Tunable, Regioselective control of iodine-catalyzed allylic substitution of cyclic Baylis-Hillman adducts with indoles

Article abstract of DOI:10.1055/s-0029-1218275

Regioselective control over the nucleophilic substitution of cyclic Baylis-Hillman alcohols with indoles has been developed under the catalysis of molecular iodine. The reaction provided γ-substituted products in THF, whereas the α-products were obtained

Full text of DOI:10.1055/s-0029-1218275

LETTER
2965
Tunable, Regioselective Control of Iodine-Catalyzed Allylic Substitution of
Cyclic Baylis–Hillman Adducts with Indoles
A
llylic Substitu
a
tion of
C
yc
h
lic Baylis–H
i
illman
d
S
a
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, P. R. of China
Fax +86(10)62554449; E-mail: lliu@iccas.ac.cn; E-mail: yjchen@iccas.ac.cn
b
Department of Chemistry, B. Z. University, Multan-60800, Pakistan
Received 3 July 2009
some reports on their g-regioselectivity (Figure 1).9 As a
part of our continuing efforts to study the applications of
cyclic B–H adducts in organic synthesis,8a herein we wish
to report the highly a- and g-regioselective reactions of
Abstract: Regioselective control over the nucleophilic substitution
of cyclic Baylis–Hillman alcohols with indoles has been developed
under the catalysis of molecular iodine. The reaction provided g-
substituted products in THF, whereas the a-products were obtained
in TFE via an acid-catalyzed [1,3]-sigmatropic carbon skeleton re- cyclopent-2-enone-derived Baylis–Hillman adducts with
indoles,8a,10 in the presence of catalytic amounts of molec-
arrangement of allylindoles.
ular iodine in different solvents. Furthermore, the applica-
tion of allylic substitution products in the synthesis of
azepino[4,3,2-cd]indoles is also demonstrated.
Key words: Baylis–Hillman adducts, indoles, molecular iodine,
regioselectivities, allylic substitution
Nu:
R
OR'
O
Recently, Baylis–Hillman (B–H) adducts are attracting
much attentions in organic synthesis as valuable synthons
and starting materials due to their ready availability and
the presence of versatile allylic hydroxyl and Michael ac-
ceptor functionalities.1 Allylic alkylation of B–H adducts
has been used in an amazing number of applications in the
synthesis of many bioactive molecules and natural prod-
ucts.1,2
α
γ
Nu:
Figure 1 Regioselectivities of cyclic Baylis–Hillman adducts as un-
symmetrically bis-substituted allylic electrophiles in nucleophilic
substitution reactions
Of great significance in allylic substitution reactions is the
problem of regioselective control, especially for unsym-
metrically substituted substrates.3 In some cases, allylic
alkylation for monosubstituted allylic alcohols or esters
could proceed with regiocontrol by forming branched or
linear products. For example, acyclic B–H adducts could
provide the allylic substitution product either at the g-
position under metal catalysis and inorganic base promo-
tion via SN2¢ reaction,4 or at the a-position under organic
base catalysis via an SN2¢–SN2¢ reaction.5 However, the
question of how to regioselectively introduce a nucleo-
phile at either the a- or g-position of unsymmetrically bis-
substituted allylic electrophiles is still a challenge for syn-
thetic chemists.
Initially, in the presence of various Lewis acids, 2-meth-
ylindole (1a) was found to react with 2-(hydroxyphenyl-
methyl)cyclopent-2-enone (2a) to provide a mixture of
the allylic substitution products a-3a and g-4a (Table 1).
InBr3 and AgOTf catalysis were found to favor a-selectiv-
ity (entries 1 and 3). In contrast, FeCl3 generated a little
more g-product, but the conversion was still not complete
even after refluxing for 12 hours in dichloromethane (en-
try 2). Molecular iodine showed the best catalytic effi-
ciency and better g-selectivity than other catalysts (entry
4). Although palladium catalyst10a and DABCO5a–e exhib-
ited good catalytic reactivity for the reaction of acyclic B–
H adducts with various nucleophiles, the Pd-catalyzed re-
action of cyclic B–H adduct 2a with 1,2-dimethylindole
Cyclic B–H adducts derived from cyclic enones are im- 1d provided mainly the a-product (a:g = 7:1, entry 6).
portant starting materials in the Baylis–Hillman reaction,6 DABCO lost its catalytic ability in the allylic substitution
and could be used to generate fused cyclic frameworks.7 reaction of cyclic B–H adduct 1a and only starting mate-
However, a mixture of regioisomers may form from the rials were recovered (entry 5). Molecular iodine, as a
cyclic B–H adducts due to their cyclic, unsymmetrically readily available, non-toxic catalyst, has been widely used
disubstituted allylic structures and this certainly creates in various organic transformations.11 We and others have
some disadvantages. In some cases, cyclic B–H adducts demonstrated that the nucleophilic substitution of allylic
could react with high a-regioselectivity in the presence of alcohols or esters with C-, N- or S-nucleophiles could be
transition-metal catalysis,8 however, there have been catalyzed by iodine.12 Inspired by the highly efficient I2-
catalyzed allylic substitution reaction of B–H adduct 2a
with 1a, various solvents were used in this reaction in or-
SYNLETT 2009, No. 18, pp 2965–2970
Advanced online publication: 09.10.2009
DOI: 10.1055/s-0029-1218275; Art ID: W10509ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9
der to optimize the regioselectivity of the reaction
(Table 2). Non-protic solvents such as dichloromethane,
toluene, Et2O and THF favored g-regioselectivity, and
4a13 was obtained as the major product (Table 2, entries

2966
Z. Shafiq et al.
LETTER
Table 1 Nucleophilic Substitution of B–H Adduct 2a with Indole 1a under Different Conditions
O
NH
OH
O
catalyst (10 mol%)
solvent
O
+
+
N
H
HN
1a
2a
3a
4a
Entry
Catalyst
InBr3
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF–H2O
AcOH
Temp. (°C)
reflux
reflux
reflux
r.t.
Time (h)
Conv. (%)a
100
Ratio a:ga
1
2
3
4
5
6c
12
12
6
4:1
FeCl3
86
1:1.6
1.2:1
1:2.7
–
AgOTf
I2
100
3
100
DABCOb
r.t.
24
0.5
n.r.d
Pd(acac)2/Ph3P
80
100
7:1
a Determined by 1H NMR.
b DABCO (1.1 equiv).
c Reaction conditions: Pd(acac)2 (10 mol%), Ph3P (20 mol%), 1,2-dimethylindole 1d instead of 1a.
d No reaction.
2–4; Table 1, entry 4); THF provided the best g-regiose- could be entirely controlled simply by switching the sol-
lectivity (a:g = 1:16). In protic solvents such as MeOH vent. The scope of the reaction was explored with respect
and EtOH, the reaction afforded an almost 1:1 mixture of to various indoles and cyclic B–H adducts, and the substi-
a- and g-products. However, when trifluoroethanol (TFE) tution products were obtained in good to excellent yields
under reflux was used as the solvent, the a-product 3a13 (Table 3). In the presence of iodine (10 mol%), the reac-
was formed as the major product (a:g = 24:1). Without tion mainly provided g-products 4 in THF, whereas a-
any catalyst, no reaction was observed in either THF or products 3 were obtained in TFE in a relative longer reac-
TFE (entries 9 and 10).
tion time. The substituents in the phenyl ring of cyclic B–
H adducts have little effect on the reaction (entries 1–7).
However, there were two exceptions: the reaction of sim-
ple indole 1b with 2a in THF also showed low g-selectiv-
ity (g:a = 2.8:1) based on isolated yields (entry 14), and
the reaction of 1e with 2a in TFE provided low a-selectiv-
ity (g:a = 1:2.8; entry 19).
Under the optimized reaction conditions, the regioselec-
tivities of the reactions of indoles with cyclic B–H adducts
Table 2 Solvent Effects in I2-Catalyzed Reaction of B–H Adduct 2a
with Indole 1aa
Interestingly, when the reactions were carried out in TFE,
it was found that the ratios of a- to g-products increased as
the reaction proceeded. For example, when 2-methylin-
dole (1a) was reacted with B–H adduct 2a, in the presence
of iodine in refluxing TFE, the products were obtained
with an a/g ratio of 1.2:1 after 30 minutes, and a 1.9:1 ra-
tio after one hour. After B–H adduct 2a was completely
consumed (1.5 h), the ratio of a-3a to g-4a increased to
9:1. When stirring of the reaction mixture was continued
under the same conditions for an additional 1.5 hours (to-
tal reaction time: 3 h), the ratio of a/g-product reached
24:1. The results demonstrated that there should be a con-
version from the g-product 4a into the a-product 3a dur-
ing the course of the reaction of 1a with 2a.
Entry Solvent Temp. (°C) Time (h) Conv. (%)b Ratio a:gb
1
2
Toluene r.t.
2
80
1:2.2
1:5.5
1:16
1:6.1
1:1.1
1:1
Et2O
THF
r.t.
r.t.
9
66
3
10
1
100
100
100
100
100
–
4
Dioxane r.t.
6
MeOH
EtOH
TFE
r.t.
2
7
reflux
reflux
reflux
reflux
3
8
3
24:1
n.r.d
n.r.d
9c
10c
TFE
3
Further investigations verified the rearrangement of g-4a
into a-3a (Scheme 1). In the presence of iodine (10 mol%)
in refluxing TFE, 82% of g-4a was converted into a-3a
after three hours. However, no conversion from a-3a into
g-4a could be observed under the same conditions
THF
3
–
a Cat: 10 mol%.
b Determined by 1H NMR.
c Without catalyst.
d No reaction.
Synlett 2009, No. 18, 2965–2970 © Thieme Stuttgart · New York

LETTER
Allylic Substitution of Cyclic Baylis–Hillman Adducts with Indoles
2967
(Scheme 1). Since the reaction of iodine with TFE under
reflux conditions could generate HI, the direct use of
aqueous HI was tested and also found to result in a high
conversion (90%). TFE is the best solvent and, even with-
out any catalyst, 4a in refluxing TFE could also be con-
verted into 3a in 11% yield after three hours.14 However,
in the presence of 10 mol% iodine in refluxing THF, no
rearrangement was observed and 4a was recovered after
12 hours. Based on these experimental results, it could be
concluded that the excellent a-regioselectivity in the
iodine-catalyzed reaction of 1a with 2a in TFE could be
ascribed to a 1,3-shift of the indolyl group from product
4a to 3a.15
O
NH
I2 (10 mol%)
TFE, reflux, 3 h
O
HN
4a
3a
Scheme 1 [1,3]-Sigmatropic carbon rearrangement of 4a to 3a
Table 3 I2-Catalyzed Regioselective Reaction of Indoles 1 with Cyclic B–H Adducts 2 in THF and TFE
R3
R4
R1
O
N
OH
O
R2
I2 (10 mol %)
solvent, reflux
O
R2
R1
R2
+
+
N
R1
R3
R4
N
1
2
R4
R3
3a–k
4a–k
Entry
1
2
Solvent
Time (h)
Yield of 3/4 (%)a
78/–, 3a/4a
OH
O
1
2
TFE
THF
3
N
H
1a
1a
2a
2a
0.5
–/92, 3a/4a
OH
O
O
O
3
4
5
6
7
1a
1a
1a
1a
1a
TFE
THF
TFE
THF
TFE
2
81/–, 3b/4b
–/93, 3b/4b
76/–, 3c/4c
–/80, 3c/4c
82/–, 3d/4d
F
2b
2b
0.5
3
OH
Cl
2c
2c
1
OH
8
O2N
2d
2d
8
9
1a
1a
1a
THF
TFE
THF
0.5
4
–/87, 3d/4d
95/–, 3e/4e
–/84, 3e/4e
OH
O
Br
2e
2e
10
1
Synlett 2009, No. 18, 2965–2970 © Thieme Stuttgart · New York

2968
Z. Shafiq et al.
LETTER
Table 3 I2-Catalyzed Regioselective Reaction of Indoles 1 with Cyclic B–H Adducts 2 in THF and TFE (continued)
R3
R4
R1
O
N
OH
O
R2
I2 (10 mol %)
solvent, reflux
O
R2
R1
R2
+
+
N
R1
R3
R4
N
1
2
R4
R3
3a–k
4a–k
Entry
11
1
2
Solvent
Time (h)
6
Yield of 3/4 (%)a
OH
O
O2N
1a
TFE
93/–, 3f/4f
2f
2f
12
13
14
1a
THF
TFE
THF
1
3
2
–/78, 3f/4f
65/–, 3g/4g
16/60, 3g/4g
2a
2a
N
H
1b
1b
15
16
17
18
2a
2a
2a
2a
TFE
THF
TFE
THF
4
69/–, 3h/4h
–/70, 3h/4h
82/–, 3i/4i
–/72, 3i/4i
N
Me
1c
1c
0.5
2.5
N
Me
1d
1d
10 min
MeO
19
20
21
22
2a
2a
TFE
THF
TFE
THF
4
61/18, 3j/4j
–/71, 3j/4j
71/–, 3k/4k
–/77, 3k/4k
N
Me
1e
1e
0.5
2.5
2
OH
O
Et
N
H
Br
1f
1f
2g
2g
a Isolated yield.
We believed that hydrogen-bonding interactions could be moderating the strength of the hydrogen-bonding interac-
used to explain the remarkable g-regioselective control of tions. In a comparison of the b-values (which reflects the
the reaction in THF (Figure 2). Generally, under the catal- acceptor-ability of the forming hydrogen bond) of THF
ysis of Lewis acids or Brønsted acids, both the carbonyl (b = 0.55), with diethyl ether (0.47), 1,4-dioxane (0.38),
and the hydroxy groups in the B–H adduct could be acti- toluene (0.11) and dichloromethane (0), THF is found to
vated, resulting in possible nucleophilic attack on both the be a better hydrogen-bond acceptor (HBA).16 When the
a- and g-positions. When iodine was used as a weak reaction was carried out in THF, the six-membered ring
Lewis acid, the solvent could play an important role by chelation between the OH and the carbonyl group in the
Synlett 2009, No. 18, 2965–2970 © Thieme Stuttgart · New York

LETTER
Allylic Substitution of Cyclic Baylis–Hillman Adducts with Indoles
2969
B–H adduct could be destroyed by solvation due to the
strong hydrogen-bond acceptor ability of THF; at the
same time, the carbonyl of B–H adduct should be activat-
ed by iodine to yield the g-product via a Michael-type ad-
dition–elimination reaction (Figure 2, B). In contrast,
when the reaction was carried out in protic solvent, which
can be considered as a hydrogen-bond donor (HBD),16 the
hydroxy group of the B–H adduct could be activated to
provide a mixture of a- and g-products (Figure 2, A).
Acknowledgment
The research was financially supported by the National Natural Sci-
ence Foundation of China, Ministry of Science and Technology
(No. 2009ZX09501-006) and the Chinese Academy of Sciences.
We thank Professor Zhi-Xiang Yu in Peking University for scienti-
fic discussions.
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O
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Nu:
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pot reduction and in situ aza-Michael addition
(Scheme 2).8a
O
O
R
Pd/C
H2
HN
NO2
R
N
N
H
H
5
5a R = H
5b R = 3-MeOC6H4
80%
51%
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α-product 3l–m
Scheme 2 Syntheses of azepino[4,3,2-cd]indoles 5
In conclusion, we have reported a highly regioselective
reaction of indoles with cyclic B–H adducts catalyzed by
molecular iodine. Preliminary mechanistic investigations
have revealed that the reaction provided kinetic controlled
g-products in THF, whereas a-products were obtained as
thermodynamic products in TFE. The latter were generat-
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ton rearrangement of allylindoles. The present method
could be conveniently used in the synthesis of azepi-
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Synlett 2009, No. 18, 2965–2970 © Thieme Stuttgart · New York

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LETTER
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J. T.; Yao, C. F. Tetrahedron 2005, 61, 11751. (j) Periana,
R. A.; Mirinov, O.; Taube, D. J.; Gamble, S. Chem.
Commun. 2002, 2376. (k) Togo, H.; Iida, S. Synlett 2006,
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heated under reflux until completion as judged by TLC, or
for the time indicated. After cooling, the reaction mixture
was diluted with CH2Cl2 and extracted into sat. Na2S2O3
(3 × 5 mL). The combined organic extract was dried over
anhydrous Na2SO4, concentrated in vacuum and purified by
column chromatography over silica gel (petroleum ether–
EtOAc, 8:1) to afford the desired a-product 3a (or g-product
4a when THF was used as the solvent).
2-[(2-Methylindolyl)phenylmethyl]cyclopent-2-enone (3a):
Off-white solid, mp 135–136 °C; IR (KBr): 3393, 2919,
1694, 1456, 1229, 1007, 751 cm–1; 1H NMR (CDCl3, 300
MHz): d = 2.20 (s, 3 H), 2.25–2.62 (m, 4 H), 5.29 (s, 1 H),
6.82–6.87 (m, 1 H), 6.96 (t, J = 7.41 Hz, 1 H), 7.06–7.18 (m,
7 H), 7.23 (s, 1 H), 7.84 (br s, 1 H); 13C NMR (CDCl3, 75
MHz): d = 11.0, 25.3, 33.7, 36.8, 109.3, 110.1, 118.0, 118.1,
119.6, 125.0, 126.8, 127.1, 127.2, 131.4, 134.3, 140.8,
147.5, 158.8, 207.7; EI-MS: m/z (%) = 301, 286, 284, 270,
244, 146, 130 (100); HRMS: m/z calcd. for C21H19NO:
301.1467; found: 301.1466.
(E)-2-Benzylidene-3-(2-methyl-1H-indol-3-yl)cyclopentan-
one (4a): Yellow solid; mp 184–185 °C; IR (KBr): 3397,
2925, 1704, 1615, 1456, 1223, 1179, 691 cm–1; 1H NMR
(CDCl3, 300 MHz): d = 2.13–2.22 (m, 1 H), 2.31 (s, 3 H),
2.35–2.65 (m, 3 H), 4.71 (t, J = 2.53 Hz, 1 H), 7.04–7.46 (m,
9 H), 7.61 (s, 1 H), 7.79 (br s, 1 H); 13C NMR (CDCl3, 75
MHz): d = 12.6, 30.1, 36.7, 37.9, 110.3, 112.4, 118.3, 119,4,
121.1, 127.7, 128.3, 129.2, 130.7, 130.8, 134.3, 134.7,
135.1, 138.7, 208.9; EI-MS: m/z (%) = 301 (100), 286, 272,
258, 244, 168, 130; HRMS: m/z calcd. for C21H19NO:
301.1467; found: 301.1469.
(14) Berkessel, A.; Adrio, J. A.; Hüttenhain, D.; Neudörfl, J. M.
J. Am. Chem. Soc. 2006, 128, 8421.
(15) 1,3-Isomerization of allylic alcohols or esters, selected
examples: (a) Kobbelgaard, S.; Brandes, S.; Jørgensen,
K. A. Chem. Eur. J. 2008, 14, 1464. (b) Shanmugam, P.;
Rajasingh, P. Tetrahedron 2004, 60, 9283. (c) Kim, H. S.;
Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H. J.; Kim, J. N.
Tetrahedron Lett. 2000, 41, 2613. (d) Morrill, C.; Grubbs,
R. H. J. Am. Chem. Soc. 2005, 127, 2842. (e) Shekhar, S.;
Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 11770.
(16) (a) Nielsen, M. F.; Ingold, K. U. J. Am. Chem. Soc. 2006,
128, 1172. (b) Kamlet, M. J.; Taft, R. W. J. Am. Chem. Soc.
1976, 98, 377.
(17) (a) Matthews, J. M.; Greco, M. N.; Hecker, L. R.; Hoekstra,
W. J.; Andrade-Gordon, P.; De Garavilla, L.; Demarest,
K. T.; Ericson, E.; Gunnet, J. W.; Hageman, W.; Look, R.;
Moore, J. B.; Maryanoff, B. E. Bioorg. Med. Chem. Lett.
2003, 13, 753. (b) Hester, J. B. J. Org. Chem. 1967, 32,
4095. (c) Nagasaka, T.; Ohki, S. Chem. Pharm. Bull. 1977,
25, 3023.
(12) (a) Liu, Z.; Liu, L.; Shafiq, Z.; Wu, Y. C.; Wang, D.; Chen,
Y. J. Tetrahedron Lett. 2007, 48, 3963. (b) Rao, W.; Tay, A.
H. L.; Goh, P. J.; Choy, J. M. L.; Ke, J. K.; Chan, P. W. H.
Tetrahedron Lett. 2008, 49, 122. (c) Wu, W. H.; Rao,
W. D.; Er, Y. Q.; Loh, J. K.; Poh, C. Y.; Chan, P. W. H.
Tetrahedron Lett. 2008, 49, 2620.
(13) To a solution of Baylis–Hillman adduct 2a (0.2 mmol) and
indole 1a (0.2 mmol) in TFE (or THF) (5 mL), was added
iodine (0.02 mmol). The resulting reaction mixture was
Synlett 2009, No. 18, 2965–2970 © Thieme Stuttgart · New York

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