Phenylsulfonyl as a directing group for nitrile oxide cycloadditions and mCPBA epoxidations

Article abstract of DOI:10.1016/j.tetlet.2009.06.100

An unexpected selectivity trend in the nitrile oxide cycloaddition and epoxidation reactions of 4,4-disubstituted cyclopentenes is reported. A variety of facially distinct, 'X-' and 'Y-substituted' cyclopentenes were investigated.

Full text of DOI:10.1016/j.tetlet.2009.06.100

Tetrahedron Letters 50 (2009) 5110–5112
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Phenylsulfonyl as a directing group for nitrile oxide cycloadditions
and mCPBA epoxidations
*
Jeffrey D. Butler, Michael B. Donald, Zhensheng Ding, James C. Fettinger, Mark J. Kurth
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An unexpected selectivity trend in the nitrile oxide cycloaddition and epoxidation reactions of 4,4-disub-
stituted cyclopentenes is reported. A variety of facially distinct, ‘X-’ and ‘Y-substituted’ cyclopentenes
were investigated.
Received 1 May 2009
Revised 18 June 2009
Accepted 19 June 2009
Available online 25 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Nitrile oxide cycloadditions are exploited to deliver both the
saturated (isoxazolines) and unsaturated (isoxazoles) heterocy-
cles;1 these products have considerable synthetic application as
natural product precursors2,3 and biological probes.4,5 However,
their usefulness is often handicapped by the inherent generation
of regio- and/or stereoisomers.6 Synthetic methodologies continue
to be developed to address these issues,6 with allylic H-bonding,7,8
Lewis acids,9 metal chelation,10–12 and coulombic interactions13
having been exploited as control elements. Examples of regioselec-
tive nitrile oxide cycloadditions to vinyl sulfone14 and phospho-
nate15 dipolarophiles are also represented in the literature.
Computational and experimental studies16 have provided insights
in the cycloadditions of unsymmetrical dipolarophiles and regiose-
lectivities are often explained by examining HOMO/LUMO interac-
tions between the dipole and dipolarophile.15 Herein, we report
variable nitrile oxide cycloaddition selectivity in cyclopentene-
based systems which are related to our previous report of a selec-
tive mCPBA-mediated epoxidation.17
Our investigation began as an effort to synthesize an array of
3aH-cyclopenta[d]isoxazoles. The effort began on two fronts as de-
tailed in Schemes 1 and 2. Following Scheme 1, base-mediated
dialkylation of 2-phenylacetonitrile (?1) and methyl 2-phenylace-
tate (?2) followed by nitrile oxide cycloaddition utilizing Huis-
gen’s method (e.g., an aryl oxime + bleach in DCM) gave 3a/3b
and 4a/4b. Despite the fact that the A-value18 of phenyl
(ꢀ3.0 kcal/mol) is significantly greater than the A-value of either
nitrile or carbomethoxy (0.2 and 1.2 kcal/mol, respectively), there
was essentially no facial selectivity observed in these cycloaddi-
tions (Table 1, entries 1–4).
cis-1,4-dichloro-2-butene) gave cyclopentene 6a in 70% overall
yield. Nitrile oxide cycloadditions (aryl oxime + bleach in DCM)
with this dipolarophile delivered 9a and 9b in P19:1 diastereose-
lectivity (Table 1, entry 5). The stereochemistry of 9a (Ar = m-
BrC6H4) was established by X-ray crystallography (see Fig. 1). Fa-
cial selectivity with a slightly more reactive nitrile oxide (entry
6) is comparable.
Initially, we expected the system with the largest A-value18 dis-
crepancy between the two substituents to deliver the greatest fa-
cial selectivity. However, when the A-values of phenylsulfonyl
(ꢀ2.5 kcal/mol) and nitrile (ꢀ0.2 kcal/mol) are contrasted with
those of the phenyl-substituted cases from Scheme 1, this simple
expectation is not met.
With these contrasting results (Table 1 entries 1–4 vs entries
5–6) in hand, we set out to make a small collection of phenylsulfo-
nyl-substituted examples to further probe the limits of their
unexpected facial selectivity. Ester (7) and amide (8) (phenylsul-
fon-4-yl)cyclopentene analogs were prepared by nitrile hydrolysis
(6a?6b) followed by Fisher esterification (6b?7) and amidation
NaH, THF
R
R
Cl
R = CN, CO2Me
Cl
1; R = CN
2; R = CO2Me
R
R
However, in the parallel route (Scheme 2) utilizing chemistry
similar to that presented in Scheme 1, sulfone 5 was prepared by
S-alkylation of sodium benzenesulfinate with chloroacetonitrile
in ethylene glycol.19 Subsequent dialkylation (sodium hydride +
bleach
+
HO
O
O
N
Ar
Ar
Ar
N
3b
4b
N
3a
4a
DCM
3
4
; R = CN
; R = CO2Me
* Corresponding author. Tel.: +1 530 752 8192; fax: +1 530 752 8995.
E-mail address: mjkurth@ucdavis.edu (M.J. Kurth).
Scheme 1. Synthetic route to selected phenyl-substituted cyclopentenes and their
isoxazoline derivatives.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.100

J. D. Butler et al. / Tetrahedron Letters 50 (2009) 5110–5112
5111
O
S
O O
S
N
Cl
Cl
ClH2CC N
ONa
ethylene
glycol
NaH, THF
5
O
O O
S
O O
S
R
MeOH
OMe
cat. H2SO4
7
KOH
6a
: R = CN
IPA/H2O
6b: R = CO2H
O
O O
S
EDC,HOBt
isopropyl amine
DCM/DMF
N
H
Figure 1. X-ray crystal structure of cycloadduct 9a.
8
6a
7 8
/
/
O O
S
O O
S
(6b?8), respectively. These dipolarophiles undergo nitrile oxide
cycloadditions to give predominately diastereomers 10a and 11a
with quite good selectivity (85:15–93:7; see Table 1, entries 7–10).
These facially selective cycloaddition results with (phenylsul-
fon-4-yl)cyclopentenes (e.g., Table 1, entries 5–10) led us to pre-
pare analogs where the phenylsulfonyl substituent was matched
with a phenyl substituent (13). This analog was chosen to explore
the selectivity when both substituents (X and Y) have increased
steric bulk.
No. R=
R
R
bleach
CN
+
9
HO
Ar
N
CO2Me
10
11
O
O
DCM
Ar
Ar
N
N
CONHi-Pr
9-11b
9-11a
Scheme 2. Synthetic route to various phenylsulfonyl-substituted cyclo-pentenes
and their 3aH-cyclopenta[d]isoxazole derivatives.
Following the literature procedures,17 the synthesis of 12 began
with the S-alkylation of sodium benzenesulfinate with benzyl bro-
mide, generating benzylsulfonylbenzene 13 in excellent yield. a,a-
Dialkylation of 13 using strong base and cis-1,4-dichloro-2-butene
gave 12 in 65% overall yield. Nitrile oxide cycloadditions were then
performed (aryl oxime + bleach in DCM) to give 14a/14b (Scheme
3). Employing 3-bromobenzaldehyde oxime resulted in an 83:17
ratio of diastereomers (Table 1, entry 11). The resulting mixture
was recrystallized from ethyl acetate/hexanes and the major dia-
stereomer was analyzed by X-ray crystallography to establish that
this cycloaddition reaction also proceeded predominantly with the
nitrile oxide adding trans to the phenylsulfone moiety (see Fig. 2).
In an attempt to probe whether coulombic interactions with the
sulfone or steric effects of the phenyl ring leads to a destabilizing
Table 1
Summary of nitrile oxide cycloaddition selectivity data
X
Y
X
Y
X
Y
bleach
O
+
O
Ar
Ar
HO
DCM
rt, 12h
N
N
N
R
( )
( )
Yield
(%)**
a b
% * % *
entry X=
Y=
R=
1
CN
CN
m-Br
55
86
75
70
60
45
47
46
48
Ph
O
S
BnBr, Et3N
DMF/THF
BuLi
THF
O
O
2
3
4
p-OCH3
m-Br
Ph
Ph
Ph
53
54
52
S
Cl
Cl
ONa
CO2Me
CO2Me
CN
13
p-OCH3
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
68
52
61
57
64
54
80
79
41
50
54
60
55
45
61
50
5
6
m-Br
95
96
91
93
85
87
5
O
O
O
O
N
O
O
HO
S
S
Ar
CN
S
p-OCH3
N
4
+
Bleach
DCM
CO2Me
CO2Me
7
m-Br
9
O
O
p-OCH3
8
7
Ar
12
Ar
N
9
CONHi-Pr m-Br
15
13
17
27
49
48
10
11
45
14a
14b
10
p-OCH3
SO2Ph
SO2Ph
CONHi-Pr
Scheme 3. Synthetic route to (1-phenylcyclopent-3-enylsulfonyl)benzene (12) and
3aH-cyclopenta[d]isoxazole derivatives (14a/14b).
11
12
13
14
15
16
17
18
19
20
Ph
Ph
m-Br
83
73
51
52
90
89
55
49
51
50
SO2Ph
SPh
p-OCH3
m-Br
CN
SPh
p-OCH3
CN
CN
CN
SO2Me
SO2Me
PO(OEt)2
PO(OEt)2
m-Br
p-OCH3
m-Br
Ph
Ph
p-OCH3
m-Br
51
49
50
PO(OEt)2 CN
PO(OEt)2 CN
p-OCH3
*
Percentages calculated by LC trace and NMR integration.
Combined yield.
**
Figure 2. X-ray crystal structure of cycloadduct 14a.

5112
J. D. Butler et al. / Tetrahedron Letters 50 (2009) 5110–5112
interaction with the nitrile oxide and hence the unexpectedly high
trans (e.g., 9a/10a/11a/14a) selectivity observed, we next prepared
cyclopentenes with sulfide (15), methylsulfone (16), and diethyl
phosphonate (17 and 18) substituents (Scheme 4).
Sulfide analog 15 shows little facial selectivity. In contrast,
methylsulfone analog 16 shows good diastereoselectivity (Table
1, entries 13–16). The examples employing a diethyl phosphonate
group in place of the phenylsulfonyl show little facial selectivity
and, in this regard, are similar to the phenyl-substituted cases from
Scheme 1. These data are tabulated in Table 1, entries 17–20.
To extend and further generalize the facial directing properties
of the phenylsulfonyl moiety in mCPBA-mediated epoxidations, we
exposed a selection of our 4,4-disubstituted cyclopentenes (2, 7,
and 12; Table 2) to epoxidation conditions yielding 19a/19b, 20a/
20b, and 21a/21b. The mCPBA-mediated epoxidation of 12 gives
only 21a and, in parallel, the epoxidation of 7 is also completely
selective yielding only 20a. Diastereomer 20a was analyzed by
X-ray crystallography to establish that epoxidation also proceeds
trans to the phenylsulfone moiety (see Fig. 3). This is contrasted
by the mediocre selectivity observed in the epoxidation of 2 which
yields a 2.5:1 mixture of 19a and 19b.
Figure 3. X-ray crystal structure of epoxide 20a.
tions of these selective trends are currently under investigation
and will be reported in due course.
Although the origin of this sulfone-based facial selectivity
remains unclear, an interesting trend in our 4,4-disubstituted
cyclopentenes is observed. All of the sulfone-substituted cyclo-
pentenes are quite selective, even when steric disparity between
the two cyclopentene substituents is not large (compare entries
5–12 and 15–16, Table 1). This suggests that cyclopentene confor-
mation as well as sulfone-based coulombic interactions lead to the
observed selectivity trend. As a consequence, the sulfide analog of
sulfone 6a, cyclopentene 15, shows no selectivity (entries 5–6 and
13–14)13 and exchanging the sulfone substituent for a phenyl sub-
stituent also leads to negligible selectivity (entries 1–4, Table 1).
Likewise, exchanging the sulfone for a diethyl phosphonate leads
to much reduced facial selectivity (entries 17–20, Table 1). Applica-
Acknowledgments
The authors thank the National Science Foundation (CHE-
0614756) for their financial support of this work. NMR spectrome-
ters used were partially funded by the National Science Foundation
(CHE-0443516 and CHE-9808183).
Supplementary data
1H NMR and 13C NMR data are provided. Crystallographic data
(excluding structure factors) for the structures in this Letter have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication nos. CCDC 730064, 730065, and
730066. Copies of these data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.100.
O
P
O
O
EtO
EtO
S
CN
S
CN
R
Ph
Me
15
16
17; R = CN
18; R = Ph
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+
CHCl3
60oC
2, 7, 12
O
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(%)
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Ph
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a
%
%
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