Bi(OTf)3-catalyzed 5-exo-trig cyclization via halide activation

Article abstract of DOI:10.1016/j.tetlet.2008.04.067

Lewis acid activation of allyl halides utilizing Bi(OTf)₃ resulted in cationic cyclization of alkenes with high efficiency. While other Lewis acids could catalyze this process with highly substituted alkenes, bismuth salts demonstrated unique r

Full text of DOI:10.1016/j.tetlet.2008.04.067

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Tetrahedron Letters 49 (2008) 3888–3890
Bi(OTf)3-catalyzed 5-exo-trig cyclization via halide activation
Ryuji Hayashi, Gregory R. Cook *
Department of Chemistry and Molecular Biology, North Dakota State University, Fargo, ND 58105, United States
Received 7 March 2008; revised 3 April 2008; accepted 10 April 2008
Available online 14 April 2008
Abstract
Lewis acid activation of allyl halides utilizing Bi(OTf)3 resulted in cationic cyclization of alkenes with high efficiency. While other
Lewis acids could catalyze this process with highly substituted alkenes, bismuth salts demonstrated unique reactivity in come cases. This
suggested that bismuth triflate possesses interesting halophilic properties.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
chlorides with arenes.5 We recently reported the In(III)-cat-
alyzed atom transfer cyclization6 and ring-closing Friedel–
Craft reaction7 proceeding via efficient and mild activation
of allylic bromides. During our investigation of these cat-
ionic processes we discovered that Bi(OTf)3 was also able
to activate allylic halides catalytically with high efficiency.
Bismuth Lewis acids are intriguing and have been known
to catalyze a variety of reactions8 including an interesting
BiBr3-catalyzed silyl-Prins reaction. Herein, we disclose
another application driven by Lewis acid catalyzed halide
activation.9
The formation of carbocations1 from a variety of
organohalogen compounds2 by Lewis acid activation is
an important process in the field of organic chemistry.
The trapping of in situ generated cations by nucleophiles
(Scheme 1) is a useful synthetic strategy if the reactions
can be well controlled.3 Weak nucleophiles can readily take
part in such processes.
There are a number of examples of halide activation by
Lewis or Brønsted acids to generate carbocations. Typi-
cally Lewis acids such as Ag(I), B(III), Ti(IV), Al(III),
and Sn(IV) are used to cleave carbon–halide bonds.4 How-
ever, major limitations for this chemistry are that the con-
ditions are often severe and the use of stoichiometric
amount of Lewis acids is often required. Strongly acidic
byproducts (e.g., HCl, HBr) can poison Lewis acids and
perturb their catalytic turnover. Thus, reactions driven by
catalytic halide activation by Lewis acids are rare. Recently,
Hua and co-workers reported that catalytic amounts of
BiCl3 catalyzed the Friedel–Crafts reaction of acyl or vinyl
Similar to our atom transfer cyclization of alkynes and
allyl bromides, we envisioned that the dimethyl substituted
alkene-allylic bromide substrate 1a (Scheme 2) would also
undergo a similar process.6 However, in the presence of
20 mol % of InCl3 in CH2Cl2 1a decomposed. Interestingly,
˚
in the presence of 4 A molecular sieves, the diene product 2
was obtained via proton elimination cleanly in 68%
isolated yield. We believe that molecular sieves in this reac-
tion play the role of a neutral base to trap HBr after the
reaction takes place.
Nuc
EtO2C
+
+
+
R Nuc HX
MLn
R
InCl3 (20 mol%), 4Å MS
R X
X MLn
EtO2C
EtO2C
CH2Cl2 (0.05M), 16 h, rt
68%
EtO2C
Scheme 1.
1a
Br
2a
No 4Å MS = dec
*
Corresponding author. Tel.: +1 701 231 7413; fax: +1 701 231 1057.
Scheme 2.
E-mail address: Gregory.cook@ndsu.edu (G. R. Cook).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.067

R. Hayashi, G. R. Cook / Tetrahedron Letters 49 (2008) 3888–3890
3889
Table 2
We next turned our attention to screening a variety of
Phenyl-substituted substrates
metals for the cyclization to determine which catalysts
would be capable of effecting the reaction in substoichio-
metric amounts (Table 1). Thus 1a was treated with
20 mol % of Lewis acids in CH2Cl2 (0.5 M) at room tem-
perature for 16 h. Most of the Lewis acids failed to catalyze
the reaction. Surprisingly, Lewis acids known to cleave car-
bon–halide bonds including AlCl3, AgSbF6, and AgOTf
yielded less than 20% (entries 3, 21, and 22). From this
study, we found Fe(ClO4)3, ZnBr2, ZnI2, Bi(OTf)3, InBr,
InI, In(OTf)3, InBr3, and InCl3 (entries 5, 8, 9, 14, and
23–27) demonstrated promising catalytic ability for this
reaction.
Ph
EtO2C
Ph
Cat. LA, MS
EtO2C
EtO2C
EtO2C
CH2Cl2 (0.05M), 16 h, rt
Br
1b
2b
Entry
LA
MS
˚
Yield
1
2
ZnBr2 (20 mol %)
ZnI2 (20 mol %)
4 A
dec
dec
dec
˚
˚
˚
˚
4 A
4 A
4 A
4 A
4 A
None
3 A
4 A
3
4
Fe(ClO4)3 (20 mol %)
InI (20 mol %)
SM and dec
Trace and dec
Trace and dec
5
6
7
8
In(OTf)3 (20 mol %)
InBr3 (20 mol %)
InCl3 (20 mol %)
InCl3 (20 mol %)
InCl3 (20 mol %)
InCl3 (20 mol %)
InCl3 (20 mol %)
InCl3 (20 mol %)
Bi(OTf)3 (10 mol %)
Bi(OTf)3 (10 mol %)
Bi(OTf)3 (10 mol %)
Bi(OTf)3 (10 mol %)
Bi(OTf)3 (10 mol %)
Bi(OTf)3 (10 mol %)
˚
dec
SM
We next examined the phenyl-substituted substrate 1b
utilizing several of the most promising Lewis acid catalysts
(Table 2). Again, we were surprised to find that none of the
catalysts tested resulted in success with the exception of
Bi(OTf)3 (entry 15). ZnBr2, ZnI2, and Fe(ClO4)3 decom-
posed the starting material (entries 1–3). In the presence
of 20 mol % InI mostly starting material was observed
along with some decomposition (entry 4). When In(III)
salts were employed (InCl3, InBr3, and In(OTf)3) in the
˚
˚
9
SM and dec
SM
10
11
12
13
14
15
16
17
18
a
13X
Na+13Y
SM
SM
dec
NH4þ13Y
None
3 A
4A
13X
Na+13Y
NH4þ13Y
˚
˚
SM
78%a
SM
SM
SM
˚
presence of 4 A molecular sieves, trace amounts of the cyc-
lized product 2b were seen; however, yields were very poor
and mostly decomposition was observed (entries 5, 6, and
9). In the absence of molecular sieves the starting material
also decomposed (entry 7). The combination of InCl3 with
other types of molecular sieves was also tested; however, all
NMR yield (internal standard), E/Z = 5:1.
+
of them (3 A, 13X, Na 13Y, or NH4þ13Y) interfered with
catalysis, and the starting material was recovered quantita-
tively (entries 8, and 10–12). On the other hand, employing
˚
˚
only 10 mol % of Bi(OTf)3 with 4 A molecular sieves
resulted in successful catalysis of cyclization to yield 2b in
78% isolated yield. The combination of Bi(OTf)3 with other
types of molecular sieves in this reaction was found to be
ineffective (entries 14, and 16–18).
Table 1
Lewis acid screen
EtO2C
Metal (20 mol%), 4Å MS
EtO2C
A variety of substrates were tested in the exo-trig cycli-
zation catalyzed by Bi(OTf)3, and the results are shown in
EtO2C
CH2Cl2 (0.05M), 16 h, rt
EtO2C
1a
Br
2a
˚
Table 3. In the presence of 10 mol % of Bi(OTf)3 and 4 A
Entry Metal
Yield
Entry Metal
Yield
molecular sieves in 0.05 M CH2Cl2, carbocycle 2a, where
both R1 and R2 were methyl, was synthesized in 58%
1
2
3
4
5
MgI2
Mg(OTf)2
AlCl3
Sc(OTf)3
Fe(ClO4)3
CuCl2
Cu(OTf)2
ZnBr2
ZnI2
SM
SM
8%
SM
63%
Trace
SM
91%
86%
21
22
23
24
25
26
27
28
29
AgSbF6
AgOTf
InBr
18%
20%
63%
81%
66%
71%
68%
Trace
SM
InI
Table 3
Substrate modification
In(OTf)3
InBr3
InCl3
6
7
8
R1
R1
Sn(OTf)2
Ho(OTf)3
Lu(OTf)3
WO2(OH)2 SM
IrCl(oct)
PtCl2
R2
Bi(OTf)3 (10 mol%), 4Å MS
CH2Cl2 (0.05M), 16 h, rt
R2
X
X
9
10
11
12
13
14
15
Zn(OTf)2
TiCl4
Cp2ZrCl2
Zr(OC3H7)4
Bi(OTf)3
Grubbs II
SM + dec 30
SM
Br
SM
SM
SM
58%
SM
31
32
33
34
35
SM
SM
Entry
R1
R2
X
Yield
Prod
58%a
60%b
dec
2a
3a
Au(PPh3)Cl SM
AuCl
1
2
3
4
5
6
a
Me
Me
Me
H
H
H
Me
Me
Me
Ph
Me
H
C(CO2Et)2
NSO2Ph
O
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
SM and
dec
SM and
dec
SM
SM
SM
SM
78%c
SM
2b
16
Wilkinson’s
SM
SM
36
NaAuBr4
17
18
19
20
[RhCl(C2H4)2]2
Pd2(dba)3 + dppf SM
Pd2(dba)3
PdCl2
37
38
39
40
La(OTf)3
Eu(OTf)3
YbCl3
SM
Isolated yield.
NMR yield (internal standard).
NMR yield (E/Z = 5:1).
SM
SM
b
c
Yb(OTf)3

3890
R. Hayashi, G. R. Cook / Tetrahedron Letters 49 (2008) 3888–3890
ture was stirred 16 h. Upon completion, the mixture was
Bi(OTf)3 (cat), 4Å MS
directly loaded onto a silica gel column and eluted with
95:5 hexane/EtOAc to obtain pure cyclized product 2a.
General procedure for exo-trig cyclization (2b, 3a):
Bi(OTf)3 (0.01 mol) was added to the solution of allyl bro-
X
+
HBr
X
Br
C
A
˚
Bi(OTf)3
mide (0.1 mmol) and 4 A molecular sieves (50 mg) in
H
X
CH2Cl2 (2 mL). The mixture was stirred 16 h. Upon com-
pletion, the mixture was filtered through a short plug of sil-
ica gel with EtOAc (10 mL). Solvent was removed under
reduced pressure and an internal standard (1,2,3-trime-
thoxybenzene, 0.1 mmol) was added. Yield was obtained
B
+
Br Bi(OTf)3
Scheme 3. Proposed mechanism.
1
by the integration of H NMR resonances as compared
to the internal standard.
isolated yield (entry 1). Nitrogen heterocycle 3a was pro-
duced in 60% yield (entry 2). If X was oxygen, the starting
material decomposed (entry 3). Alkene substitution was
also varied with mixed results. In the case of phenyl substi-
tuted alkene, 2b was obtained in 78% yield (entry 4). How-
ever, with alkyl disubstituted alkene or terminal alkene, the
substrate was recovered unreacted (entries 5 and 6).
A proposed mechanism is shown in Scheme 3. When
treated with a catalytic amount of Bi(OTf)3 to activate the
allylic bromide, substrate A undergoes ionization to gener-
Acknowledgments
We are grateful to the National Science Foundation
(NSF-CHM-0616485) and the National Institutes of
Health (NCRR-P20-RR15566) for financial support of this
project. We also thank the NDSU Graduate School for a
doctoral dissertation fellowship for R.H.
References and notes
ate an allyl carbocation. Attack of the nucleophilic alkene
ꢀ
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.
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yields the 1,3-diene product C and HBr as a byproduct.
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decomposition of substrate and/or product.7
´
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In conclusion, a Bi(OTf)3 catalyzed exo-trig cyclization
via halide activation was demonstrated. The choice of
˚
molecular sieves was critical as only 4 A molecular sieves
were effective in this particular reaction. Screening of Lewis
acis showed that Zn(II), Fe(III), In(I), In(III), and Bi(III)
catalysts were capable of activating the allylic halide; how-
ever, Bi(OTf)3 was optimal for the phenyl substituted
alkene. Further investigation into the unique role of
bismuth Lewis acids is currently underway.
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2. Experimental procedure
Procedure for exo-trig cyclization (2a): Bi(OTf)3 (0.01
mol) was added to a solution of 1a (0.1 mmol) and 4 A
molecular sieves (50 mg) in CH2Cl2 (2 mL). The mix-
˚
9. Lian, Y.; Hinkle, R. J. J. Org. Chem. 2006, 71, 7071.