Copper-catalyzed regioselective allylic substitution reactions with indium organometallics

Article abstract of DOI:10.1021/jo0265939

The first nucleophilic allylic substitution reactions of triorganoindium compounds with allylic halides and phosphates are reported. The reactions of trialkyl- and triarylindium reagents with cinnamyl and geranyl halides and phosphates, with the aid of co

Full text of DOI:10.1021/jo0265939

Cop p er -Ca ta lyzed Regioselective Allylic
Su bstitu tion Rea ction s w ith In d iu m
Or ga n om eta llics
and stereoselectivity to as well as the application of
different types of nucleophiles is a desirable goal. This
reaction can be performed using soft nucleophiles and
organometallic reagents under transition metal catalysis
7
8
(
generally palladium or nickel) or, alternatively, by the
David Rodr ´ı guez, J os e´ P e´ rez Sestelo,* and
Luis A. Sarandeses*
9
stoichiometric use of organocopper species and copper-
catalyzed reactions of several organometallics.1 From the
standpoint of organic synthesis, palladium and copper
are the most important metals for selective metal-
catalyzed nucleophilic allylic substitution.
0
Departamento de Qu ı´ mica Fundamental, Universidade da
Coru n˜ a, E-15071 A Coru n˜ a, Spain
qfsarand@udc.es
As part of a project aimed at finding new applications
for indium organometallics in organic synthesis, we
explored the synthetic utility of triorganoindium reagents
in the nucleophilic allylic substitution reaction. The only
examples of the use of group 13 organometallics in allylic
substitution involved a few examples of the palladium-
catalyzed reactions of boron reagents11 and the copper-
catalyzed reactions of aluminum alkyls.12 Hitherto, the
use of indium organometallics has been limited to
Received October 22, 2002
Abstr a ct: The first nucleophilic allylic substitution reac-
tions of triorganoindium compounds with allylic halides and
phosphates are reported. The reactions of trialkyl- and
triarylindium reagents with cinnamyl and geranyl halides
and phosphates, with the aid of copper catalysis [Cu(OTf)2/
P(OEt)3], are described. In general, the reaction proceeds
efficiently to give good yields and regioselectively to afford
the SN2′ product.
13
tetraorganoindates and to the recently published pal-
ladium-catalyzed allylic substitution using allylindium
reagents generated in situ.14 In this paper, we wish to
report the first use of triorganoindium reagents (R
in nucleophilic allylic substitution under copper catalysis
eq 1).
3
In)
Over the past decade, indium has received a great deal
of attention from organic chemists due to its interesting
chemical properties, which include a low first oxidation
potential, stability under aqueous conditions, and low
(
1
toxicity. As a consequence, indium metal has been widely
used in the addition reactions of allylic systems to
carbonyls and related derivatives under aqueous or
anhydrous conditions. More recently, indium organo-
2
Our investigation started with a study of the reactions
of tri-n-butylindium (n-Bu In) and triphenylindium
Ph In) with cinnamyl bromide (1a , Table 1). In the
absence of catalyst the reaction failed, but the addition
of a catalytic amount of a copper salt promoted a rapid
reaction that gave the nucleophilic allylic substitution
products in moderate yields. These products were ob-
metallics have emerged as useful reagents for funda-
mental reactions in organic synthesis, such as conjugate
3
(
3
additions,3 cross-coupling reactions,4,5 or additions to
6
triple bonds. Despite the increasing synthetic utility of
indium reagents in organic synthesis, a number of
important reactions remain unexplored.
Nucleophilic allylic substitution constitutes a powerful
reaction in synthesis and the ability to control the regio-
(
7) For a general overview, see: Tsuji, T. Transition Metal Reagents
and Catalysts; Wiley: New York, 2000; Chapter 4, pp 109-168.
8) (a) Godleski, S. A. In Comprehensive Organic Synthesis; Trost,
(
(
1) (a) Cintas, P. Synlett 1995, 1087-1096. (b) Marshall, J . A.
B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 4, Chapter
3.3, pp 585-661. (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996,
96, 395-422. (c) Heumann, A. In Transition Metals for Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998;
Chapter 2.15, pp 251-264.
Chemtracts: Org. Chem. 1997, 10, 481-496. (c) Li, C.-J .; Chan, T.-H.
Organic Reactions in Aqueous Media; Wiley: New York, 1997; Chapter
4
, pp 64-114. (d) Paquette, L. A. In Green Chemistry: Frontiers in
Benign Chemical Synthesis and Processing; Anastas, P. T., Williamson,
T. C., Eds.; Oxford University Press: Oxford, U.K., 1998; Chapter 15,
pp 250-264.
(9) Lipshutz, B. H. In Comprehensive Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford,
U.K., 1995; Vol. 12, Chapter 3.2, pp 59-130.
(
2) (a) Li, C.-J .; Chan, T.-H. Tetrahedron 1999, 55, 11149-11176.
(
b) Ranu, B. C. Eur. J . Org. Chem. 2000, 2347-2356. (c) Pae, A. N.;
Cho, Y. S. Curr. Org. Chem. 2002, 6, 715-737.
3) (a) Araki, S.; Shimizu, K.; J in, S.-J .; Butsugan, Y. J . Chem. Soc.,
(10) (a) Yanagisawa, A.; Yamamoto, H. In Transition Metal Cataly-
sed Reactions; Murahashi, S.-I., Davies, S. G., Eds.; Blackwell Sci-
ence: Oxford, U.K., 1999; Chapter 11, pp 225-240. (b) Sofia, A.;
Karlstr o¨ m, E.; B a¨ ckvall, J .-E. In Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinheim: 2002; Chapter 8, pp 259-
288. For recent examples, see: (c) D u¨ bner, F.; Knochel, P. Angew.
Chem., Int. Ed. 1999, 38, 379-381. (d) Meuzelaar, G. J .; Karlstr o¨ m,
A. S. E.; van Klaveren, M.; Persson, E. S. M.; del Villar, A.; van Koten,
G.; B a¨ ckvall, J .-E. Tetrahedron 2000, 56, 2895-2903. (e) Luchaco-
Cullis, C.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2001, 40, 1456-1460. (f) Malda, H.; van Zijl, A. W.; Arnold,
L. A.; Feringa, B. L. Org. Lett. 2001, 3, 1169-1171.
(
Chem. Commun. 1991, 824-825. (b) P e´ rez, I.; P e´ rez Sestelo, J .;
Maestro, M. A.; Mouri n˜ o, A.; Sarandeses, L. A. J . Org. Chem. 1998,
6
3, 10074-10076.
4) For contributions from this group, see: (a) P e´ rez, I.; P e´ rez
(
Sestelo, J .; Sarandeses, L. A. Org. Lett. 1999, 1, 1267-1269. (b) P e´ rez,
I.; P e´ rez Sestelo, J .; Sarandeses, L. A. J . Am. Chem. Soc. 2001, 123,
4
155-4160. (c) Pena, M. A.; P e´ rez, I.; P e´ rez Sestelo, J .; Sarandeses,
L. A. Chem. Commun. 2002, 2246-2247.
5) (a) Nomura, R.; Miyazaki, S.-I.; Matsuda, H. J . Am. Chem. Soc.
(
1
992, 114, 2738-2740. (b) Takami, K.; Yorimitsu, H.; Shinokubo, H.;
(11) (a) Moreno-Ma n˜ as, M.; Pajuelo, F.; Pleixats, R. J . Org. Chem.
1995, 60, 2396-2397. (b) Cort e´ s, J .; Moreno-Ma n˜ as, M.; Pleixats, R.
Eur. J . Org. Chem. 2000, 239-243.
Matsubara, S.; Oshima, K. Org. Lett. 2001, 3, 1997-1999. (c) Lee, P.
H.; Sung, S.; Lee, K. Org. Lett. 2001, 3, 3201-3204.
(6) (a) Araki, S.; Imai, A.; Shimizu, K.; Yamada, M.; Mori, A.;
(12) Flemming, S.; Kabbara, J .; Nickisch, K.; Westermann, J .; Mohr,
J . Synlett 1995, 183-185.
Butsugan, Y. J . Org. Chem. 1995, 60, 1841-1847. (b) Ranu, B. C.;
Majee, A. Chem. Commun. 1997, 1225-1226. (c) Fujiwara, N.; Yama-
moto, Y. J . Org. Chem. 1999, 64, 4095-4101. (d) Klaps, E.; Schmid,
W. J . Org. Chem. 1999, 64, 7537-7546. (e) Takami, K.; Yorimitsu, H.;
Oshima, K. Org. Lett. 2002, 4, 2993-2995.
(13) Araki, S.; J in, S.-J .; Butsugan, Y. J . Chem. Soc., Perkin Trans.
1 1995, 549-552.
(14) Lee, P. H.; Sung, S.-Y.; Lee, K.; Chang, S. Synlett 2002, 146-
148.
1
0.1021/jo0265939 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/21/2003
2
518
J . Org. Chem. 2003, 68, 2518-2520

TABLE 1. Effect of Ca ta lyst on th e Rea ction of
TABLE 2. Resu lts of th e Cop p er -Ca ta lyzed Rea ction of
Tr ior ga n oin d iu m Com p ou n d s w ith Cin n a m yl Der iva tives
(1a -e)
Tr ior ga n oin d iu m Com p ou n d s w ith Cin n a m yl Br om id e
a
(
1a )
yield (%) ratio 2/3c
b
yielda (%) ratio 2/3b
entry no.
R
Cu catalyst
ligand
entry no.
X
R
1
2
3
4
5
6
7
8
9
n-Bu Cu(OTf)2
40
65
33
50
85
19
32
13
80
72:28
80:20
68:32
88:12
82:18
76:24
67:33
67:33
76:24
1
2
3
4
5
6
7
8
9
Br (1a )
Cl (1b)
n-Bu
Me
Ph
85
73
80
93
70
38
30
-
82:18
92:8
76:24
86:14
96:4
91:9
66:34
-
CuCN
CuBr‚SMe2 P(OEt)3
CuCN
P(OEt)3
P(OEt)3
Me SiCH2
3
n-Bu
Me
Cu(OTf)2
CuBr‚SMe2
Ph
CuBr‚SMe2 P(OEt)3
Ph
n-Bu
n-Bu
CuI
P(OEt)3
P(OEt)3
OAc (1c)
OBoc (1d )
OP(O)(OEt)2 (1e) n-Bu
Cu(OTf)2
-
-
1
1
1
0
1
2
70
79
83
99:1
92:8
50:50
a
Reaction conditions: 120 mol % of R3In, 100 mol % of 1a , 15
mol % of copper catalyst, 30 mol % of P(OEt)3, -30 °C to rt, 3 h.
Isolated yield of 2 + 3. Determined by GC.
Me
Ph
b
c
a
Isolated yield of 2 + 3. b Determined by GC.
tained as mixtures of S
respectively) where the major regioisomer was the S
product. Table 1 lists the results obtained in the reactions
of n-Bu In and Ph In with 1a using copper catalysis
N
2′ and S
N
2 products (2 and 3,
N
2′
After the most appropriate reaction conditions had
been established, we explored the scope of the reaction
using other indium organometallics and different allylic
substrates. In the reaction of cinnamyl halides, we
observed that alkyl and aryl groups can be efficiently
transferred using Cu(OTf) /P(OEt) as a catalytic system.
The best results were obtained in the reaction of tri-
organoindium reagents with cinnamyl bromide (1a ) (73-
93%, Table 2, entries 1-4). Under the same reaction
conditions, cinnamyl chloride (1b) showed a lower reac-
tivity, although high regioselectivities were obtained for
tri-n-butyl- and trimethylindium compounds (Table 2,
entries 5 and 6).
At this point, we were also interested in extending the
reaction to other electrophiles such as allylic alcohol
derivatives. With this aim in mind, we first studied the
behavior of oxygenated cinammyl derivatives. Acetate 1c
and carbonate 1d were both found to be unreactive, but
the cinammyl phosphate 1e reacted efficiently, under
copper catalysis conditions, with triorganoindium re-
agents to give high yields of products (Table 2, entries
3
3
under a variety of reaction conditions.
The reaction of triorganoindium compounds (120 mol
%
) with cinnamyl bromide in the presence of 15 mol %
of various copper salts [e.g., CuBr‚SMe , Cu(OTf) , or
CuCN] afforded the S 2′ product (2) in low-to-moderate
yields but with good regioselectivity (Table 1, entries 1,
, and 6). Interestingly, in this series of reactions we
found that the addition of a copper ligand such as triethyl
phosphite (30 mol %), in combination with Cu(OTf) as a
2
3
2
2
N
2
2
catalyst, increased the yields markedly (up to 85%) while
maintaining the regioselectivity (Table 1, entries 5 and
1
5
9
3
). Curiously, the combination of P(OEt) with Cu(I)
salts gave rise to lower yields (Table 1, entries 3, 4, 7,
and 8). In these studies, we also found that the temper-
ature had an influence on the regioselectivity, with the
best results obtained when the reaction was performed
3
at -30 °C. The use of lower amounts of R In decreased
the yields which suggest that, under these conditions,
indium organometallics are able to transfer only one of
the groups attached to the metal.16
1
0-12). The regioselectivity obtained in the reactions was
excellent for trialkylindium reagents (up to 99:1, Table
2, entries 10 and 11), but triphenylindium gave only a
1:1 mixture of regioisomers. This result can be explained
according to the reaction pathways proposed for allylic
substitution using organocopper reagents:18 the presence
of aryl or sterically hindered ligands could slow the rate
of the reductive elimination in the initial σ-Cu complex
The mechanism for this process is unclear, but accord-
ing to the proposal for the copper-catalyzed allylic
substitution with Grignard or organozinc reagents, cop-
2
per species of the type (RCuOTf)InR , derived from a
transmetalation of the organic group from indium to
copper, could be involved in the reaction. The reactivity
of this species is dependent on the nature of the initial
metal, which in many cases is still intimately associated
with the resulting copper reagent.1
leading the S
formation of a π-allyl-Cu complex, which increases the
ratio of the S 2 product (3). Interestingly, indium orga-
N
2′ product (2) and thus favoring the
7,18
N
nometallics are useful alternatives to diorganozinc re-
agents, which in some cases have proven to be unreactive
toward allylic phosphates.1 In this sense, the reactivity
(
15) Phosphorus ligands have been successfully used in enantio-
0f
selective copper-catalyzed allylic substitution reactions with diorga-
nozinc reagents; see ref 10f.
(
16) This result is coincident with the observed in the nickel-
catalyzed 1,4-conjugate addition of R In to electron deficient olefins
ref 3b), but contrary to the palladium-catalyzed cross-coupling reaction
3
(18) For a mechanistic proposal for the reaction, see ref 10b and:
(a) B a¨ ckvall, J .-E.; Sell e´ n, M.; Grant, B. J . Am. Chem. Soc. 1990, 112,
6615-6621. (b) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000,
39, 3750-3771. (c) Mori, S.; Nakamura, E.; Morokuma, K. J . Am.
Chem. Soc. 2000, 122, 7294-7307. (d) Bertozzi, F.; Crotti, P.; Macchia,
F.; Pineschi, M.; Feringa, B. L. Angew. Chem., Int. Ed. 2001, 40, 930-
932.
(
3
with R In to organic halides and pseudohalides where all three groups
attached to indium are transferred (ref 4).
(
meier, B. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: Weinheim: 2002; Chapter 2, pp 45-78.
17) (a) Wipf, P. Synthesis 1993, 537-557. (b) Knochel, P.; Betze-
J . Org. Chem, Vol. 68, No. 6, 2003 2519

TABLE 3. Resu lts of th e Cop p er -Ca ta lyzed Rea ction of
Tr ior ga n oin d iu m Com p ou n d s w ith Ger a n yl Der iva tives
and with high S
anism for this reaction involves the formation of orga-
nocopper species by indium transmetalation.
N
2′ regioselectivities. A plausible mech-
(
4a -c)
17,18
Al-
though the transmetalation from indium to nickel and
palladium has been reported in conjugate additions and
in cross-coupling reactions, this is the first example of a
transmetalation from indium to copper to be applied in
organic synthesis. Additionally, the use of phosphorus
compounds as copper ligands opens up the possibility of
1
0f
performing the reaction enantioselectively.
Further
entry no.
X
R
yielda (%) ratio 5/6b
investigations in this direction are currently underway.
1
2
3
4
5
6
7
8
Br (4a )
Cl (4b)
n-Bu
74
75
84
96
50
83
60
80
96:4
92:8
Me
Ph
Exp er im en ta l Section
79:21
60:40
76:24
90:10
98:2
Me3SiCH2
n-Bu
Gen er a l Meth od s. All reactions were conducted in flame-
dried glassware under a positive pressure of argon. Reaction
temperatures refer to external bath temperatures. All dry
solvents were distilled under argon immediately prior to use.
Tetrahydrofuran (THF) was dried by distillation from the sodium
ketyl of benzophenone. Liquid reagents or reagent solutions were
added by syringe or cannula. The total volume of solvent is given
for these additions. Usually the compound was dissolved in 80%
of the stated volume and the flask was then rinsed with the
remaining 20% of fresh solvent. Organic extracts were dried over
OP(O)(OEt)2 (4c) n-Bu
Me
Ph
50:50
a
Isolated yield of 5 + 6. b Determined by GC.
3
of R In with oxygenated allylic substrates is more similar
1
2
to that observed with trialkylaluminum reagents, pre-
sumably because the copper species generated by the
transmetalation from indium or aluminum to copper are
close in reactivity.
Prompted by the results obtained in the copper-
catalyzed allylic substitution of cinnamyl derivatives with
triorganoindium, we explored the reactivity of geranyl
derivatives. These substrates serve as interesting models
to explore the formation of quaternary centers by an S
reaction.
3
The reaction of R In with geranyl derivatives followed
the same reaction patterns as cinnamyl derivatives. The
reaction of geranyl bromide (4a ) with trialkyl- and
4
anhydrous MgSO , filtered, and concentrated using a rotary
evaporator at aspirator pressure (20-30 mmHg). Thin-layer
chromatography was effected on silica gel 60 F254 (layer thick-
ness 0.2 mm), and components were located by observation
under UV light and/or by treating the plates with a phospho-
molybdic acid or p-anisaldehyde reagent followed by heating.
Flash chromatography was performed on silica gel 60 (230-400
mesh) by Still’s method.20
Triorganoindium compounds were prepared according to
previously published methods by treatment of the corresponding
3
organolithium or Grignard reagents (3 equiv) with InCl (1.1
4
N
2′
equiv) in dry THF at -78 °C and warming up to room temper-
ature. All other reagents were commercial products and used
as received.
Gen er a l P r oced u r e for th e Allylic Su bstitu tion Rea c-
t ion . To a cooled (-30 °C) solution of Cu(OTf)
mmol) and P(OEt) (50 µL, 0.30 mmol) in dry THF (2 mL) was
slowly added a solution of R
2
(54 mg, 0.15
N
triarylindium reagents afforded the corresponding S 2′
3
products regioselectively (up to 92:8 of ratio 5:6) and with
high yields (74-84%, Table 3, entries 1-3). The use of
bulkier reagents, such as tris(trimethylsilylmethyl)in-
dium, also afforded the nucleophilic substitution product
in excellent yield but without the same level of regiose-
lectivity (Table 3, entry 4). As observed previously, the
reactivity of geranyl chloride with triorganoindium com-
pounds was low (Table 3, entry 5). As for cinnamyl
derivatives, the reaction of geranyl phosphate 4c with
trialkylindium reagents proceeded with good yields and
3
In (1.20 mmol, ∼0.05 M in dry
THF). The reaction mixture was stirred for 10 min, and a
solution of the allylic substrate (1.00 mmol) in dry THF (4 mL)
was added. The resulting mixture was stirred at -30 °C for 2 h
and allowed to warm to room temperature for 1 h. The reaction
was quenched by the addition of few drops of MeOH, the mixture
was concentrated in vacuo, and Et
organic phase was washed with aqueous HCl (5%, 10 mL),
saturated aqueous NaHCO (15 mL), and saturated aqueous
2
O (30 mL) was added. The
3
NaCl (15 mL), dried, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography to afford, after
concentration and high-vacuum-drying, the allylic substitution
products. All compounds obtained were fully characterized by
NMR and mass spectrometry and exhibit identical physical data
to those reported in the literature (see the Supporting Informa-
tion).
high S
dium, despite giving a good yield, was not regioselective
Table 3, entries 6-8). These results show indium orga-
nometallics to be useful reagents for the preparation of
quaternary centers by regioselective S 2′ nucleophilic
N
2′ regioselectivity but the addition of triphenylin-
(
N
Ack n ow led gm en t. We are grateful to the Ministe-
rio de Ciencia y Tecnolog ´ı a (Spain, BQU2000-0249) for
financial support. D.R. acknowledges a fellowship from
the University of A Coru n˜ a.
allylic substitution reactions, a central feature of copper
reagents.19
In conclusion, we have discovered that triorganoindium
reagents react with allylic halides and phosphates under
copper catalysis conditions. In the reaction, alkyl and aryl
organic groups are efficiently transferred in good yields
Su p p or tin g In for m a tion Ava ila ble: Relevant spectral
and analytical (GC) data for compounds 1e, 2, 4c, and 5. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) For some other methods for the preparation of quaternary
carbon centers by copper-catalyzed allylic substitution of organome-
tallics, see refs 12, 18a, and: (a) Yanagisawa, A.; Nomura, N.;
Yamamoto, H. Synlett 1993, 689-690. (b) Yanagisawa, A.; Nomura,
N.; Yamamoto, H. Tetrahedron 1994, 50, 6017-6028. (c) Reddy, C. K.;
Knochel, P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1700-1701.
J O0265939
(20) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
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