Lewis acid catalyzed cascade reaction of 3-(2-benzenesulfonamide)propargylic alcohols to spiro[indene-benzosultam]s

Article abstract of DOI:10.1021/ol503316e

A highly efficient and convenient construction of the spiro[indene-benzosultam] skeleton from propargylic alcohols has been developed. The reaction proceeded in a Lewis acid catalyzed cascade process, including the trapping of allene carbocation with sulfonamide, electrophilic cyclization, and intramolecular Friedel-Crafts alkylation. In the presence of NIS or NBS, iodo/bromo-substituted spiro[indene-benzosultam]s could be prepared in excellent yields.

Full text of DOI:10.1021/ol503316e

Letter
pubs.acs.org/OrgLett
Lewis Acid Catalyzed Cascade Reaction of 3‑(2-
Benzenesulfonamide)propargylic Alcohols to Spiro[indene-
benzosultam]s
Lang Sun, Yuanxun Zhu, Jing Wang, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient and convenient construction of the
spiro[indene-benzosultam] skeleton from propargylic alcohols has been
developed. The reaction proceeded in a Lewis acid catalyzed cascade
process, including the trapping of allene carbocation with sulfonamide,
electrophilic cyclization, and intramolecular Friedel−Crafts alkylation. In
the presence of NIS or NBS, iodo/bromo-substituted spiro[indene-
benzosultam]s could be prepared in excellent yields.
oth indene1 and benzosultam2 are privileged motifs in
hydroxy group in the presence of Brønsted acid or Lewis acid,
Bpharmaceutically active compounds and also exist widely in trapping of allenic carbocation by various nucleophiles presents
more prosperous and diverse chemistry of propargylic alcohols
and opens a new window to efficiently obtain various carbocycles
and heterocycles in recent years.8 Here, we report the synthesis
of spiro[indene-benzosultam]s through an intramolecular
trapping of allene carbocation and a sequential electrophilic
cyclization (Scheme 1, this work). In this way, a spiro carbon was
ideally constructed.
nature. Although spiro indene and others, such as spiro[indene-
indolin-3-one]s3 or spiro benzosultam with spiro[benzo[d]-
isothiazole-indane]s4 are well documented in the literature, the
connection of indene with benzosultam by sharing a spiro carbon
has been seldom reported. As a successful example, Dong and co-
workers reported a Rh-catalyzed [3 + 2] annulation of cyclic N-
sulfonylketimines with internal alkynes to give synthetically
challenging spiro[indene-benzosultam]s in the presence of
AgSbF6 in high yields (Scheme 1).5
Based on this consideration, we designed the substrate 1a,
which integrated propargylic alcohol and sulfonamide in a single
molecule. At room temperature, a Meyer−Schuster rearrange-
ment of 1a occurred in the presence of BF3·Et2O and afforded 2a
in 97% yield (Table 1, entry 1). When the reaction time was
extended to 8 h, 2a was still the predominant product (Table 1,
entry 2). The situation changed when the reaction was
conducted at 80 °C. Compound 2a could be formed and
isolated after the reaction was stirred for 5 min (Table 1, entry 3).
Extension of the reaction time to 4 h, spiro[indene-benzosultam]
(3a) was isolated in 95% yield (Table 1, entry 4). These time-
controlled experiments also indicated that 2a could be converted
into 3a at 80 °C under the reaction conditions. Without the
addition of 4 Å molecular sieves, the yield of 3a decreased to 78%
(Table 1, entry 5). By altering the Lewis acid catalyst to
Yb(OTf)3 and AgOTf, a mixture of 2a and 3a was observed
(Table 1, entries 6 and 7). Toluenesulfonic acid catalyzed the
reaction but gave a relatively lower yield of 3a (Table 1, entry 8).
Finally, the optimal solvent was determined to be dichloroethane
(DCE).
Scheme 1. Approaches to Spiro[indene-benzosultam]s
With the optimized reaction conditions in hand, we
investigated the substrate scope (Table 2). Ten spiro[indene-
benzosultam] compounds were prepared in yields varying from
57% to 95%. A variety of substituents, such as halogen, alkoxy,
and alkyl, tolerated the reaction conditions. Chlorine-substituted
Recent achievements on the cascade rearrangement of
propargylic alcohols have attracted much attention to organic
chemists because these reactions provide many efficient ways in
making complicated organic compounds.6 In comparison with
the classical Meyer−Schuster rearrangement of propargylic
alcohols to α,β-unsaturated ketones7 via a 1,3-shift of the
Received: November 15, 2014
Published: December 26, 2014
© 2014 American Chemical Society
242
DOI: 10.1021/ol503316e
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Organic Letters
Letter
a
efficiently converted into 3d in 95% yield (Table 2, entry 4).
When the propargylic alcohol was derived from acetophenone,
such as 1e, spiro compound 3e could also be prepared in 85%
yield (Table 2, entry 5). Without the methyl on the nitrogen of
sulfonamide, 3f and 3g were prepared in 87% and 88% yields,
respectively (Table 2, entries 6 and 7). The substituent on the
nitrogen of sulfonamide could be altered to other alkyl groups,
such as ethyl or benzyl. Thus, 3h and 3i were produced in
excellent yields (Table 2, entries 8 and 9). However, the
substituent on nitrogen could not be changed into aryl group.
For example, when 4-methylphenyl was substituted on the
nitrogen (1j), instead of a spiro product we obtained α,β-
unsaturated ketone 2b in 95% yield (Table 2, entry 10). Similarly,
the propargylic alcohol 1k which was derived from fluorenone
gave 2c in 94% yield (Table 2, entry 11). The electronic effect on
the nitrogen and the steric hindrance arising from the tertiary
alcohol would largely influence the outcome of the product.
Unsymmetrical acetylene 1l was also examined, and the desired
spiro product 3j was isolated in 85% yield (Table 2, entry 12).
If we subjected additional electrophile, such as NIS, to the
above reaction the electrophilic spirocyclization did occur and
afforded the products with iodo substitution. For instance, when
the reaction of 1a in the presence of trifluoroboron etherate was
conducted with an equivalent molar ratio of NIS at 25 °C for 30
min, 4a was isolated in 99% yield (Table 3, entry 1). The
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
temp (°C)
time
solvent
3a/2a yield (%)
1
2
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
Yb(OTf)3
25
25
80
80
80
80
80
80
80
80
5 min
8 h
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
PhMe
0/97
0/96
0/97
95/0
3
5 min
4 h
4
d
5
4 h
78/0
c
6
8 h
20/71
35/47
76/0
c
7
AgOTf
8 h
c
8
TsOH
6 h
9
BF3·Et2O
BF3·Et2O
3 h
57/0
10
8 h
83/0
a
Reaction conditions: 1a (0.1 mmol), catalyst (0.1 mmol), solvent (3
mL), 4 Å MS (100 mg). Isolated yields refer to 1a. Catalyst (0.01
b
c
d
mmol) was used. Without 4 Å MS.
Table 2. BF3.Et2O-Mediated Electrophilic Spirocyclization of
a
1
Table 3. BF3·Et2O/NIS-Mediated Electrophilic Spiro-
a
cyclization of 1
b
entry
1 (R1/R2/R3)
product
yield (%)
1
1a (H/C6H5/Me)
4a
4b
4c
4d
4e
4f
99
62
90
78
92
2
1b (Cl/4-ClC6H4/Me)
1c(OMe/4-MeOC6H4/Me)
1d (Me/4-MeC6H4/Me)
1e (H/Me/Me)
3
4
5
c
6
1f (H/C6H5/H)
96
c
7
1g (Me/4-MeC6H4/H)
1h (H/C6H5/Et)
4g
4h
4i
92
8
90
84
93
9
1i (H/C6H5/CH2C6H5)
1j (H/C6H5/4-MeC6H4)
1l (H/4-NO2C6H4/Me)
10
11
4j
d
4k
57
a
Reaction conditions: 1 (0.1 mmol), NIS (0.1 mmol), DCE (3 mL),
b
BF3·Et2O (0.1 mmol), 25 °C, 30 min. Isolated yields refer to 1.
c
d
Reflux. 48 h.
structure of 4a was established by its single-crystal analysis.9
Altering the acids or changing the reaction solvents would
decrease the yield of 4a (Table S1, Supporting Information).
When other substrates (1b−i) were used, the corresponding
spiro compounds 4b−i were obtained in yields varying from 62%
to 96% (Table 3, entries 2−9). In comparison with the yields
observed for 3a−i and the reaction time and temperature
applied, a preliminary result could indicate that 4a−i were easier
to prepare with the aid of the additional electrophile (I+). As
evidence for this conclusion, 1j provided the corresponding spiro
compound 4j with iodo substitution in 93% yield when the
reaction mixture was reacted at 25 °C for 30 min (Table 3, entry
a
Reaction conditions: 1 (0.1 mmol), DCE (3 mL), 4 Å MS (100 mg),
b
c
d
e
BF3·Et2O (0.1 mmol), 4 h. Isolated yields refer to 1. 8 h. 72 h. 56
h. 24 h.
f
substrate 1b afforded the corresponding spiro compound 3b in
57% yield. In this case, the reaction was conducted for 8 h (Table
2, entry 2). A longer reaction time (72 h) was required when the
chloro was replaced by methoxy (Table 2, entry 3). When the
substituent effect was moderate, such as methyl, 1d was
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Letter
10). Without I+, only the α,β-unsaturated ketone was obtained,
although the reaction mixture was reacted at 80 °C for 4 h (Table
2, entry 10). Unsymmetrical acetylene 1l gave the spiro product
4k in 57% yield (Table 3, entry 11). By applying a similar
strategy, we conducted this electrophilic spirocyclization in the
presence of NBS. Accordingly, the corresponding bromo-
substituted spiro compounds 5a−f were obtained in yields
varying from 63% to 98% (Table 4).
Scheme 3. Formation of 4f via 6
Table 4. BF3·Et2O/NBS-Mediated Electrophilic Spiro-
Based on the above observations, we postulated a possible
mechanism for this cascade process (Scheme 4). In the presence
a
cyclization of 1
Scheme 4. Proposed Mechanism for the Formation of 2a, 3a,
and 4a
b
entry
1 (R1/R2/R3)
product
yield (%)
1
2
3
4
5
6
1a (H/C6H5/Me)
5a
5b
5c
5d
5e
5f
98
c
1f (H/C6H5/H)
95
1j (H/C6H5/4-MeC6H4)
1b (Cl/4-ClC6H4/Me)
1c (OMe/4-MeOC6H4/Me)
1l (H/4-NO2C6H4/Me)
97
63
89
d
67
a
Reaction conditions: 1 (0.1 mmol), NBS (0.1 mmol), DCE (3 mL),
b
BF3·Et2O (0.1 mmol), 25 °C, 30 min. Isolated yields refer to 1.
c
d
Reflux. 48 h.
In order to understand the mechanism, we isolated the
intermediates and did several condition-controlled experiments.
As noted in the discussion of the screening of reaction
conditions, 1a could be converted into 2a and 3a by controlling
the reaction time. Upon direct subjection of 2a into the reaction,
3a could also be prepared (Scheme 2). More significantly, 4a
could be prepared from either 2a or 3a.
of trifluoroboron etherate, 1a was converted into allenesulfona-
mide intermediate A by intramolecular trapping of allene
carbocation formed from propargylic alcohol. Intermolecular
trapping of allene carbocation with sulfonamide11 or phosphor-
amide12 had been realized in our previous studies. Without the
additional electrophile, B was formed via an electrophilic
cyclization. B equilibrated with 2a by hydration and dehydration.
Alternatively, B could be further spirocyclized via an intra-
molecular Friedel−Crafts alkylation, leading to the formation of
3a. With the participation of additional electrophile, NIS or NBS,
the allenesulfonamide A was converted into D via an electrophilic
cyclization. Isolation of compound 6 was a good evidence for the
existence of D. Through any intramolecular Friedel−Crafts
alkylation, 4a was formed via intermediate E. For the formation
of 4a from 3a, electrophilic substitution on the electron-rich
alkene was proposed.
Scheme 2. Transformations between 1a, 2a, 3a, and 4a
Further studies indicated that halogen-substituted spiro-
[indene-benzosultam]s 4 and 5 could be transferred into aryl-
substituted spiro[indene-benzosultam]s through transition-
metal-catalyzed coupling reactions while maintaining the spiro
structure. For instance, reaction between 4a and arylboronic acid
in the presence of Pd(PPh3)4 provided 7a−c in high yields under
the normal Suzuki coupling conditions (Scheme 5).
In conclusion, we have developed an efficient and convenient
method for the construction of a spiro[indene-benzosultam]
skeleton from propargylic alcohols using Lewis acid as a catalyst.
The reaction proceeded in a cascade process, which included the
trapping of allene carbocation with sulfonamide, electrophilic
cyclization, and intramolecular Friedel−Crafts alkylation. In the
presence of NXS, iodo/bromo-substituted spiro[indene-
benzosultam]s were prepared in excellent yields. Moreover,
these halogen-substituted products were converted into their
Without the substituent on nitrogen of sulfonamide,
compound 1f provided compound 6 in 85% yield when the
reaction was carried out at room temperature for 30 min. The
structure of 6 was established by its single-crystal analysis.10 It is
noteworthy that the isolated compound 6 could be further
reacted and transferred into spirocyclized compound 4f in 93%
yield in the presence of trifluoroboron etherate at refluxing
temperature for 30 min (Scheme 3).
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Letter
(8) (a) Fang, Z. X.; Liu, J. Q.; Liu, Q.; Bi, X. H. Angew. Chem., Int. Ed.
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(9) CCDC 1011642 contains the supplementary crystallographic data
for 4a.
Scheme 5. Derivation of 4a
(10) CCDC 1011643 contains the supplementary crystallographic
data for 6.
(11) Zhu, Y. X.; Yin, G. W.; Hong, D.; Lu, P.; Wang, Y. G. Org. Lett.
2011, 13, 1024.
aryl-substituted derivatives without changing the spiro[indene-
benzosultam] skeleton.
(12) Yin, G. W.; Zhu, Y. X.; Zhang, L.; Lu, P.; Wang, Y. G. Org. Lett.
2011, 13, 940.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds and X-ray data (CIF) for compounds 4a and 6. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pinglu@zju.edu.cn
*E-mail: orgwyg@zju.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Natural
Science Foundation of China (Nos. 21032005, 21272203, and
21302166).
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