Selectivity control in lewis acid catalyzed regiodivergent tandem cationic cyclization/ring expansion terminated by pinacol rearrangement

Full text of DOI:10.1002/anie.200901628

Angewandte
Chemie
DOI: 10.1002/anie.200901628
Domino Reactions
Selectivity Control in Lewis Acid Catalyzed Regiodivergent Tandem
Cationic Cyclization/Ring Expansion Terminated by Pinacol
Rearrangement**
Lu Liu and Junliang Zhang*
Cationic domino reactions are highly attractive and signifi-
cant in the synthesis of polycyclic compounds owing to their
unrivalled power of forming many bonds in only one step.[1]
Within this context, tandem cationic cyclization reactions that
are terminated by pinacol rearrangement are truly fascinat-
ing.[2,3] Overman and co-workers have developed a Prins
cyclization terminated by pinacol rearrangement and applied
this reaction in the total synthesis of several natural products
such as sclerophytinA, (À)-citreoviral, and (+)-shahaminK.[4]
Cationic cyclization or rearrangement reactions of substrates
tethered by alkynes have been investigated by many groups,[5]
however, most of these reactions were realized by metal
activation of the alkyne moiety where the alkyne act as an
electrophile. Herein, we report a Lewis acid catalyzed
intramolecular regiodivergent[6,7] tandem cationic reaction
featuring cyclization/ring expansion terminated by pinacol
rearrangement. In this sequence the alkyne moiety may act as
a nucleophile[8] to react with the carbonyl group which is
activated by a Lewis acid.[9]
Our recent work on silver(I)-catalyzed cyclization of
ortho-alkynyaryl aldehyde oxime derivatives led to different
products and was dependent upon the substituent on the
oxime unit.[10] These results promoted us to study the
cyclization of the substrates 1 in which the nucleophilic
aldehyde oximes were replaced by the electrophilic a,b-
unsaturated ketones (Scheme 1).[11,12] Pleasingly, the reaction
of 1 proceeded smoothly in DCE at room temperature under
AuCl3 (5 mol%)/AgOTf (15 mol%) catalysis to afford the
benzo[a]-fluorenol 2 in moderate to high yields.
Scheme 1. Gold(III)-catalyzed cationic domino cyclization and the
plausible mechanism. DCE=1,2-dichloroethane, M=gold, Tf=trifluo-
romethanesulfonyl
In the proposed mechanism,[13] intermediate alkenyl
cation B, which is generated from intermediate A through
the intramolecular cyclization, prompted us toward further
design to control the outcome of the reaction (Scheme 1). As
we know, the cyclopropyl alkenyl cation would immediately
undergo ring expansion to afford an allylic cation, which
could be trapped by a nucleophile to afford two regioisomeric
products.[14] However, the question of how to regioselectively
trap allylic carbocations is still yet to be answered by
chemists.[15] Herein, we envisaged that the phenyl group of
B can be replaced by a cyclopropyl group, as in intermediate
E, which could further convert into two interconvertible
allylic carbocations F and G (Scheme 2). The intermediate G
might be terminated by a pinacol rearrangement to afford
naphthalen-2(1H)-one 3, whereas intermediate F could be
terminated by a tandem rearrangement to provide another
product 4.
[*] L. Liu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and
Chemical Processes
Department of Chemistry, East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
Fax: (+86)21-6223-5039
E-mail: jlzhang@chem.ecnu.edu.cn
Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P.R. China)
[**] We are grateful to the NSFC (20702015) for financial support. This
work was also sponsored by the 973 program (2009CB825300), the
Shanghai Shuguang Program (07SG27), the Shanghai Pujiang
Program (07pj14039), and the Shanghai Leading Academic Dis-
cipline Project (B409).
Initially, we tested the tandem reactions of cyclopropyl
substituted 1e under the same conditions as in Scheme 1,
AuCl3 (5 mol%)/AgOTf (15 mol%). The cyclization of 1e
indeed produced two products, that is, naphthalen-2(1H)-one
3e (63% yield) and naphthalene 4e (31% yield).[16] Com-
pound 3e is the exact product formed from intermediate G by
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901628.
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selectivity, that is, the ease of migration was beneficial to the
formation of product 3. Interestingly, the ethyl group is a
much better migrating group than the methyl group under
these conditions (compare 1k and 1o; Table 1, entries 11, 12,
19, and 20); 3) The substituents on the phenyl group (R2)
probably have little effect on the selectivity.
Furthermore substrates 5–8, which have substituents on
the cyclopropane group, were prepared and tested. These
results showed that substituents on the cyclopropane ring
have a significant effect on the transformations. The reactions
of 5 and 6, which have substituent at the a position of the
cyclopropane ring, produced naphthalen-2(1H)-ones (5a and
6a) in excellent yields and as single isomers under Con-
ditions A and Conditions B [Eq. (2)]. The cyclization reaction
of 7, which had substituents -(CH2)4- at both b positions of the
Scheme 2. Projected divergent termination of tandem cationic cycliza-
tion/ring expansion reactions of a cyclopropyl substituted substrate.
pinacol rearrangement, while 4e must be the product formed
from intermediate F by a tandem rearrangement. After
numerous attempts, we were pleased to find that the tandem
cationic cyclization/ring expansion/pinacol rearrangement
sequence for 1e proceeded smoothly in DCE at 808C under
AgSbF6 (5 mol%) catalysis and afforded 3e in 93% yield
[Eq. (1); Conditions A]. We found that the nucleophilicity of
the counterion affected the ratio of the two products (see
Table 1 in the Supporting Information). Thus, the addition of
more nucleophile to the reaction might be beneficial in
producing 4e. Among the nucleo-
philes we tested, MeOH was the
Table 1: Scope of regiodivergent tandem reactions.
most effective. Finally, we are
pleased to find that 4e could be
obtained in the highest yield (55%)
under
Conditions B
(In(OTf)3
(5 mol%), MeOH (4 equiv), 508C).
Furthermore, Brønsted acids such as
TfOH (2 mol%) and HNTf2
(5 mol%) can also catalyze this
transformation at room temperature
to afford 3e as the major product and
in high yield.[17] Notably, the reaction
of 1e could be scaled up to 2 grams
under Conditions A and gave the
same excellent yield.
To study the scope of this trans-
formation, various substituted sub-
strates 1 were examined and the
results are summarized in Table 1.
Several points are noteworthy:
1) The R4 group can be either an
ester or a ketone group. The reac-
tions of both E and Z isomers of 1 f–j
and 1m proceeded smoothly and
afforded the corresponding products
in the same yields (Table 1, entries 1–
10 and 15–16). This result indicated
that in this transformation both E
and Z isomers probably proceed
through the same intermediate;
2) The migration ability of the R3
Entry Substrate 1
R2/R3/R4
Cond.[a] t [h] Ratio of 3/4[b] Product Yield [%][c]
1
1 f (E/Z=10:1) H/Ph/CO2Me
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
12
48
12
36
5
60
12
72
12
72
10
25
5
36
3
48
6
32
12
12
>20:1
1:2.7
>20:1
1:2.5
>20:1
>20:1
>20:1
1:0.6
5.6:1
1:12.5
1:1
<1:20
>20:1
1:6.7
>20:1
1:4.3
3 f
4 f
3g
4g
3h
3h
3i
4i
3j
4j
80
44
84
40
86
77
82
2
1 f
3[d]
4
1g (E/Z=10:1) H/Ph/CO2Et
1g
5
1h (E)
H/4-MeOC6H4/CO2Me
6
1h
7
1i (E/Z=20:1) H/4-MeC6H4/CO2Me
8
1i
31[e]
56[f]
68
9
1j (E)
1j
1k
1k
1l
H/4-ClC6H4/CO2Me
H/Me/COMe
10
11
12
13
14
15
16
17
18
19
20
3k
4k
3l
40[g]
70
MeO/Ph/COPh
MeO/Ph/CO2Et
5-F (4-H)/Ph/COPh
H/Et/COEt
90
63
70
40
90
61
1l
4l
1m (E)
1m
1n
1n
1o
3m
4m
3n
4n
3o
4o
12.5:1
1:4.4
>20:1
1.5:1
88
1o
30[h]
[a] Conditions A: substrate (0.1m) in DCE, AgSbF6 (5 mol%), 608C (except entries 11 and 13, 808C);
Conditions B: substrate (0.1m) in DCE, In(OTf)3 (5 mol%), MeOH (4 equiv), 508C. [b] Determined by
1H NMR spectroscopy of the crude product. [c] Yield of isolated product. [d] The reactions of E-1g and Z-
1g gave the same yields under Conditions A. [e] 3i was isolated in 42% yield. [f] 4j was isolated in 12%
group had a significant impact on yield. [g] 4k was isolated in 41% yield. [h] 3o was isolated in 43% yield.
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cyclopropane ring, afforded the naphthalen-2(1H)-one 7a in
63% yield under Conditions A [Eq. (3)].[18] However, the
reaction of 8, which had a phenyl group at the b position of
cyclopropane ring, gave the naphthalen-2(1H)-one 8a[16] in
only 24% yield, along with some unidentified products
[Eq. (4)].
Scheme 3. Plausible mechanism of Lewis acid catalyzed regiodivergent tandem
cyclization.
for the synthesis of benzo[a]-fluorenol by a gold-catalyzed
cascade reaction was also demonstrated. The scope, mecha-
nism, synthetic applications of this transformation, and design
of other related cascade reactions from intermediate B are
ongoing in our laboratory.
Based on the above results, a plausible mechanism of this
Lewis acid catalyzed regiodivergent tandem reaction is
depicted in Scheme 3. The carbonyl group of 1e is activated
by a Lewis acid, and the alkyne group attacks the carbonyl
unit to produce cyclopropyl alkenyl cation E. Then the
cyclopropyl alkenyl cation E undergoes ring expansion to
form two interconvertible allylic cations F and G. Under
Conditions A, cation G would undergo a pinacol rearrange-
ment to afford product 3 and regenerate the catalyst. Under
Conditions B, cation F is trapped by MeOH to produce the
intermediate H, which would undergo aromatization through
the elimination of MOH to give I, before a pinacol rearrange-
ment to form the oxonium ion intermediate J. The addition of
MOH to intermediate J regenerates the catalyst and affords
the hemiacetal K, which could immediately produce 4. In the
absence of MeOH, intermediate F could undergo cyclization
to produce L, before isomerization and pinacol rearrange-
ment to give 4.
Received: March 25, 2009
Revised: May 27, 2009
Published online: July 11, 2009
Keywords: cyclization · domino reactions · Lewis acids ·
.
pinacol rearrangement · regioselectivity
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[17] More reaction conditions were screened and can be found in
Table 1 of the Supporting Information.
[18] Under Conditions B, the reaction of 7 gave no aldehyde product
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