Benzothiazines in synthesis: A route to chiral cyclobutanes

Article abstract of DOI:10.1055/s-2008-1032146

Using enantiomerically pure benzothiazines as templates, enantiomerically pure cyclobutanes were prepared. Such compounds are potentially interesting synthetic intermediates. The sequence developed for the preparation of these compounds, as well as some of their chemistry, is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032146

594
PAPER
Benzothiazines in Synthesis: A Route to Chiral Cyclobutanes
Synthesis of Chiral
C
y
i
clobuta
c
nes
U
sing
h
enzothiazin
a
es
a
s
T
emp
e
lates l Harmata,* Weijiang Ying, Xuechuan Hong, Charles L. Barnes
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Fax +1(573)8822754; E-mail: HarmataM@missouri.edu
Received 27 August 2007
Dedicated to Professor Lutz F. Tietze on the occasion of his 65th birthday
Me
CO2Et
Me
CH2I
Abstract: Using enantiomerically pure benzothiazines as tem-
plates, enantiomerically pure cyclobutanes were prepared. Such
compounds are potentially interesting synthetic intermediates. The
sequence developed for the preparation of these compounds, as well
as some of their chemistry, is described.
H
H
Me
Me
1. LiAlH4
2. TsCl
3. NaI
O
O
S
S
N
N
Ph
Ph
H
62%
OMe
OMe
Key words: benzothiazines, enantiomerically pure, cyclobutanes,
stereoselective, metalation
1h
4h
Me
Me
Li
H
Due to their high degree of ring strain, the use of cyclo-
butanes as synthetic intermediates has flourished over the
last 30 years.1–5 There are four main synthetic strategies
for the creation of these four-membered-ring systems:
[2+2] cycloadditions, cyclization of acyclic precursors,
ring expansion of cyclopropanes, and ring contraction of
cyclopentanes.1–5 The utility of cyclobutanes in synthesis
makes their preparation both of interest and importance,
and the synthesis of enantiomerically pure cyclobutanes
leads to useful starting materials from which other chiral,
nonracemic products can be formed.
Me
H
O
Me
SO2(p-Tol)
83%
S
N
Ph
OMe
5h
Scheme 1
CH2I
Me
Me
+
Ph
MgBr
S
We recently published the synthesis of pseudopteroxazole
conducted using benzothiazine chemistry that we have de-
veloped.6,7 During the course of that synthesis we had oc-
casion to attempt the reactions shown in Schemes 1 and 2.
Rather than serve as nucleophiles, the organometallic re-
agents acted as bases, deprotonating the starting benzothi-
azines, which then cyclized intramolecularly to afford the
cyclobutanes 5h and 5a. We subsequently undertook a
broader study of this process. This report details our re-
sults.
Me
N
O
4a
cat. CuI, THF, –40 °C
0 °C, 30 min
Ph
O
S
Me
N
5a
Scheme 2
We found that treatment of 4a with potassium hydride af-
forded 5a in 83% yield, while bases such as n-butyllithi-
um and lithium hexamethyldisilazide did not afford this
product and led to recovery of starting material. The rea-
sons for this are not clear.
–78 °C and allowing the reaction to warm to room temper-
ature overnight. Examples are shown in Table 1.
The metalation of sulfoximines is of current interest8 and
we thus conducted a small study of the metalation of cy-
clobutane 5g and trapping of the resultant anion with elec-
trophiles. The results are illustrated in Table 2. As has
been the case for other benzothiazines that we have meta-
lated, the procedure consisted simply of treating 5g with
n-butyllithium for 60 minutes at –78 °C, followed by ad-
dition of an electrophile. Noteworthy and unfortunate is
that diastereocontrol in the reaction with aldehydes was
poor; however, diastereomeric pairs 6c/6d and 6e/6f could
be separated by chromatography. When chlorodiphe-
nylphosphine or chlorodicyclohexylphosphine was used
as an electrophile, the products oxidized rather quickly
and were isolated and characterized as the corresponding
phosphine oxides 6i and 6j, respectively.
As this process seemed a simple one for the synthesis of
substituted, enantiomerically pure cyclobutanes, we de-
cided to explore the scope of the reaction. Starting mate-
rials for the ring closure were prepared from the
corresponding esters, as illustrated for 1g in Scheme 3.
The basic procedure for cyclization consisted of treating
iodides 4 with 1.5 equivalents of potassium hydride at
SYNTHESIS 2008, No. 4, pp 0594–0604
x
x
.
x
x
.2
0
0
8
Advanced online publication: 31.01.2008
DOI: 10.1055/s-2008-1032146; Art ID: M06007SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Chiral Cyclobutanes Using Benzothiazines as Templates
595
Table 1 Cyclization Reactions of Iodoethyl-Substituted Benzothi-
azines To Form Cyclobutanes
CO2Me
CH2OH
CH2I
LiAlH4
Ph
S
O
Ph
S
O
THF, 0 °C, 3 h
75%
N
N
2g
1.5 equiv KH,THF
1g
S
–78 °C, 0.5 to 1 h
r.t., overnight
S
Ph
Ph
R
R
N
N
O
CH2OTs
O
DMAP (0.1 equiv)
Et3N (3.0 equiv)
TsCl (1.5 equiv)
4
5
Ph
S
O
Starting Material
Product
Yield (%)
83
82%
N
3g
I(H2C)2
CH2I
S
Ph
Ph
S
Ph
NaI (3 equiv)
Me
N
Me
N
O
O
Ph
S
O
acetone, reflux, 4 h
94%
5a
N
4g
4a
(CH2)2I
BnO
BnO
Scheme 3
84
58
64
S
Ph
S
N
N
O
O
5b
When diphenyl disulfide was used as an electrophile, 6a
could be isolated in high yield; however, 6a was not stable
and decomposed in deuterated chloroform and other mild-
ly acidic media to afford two new products, 7 and 8, in
moderate yield as single stereoisomers (Scheme 4). The
structure of 7 was assigned on the basis of NOESY and
HMBC data. In Figure 1a, the correlations of C-5 and H-
4 and C-5 and H-3 (HMBC) indicate that the phenylsulfa-
nyl group is located on C-1. The NOESYcorrelations of
H-12 (or H-16) and H-9 indicate that they are close in
space. In Figure 1b, the correlation of H-21 (or H-19) and
H-4 is shown and suggests that H-4 and the phenylsulfa-
nyl group are cis to each other. The structural assignment
was ultimately confirmed by X-ray crystal structure anal-
ysis of 7.9 The second product, 8, possessed an exchange-
able proton as determined by examining the proton NMR
and IR spectra. The presence of two olefinic quaternary
carbons and two monosubstituted benzene rings led us to
the structure shown.
4b
(CH2)2I
S
S
Ph
Ph
S
S
N
N
O
O
5c
4c
(CH2)2I
O
O
O
O
O
O
S
S
N
N
Ph
Ph
5d
4d
(CH2)2I
71a
Ph
Ph
S
S
N
N
N
N
O
O
Me
Me
5e
4e
(CH2)2I
Me
Me
A reasonable rationalization for the formation of 7 and 8
consists of initial protonation of 6a followed by ring open-
ing to form the thiocarbenium ion 10 (Scheme 5). Cy-
clization with the sulfinamide nitrogen as the nucleophile
produces 7, while E1 elimination affords 8. Interestingly,
the oxidation of 7 to the corresponding sulfoxide with m-
chloroperoxybenzoic acid (Scheme 6) proceeded with
complete diastereoselectivity, as evidenced by H NMR
data. However, the relative stereochemistry was not estab-
lished.
78
O
O
S
S
N
N
Ph
Ph
OMe
OMe
5f
4f
(CH2)2I
88a
1
O
O
S
S
N
N
Ph
Ph
5g
4g
Me
In summary, we have developed a simple route to enan-
tiomerically pure cyclobutanes based on an intramolecu-
lar cyclization of iodoethyl-substituted benzothiazines
(cyclic sulfoximines). The successful metalation and elec-
trophilic trapping of one such cyclobutane has been dem-
onstrated. Further studies will involve taking advantage of
the ring strain of the cyclobutane to obtain enantio-
merically pure compounds of greater complexity.
Me
CH2I
Me
Me
96b
O
S
O
S
N
N
Ph
Ph
OMe
OMe
4h
5h
a X-ray crystal structure obtained.9
b Diastereomeric ratio = 2.6:1.
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York

596
M. Harmata et al.
PAPER
Table 2 Metalation and Trapping of 5g
E
n-BuLi
electrophile
Ph
S
Ph
S
Ph
S
N
O
N
N
O
O
5g
6
Electrophile
(PhS)2
Product(s)
Yield (%)
93a
SPh
Ph
S
N
O
6a
CH2=CHCH2Br
57
S
Ph
N
O
6b
OH
OH
Ph
Ph
Ph
PhCHO
96b
81c
86d
99
S
Ph
S
N
N
O
O
6c
6d
6f
OH
Ph
OH
CH3CH2CHO
CH3(CH2)2CHO
Ph2CO
S
S
Ph
N
N
O
O
6e
OH
Ph
S
N
O
6g
OH
Ph
Ph
Ph
S
N
O
6h
O
P
Ph
Ph
Ph2PCl
86e
Ph
S
S
N
O
O
6i
O
P
Cy
Cy
Cy2PCl
50f
Ph
N
6j
a X-ray crystal structure obtained.9
b Diastereomers separated, ratio 6c/6d = 1.4–1.6:1.
c Diastereomers separated, ratio 6e/6f = 1.3–1.5:1.
d Diastereomers separated, ratio = 1.4:1.
e Initial product oxidized with H2O2.
f Initial product oxidized by air.
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York

PAPER
Synthesis of Chiral Cyclobutanes Using Benzothiazines as Templates
597
Sigma–Aldrich silica gel TLC plates containing UV indicator.
Melting points were measured with a Fisher–Johns melting point
apparatus. IR spectra were recorded (film) on a Perkin Elmer 1600
series FT-IR spectrometer. Optical rotations were measured on a
Jasco DIP-370 digital polarimeter. 1H NMR spectra were recorded
on a Bruker ARX-250 (250 MHz), DRX-300 (300 MHz), or DRX-
500 (500 MHz) spectrometer and the chemical shifts (d) are report-
ed in ppm relative to tetramethylsilane (TMS: d = 0.0). Data are re-
ported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublets, ddd = doublet of doublet of doublets), coupling constants
(Hz), and integration. 13C NMR spectra were recorded on a Bruker
ARX-250 (62.5 MHz), DRX-300 (75 MHz), or DRX-500 (125
MHz) spectrometer with complete proton decoupling. Chemical
shifts (d) are reported in ppm from TMS with the solvent resonance
as the internal standard (CDCl3: d = 77.0). HRMS were recorded
with a Bruker 12 Tesla Apex-Qe FTICR-MS with an Apollo II ion
source.
SPh
Ph
H+
SPh
S
+
SPh
Ph
N
N
NH
S
O
S
O
O
Ph
6a
7, 34%
8, 36%
Scheme 4
H
H
21
H
H
H
H
H
21
19
6
3
H
5
6
4
4
17
S
S
1
1
N
N
9
H
H
S
O
S
O
16
Alcohol 2g; Typical Procedure for the Preparation of Alcohols 2
To ester 1g (1.059 g, 3.363 mmol) in THF (9 mL) at 0 °C, LiAlH4
(380.9 mg, 10.09 mmol) was added carefully. The mixture was
stirred for another 3 h before the reaction was quenched with H2O
(386 mL), 15% aq NaOH (386 mL), and H2O (1.2 mL). After stirring
for 30 min at r.t., the mixture was filtered through Celite® and dried
(MgSO4). Chromatography (EtOAc–hexanes, 7:3) gave 2g as a
pale-yellow semisolid; yield: 724 mg (75%).
H 12
a
NOESY
HMBC
b
14
Figure 1 HMBC and NOESY correlations seen in compound 7
H
SPh
H+
[a]D25 –0.4 (c 1.0, CHCl3).
SPh
Ph
S
Ph
S
S
IR (film): 3367, 3056, 3007, 2958, 2921, 2876, 1589, 1565, 1479,
1446, 1405, 1295, 1262, 1213, 1111, 1046 cm–1.
N
N
H
Ph
O
O
NH
S
6a
10
9
1H NMR (300 MHz, CDCl3): d = 8.06 (dd, J = 1.5, 7.2 Hz, 2 H),
7.66 (tt, J = 2.0, 7.2 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 2 H), 7.21 (t,
J = 7.2 Hz, 2 H), 7.13 (dd, J = 1.2, 7.8 Hz, 1 H), 6.93 (td, J = 1.5,
7.5 Hz, 1 H), 3.73 (t, J = 5.1 Hz, 2 H), 3.63 (dd, J = 4.5, 11.7 Hz, 1
H), 3.58–3.50 (m, 1 H), 3.08 (dd, J = 7.5, 12.0 Hz, 1 H), 2.43 (qd,
J = 6.0, 12.0 Hz, 1 H), 2.00–1.80 (m, 2 H).
O
Ph
– H+
SPh
13C NMR (75 MHz, CDCl3): d = 145.0, 139.1, 133.8, 129.4, 128.9,
SPh
Ph
NH
S
N
125.8, 125.3, 124.0, 120.8, 59.8, 52.5, 34.1, 31.6.
S
7
8
HRMS: m/z [M + H]+ calcd for C16H18NO2S: 288.1053; found:
O
Ph
O
288.1055.
Scheme 5 Proposed mechanism for the formation of 7 and 8
2b
Yield: 80%; pale-yellow semisolid.
[a]D25 –13.9 (c 3.2, CHCl3).
MCPBA, CH2Cl2,
–30 °C, 1 h
IR (film): 3371, 3064, 3027, 3007, 2925, 2872, 1610, 1573, 1483,
1442, 1417, 1381, 1283, 1221, 1099, 1021 cm–1.
SPh
Ph
N
S
1H NMR (300 MHz, CDCl3): d = 8.04 (dd, J = 7.7, 1.4 Hz, 2 H),
7.63 (t, J = 7.6 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 2 H), 7.45–7.26 (m, 5
H), 7.03 (d, J = 8.5 Hz, 1 H), 6.90–6.84 (dd, J = 2.3, 7.1 Hz, 1 H),
6.83 (d, J = 2.3 Hz, 1 H), 5.02 (s, 2 H), 3.70–3.40 (m, 4 H), 3.08 (dd,
J = 10.1, 12.2 Hz, 1 H), 2.23 (qd, J = 5.1, 11.8 Hz, 1 H), 1.96 (s, 1
H), 1.82 (qd, J = 5.5, 11.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 153.2, 139.3, 138.4, 137.3, 133.7,
129.3, 128.8, 128.5, 127.8, 127.5, 126.4, 124.5, 114.4, 113.6, 70.6,
59.7, 52.6, 34.2, 32.0.
O
7
+
O
S
SO2Ph
N
S
N
S
Ph
Ph
O
O
Ph
sulfoxide of 7
sulfone of 7
Scheme 6
HRMS: m/z [M + H – H2O]+ calcd for C23H22NO2S: 376.1366;
found: 376.1369.
All reactions were carried out under an atmosphere of nitrogen in
flame-dried glassware. THF was distilled over sodium/benzophe-
none before use. Toluene and CH2Cl2 were distilled over CaH2.
Chromatographic separations were carried out using Sorbent stan-
dard silica gel (230–400 mesh). Analytical TLC was performed on
2c
Yield: 71%; pale-yellow semisolid.
[a]D25 +6.8 (c 3.1, CHCl3).
IR (film): 3350, 3097, 3064, 2925, 2872, 1581, 1520, 1442, 1377,
1238, 1107 cm–1.
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York

598
M. Harmata et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 8.10 (td, J = 1.5, 7.1 Hz, 2 H), 7.71
(tt, J = 1.3, 7.5 Hz, 1 H), 7.60 (tt, J = 1.1, 7.8 Hz, 2 H), 7.12 (dd,
J = 1.0, 5.3 Hz, 1 H), 6.85 (d, J = 5.2 Hz, 1 H), 3.86 (dd, J = 5.0, 9.0
Hz, 2 H), 3.82–3.72 (m, 1 H), 3.62 (dd, J = 4. 8, 11.6 Hz, 1 H), 2.74
(dd, J = 11.7, 13.7 Hz, 1 H), 2.45–2.25 (m, 1 H), 2.10–1.85 (m, 1
H), 1.70 (t, J = 3.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 142.8, 136.7, 134.2, 129.4, 129.3,
125.5, 121.6, 115.3, 60.2, 51.4, 37.7, 30.1.
HRMS: m/z [M + H]+ calcd for C14H16NO2S2: 294.0617; found:
294.0618.
Tosylate 3g; Typical Procedure for the Preparation of Tosylates
3
To alcohol 2g (445.7 mg, 1.552 mmol) in CH2Cl2 (16 mL) in a 25-
mL round-bottomed flask at 0 °C, DMAP (19.1 mg, 0.156 mmol),
Et3N (0.652 mL, 473.6 mg, 4.680 mmol), and TsCl (446.1 mg,
2.340 mmol) were added. After the mixture was stirred at r.t. over-
night, TLC showed that no starting materials remained. The solvent
was removed; chromatography (EtOAc–hexanes, 4:6) gave 3g as a
pale-yellow semisolid; yield: 560 mg (82%).
[a]D25 +12.3 (c 1.9, CHCl3).
IR (film): 3056, 3027, 2958, 2921, 2856, 1593, 1478, 1442, 1356,
1274, 1176 cm–1.
2d
Yield: 70%; pale-yellow semisolid.
[a]D25 –17.7 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.04 (dd, J = 1.5, 7.4 Hz, 2 H),
7.74 (d, J = 8.1 Hz, 2 H), 7.67 (tt, J = 1.5, 7.5 Hz, 1 H), 7.58 (t,
J = 7.2 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.21 (m, 1 H), 7.11 (dd,
J = 1.2, 7.8 Hz, 1 H), 6.94 (d, J = 6.3 Hz, 1 H), 6.85 (dt, J = 1.2, 7.5
Hz, 1 H), 4.03 (t, J = 6.0 Hz, 2 H), 3.48 (dd, J = 4.8, 12.3 Hz, 1 H),
3.44–3.35 (m, 1 H), 3.17 (dd, J = 7.8, 12.0 Hz, 1 H), 2.45 (s, 3 H),
2.31 (qd, J = 6.6, 12.6 Hz, 1 H), 1.96 (qd, J = 6.3, 12.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 145.1, 144.7, 139.1, 133.9, 132.5,
130.0, 129.5, 128.7, 128.7, 127.8, 126.2, 124.4, 124.0, 121.0, 67.2,
31.9, 31.1, 21.6.
IR (film): 3399, 3056, 3003, 2884, 1650, 1479, 1417, 1230, 1033
cm–1.
1H NMR (250 MHz, CDCl3): d = 8.06 (td, J = 1.1, 6.9 Hz, 2 H), 7.67
(td, J = 1.2, 7.5 Hz, 1 H), 7.58 (td, J = 1.1, 7.3 Hz, 2 H), 6.69 (dd,
J = 1.8, 3.0 Hz, 2 H), 5.90 (dd, J = 1.4, 3.9 Hz, 1 H), 3.72 (q, J = 5.9
Hz, 2 H), 3.60 (dd, J = 4.5, 12.8 Hz, 1 H), 3.53–3.40 (m, 1 H), 3.15
(dd, J = 9.6, 12.8 Hz, 1 H), 2.23 (qd, J = 6.1, 14.2 Hz, 1 H), 1.83
(qd, J = 7.6, 14.0 Hz, 1 H), 1.50 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 147.3, 142.1, 139.5, 139.3,
133.7, 129.4, 128.8, 117.7, 106.1, 105.6, 100.9, 76.5, 60.0, 53.4,
34.6, 32.1.
HRMS: m/z [M + H]+ calcd for C23H24NO4S2: 442.1141; found:
442.1135.
3a
HRMS: m/z [M + H]+ calcd for C17H18NO4S: 332.0951; found:
332.0949.
Yield: 82%; white semisolid.
1H NMR (500 MHz, CDCl3): d = 8.01 (dd, J = 1.3, 7.4 Hz, 2 H),
7.72 (d, J = 8.2 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.55 (t, J = 8.0
Hz, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 6.93 (s, 1 H), 6.82 (d, J = 7.8 Hz,
1 H), 6.65 (dd, J = 1.0, 7.7 Hz, 1 H), 4.10–3.92 (m, 2 H), 3.50–3.33
(m, 2 H), 3.12 (dd, J = 8.7, 12.7 Hz, 1 H), 2.42 (s, 3 H), 2.35–2.22
(m, 4 H), 1.91 (qd, J = 6.8, 13.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 144.9, 144.3, 139.0, 138.3, 133.7,
132.3, 129.8, 129.3, 128.5, 127.7, 125.9, 124.8, 121.6, 120.8, 67.2,
52.7, 31.3, 31.0, 21.4, 20.9.
2e
Yield: 83%; pale-yellow semisolid.
[a]D25 –40.4 (c 3.2, CHCl3).
IR (film): 3416, 3052, 2999, 2917, 2864, 1961, 1900, 1818, 1716,
1614, 1577, 1471, 1442, 1409, 1356, 1225, 1131, 1103, 1013 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.08 (d, J = 7.6 Hz, 2 H), 7.69 (t,
J = 7.2 Hz, 1 H), 7.59 (t, J = 7.4 Hz, 2 H), 7.41 (dd, J = 3.2, 8.2 Hz,
1 H), 7.20 (dd, J = 5.3, 6.8 Hz, 1 H), 7.10–6.90 (m, 2 H), 4.00–3.70
(m, 3 H), 3.67 (s, 3 H), 3.56 (dd, J = 5.3, 12.1 Hz, 1 H), 3.08 (t,
J = 11.8 Hz, 1 H), 2.60–2.38 (m, 1 H), 2.02 (qd, J = 6.8, 13.6 Hz, 1
H), 1.74 (s, 1 H).
Anal. Calcd for C24H25NO4S2: C, 63.27; H, 5.53; N, 3.07. Found: C,
63.12; H, 5.41; N, 3.14.
3b
13C NMR (62.5 MHz, CDCl3): d = 142.8, 137.1, 134.3, 133.8,
129.5, 129.0, 126.0, 119.3, 118.3, 117.1, 108.3, 88.3, 60.3, 53.0,
35.3, 29.3, 27.6.
HRMS: m/z [M + Na]+ calcd for C19H20N2O2SNa: 363.1138; found:
363.1143.
Yield: 74%; pale-yellow semisolid.
IR (film): 3064, 3032, 2958, 2921, 2868, 1601, 1565, 1479, 1442,
1360, 1274, 1225, 1189, 1172 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.05 (td, J = 1.0, 7.1 Hz, 2 H), 7.73
(td, J = 1.3, 8.3 Hz, 2 H), 7.67 (tt, J = 1.3, 7.4 Hz, 1 H), 7.58 (tt,
J = 7.1, 1.5 Hz, 2 H), 7.50–7.25 (m, 7 H), 7.04 (d, J = 8.7 Hz, 1 H),
6.87 (dd, J = 2.9, 8.7 Hz, 1 H), 6.67 (d, J = 2.8 Hz, 1 H), 5.01 (s, 2
H), 4.10–3.90 (m, 2 H), 3.46 (dd, J = 4.7, 10.3 Hz, 1 H), 3.50–3.32
(m, 1 H), 3.19 (dd, J = 7.9, 12.5 Hz, 1 H), 2.40 (s, 3 H), 2.27 (qd,
J = 5.6, 11.5 Hz, 1 H), 1.94 (qd, J = 5.5, 11.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 153.4, 145.1, 139.3, 138.1, 137.2,
133.8, 132.6, 130.0, 129.5, 128.8, 128.6, 127.9, 127.8, 127.5, 125.1,
125.1, 114.9, 113.8, 70.6, 67.2, 53.2, 32.4, 31.2, 21.6.
2f
Yield: 81%; pale-yellow semisolid.
[a]D25 +23.0 (c 4.3, CHCl3).
IR (film): 3416, 3056, 2991, 2925, 2872, 2831, 1609, 1569, 1462,
1417, 1328, 1258, 1193, 1156 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.05 (d, J = 8.0 Hz, 2 H), 7.61 (t,
J = 7.2 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 6.68 (s, 1 H), 6.62 (s, 1
H), 3.87 (s, 3 H), 3.63 (s, 2 H), 3.57 (dd, J = 4.5, 13.0 Hz, 1 H),
3.50–3.37 (m, 1 H), 3.12 (t, J = 10.8 Hz, 1 H), 2.31 (s, 3 H), 2.24
(qd, J = 6.0, 12.9 Hz, 1 H), 1.85–1.70 (qd, J = 6.8, 13.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 152.2, 139.5, 133.5, 131.4, 130.1,
129.2, 128.9, 126.5, 118.7, 111.3, 107.4, 59.7, 55.9, 53.1, 34.3,
32.0, 21.3.
HRMS: m/z [M + H]+ calcd for C30H30NO5S2: 548.1560; found:
548.1563.
3c
Yield: 89%; pale-yellow semisolid.
[a]D25 –9.6 (c 9.1, CHCl3).
HRMS: m/z [M + H]+ calcd for C18H22NO3S: 332.1315; found:
332.1314.
IR (film): 3060, 3023, 2962, 2921, 2860, 1597, 1520, 1442, 1381,
1352, 1242, 1172, 1107 cm–1.
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York

PAPER
Synthesis of Chiral Cyclobutanes Using Benzothiazines as Templates
3h
599
1H NMR (250 MHz, CDCl3): d = 8.10–8.00 (m, 2 H), 7.80–7.65 (m,
3 H), 7.65–7.50 (m, 2 H), 7.33 (d, J = 6.6 Hz, 2 H), 7.08 (dd, J = 2.0,
5.2 Hz, 1 H), 6.80 (dd, J = 3.2, 5.2 Hz, 1 H), 4.20 (dt, J = 3.0, 6.2
Hz, 2 H), 3.78–3.55 (m, 1 H), 3.36 (td, J = 4.6, 11.5 Hz, 1 H), 2.63
(td, J = 2.7, 11.6 Hz, 1 H), 2.42 (d, J = 2.6 Hz, 3 H), 2.45–2.25 (m,
1 H), 2.20–1.90 (m, 1 H).
Yield: 84%; pale-yellow semisolid consisting of two inseparable
diastereomers (dr = 1.1:1).
[a]D25 –4.9 (c 1.8, CHCl3).
IR (film): 3064, 2974, 2925, 1577, 1462, 1356, 1258, 1172 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.16–8.00 (t, J = 6.9 Hz, 2 H), 7.76
(d, J = 8.1 Hz, 1 H), 7.70–7.46 (m, 4 H), 7.40–7.26 (m, 2 H), 6.68
(s, 1 H), 6.49 (s, 1 H), 6.44 (s, 1 H), 4.00–3.75 (m, 5 H), 3.53 (dd,
J = 5.4, 9.9 Hz, 1 H), 3.48–3.10 (m, 2 H), 2.70–2.47 (m, 1 H), 2.44
(s, 3 H), 2.27 (d, J = 8.1 Hz, 2 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.67 (d,
J = 6.9 Hz, 3 H).
13C NMR (62.5 MHz, CDCl3): d = 145.1, 143.0, 136.3, 134.3,
132.3, 130.0, 129.4, 129.2, 127.8, 125.5, 121.8, 113.7, 67.1, 50.5,
34.0, 29.6, 21.6.
HRMS: m/z [M + H]+ calcd for C21H22NO4S3: 448.0705; found:
448.0707.
13C NMR (75 MHz, CDCl3): d = 152.8, 152.7, 144.9, 144.8, 139.2,
139.0, 133.6, 133.6, 132.5, 132.1, 131.2, 131.1, 130.5, 130.3, 129.8,
129.8, 129.2, 129.2, 128.9, 128.9, 127.8, 127.7, 125.0, 124.9, 119.7,
119.6, 111.6, 111.5, 72.6, 71.4, 55.9, 50.7, 50.4, 38.7, 37.6, 32.2,
31.8, 21.5, 21.2, 21.2, 16.0, 12.9.
3d
Yield: 68%; pale-yellow semisolid.
[a]D25 –29.2 (c 2.0, CHCl3).
IR (film): 3060, 3015, 2970, 2897, 1961, 1920, 1618, 1597, 1499,
1475, 1413, 1364, 1238, 1172 cm–1.
HRMS: m/z [M + Na]+ calcd for C26H29NO5S2Na: 522.1379; found:
1H NMR (300 MHz, CDCl3): d = 8.05 (dd, J = 1.4, 7.3 Hz, 2 H),
7.76 (d, J = 8.3 Hz, 2 H), 7.69 (t, J = 7.3 Hz, 1 H), 7.60 (t, J = 7.1
Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 6.67 (s, 1 H), 6.38 (s, 1 H), 5.90
(dd, J = 1.3, 4.9 Hz, 2 H), 4.10–3.90 (m, 2 H), 3.49 (q, J = 16.6 Hz,
1 H), 3.35–3.20 (m, 2 H), 2.46 (s, 3 H), 2.24 (qd, J = 5.8, 11.9 Hz,
1 H), 1.90 (qd, J = 5.7, 12.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 147.7, 145.2, 142.2, 139.3, 139.1,
133.9, 132.5, 130.0, 129.5, 128.7, 127.9, 116.4, 106.5, 106.1, 100.9,
67.3, 54.1, 32.5, 31.6, 21.7.
522.1375.
Iodide 4g; Typical Procedure for the Preparation of Iodides 4
To tosylate 3g (508 mg, 1.152 mmol) in acetone (5 mL), NaI (524.7
mg, 3.500 mmol) was added. The mixture was refluxed for 4 h. The
reaction mixture was filtered and the filtrate was dried (MgSO4) and
concentrated. Chromatography (EtOAc–hexanes, 4:6) gave 4g as a
pale-yellow semisolid; yield: 430 mg (94%).
IR (film): 3097, 3056, 3019, 3003, 2958, 2929, 2848, 1597, 1475,
1446, 1295, 1270, 1209, 1119, 1099, 1013 cm–1.
HRMS: m/z [M + H]+ calcd for C24H24NO6S2: 486.1040; found:
486.1038.
1H NMR (300 MHz, CDCl3): d = 8.06 (d, J = 7.5 Hz, 2 H), 7.66 (t,
J = 7.5 Hz, 1 H), 7.56 (t, J = 7.8 Hz, 2 H), 7.23 (dt, J = 1.2, 7.6 Hz,
1 H), 7.16 (d, J = 7.2 Hz, 1 H), 7.12 (dd, J = 1.5, 7.6 Hz, 1 H), 6.94
(dt, J = 7.5, 0.9 Hz, 1 H), 3.51 (dd, J = 4.8, 12.0 Hz, 1 H), 3.48–3.38
(m, 1 H), 3.19 (dd, J = 8.4, 12.3 Hz, 1 H), 3.15–2.96 (m, 2 H), 2.49
(qd, J = 6.9, 14.1 Hz, 1 H), 2.07 (qd, J = 6.9, 14.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 144.6, 139.0, 133.7, 129.3, 128.5,
128.5, 126.1, 124.2, 124.0, 120.9, 52.1, 35.8, 35.4, 2.1.
HRMS: m/z [M + H]+ calcd for C16H17INOS: 398.0070; found:
398.0070.
3e
Yield: 83%; pale-yellow semisolid.
[a]D25 –45.7 (c 0.9, CHCl3).
IR (film): 3060, 2917, 2860, 1597, 1528, 1471, 1442, 1356, 1230,
1176, 1099, 1013 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.07 (td, J = 1.0, 7.1 Hz, 2 H),
7.80–7.55 (m, 5 H), 7.26 (d, J = 8.2 Hz, 2 H), 7.18 (td, J = 1.4, 6.0
Hz, 2 H), 7.10–6.90 (m, 2 H), 4.22–4.05 (m, 2 H), 3.90–3.75 (m, 1
H), 3.66 (s, 3 H), 3.42 (dd, J = 5.5, 12.1 Hz, 1 H), 2.99 (t, J = 11.7
Hz, 1 H), 2.60–2.45 (m, 1 H), 2.42 (s, 3 H), 2.28–2.10 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 144.9, 143.0, 136.8, 134.5,
133.8, 132.6, 129.9, 129.6, 129.0, 127.7, 125.6, 119.4, 118.4, 116.5,
108.3, 87.0, 68.0, 52.4, 31.9, 29.0, 27.6, 21.6.
4a
Yield: 91%; yellow solid; mp 138–140 °C.
[a]D25 +25.0 (c 0.84, CHCl3).
IR (film): 3060, 2933, 2913, 2856, 1610, 1491, 1446, 1397, 1295,
1213, 1140, 1127 cm–1.
HRMS: m/z [M + Na]+ calcd for C26H26N2O4S2Na: 517.1226;
found: 517.1221.
1H NMR (500 MHz, CDCl3): d = 8.06 (dd, J = 1.1, 8.4 Hz, 2 H),
7.65 (t, J = 7.5 Hz, 1 H), 7.56 (t, J = 7.5 Hz, 2 H), 7.04 (d, J = 7.8
Hz, 1 H), 6.96 (d, J = 0.8 Hz, 1 H), 6.75 (dd, J = 1.2, 7.8 Hz, 1 H),
3.50 (dd, J = 4.8, 13.0 Hz, 1 H), 3.46–3.37 (m, 1 H), 3.16 (dd,
J = 8.9, 13.0 Hz, 1 H), 3.13–3.00 (m, 2 H), 2.47 (qd, J = 6.8, 14.5
Hz, 1 H), 2.31 (s, 3 H), 2.06 (qd, J = 6.7, 14.4 Hz, 1 H).
3f
Yield: 86%; pale-yellow semisolid.
[a]D25 +31.2 (c 1.7, CHCl3).
IR (film): 3056, 2974, 2921, 2856, 2835, 1597, 1573, 1462, 1356,
1266, 1176 cm–1.
13C NMR (125 MHz, CDCl3): d = 144.4, 139.2, 138.5, 133.7, 129.3,
128.6, 126.0, 124.9, 121.8, 120.9, 52.4, 35.7, 35.6, 21.0, 2.1.
1H NMR (250 MHz, CDCl3): d = 8.07 (td, J = 1.4, 7.1 Hz, 2 H), 7.75
(d, J = 8.3 Hz, 2 H), 7.66 (t, J = 7.2 Hz, 1 H), 7.55 (t, J = 7.0 Hz, 2
H), 7.33 (d, J = 8.0 Hz, 2 H), 6.68 (s, 1 H), 6.40 (s, 1 H), 3.98 (t,
J = 5.8 Hz, 2 H), 3.87 (s, 3 H), 3.55–3.40 (m, 1 H), 3.40–3.20 (m, 2
H), 2.45 (s, 3 H), 2.35–2.15 (m, 4 H), 1.91 (qd, J = 6.3, 12.5 Hz, 1
H).
13C NMR (62.5 MHz, CDCl3): d = 152.8, 145.0, 139.6, 133.7,
132.7, 131.1, 130.7, 129.9, 129.3, 128.9, 127.9, 125.2, 119.3, 111.9,
67.5, 56.0, 54.1, 32.7, 31.4, 21.6, 21.3.
Anal. Calcd for C17H18INOS: C, 49.64; H, 4.41; N, 3.41. Found: C,
49.44; H, 4.48; N, 3.37.
4b
Yield: 85%; yellow semisolid.
[a]D25 –1.8 (c 8.0, CHCl3).
IR (film): 3052, 3027, 2921, 2864, 1610, 1565, 1479, 1270, 1221,
1013 cm–1.
HRMS: m/z [M + H]+ calcd for C25H28NO5S2: 486.1403; found:
486.1403.
1H NMR (500 MHz, CDCl3): d = 8.07 (td, J = 1.4, 7.1 Hz, 2 H), 7.65
(tt, J = 1.3, 7.2 Hz, 1 H), 7.56 (tt, J = 1.2, 7.0 Hz, 2 H), 7.46–7.25
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M. Harmata et al.
PAPER
(m, 5 H), 7.05 (d, J = 9.2 Hz, 1 H), 6.89 (dd, J = 2.9, 8.6 Hz, 1 H),
6.81 (d, J = 2.8 Hz, 1 H), 5.04 (s, 2 H), 3.50 (dd, J = 4.7, 12.9 Hz, 1
H), 3.44–3.30 (m, 1 H), 3.22 (dd, J = 8.0, 12.9 Hz, 1 H), 3.10–2.90
(m, 2 H), 2.44 (qd, J = 5.9, 11.9 Hz, 1 H), 2.02 (qd, J = 6.0, 11.8 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 153.3, 139.4, 138.0, 137.1, 133.7,
129.4, 128.7, 128.5, 127.9, 127.5, 125.1, 125.1, 114.9, 113.9, 70.5,
52.8, 36.5, 35.7, 2.2.
IR (film): 3063, 2922, 2859, 2820, 1571, 1459, 1322, 1268, 1151
cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12 (d, J = 7.6 Hz, 2 H), 7.66 (t,
J = 7.5 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 2 H), 6.72 (d, J = 1.0 Hz, 1 H),
6.62 (s, 1 H), 3.90 (s, 3 H), 3.60–3.50 (m, 1 H), 3.40–3.30 (m, 2 H),
3.10–3.00 (m, 2 H), 2.48 (qd, J = 7.1, 14.1 Hz, 1 H), 2.34 (s, 3 H),
2.03 (qd, J = 7.1, 13.7 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 152.8, 139.7, 133.6, 131.1, 130.7,
129.3, 128.9, 125.3, 119.3, 111.9, 56.0, 53.7, 36.9, 35.8, 21.3, 2.8.
HRMS: m/z [M + H]+ calcd for C23H23INO2S: 504.0489; found:
504.0485.
HRMS: m/z [M + H]+ calcd for C18H21INO2S: 442.0332; found:
442.0333.
4c
Yield: 85%; yellow semisolid.
4h
IR (film): 3403, 3110, 2933, 2876, 1524, 1450, 1397, 1389, 1266,
1238, 1201, 1160, 1107, 1046 cm–1.
Yield: 81%; pale-yellow semisolid consisting of two inseparable
diastereoisomers (dr = 1.6:1).
1H NMR (250 MHz, CDCl3): d = 8.08 (d, J = 8.2 Hz, 2 H), 7.69 (t,
J = 6.9 Hz, 1 H), 7.58 (t, J = 7.1 Hz, 2 H), 7.11 (d, J = 5.2 Hz, 1 H),
6.82 (d, J = 5.3 Hz, 1 H), 3.80–3.60 (m, 1 H), 3.44 (dd, J = 4.9, 11.4
Hz, 1 H), 3.32 (td, J = 5.2, 9.6 Hz, 1 H), 3.17 (q, J = 8.2 Hz, 1 H),
2.65 (dd, J = 11.5, 13.0 Hz, 1 H), 2.55 (qd, J = 7.6, 12.8 Hz, 1 H),
2.22 (qd, J = 8.2, 13.9 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 142.8, 136.3, 134.2, 129.4,
129.1, 125.3, 121.8, 113.6, 50.0, 38.6, 33.3, 0.3.
HRMS: m/z [M + H]+ calcd for C14H15INOS2: 403.9634; found:
403.9632.
IR (film): 3060, 2962, 2933, 2831, 1573, 1479, 1458, 1442, 1328,
1254, 1189, 1156, 1099, 1013, 1005 cm–1.
1H NMR (300 MHz, CDCl3) (major isomer): d = 8.20–8.10 (m, 2
H), 7.66 (tt, J = 1.2, 7.5 Hz, 1 H), 7.57 (tt, J = 1.2, 6.0 Hz, 2 H), 6.71
(s, 2 H), 3.88 (s, 3 H), 3.60 (dd, J = 5.7, 14.4 Hz, 1 H), 3.50–3.35
(m, 1 H), 3.20 (dd, J = 4.5, 9.9 Hz, 1 H), 3.15–3.00 (m, 2 H), 2.33
(s, 3 H), 2.15–2.00 (m, 1 H), 0.66 (d, J = 6.6 Hz, 3 H).
(minor isomer): d = 8.20–8.10 (m, 2 H), 7.66 (tt, J = 1.2, 7.5 Hz, 1
H), 7.57 (tt, J = 1.2, 6.0 Hz, 2 H), 6.71 (s, 1 H), 6.56 (s, 1 H), 3.88
(s, 3 H), 3.50–3.35 (m, 2 H), 3.15–3.00 (m, 2 H), 2.51 (dd, J = 7.2,
9.9 Hz, 1 H), 2.33 (s, 3 H), 2.27–2.15 (m, 1 H), 1.00 (d, J = 6.6 Hz,
3 H).
4d
Yield: 96%; yellow semisolid.
[a]D25 –27.9 (c 7.3, CHCl3).
13C NMR (75 MHz, CDCl3): d = 152.9, 152.8, 139.4, 139.3, 133.6,
133.6, 131.2, 130.7, 130.5, 129.3, 129.2, 128.9, 128.8, 125.9, 125.6,
120.3, 119.9, 111.7, 111.6, 55.9, 51.5, 50.7, 42.3, 41.3, 33.1, 33.0,
21.3, 21.3, 19.4, 17.5, 16.8, 12.7.
HRMS: m/z [M + Na]+ calcd for C19H22INO2SNa: 478.0308; found:
478.0306.
IR (film): 3056, 2970, 2889, 2770, 1912, 1614, 1495, 1475, 1417,
1234, 1185, 1148, 1033 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.06 (td, J = 1.4, 7.3 Hz, 2 H), 7.66
(tt, J = 1.2, 7.4 Hz, 1 H), 7.58 (t, J = 8.0 Hz, 2 H), 6.67 (s, 1 H), 6.67
(s, 1 H), 5.90 (dd, J = 1.5, 6.9 Hz, 2 H), 3.52 (dd, J = 4.3, 12.7 Hz,
1 H), 3.36–3.30 (m, 1 H), 3.27 (dd, J = 7.6, 12.8 Hz, 1 H), 3.08–3.00
(m, 2 H), 2.42 (qd, J = 6.9, 14.0 Hz, 1 H), 1.99 (qd, J = 7.3, 13.7 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 147.5, 142.1, 139.2, 139.0, 133.7,
129.4, 128.6, 116.4, 106.4, 105.9, 100.8, 53.4, 36.4, 35.8, 2.5.
HRMS: m/z [M + H]+ calcd for C17H17INO3S: 441.9968; found:
441.9966.
Cyclobutane 5g; Typical Procedure for the Preparation of
Cyclobutanes 5
To iodide 4g (215 mg, 0.542 mmol) in THF (10 mL) at –78 °C, KH
(30% in mineral oil; 108.3 mg, 0.812 mmol) was added. After stir-
ring for 1 h at –78 °C, the reaction mixture was warmed to r.t. and
stirred overnight. TLC showed that no starting material remained.
The reaction was quenched with H2O (10 mL) and extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were washed
with brine (15 mL), dried (MgSO4), and concentrated. Chromatog-
raphy (EtOAc–hexanes, 4:6) gave 5g as a pale-yellow solid; yield:
128 mg (88%); mp 138–141 °C.
4e
Yield: 83%; pale-yellow semisolid.
[a]D25 –34.8 (c 1.5, CHCl3).
IR (film): 3056, 2954, 2925, 2856, 1720, 1524, 1467, 1446, 1234,
1099, 1009 cm–1.
IR (film): 3015, 2974, 2954, 2933, 1597, 1565, 1479, 1446, 1250
cm–1.
1H NMR (500 MHz, CDCl3): d = 8.10 (td, J = 1.0, 7.3 Hz, 2 H), 7.73
(tt, J = 1.1, 7.5 Hz, 1 H), 7.63 (tt, J = 1.7, 8.1 Hz, 2 H), 7.44–7.39
(m, 1 H), 7.24–7.19 (m, 1 H), 7.10–7.04 (m, 2 H), 3.86–3.79 (m, 1
H), 3.69 (s, 3 H), 3.48 (dd, J = 5.5, 12.0 Hz, 1 H), 3.25 (td, J = 5.1,
9.6 Hz, 1 H), 3.05 (td, J = 7.3, 9.4 Hz, 1 H), 2.99 (t, J = 11.8 Hz, 1
H), 2.75–2.66 (m, 1 H), 2.44–2.35 (m, 1 H).
1H NMR (250 MHz, CDCl3): d = 8.11 (d, J = 7.4 Hz, 2 H), 7.67 (t,
J = 7.2 Hz, 1 H), 7.55 (t, J = 7.2 Hz, 2 H), 7.15 (t, J = 7.4 Hz, 1 H),
7.07 (d, J = 7.5 Hz, 1 H), 7.03–6.80 (m, 2 H), 4.18 (q, J = 8.5 Hz, 1
H), 4.07 (q, J = 8.4 Hz, 1 H), 2.65 (qd, J = 8.6, 8.6 Hz, 1 H), 2.35
(qd, J = 8.4, 8.4 Hz, 1 H), 2.30–1.80 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 142.9, 137.1, 134.5, 133.8, 129.6,
129.0, 125.8, 119.6, 118.6, 116.6, 108.4, 87.1, 51.9, 37.2, 32.5,
27.7, 1.1.
HRMS: m/z [M + H]+ calcd for C19H20IN2OS: 451.0336; found:
451.0340.
13C NMR (62.5 MHz, CDCl3): d = 142.5, 134.7, 133.6, 129.1,
128.4, 127.8, 125.3, 125.2, 121.7, 54.5, 37.4, 29.5, 23.5.
HRMS: m/z [M + H]+ calcd for C16H16NOS: 270.0947; found:
270.0949.
5a
4f
Yield: 83%; yellow solid; mp 85–86 °C.
[a]D25 –24.2 (c 2.5, CHCl3).
Yield: 60%; pale-yellow semisolid.
[a]D25 +29.0 (c 3.4, CHCl3).
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York

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Synthesis of Chiral Cyclobutanes Using Benzothiazines as Templates
601
IR (film): 3060, 3032, 2954, 2921, 2856, 1724, 1610, 1565, 1495,
1442, 1405, 1291, 1270, 1205, 1156, 1119, 1099, 1074, 1037 cm–1.
[a]D25 –125.9 (c 1.5, CHCl3).
IR (film): 3072, 3052, 2999, 2958, 2913, 1540, 1471, 1438, 1225,
1H NMR (250 MHz, CDCl3): d = 8.13 (dt, J = 1.6, 6.9 Hz, 2 H), 7.69
(tt, J = 1.5, 7.1 Hz, 1 H), 7.60 (tt, J = 1.6, 7.5 Hz, 2 H), 6.94 (s, 1 H),
6.88 (d, J = 7.7 Hz, 1 H), 6.77 (dd, J = 1.1, 7.7 Hz, 1 H), 4.19 (q,
J = 8.7 Hz, 1 H), 4.13–4.02 (m, 1 H), 2.77–2.56 (m, 1 H), 2.49–2.34
(m, 1 H), 2.31 (s, 3 H), 2.13–1.91 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 142.2, 137.8, 135.0, 133.7,
129.3, 129.1, 128.3, 126.0, 122.9, 122.1, 54.7, 37.3, 29.6, 23.6,
21.0.
1189, 1099, 1037 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.13 (td, J = 1.5, 7.2 Hz, 2 H), 7.70
(tt, J = 1.2, 7.5 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 2 H), 7.30–7.18 (m, 2
H), 7.10–7.02 (m, 2 H), 4.32–4.25 (m, 1 H), 4.17 (td, J = 8.0, 10.2
Hz, 1 H), 3.71 (s, 3 H), 2.65–2.56 (m, 1 H), 2.44 (qd, J = 10.5, 10.9
Hz, 1 H), 2.03 (t, J = 9.8 Hz, 1 H), 1.88–1.80 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 140.8, 134.5, 134.1, 134.1, 129.5,
129.3, 126.1, 119.1, 118.7, 115.7, 108.2, 88.4, 54.2, 33.6, 27.6,
27.3, 24.7.
HRMS: m/z [M + H]+ calcd for C17H18NOS: 284.1104; found:
284.1105.
HRMS: m/z [M + H]+ calcd for C19H19N2OS: 323.1213; found:
323.1220.
5b
Yield: 84%; yellow semisolid.
[a]D25 –42.9 (c 0.9, CHCl3).
5f
Yield: 78%; pale-yellow solid; mp 192–194 °C.
IR (film): 3060, 3032, 2942, 2852, 1605, 1483, 1262, 1221, 1099,
1033 cm–1.
[a]D25 –33.3 (c 1.4, CHCl3).
IR (film): 3060, 2995, 2966, 2942, 1573, 1471, 1446, 1336, 1217,
1180, 1148, 1091, 1025 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12 (td, J = 1.1, 7.1 Hz, 2 H), 7.67
(t, J = 7.3 Hz, 1 H), 7.58 (t, J = 7.0 Hz, 2 H), 7.45–7.25 (m, 5 H),
7.02 (d, J = 8.7 Hz, 1 H), 6.84 (dd, J = 2.9, 8.7 Hz, 1 H), 6.62 (d,
J = 2.9 Hz, 1 H), 5.02 (s, 2 H), 4.25–4.10 (q, J = 8.5 Hz, 1 H), 4.10–
3.90 (m, 1 H), 2.80–2.55 (m, 1 H), 2.50–2.25 (m, 1 H), 2.15–1.80
(m, 2 H).
13C NMR (75 MHz, CDCl3): d = 153.9, 137.3, 136.0, 134.9, 133.7,
129.4, 129.2, 128.5, 127.8, 127.5, 126.3, 126.1, 114.9, 114.8, 70.5,
54.6, 37.9, 29.5, 23.6.
1H NMR (500 MHz, CDCl3): d = 8.17 (td, J = 1.5, 8.0 Hz, 2 H), 7.66
(tt, J = 1.5, 7.5 Hz, 1 H), 7.57 (t, J = 2.0, 8.5 Hz, 2 H), 6.63 (d,
J = 1.5 Hz, 1 H), 6.44 (d, J = 1.0 Hz, 1 H), 4.17 (q, J = 8.0 Hz, 1 H),
4.10–4.02 (m, 1 H), 3.89 (s, 3 H), 2.66 (qd, J = 8.5, 9.0 Hz, 1 H),
2.41 (dqd, J = 1.5, 9.0, 12.0 Hz, 1 H), 2.29 (s, 3 H), 2.12–2.04 (m,
1 H), 2.04–1.94 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 153.0, 135.0, 133.6, 131.2, 129.6,
129.3, 129.0, 125.9, 120.8, 111.0, 56.1, 54.9, 37.6, 29.5, 23.6, 21.2.
HRMS: m/z [M + H]+ calcd for C18H20NO2S: 314.1209; found:
314.1210.
HRMS: m/z [M + H]+ calcd for C23H22NO2S: 376.1366; found:
376.1364.
5c
5h
Yield: 58%; yellow semisolid.
Yield: 96%; pale-yellow solid consisting of two diastereomers
IR (film): 3085, 3068, 2958, 2921, 1532, 1450, 1381, 1377, 1242,
1180, 1099, 1050 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.11 (td, J = 1.2, 6.1 Hz, 2 H), 7.69
(t, J = 7.3 Hz, 1 H), 7.59 (t, J = 7.0 Hz, 2 H), 7.16 (d, J = 5.4 Hz, 1
H), 6.81 (d, J = 5.3 Hz, 1 H), 4.23–4.06 (m, 2 H), 2.80–2.45 (m, 2
H), 2.07 (t, J = 8.4 Hz, 1 H), 1.97–1.80 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 140.9, 134.4, 130.0, 129.6, 129.3,
125.9, 122.9, 116.2, 53.5, 35.8, 30.0, 24.1.
HRMS: m/z [M + H]+ calcd for C14H14NOS2: 276.0511; found:
276.0511.
(dr = 2.6:1).
IR (film): 3089, 3060, 2938, 2860, 2831, 2827, 1610, 1569, 1462,
1446, 1328, 1266, 1234, 1217, 1180, 1095, 1029, 1013 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.17 (d, J = 7.5 Hz, 2 H), 8.15 (dd,
J = 2.0, 7.5 Hz, 2 H), 7.67–7.60 (m, 2 H), 7.60–7.50 (m, 4 H), 6.63
(d, J = 1.0 Hz, 1 H), 6.62 (d, J = 1.0 Hz, 1 H), 6.42 (s, 1 H), 6.30 (s,
1 H), 4.25–4.17 (m, 1 H), 4.15–4.05 (m, 2 H), 3.88 (s, 3 H), 3.87 (s,
3 H), 3.55–3.47 (m, 1 H), 2.97–2.83 (m, 1 H), 2.62–2.50 (m, 1 H),
2.29 (s, 3 H), 2.27 (s, 3 H), 2.11–2.03 (m, 1 H), 2.03–1.95 (m, 1 H),
1.81 (s, 1 H), 1.75–1.65 (m, 1 H), 1.22 (d, J = 7.0 Hz, 3 H), 0.73 (d,
J = 7.0 Hz, 3 H).
5d
13C NMR (125 MHz, CDCl3): d = 153.2, 153.0, 134.8, 134.8, 133.5,
133.4, 131.2, 130.1, 130.1, 129.5, 129.4, 129.0, 128.9, 128.9, 126.9,
126.2, 122.8, 121.1, 120.3, 111.3, 110.9, 56.0, 55.9, 55.1, 52.0,
45.3, 41.3, 37.4, 33.1, 32.1, 30.2, 21.2, 21.2, 21.0, 17.7.
HRMS: m/z [M + Na]+ calcd for C19H21NO2SNa: 350.1185; found:
350.1190.
Yield: 64%; yellow semisolid.
[a]D25 +47.5 (c 2.2, CHCl3).
IR (film): 3064, 2942, 2884, 2770, 1728, 1617, 1499, 1475, 1426,
1209, 1148, 1103, 1033 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12 (td, J = 1.0, 7.1 Hz, 2 H), 7.68
(tt, J = 1.2, 7.4 Hz, 1 H), 7.60 (t, J = 8.0 Hz, 2 H), 6.64 (s, 1 H), 6.45
(s, 1 H), 5.89 (dd, J = 1.4, 11.0 Hz, 2 H), 4.16 (q, J = 8.0 Hz, 1 H),
4.05–3.97 (m, 1 H), 2.65 (qd, J = 8.5, 10.5 Hz, 1 H), 2.36 (dqd,
J = 0.9, 9.5, 11.3 Hz, 1 H), 2.10–1.93 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 147.2, 142.7, 136.9, 134.7, 133.7,
129.3, 129.2, 117.6, 107.6, 106.6, 100.8, 54.8, 37.8, 29.5, 23.5.
6a; Typical Procedure for the Alkylation of Cyclobutane 5g
To a soln of cyclobutane 5g (181.1 mg, 0.672 mmol) in THF (8.5
mL) at –78 °C, 2.2 M n-BuLi in hexanes (458 mL, 1.000 mmol) was
added dropwise. After stirring for 45 min, a soln of diphenyl disul-
fide (234 mg, 1.075 mmol) in THF (3.5 mL) was added dropwise.
The mixture was stirred for another 3 h before the reaction was
quenched with H2O (5 mL). The mixture was extracted with EtOAc
(3 × 10 mL) and the organic layer was washed with H2O (10 mL),
dried (Na2SO4), and concentrated. The crude product was purified
by fast flash chromatography (EtOAc–hexanes, 2:8, 4:6), which af-
forded 6a as a white solid; yield: 232.3 mg (93%); mp 139–141 °C.
HRMS: m/z [M + H]+ calcd for C17H16NO3S: 314.0845; found:
314.0848.
5e
Yield: 71%; yellow solid; mp 200–202 °C.
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York

602
M. Harmata et al.
PAPER
IR (film): 3064, 2991, 2946, 1597, 1569, 1475, 1442, 1266, 1246,
1230, 1205, 1115 cm–1.
13C NMR (125 MHz, CDCl3): d = 142.8, 139.4, 134.9, 133.3, 130.4,
128.5, 128.5, 128.3, 128.1, 127.7, 127.4, 127.2, 125.4, 122.3, 76.0,
73.3, 43.1, 25.4, 24.3.
HRMS: m/z [M + Na]+ calcd for C23H21NO2SNa: 398.1185; found:
398.1187.
1H NMR (500 MHz, CDCl3): d = 8.25 (dd, J = 1.5, 7.5 Hz, 2 H),
7.73 (t, J = 7.5 Hz, 1 H), 7.61 (dt, J = 1.0, 7.5 Hz, 4 H), 7.35 (tt,
J = 1.6, 7.5 Hz, 1 H), 7.31 (tt, J = 7.5, 1.5 Hz, 2 H), 7.16 (dt, J = 1.0,
7.5 Hz, 1 H), 7.11 (dd, J = 1.0, 7.5 Hz, 1 H), 6.92 (td, J = 1.0, 7.5
Hz, 1 H), 6.85 (dd, J = 1.0, 7.5 Hz, 1 H), 3.85–3.79 (m, 1 H), 2.88–
2.74 (m, 2 H), 2.08–2.00 (m, 1 H), 1.95–1.85 (m, 1 H).
6e
Yield: 45%; white solid; mp 165–167 °C.
13C NMR (125 MHz, CDCl3): d = 141.8, 135.6, 134.0, 132.8, 130.8,
130.4, 129.2, 128.9, 128.9, 128.3, 128.2, 127.4, 125.7, 122.1, 70.2,
45.0, 31.5, 27.9.
HRMS: m/z [M + Na]+ calcd for C22H19NOS2Na: 400.0800; found:
400.0798.
IR (film): 3473, 3452, 3064, 2987, 2950, 2938, 2921, 1593, 1479,
1450, 1267, 1246, 1180, 1115, 1091 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.18 (dd, J = 1.0, 8.0 Hz, 2 H),
7.72 (tt, J = 1.0, 8.0 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 2 H), 7.20 (dt,
J = 1.0, 7.5 Hz, 1 H), 7.12 (dd, J = 1.0, 7.5 Hz, 1 H), 7.06–6.92 (m,
2 H), 4.15 (t, J = 2.0 Hz, 1 H), 4.09 (t, J = 8.0 Hz, 1 H), 3.93 (td,
J = 2.0, 11.0 Hz, 1 H), 2.55–2.38 (m, 2 H), 2.10–2.00 (m, 1 H),
1.90–1.76 (m, 2 H), 1.76–1.65 (m, 1 H), 1.11 (t, J = 7.5 Hz, 3 H).
6b
Yield: 57%; pale-yellow semisolid.
[a]D25 –80.5 (c 1.6, CHCl3).
13C NMR (125 MHz, CDCl3): d = 141.6, 134.0, 132.4, 130.5, 129.2,
128.1, 128.0, 127.8, 125.6, 122.6, 73.1, 68.3, 37.8, 27.4, 25.4, 23.9,
11.0.
HRMS: m/z [M + H]+ calcd for C19H22NO2S: 328.1366; found:
328.1369.
IR (film): 3060, 2978, 2946, 2852, 1634, 1597, 1564, 1479, 1442,
1262, 1238, 1197 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.13 (d, J = 8 Hz, 2 H), 7.69 (t,
J = 7.5 Hz, 1 H), 7.60 (t, J = 8 Hz, 2 H), 7.18 (dt, J = 2.0, 7.5 Hz, 2
H), 7.11 (dt, J = 2.0, 7.5 Hz, 1 H), 7.05–6.90 (m, 2 H), 5.95–5.80
(m, 1 H), 5.26 (d, J = 17.0 Hz, 1 H), 5.20 (d, J = 10.0 Hz, 1 H), 3.73
(s, 1 H), 2.87 (dd, J = 7.0, 14.5 Hz, 1 H), 2.65–2.59 (m, 2 H), 2.58–
2.46 (m, 1 H), 2.06–1.95 (m, 1 H), 1.94–1.83 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 142.3, 133.7, 133.3, 131.5, 130.5,
128.9, 128.0, 128.0, 127.5, 125.4, 122.0, 120.1, 63.6, 42.3, 39.6,
27.0, 26.4.
6f
Yield: 36%; pale-yellow semisolid.
IR (film): 3340, 3064, 2962, 2933, 2872, 1597, 1573, 1483, 1446,
1270, 1238, 1201, 1172, 1111, 1013 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.18 (d, J = 7.5 Hz, 2 H), 7.68 (t,
J = 7.5 Hz, 1 H), 7.59 (t, J = 7.5 Hz, 2 H), 7.19 (t, J = 7.0 Hz, 1 H),
7.09 (d, J = 7.5 Hz, 1 H), 7.02 (d, J = 7.0 Hz, 1 H), 6.95 (t, J = 7.5
Hz, 1 H), 4.02 (t, J = 8.0 Hz, 1 H), 3.80 (t, J = 10.0 Hz, 1 H), 3.23
(d, J = 10.5 Hz, 1 H), 2.60–2.34 (m, 2 H), 2.32–2.20 (m, 1 H), 2.10–
1.90 (m, 1 H), 1.70–1.55 (m, 1 H), 1.50–1.30 (m, 1 H), 1.00 (t,
J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 142.0, 135.3, 133.8, 130.5, 129.0,
128.3, 127.7, 127.6, 125.2, 122.5, 79.5, 71.3, 43.3, 25.8, 25.3, 11.7.
HRMS: m/z [M + H]+ calcd for C19H22NO2S: 328.1366; found:
328.1368.
HRMS: m/z [M + Na]+ calcd for C19H19NOSNa: 332.1080; found:
332.1083.
6c
Yield: 60%; white solid; mp 84–86 °C.
[a]D25 –68.9 (c 1.3, CHCl3).
IR (film): 3448, 3060, 3007, 2950, 1597, 1577, 1479, 1442, 1262,
1238, 1168, 1111, 1095 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.18 (d, J = 7.5 Hz, 2 H), 7.76 (t,
J = 7.5 Hz, 1 H), 7.65 (t, J = 7.5 Hz, 2 H), 7.44–7.38 (m, 2 H), 7.38–
7.33 (m, 3 H), 7.21 (dt, J = 1.5, 7.0 Hz, 1 H), 7.13 (d, J = 7.5 Hz, 1
H), 7.03 (dd, J = 1.5, 7.5 Hz, 1 H), 7.00 (dt, J = 1.0, 7.5 Hz, 1 H),
5.14 (d, J = 1.0 Hz, 1 H), 4.59 (d, J = 1.5 Hz, 1 H), 4.30–4.22 (m, 1
H), 2.40–2.30 (m, 1 H), 1.76–1.62 (m, 2 H), 1.60–1.48 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 141.4, 138.0, 134.2, 131.9, 130.5,
129.3, 128.5, 128.4, 128.2, 128.1, 127.9, 127.7, 125.7, 122.7, 73.5,
67.7, 37.5, 26.9, 25.5.
6g, Isomer A
Yield: 51%; pale-yellow solid; mp 142–144 °C.
[a]D25 –17.2 (c 2.7, CHCl3).
IR (film): 3477, 3064, 2958, 2925, 2864, 1475, 1446, 1262, 1176,
1111, 1095, 1013 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.17 (dd, J = 1.0, 8.5 Hz, 2 H),
7.72 (tt, J = 1.0, 7.5 Hz, 1 H), 7.63 (t, J = 7.5 Hz, 2 H), 7.20 (dd,
J = 1.0, 7.5 Hz, 1 H), 7.19 (td, J = 1.5, 7.5 Hz, 1 H), 7.00 (dd,
J = 1.5, 7.5 Hz, 1 H), 6.96 (dt, J = 1.0, 7.5 Hz, 1 H), 4.14–4.12 (t,
J = 7.0 Hz, 1 H), 4.11–4.07 (m, 1 H), 4.03 (td, J = 2.0, 10.5 Hz, 1
H), 2.54–2.38 (m, 2 H), 2.04 (qd, J = 5.5, 11.5 Hz, 1 H), 1.88–1.71
(m, 3 H), 1.59–1.51 (m, 1 H), 1.45–1.34 (m, 1 H), 0.96 (t, J = 7.5
Hz, 3 H).
HRMS: m/z [M + Na]+ calcd for C23H21NO2SNa: 398.1185; found:
398.1183.
6d
Yield: 36%; white semisolid.
[a]D25 +0.9 (c 0.2, CHCl3).
13C NMR (125 MHz, CDCl3): d = 141.6, 134.0, 132.4, 130.5, 129.2,
128.2, 128.1, 127.8, 125.6, 122.6, 71.4, 68.3, 37.8, 33.0, 27.4, 25.4,
19.6, 14.0.
IR (film): 3334, 3060, 2999, 2950, 1597, 1475, 1446, 1262, 1242,
1197 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.91 (dd, J = 1.0, 8.0 Hz, 2 H),
7.58 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.40–7.32 (m, 5
H), 7.25–7.18 (m, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 6.95 (d, J = 4.0
Hz, 2 H), 5.43 (d, J = 7.0 Hz, 1 H), 3.72 (dd, J = 7.0, 9.0 Hz, 1 H),
3.17 (d, J = 7.0 Hz, 1 H), 2.53–2.42 (m, 1 H), 2.28–2.15 (m, 2 H),
2.01–1.90 (m, 1 H).
HRMS: m/z [M + Na]+ calcd for C20H23NO2SNa: 364.1342; found:
364.1340.
6g, Isomer B
Yield: 35%; pale-yellow solid; mp 137–139 °C.
[a]D25 –35.1 (c 1.7, CHCl3).
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York

PAPER
Synthesis of Chiral Cyclobutanes Using Benzothiazines as Templates
603
IR (film): 3473, 3060, 2958, 2868, 1479, 1446, 1262, 1242, 1197,
1168, 1111, 1091 cm–1.
6j
Yield: 50%; white solid; mp 127–129 °C.
1H NMR (500 MHz, CDCl3): d = 8.19 (dd, J = 1.0, 8.0 Hz, 2 H),
7.69 (tt, J = 1.0, 7.5 Hz, 1 H), 7.61 (t, J = 7.5 Hz, 2 H), 7.20 (td,
J = 1.5, 7.5 Hz, 1 H), 7.09 (dd, J = 1.0, 7.5 Hz, 1 H), 7.02 (dd,
J = 1.5, 7.5 Hz, 1 H), 6.97 (td, J = 1.5, 7.5 Hz, 1 H), 4.02 (t, J = 8.0
Hz, 1 H), 3.90 (td, J = 1.5, 10.5 Hz, 1 H), 3.22 (d, J = 11.0 Hz, 1 H),
2.52–2.44 (m, 1 H), 2.43–2.35 (m, 1 H), 2.31–2.23 (m, 1 H), 1.98
(dtd, J = 1.0, 8.0, 12.5 Hz, 1 H), 1.72–1.56 (m, 2 H), 1.34–1.24 (m,
2 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 142.1, 135.4, 133.8, 130.6, 129.0,
128.4, 127.8, 127.6, 125.3, 122.5, 77.6, 71.4, 43.4, 34.4, 25.8, 25.7,
20.1, 13.8.
HRMS: m/z [M + Na]+ calcd for C20H23NO2SNa: 364.1342; found:
364.1345.
[a]D25 –29.7 (c 1.1, CHCl3).
IR (film): 3064, 2929, 2852, 1483, 1442, 1270, 1246, 1189, 1152,
1115, 1013 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.19 (d, J = 8.0 Hz, 2 H), 7.74 (t,
J = 7.5 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 2 H), 7.23 (dt, J = 2.0, 7.5 Hz,
1 H), 7.11 (d, J = 7.5 Hz, 1 H), 7.02 (dd, J = 1.0, 7.5 Hz, 1 H), 6.95
(dt, J = 1.0, 7.5 Hz, 1 H), 4.53 (q, J = 9.5 Hz, 1 H), 3.28–3.12 (qd,
J = 10.5, 11.0 Hz, 1 H), 2.87–2.72 (qd, J = 10.5, 10.5 Hz, 1 H),
2.39–2.26 (q, J = 9.5 Hz, 1 H), 2.20–0.80 (m, 22 H).
13C NMR (125 MHz, CDCl3): d = 143.3, 135.9, 134.2, 130.2, 129.1,
128.9, 127.2, 126.7, 125.0, 122.5, 71.5, 71.2, 41.0, 38.9, 38.4, 36.6,
36.1, 28.4, 28.3, 27.6, 27.6, 27.4, 27.3, 26.9, 26.9, 26.8, 26.8, 26.5,
26.5, 26.4, 26.3, 26.2, 26.1, 26.0, 25.9, 25.5.
31P NMR (101.25 MHz, CDCl3): d = 54.1.
HRMS: m/z [M + Na]+ calcd for C28H36NO2PSNa: 504.2097; found:
6h
Yield: 100%; white solid; mp 209–211 °C.
[a]D25 –181.8 (c 2.5, CHCl3).
504.2096.
IR (film): 3424, 3085, 3056, 3011, 2974, 2946, 1822, 1601, 1573,
1495, 1483, 1446, 1389, 1266, 1242, 1168, 1111, 1090, 1025, 993
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.68 (d, J = 7.5 Hz, 2 H), 7.60 (t,
J = 7.5 Hz, 1 H), 7.48 (s, 2 H), 7.40–7.32 (m, 5 H), 7.32–7.17 (m, 4
H), 7.15–6.98 (m, 5 H), 5.68 (s, 1 H), 4.24 (t, J = 9.0 Hz, 1 H), 2.83
(td, J = 9.5, 13.5 Hz, 1 H), 2.63 (ddd, J = 4.5, 10.0, 13.5 Hz, 1 H),
2.24 (dq, J = 10.0, 10.0 Hz, 1 H), 1.69 (dq, J = 4.5, 11.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 144.3, 142.4, 141.6, 134.5, 133.4,
131.0, 129.3, 128.6, 128.5, 128.3, 127.8, 127.4, 127.2, 126.7, 125.3,
122.7, 81.0, 80.1, 42.3, 27.6, 25.2.
HRMS: m/z [M + Na]+ calcd for C29H25NO2SNa: 474.1498; found:
474.1498.
7 and 8
To starting material 6a (360 mg, 0.966 mmol) in CHCl3 (20 mL) at
r.t., PTSA (9.2 mg, 0.0483 mmol) was added. After 15 min, the re-
action was quenched with H2O (10 mL) and sat. NaHCO3 soln (5
mL). The mixture was extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were washed with brine (15 mL), dried
(Na2SO4), and concentrated. Chromatography (EtOAc–hexanes,
2:8) gave 7 as a yellow semisolid [yield: 123.7 mg (34%)] and 8 as
a yellow semisolid [yield: 128.7 mg (36%)].
7
[a]D25 –200.4 (c 0.5, CHCl3).
IR (film): 3289, 3056, 2987, 2942, 2361, 2333, 1601, 1581, 1471,
1454, 1438, 1225, 1176, 1095, 1058 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.78 (td, J = 1.5, 7.5 Hz, 2 H),
7.58–7.53 (m, 2 H), 7.51 (t, J = 8.0 Hz, 2 H), 7.47 (t, J = 7.0 Hz, 1
H), 7.16–7.08 (m, 3 H), 6.84 (d, J = 7.5 Hz, 1 H), 6.76 (t, J = 7.5 Hz,
1 H), 6.66 (t, J = 7.5 Hz, 1 H), 6.52 (d, J = 8.0 Hz, 1 H), 3.98 (dd,
J = 6.3, 8.3 Hz, 1 H), 2.87–2.67 (m, 3 H), 2.15–2.06 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 145.1, 142.9, 134.4, 132.7, 130.8,
130.7, 129.3, 128.5, 128.3, 127.1, 126.3, 123.8, 121.8, 112.8, 80.2,
49.5, 36.8, 25.8.
6i
To a soln of cyclobutane 5g (29.2 mg, 0.108 mmol) in THF (2 mL)
at –78 °C, 2.2 M n-BuLi in hexanes (64 mL, 0.141 mmol) was added
dropwise. After 1 h, Ph2PCl (36.6 mg, 29.8 mL, 0.163 mmol) was
added dropwise. The mixture was stirred for another 3 h before
H2O2 (500 mL) was added. The reaction was stirred for another 5
min before it was quenched with H2O (2 mL). The mixture was ex-
tracted with EtOAc (3 × 2 mL). The organic layers were washed
with brine (5 mL), dried (Na2SO4), and concentrated. Chromatogra-
phy (EtOAc–hexanes, 2:8) gave 6i as a white solid; yield: 43.5 mg
(86%); mp 243–245 °C.
HRMS: m/z [M + Na]+ calcd for C22H19NOS2Na: 400.0800; found:
400.0800.
[a]D25 –6.1 (c 5.5, CHCl3).
8
IR (film): 3346, 3183, 3060, 2958, 2917, 2835, 1585, 1479, 1475,
IR (film): 3060, 2978, 2856, 2071, 1965, 1908, 1818, 1601, 1479,
1438, 1266, 1242, 1189, 1115, 1091, 1009 cm–1.
1442, 1291, 1262, 1242, 1225, 1091, 1062 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.80–7.73 (m, 2 H), 7.67 (s, 1 H),
7.52 (dd, J = 1.0, 7.5 Hz, 1 H), 7.35 (dd, J = 3.0, 3.0 Hz, 3 H), 7.27–
7.20 (m, 5 H), 7.11 (dd, J = 2.5, 6.0 Hz, 2 H), 7.04 (t, J = 7.5 Hz, 1
H), 2.85–2.75 (m, 2 H), 2.53–2.44 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 144.2, 143.1, 138.0, 131.8, 131.2,
129.3, 129.0, 129.0, 128.8, 128.6, 127.4, 125.3, 124.9, 122.8, 117.9,
30.2, 29.2.
1H NMR (500 MHz, CDCl3): d = 7.98 (d, J = 7.5 Hz, 1 H), 7.95 (d,
J = 7.5 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.62 (d, J = 7.5 Hz, 1 H),
7.52–7.48 (m, 5 H), 7.42–7.32 (m, 6 H), 7.24 (dt, J = 1.0, 7.5 Hz, 1
H), 7.15 (d, J = 7.5 Hz, 1 H), 6.88 (t, J = 7.5 Hz, 1 H), 6.73 (d,
J = 6.5 Hz, 1 H), 4.29 (td, J = 9.0, 13.5 Hz, 1 H), 3.39 (m, 1 H), 2.65
(dq, J = 9.5, 9.5 Hz, 1 H), 2.35–2.25 (m, 1 H), 2.00–2.15 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 143.0, 134.1, 133.6, 133.1, 133.0,
132.6, 132.6, 132.2, 132.2, 132.0, 132.0, 131.9, 131.1, 130.3, 129.0,
129.0, 128.6, 128.3, 128.2, 128.2, 128.1, 127.2, 126.6, 125.6, 122.5,
70.7, 70.3, 42.0, 26.7, 26.6, 25.1.
HRMS: m/z [M + H]+ calcd for C22H20NOS2: 378.0980; found:
378.0981.
31P NMR (101.25 MHz, CDCl3): d = 32.3.
Sulfoxide and Sulfone of 7
To starting material 7 (9.6 mg, 0.0254 mmol) in CH2Cl2 (1.2 mL) at
–30 °C, 50–60% MCPBA (16.8 mg, 0.0534 mmol) was added drop-
wise. The reaction was stirred for another 1 h before H2O (1 mL)
was added. The mixture was extracted with CH2Cl2 (3 × 2 mL). The
combined organic layers were washed with brine (5 mL), dried
HRMS: m/z [M + Na]+ calcd for C28H24NO2PSNa: 492.1158; found:
492.1154.
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York

604
M. Harmata et al.
PAPER
(Na2SO4), and concentrated. Chromatography (EtOAc–hexanes,
2:8, 3:7, 4:6) gave a yellow, solid sulfone [yield: 3.7 mg (36%)] and
a sulfoxide [yield: 5.2 mg (52%)].
Acknowledgment
This work was supported by the NIH (1R01-AI59000-01A1) to
whom we are grateful.
Sulfone of 7
Mp 100–102 °C.
References
IR (film): 3387, 3064, 2999, 2950, 1601, 1577, 1462, 1454, 1442,
1303, 1225, 1148, 1107, 927 cm–1.
(1) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449.
(2) Avenoza, A. Org. Lett. 2005, 7, 3597.
(3) Inanaga, K.; Takasu, K.; Ihara, K. J. Am. Chem. Soc. 2005,
1H NMR (250 MHz, CDCl3): d = 8.07 (d, J = 7.1 Hz, 2 H), 7.69 (dd,
J = 2.0, 7.7 Hz, 2 H), 7.52–7.40 (m, 3 H), 7.35–7.25 (m, 3 H), 6.69
(dd, J = 1.7, 6.3 Hz, 1 H), 6.54 (dt, J = 1.6, 6.8 Hz, 2 H), 6.47 (d,
J = 8.7 Hz, 1 H), 4.16 (t, J = 7.9 Hz, 1 H), 3.68 (td, J = 10.3, 12.9
Hz, 1 H), 2.80–2.50 (m, 2 H), 2.30–2.00 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 145.5, 141.9, 134.1, 133.9,
131.2, 130.6, 130.2, 129.2, 128.5, 127.1, 126.2, 123.2, 122.4, 113.8,
86.1, 45.4, 27.4, 24.5.
127, 3668.
(4) Sarkar, N.; Nayek, A.; Ghosh, S. Org. Lett. 2004, 6, 1903.
(5) Jiménez-Osés, G.; Corzana, F.; Busto, J. H.; Pérez-
Fernández, M.; Peregrina, J. M.; Avenoza, A. J. Org. Chem.
2006, 71, 1869.
(6) (a) Harmata, M.; Hong, X. Org. Lett. 2004, 6, 2201.
(b) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581.
(7) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754.
(8) For a selection of leading references, see: (a) Rajender, A.;
Gais, H.-J. Org. Lett. 2007, 9, 579. (b) Bosshammer, S.;
Gais, H.-J. Synthesis 1998, 919. (c) Muller, J. F. K.;
Neuburger, M.; Zehnder, M. Helv. Chim. Acta 1997, 80,
2182. (d) Harmata, M. Tetrahedron Lett. 1988, 29, 5229.
(9) Crystallographic data (excluding structure factors) for some
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 658446 (5e), 658447 (5g),
672249 (6a), 658448 (6c), 658567 (6e), 658449 (7), and
658450 (sulfone of 7). Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk].
HRMS: m/z [M + Na]+ calcd for C22H19NO3S2Na: 432.0699; found:
432.0700.
Sulfoxide of 7
IR (film): 3052, 2991, 2938, 2852, 1597, 1471, 1458, 1438, 1221,
1099, 1086, 1042 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.80 (dd, J = 1.0, 8.0 Hz, 2 H),
7.76 (dd, J = 1.5, 7.0 Hz, 2 H), 7.57 (t, J = 7.5 Hz, 2 H), 7.52 (t,
J = 7.5 Hz, 1 H), 7.18–7.10 (m, 3 H), 6.66 (t, J = 7.5 Hz, 1 H), 6.54
(t, J = 8.5 Hz, 2 H), 6.50 (dt, J = 1.0, 7.0 Hz, 1 H), 3.99 (t, J = 8.0
Hz, 1 H), 3.45 (td, J = 10.0, 13.0 Hz, 1 H), 2.71 (ddd, J = 3.0, 8.5,
12.0 Hz, 1 H), 2.63–2.53 (q, J = 11.0 Hz, 1 H), 2.23–2.13 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 131.6, 131.0, 129.5, 128.0, 127.0,
126.3, 125.8, 123.5, 122.4, 113.2, 88.4, 40.6, 27.4, 25.2.
HRMS: m/z [M + Na]+ calcd for C22H19NO2S2Na: 416.0749; found:
416.0753.
Synthesis 2008, No. 4, 594–604 © Thieme Stuttgart · New York