Generation and intermolecular reactions of 3-indolylacyl radicals

Article abstract of DOI:10.1021/jo025842q

The generation of 3-indolylacyl radicals from the corresponding phenyl selenoesters and the scope of their participation in intermolecular addition reactions to carbon-carbon double bonds under both reductive and nonreductive conditions have been studied.

Full text of DOI:10.1021/jo025842q

SCHEME 1
Gen er a tion a n d In ter m olecu la r Rea ction s
of 3-In d olyla cyl Ra d ica ls
M.-Llu¨ısa Bennasar,* Toma`s Roca, Rosa Griera,
Marjan Bassa, and J oan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, Barcelona 08028, Spain
bennasar@farmacia.far.ub.es
Received April 19, 2002
SCHEME 2
Abstr a ct: The generation of 3-indolylacyl radicals from the
corresponding phenyl selenoesters and the scope of their
participation in intermolecular addition reactions to carbon-
carbon double bonds under both reductive and nonreductive
conditions have been studied.
Radical reactions have become an important tool in
synthetic organic chemistry.1 In particular, inter- and
intramolecular addition of nucleophilic acyl radicals2 to
multiple (mainly C-C) bonds constitutes a useful method
for the preparation of unsymmetrical ketones. The reac-
tion of selenoesters with stannyl and tris(trimethylsilyl)-
silyl radicals is one of the most practical ways to generate
these radical intermediates.2 Boger has reported the acyl
transfer reaction of a series of alkyl and aryl phenyl
selenoesters to alkenes using n-Bu3SnH as the radical
mediator.3,4 More recently, we have described how 2-in-
dolylacyl radicals derived from phenyl selenoesters (e.g.,
1, Scheme 1) efficiently participate in intermolecular
addition reactions with electron-deficient alkenes under
reductive conditions to give 1,4-dicarbonyl compounds
bearing the 2-acylindole moiety.5 Furthermore, under
nonreductive conditions (n-Bu6Sn2, hν) 2-indolylacyl radi-
cals undergo a novel cascade reaction involving an
addition-oxidative cyclization sequence to give cyclo-
penta[b]indol-3-ones.6
starting materials for the synthesis of indole derivatives.
This Note deals with our results in the unprecedented
generation of 3-indolylacyl radicals from phenyl sele-
noester precursors7 and their role in intermolecular
reactions with alkenes.
The use of reductive conditions from selenoesters 2a ,b
(Scheme 2) and the alkene acceptors depicted in Table 1
was first investigated. Satisfactorily, the 3-indolylacyl
radical derived from 2a reacted productively with alkenes
bearing electron-withdrawing groups in yields generally
higher than those previously obtained in the 2-acylindole
series.5
Using simple, unsubstituted electron-deficient alkenes
and 2-cyclohexenone (entries 1-3) afforded the corre-
sponding addition products 3-5 in good yields (76-82%)
following Method A (n-Bu3SnH, AIBN), with little or no
competitive acyl radical reduction (0-5%) and no evi-
dence of competitive decarbonylation. More importantly,
these reactions could be conducted using only a 1.5-fold
excess of the alkene acceptor, which is unusual in
intermolecular radical additions. In fact, when reactions
reported in entries 1 and 2 were carried out with the
more common 4- or 5-fold excess of the alkene, the desired
adducts 3 and 4 were isolated in lower yields (40-50%)
together with significant amounts (15-30%) of the
respective bis-addition products 6 and 7.
On the basis of these precedents, we reasoned that the
regioisomeric 3-indolylacyl radicals should also partici-
pate in similar reactions, thus providing access to a
variety of 3-acylindole compounds, which are versatile
* Corresponding author. Phone: 34 934 024 540. Fax: 34 934 024
539.
(1) (a) Curran, D. P. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds; Pergamon: Oxford, 1991; Vol. 4, pp 715-777,
779-831. (b) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma,
G.; Kulicke, K. J .; Trach, F. Org. React. 1996, 48, 301-856. (c) Renaud,
P.; Sibi, M. P., Eds. Radicals in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2001.
(2) For recent reviews on acyl radicals, see: (a) Ryu, I.; Sonoda, N.;
Curran D. P. Chem. Rev. 1996, 96, 177-194. (b) Chatgilialoglu, C.;
Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991-2069.
(3) (a) Boger, D. L.; Mathvink, R. J . J . Org. Chem. 1989, 54, 1777-
1779. (b) Boger, D. L.; Mathvink, R. J . J . Org. Chem. 1992, 57, 1429-
1443.
(4) For more recent examples of intramolecular addition reactions
from alkyl phenyl selenoesters, see: (a) Double, P.; Pattenden, G. J .
Chem. Soc., Perkin Trans. 1 1998, 2005-2007. (b) Evans, P. A.; Raina,
S.; Ahsan, K. Chem. Commun. 2001, 2504-2505, and references
therein.
However, premature reduction of the intermediate
radical to the indolecarbaldehyde partially competed with
(5) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J . Org. Lett. 2001,
3, 1697-1700.
(6) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J . J . Org. Chem.
2001, 66, 7547-7551.
(7) For an isolated example of the generation of a 3-indolylacyl
radical from an indole-3-glyoxylic acid under oxidative (Minisci)
conditions, see: Doll, M. K.-H. J . Org. Chem. 1999, 64, 1372-1374.
10.1021/jo025842q CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/23/2002
6268
J . Org. Chem. 2002, 67, 6268-6271

TABLE 1. In ter m olecu la r Ad d ition Rea ction s of
3-In d olyla cyl Ra d ica ls Der ived fr om P h en yl Selen oester s
2a ,b
SCHEME 3
the addition process when, for electronic or steric reasons,
less reactive acceptors were used (entries 4-6). Using
the poorer hydrogen-atom donor tris(trimethylsilyl)-
silane8 (TTMSS, AIBN, Method B) as the radical media-
tor in the reactions with methyl crotonate or methyl
1-cyclohexenecarboxylate (entries 4 and 5) did not sig-
nificantly improve the yield of the addition products. In
the former case, minor amounts (17%) of tricyclic indoline
8 were also isolated (see below). In contrast, starting from
2a and a small excess of lactams 11 and 13 (entries 6
and 7) under the conditions of Method B provided good
yields of 3-indolyl 4-piperidyl ketones 12 and 14 (64 and
72%, respectively).
As expected,3,5 styrene worked reasonably well as an
acceptor (50%, entry 8) under Method A conditions. The
unexpectedly high yield (45%) obtained with an unacti-
vated alkene (1-octene, entry 9) under Method B condi-
tions was particularly noteworthy and illustrates the
high reactivity of the 3-indolylacyl radical derived from
2a . More in accordance with previous reports,2b,3,9 the
analogous reaction with an electron-rich alkene (entry
10) provided a modest yield (25%) of the adduct 17, the
indolecarbaldehyde being the major product (50%).
When some of the above reactions were extended to
selenoester 2b, which bears a strong electron-withdraw-
ing group at the nitrogen, significant differences in the
reactivity of the corresponding intermediate acyl radicals
were observed, presumably reflecting the influence of the
electronic properties of the indole ring on their nucleo-
philic character.10 In all cases (entries 11-13), the yields
of the addition products 18-20 were lower and, with the
exception of the reaction with methyl acrylate (entry 11),
reduction was a competitive process even under Method
B conditions.
We next studied the reactions of selenoester 2a
with alkene acceptors under nonreductive conditions
(n-Bu6Sn2, hν, Scheme 3). We expected a radical cascade
reaction similar to that observed from selenoester 1
(Scheme 1),6 which would now involve an intermolecular
3-indolylacyl radical addition followed by an oxidative
cyclization11 at the indole 2-position.12
As can be observed in Table 2, the desired annulation
process took place with methyl crotonate or crotonitrile
(entries 1 and 2) to give the corresponding cyclopenta-
(8) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194.
(9) Dang, H.-S.; Roberts, B. P. J . Chem. Soc., Perkin Trans. 1 1998,
67-75.
(10) Small differences in the redox properties of arylacyl radicals
depending on the substitution of the ring have been reported. However,
the relationship between these parameters and the nucleophilic
character of the radical is not well understood. For a discussion, see:
Daasbjerg, K.; Pedersen, S. U.; Lund, H. In General Aspects of the
Chemistry of Radicals; Alfassi, Z. B., Ed.; Wiley: Chichester, UK, 1999;
pp 385-427.
(11) The oxidative cyclization mechanism mediated by Me6Sn2 has
been discussed: (a) J osien, H.; Ko, S. B.; Bom, D.; Curran, D. P. Chem.
Eur. J . 1998, 4, 67-83. (b) Bowman, W. R.; Bridge, C. F.; Cloonan, M.
O.; Leach, D. C. Synlett 2001, 765-768.
a
Method A: n-Bu3SnH, AIBN, C6H6. Method B: TTMSS, AIBN,
C6H6. b Isolated yields. c Recovering of the corresponding 3-indole-
carbaldehyde in 15-25% (50% for entry 10). See text. e A 3:1
d
mixture of cis/trans stereoisomers.
J . Org. Chem, Vol. 67, No. 17, 2002 6269

TABLE 2. n -Bu 6Sn 2-Med ia ted Rea ction s of P h en yl
Selen oester 2a w ith Alk en e Accep tor s
resultant electrophilic (Z ) CO2Me or CN) radical A (or
B, if a double addition occurs) at the also electrophilic
2-position of the 3-acylindole13 giving the benzylic radical
C (or D) must be electronically unfavored.14 In fact, the
5-endo cyclization15 leading to the strained cyclopenta-
[b]indole nucleus was only observed when â-methyl-
substituted alkenes were used as acceptors, probably due
to the presence of a methyl group in the radical adduct
A, which would help to mitigate the above-mentioned
unfavorable factors (Thorpe-Ingold effect).16,17 The isola-
tion of indoline 8, which formally derives from the
reaction of radical C (Z ) CO2Me, R ) Me) with AIBN,6,18
made evident that the radical cascade addition-cycliza-
tion sequence had already occurred from methyl croto-
nate under reductive conditions (TTMSS-AIBN)
Taking into account the above mechanistic consider-
ations, we expected that using unactivated or electron-
rich alkenes in this radical cascade reaction would result
in a slower addition step, but in an electronically more
favorable cyclization of the nucleophilic radical A at the
indole 2-position. Accordingly, whereas 1-octene reacted
sluggishly with selenoester 2a (entry 3, 15%), vinyl
acetate was more efficient leading to a 1:1 mixture of
tricyclic compounds 24 and 25 in higher yield (30%, entry
4), the latter coming from the bis-addition radical B
through the benzylic radical D.
a
b
Isolated yields. A 6:1 mixture of trans/cis stereoisomers. c A
1:1 mixture of cis/trans stereoisomers.
In conclusion, a variety of 3-indolyl ketones, mainly
1,4-dicarbonyl compounds (keto esters, keto nitriles, keto
lactams, diketones), can be prepared through the reaction
of 3-indolylacyl radicals with appropriate acceptors under
reductive conditions. Since the 3-position of indole is the
preferred site for electrophilic substitution, there are
several methods for the direct acylation at this position.19
However, as these methods are not usually very compat-
ible with acid- or base-sensitive indole compounds, our
radical route can provide an alternative approach to
3-indolyl ketones under mild conditions.20 On the other
hand, under nonreductive conditions, 3-indolylacyl radi-
cals are less efficient than 2-indolylacyl radicals in
promoting the radical cascade addition-cyclization se-
quence leading to the cyclopenta[b]indole nucleus when
electron-deficient alkenes are used as acceptors, although
this annulation process is observed with electron-rich
alkenes.
SCHEME 4
(13) Aldabbagh, F.; Bowman, W. R.; Mann, E.; Slawin, A. M. Z.
Tetrahedron 1999, 55, 8111-8128.
[b]indol-1-ones 21 and 22 in moderate yields (32 and 20%,
respectively). However, only complex mixtures were
obtained with acrylonitrile or methyl acrylate, which had
proved to be the best acceptors under reductive condi-
tions. A similar result was obtained with other electron-
deficient alkenes such as dimethyl fumarate or methyl
1-cyclohexenecarboxylate.
(14) As expected from these mechanistic considerations, no produc-
tive reaction was observed from N-benzenesulfonyl selenoester 2b.
(15) For a related example, see: (a) Gribble, G. W.; Fraser, H. L.;
Badenock J . C. Chem. Commun. 2001, 805-806. For more common
5-exo cyclizations onto the indole ring, see inter alia: (b) Ziegler, F.
E.; J eroncic, L. O. J . Org. Chem. 1991, 56, 3479-3486. (c) Moody, C.
J .; Norton, C. L. J . Chem. Soc., Perkin Trans. 1 1997, 2639-2643. (d)
Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Schulte, M.; J ones, K. Chem.
Commun. 2001, 209-210 and references therein.
(16) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994; pp 682-684. (b) For a
recent example, see: Fujita, M.; Matsushima, H.; Sugimura, T.; Tai,
A.; Okuyama, T. J . Am. Chem. Soc. 2001, 123, 2946-2957.
(17) However, no reaction was observed with methyl methacrylate.
(18) For a discussion on the role of azo radical initiators in the
oxidative cyclization step onto aromatic systems, see: Allin, S. M.;
Barton, W. R. S.; Bowman, W. R.; McInally, T. Tetrahedron Lett. 2001,
42, 7887-7890.
These results can be rationalized by considering the
radical cascade reactions depicted in Scheme 4. Whereas
the intermolecular addition to the acceptor was expected
to be a fast reaction, the subsequent cyclization of the
(12) For similar radical cascade reactions involving final cyclizations
onto indoles and related heterocycles, see: (a) Chuang, C.-P.; Wang,
S.-F. Synth. Commun. 1994, 24, 1493-1505. (b) Ozaki, S.; Mitoh, S.;
Ohmori, H. Chem. Pharm. Bull. 1996, 44, 2020-2024. (c) Miranda, L.
D.; Cruz-Almanza, R.; Pavo´n, M.; Romero, Y.; Muchowski, J . M.
Tetrahedron Lett. 2000, 41, 10181-10184.
(19) Sundberg, R. J . Indoles; Academic Press: New York, 1996; pp
105-134.
(20) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.;
Yoshino, H. Org. Lett. 2000, 2, 1485-1487.
6270 J . Org. Chem., Vol. 67, No. 17, 2002

crude product, which was chromatographed (flash, hexanes-
AcOEt). The results are given in Table 1. Eluents, melting
points, NMR data, and HRMS or elemental analyses of selected
compounds are given below.
In d olin e 8: 9:1 hexanes-AcOEt; 1H NMR (300 MHz) δ 1.10
(d, J ) 6.8 Hz, 3H), 1.29 and 1.45 (2 s, 6H), 2.46 (dd, J ) 7.6, 13
Hz, 1H), 2.69 (dddd, J ) 6.8, 12.8 Hz, 1H), 2.87 (s, 3H), 3.83 (s,
3H), 4.46 (d, J ) 7.6 Hz, 1H), 6.45 (d, J ) 8 Hz, 1H), 6.73 (td, J
) 1.2, 7.6 Hz, 1H), 7.23 (td, J ) 1.2, 7.6 Hz, 1H), 7.40 (d, J )
7.6 Hz, 1H); 13C NMR (75.4 MHz) δ 12.2 (CH3), 22.0 (CH3), 22.4
(CH3), 31.5 (CH3), 38.0 (C), 49.0 (CH), 50.2 (CH), 52.6 (CH3),
64.2 (C), 70.7 (CH), 107.1 (CH), 118.1 (CH), 120.8 (C), 123.0 (C),
126.6 (CH), 130.5 (CH), 150.3 (C), 174.3 (C), 210.4 (C).
Exp er im en ta l Section
Gen er a l P r oced u r es. Reaction courses and product mixtures
were routinely monitored by TLC on silica gel (precoated F254
plates). Drying of organic extracts during the workup of reactions
was performed over anhydrous Na2SO4. Evaporation of the
solvents was accomplished under reduced pressure with
a
rotatory evaporator. Flash chromatography was carried out on
SiO2 (silica gel 60, SDS, 0.04-0.06 mm). Melting points are
uncorrected. NMR spectra were recorded in CDCl3 solution,
using TMS as internal reference. Microanalyses and HRMS were
performed by Centro de Investigacio´n y Desarrollo (CSIC),
Barcelona. Lactams 11 and 13 were prepared according to
literature procedures.21
tr a n s-1,3-Bis(ben zyloxyca r bon yl)-4-(1-m eth yl-3-in d olyl-
ca r bon yl)-2-p ip er id on e (14): AcOEt; mp 58-60 °C; 1H NMR
(200 MHz) δ 2.05 and 2.20 (2 m, 2H), 3.73 (m, 1H), 3.73 (s, 3H),
4.0 (m, 2H), 4.26 (d, J ) 10 Hz, 1H), 5.10 and 5.15 (2 d, J ) 16
Hz, 2H), 5.29 (s, 2H), 7.15-7.40 (m, 13H), 7.71 (s, 1H), 8.35 (m,
1H); 13C NMR (50.3 MHz) δ 26.8 (CH2), 33.7 (CH3), 43.3 (CH),
44.2 (CH2), 52.8 (CH), 67.3 (CH2), 68.9 (CH2), 109.8 (CH), 114.3
(C), 122.5 (CH), 123.0 (CH), 123.8 (CH), 126.4 (C), 127.8-128.5
(6 CH), 135.1 (2 C), 136.3 (CH), 137.6 (C), 153.2 (C), 167.7 (C),
168.7 (C), 192.9 (C). Anal. Calcd for C31H28N2O6: C, 70.98; H,
5.38; N, 5.34. Found: C, 70.75; H, 5.56; N, 5.54.
Gen er a l P r oced u r e for In ter m olecu la r Ad d ition Rea c-
tion s of 3-In d olyla cyl Ra d ica ls to Alk en e Accep tor s u sin g
n -Bu 3Sn H-AIBN. n-Bu3SnH (0.8 mmol) in C6H6 (3 mL) was
added over a period of 1 h (syringe pump) to a heated (reflux)
solution of selenoester 2a ,b (0.64 mmol), the alkene acceptor (0.9
or 3.2 mmol), and AIBN (0.06 mmol) in C6H6 (6 mL). After an
additional 2-3 h at reflux, the solution was concentrated under
reduced pressure. The residue was partitioned between hexanes
(5 mL) and acetonitrile (5 mL), and the polar layer was washed
with hexanes (3 × 5 mL) to remove tin compounds. The solvent
was removed, and the crude product was chromatographed
(flash, hexanes-AcOEt). The results are given in Table 1.
Eluents, melting points, NMR data, and HRMS or elemental
analyses of selected compounds are given below.
Meth yl 4-(1-Meth yl-3-in d olyl)-4-oxobu ta n oa te (3): 75:25
hexanes-AcOEt; mp 110-112 °C; 1H NMR (200 MHz) δ 2.79
(t, J ) 7 Hz, 2H), 3.19 (t, J ) 7 Hz, 2H), 3.70 (s, 3H), 3.79 (s,
3H), 7.30 (m, 3H), 7.74 (s, 1H), 8.35 (m, 1H); 13C NMR δ (50.3
MHz) δ 28.3 (CH2), 33.6 (CH3), 34.2 (CH2), 51.8 (CH3), 109.6
(CH), 115.9 (C), 122.4 (CH), 122.5 (CH), 123.3 (CH), 126.1 (C),
Gen er a l P r oced u r e for th e n -Bu 6Sn 2-Med ia ted Rea c-
tion s of P h en yl Selen oester 2a w ith Alk en es. Selenoester
2a (0.65 mmol), the alkene acceptor (2.60 mmol), and n-Bu6Sn2
(0.80 mmol) in C6H6 (30 mL) were refluxed under sun-lamp
irradiation (300 W) for 24 h. The solution was concentrated
under reduced pressure. Workup as above gave the crude
product, which was chromatographed (flash, hexanes-AcOEt).
The results are given in Table 2.
Met h yl 2,4-Dim et h yl-1-oxocyclop en t a [b]in d ole-3-ca r -
boxyla te (21): 6:1 mixture of stereoisomers; 1:1 hexanes-
AcOEt. Major trans isomer: 1H NMR (200 MHz) δ 1.48 (d, J )
7.6 Hz, 3H), 3.25 (qd, J ) 3, 7.2 Hz, 1H), 3.76 (s, 3H), 3.80 (s,
3H), 3.85 (d, J ) 3 Hz, 1H), 7.25-7.35 (m, 3H), 7.96 (m, 1H);
13C NMR (50.3 MHz) δ 17.0 (CH3), 31.3 (CH3), 47.9 (CH), 52.6
(CH), 52.9 (CH3), 110.2 (CH), 118.8 (C), 121.1 (C), 121.4 (CH),
122.6 (CH), 124.0 (CH), 143.4 (C), 160.9 (C), 170.7 (C), 195.2
(C); HRMS calcd for C15H15NO3 257.1052, found 257.1046.
135.3 (CH), 137.3 (C), 173.7 (C), 192.8 (C). Anal. Calcd for C14H15
-
NO3‚1/4H2O: C, 67.32; H, 6.25; N, 5.61. Found: C, 67.17; H,
6.40; N, 5.53.
3-(1-Meth yl-3-in dolylcar bon yl)cycloh exan on e (5): 1:1 hex-
anes-AcOEt; mp 111-112 °C; 1H NMR (200 MHz) δ 1.70-2.20
(m, 4H), 2.40 (m, 2H), 2.48 (dd, J ) 4.2, 13.8 Hz, 1H), 2.82 (dd,
J ) 11, 14.6 Hz, 1H), 3.52 (m, 1H), 3.86 (s, 3H), 7.30 (m, 3H),
7.75 (s, 1H), 8.39 (m, 1H); 13C NMR (50.3 MHz) δ 25.3 (CH2),
29.0 (CH2), 33.7 (CH3), 41.2 (CH2), 43.9 (CH2), 47.3 (CH), 109.7
(CH), 114.7 (C), 122.5 (CH), 122.9 (CH), 123.6 (CH), 126.4 (C),
135.3 (CH), 137.6 (C), 195.1 (C), 211.2 (C); HRMS calcd for
C16H17NO2 255.1259, found 255.1262.
Gen er a l P r oced u r e for th e In ter m olecu la r Ad d ition
Rea ction s of 3-In d olyla cyl Ra d ica ls to Alk en e Accep tor s
u sin g TTMSS-AIBN. TTMSS (1.28 mmol) and AIBN (1.28
mmol) in C6H6 (4 mL) were added over a period of 2 h (syringe
pump) to a heated (reflux) solution of selenoester 2a ,b (0.64
mmol) and the alkene acceptor (0.9 or 3.2 mmol) in C6H6 (12
mL). After an additional 2-3 h at reflux, the solution was
concentrated under reduced pressure. Workup as above gave the
Ackn owledgm en t. Financial support from the “Min-
isterio de Ciencia y Tecnologı´a” (Spain, Project BQU2000-
0785) is gratefully acknowledged. Thanks are also due
to the DURSI (Generalitat de Catalunya) for Grant
2001SGR00084.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for the preparation of 2a ,b, characterization data for
1
compounds 2a ,b, 4, 6, 7, 9, 10, 12, 15-20, and 22-25, and H
and 13C NMR for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Casamitjana, N.; Lo´pez, V.; J orge, A.; Bosch, J .; Molins, E.; Roig,
A. Tetrahedron 2000, 56, 4027-4042.
J O025842Q
J . Org. Chem, Vol. 67, No. 17, 2002 6271