7-hexahydroazocino[4,3-b]indol-6-one (15a). n-Bu3SnH
(0.16 mL, 0.60 mmol) and Et3B (1 M in hexanes, 0.60 mmol) were
added to a solution of the phenyl selenoester 18 (0.15 g, 0.30 mmol,
previously dried azeotropically with anhydrous C6H6) in anhydrous
C6H6 (30 mL). The reaction mixture was stirred at rt for 2 h with
dry air constantly supplied by passing compressed air through a
short tube of Drierite. The reaction mixture was concentrated. The
residue was partitioned between hexanes (15 mL) and acetonitrile
(15 mL), and the polar layer was washed with hexanes (3 ×
15 mL). The acetonitrile solution was concentrated, and the crude
product was chromatographed (3:7 hexanes-AcOEt) to give 15a
(oil, 60 mg, 75% yield): 1H NMR (300 MHz, HSQC and HMBC)
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia, Spain, for financial support (project CTQ2006-00500/
BQU) and a predoctoral grant (FPU program) to D.G.D.
Supporting Information Available: Experimental procedures
and characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO070322M
J. Org. Chem, Vol. 72, No. 12, 2007 4565