Preparation and evaluation of N-sulfinyl dienophiles for asymmetric hetero-Diels-Alder reactions

Article abstract of DOI:10.1002/jhet.5570450115

(Chemical Equation Presented) A series of N-sulfinyl dienophiles 1c-i has been screened in asymmetric hetero-Diels-Alder reactions using chiral bis(oxazoline)copper(II) and -zinc(II) triflates. The survey pointed out N-sulfine 1c (R = P(=O)(OPh)₂) as the most promising N-sulfine regarding yield and stereoselectivity (up to 97% ee). The relative configurations, and in one case the absolute configuration, of the HDA adducts were established by X-ray analysis.

Full text of DOI:10.1002/jhet.5570450115

Jan-Feb 2008
149
Preparation and Evaluation of N-Sulfinyl Dienophiles
for Asymmetric Hetero-Diels-Alder Reactions
Molla Mellese Endeshaw,a Lars K. Hansen,b Odd R. Gautun*a
aDepartment of Chemistry, Norwegian University of Science and Technology (NTNU),
NO-7491 Trondheim, Norway. E-mail: odd.gautun@chem.ntnu.no; bDepartment of Chemistry,
Faculty of Science, University of Tromsø, NO-9037 Tromsø, Norway
Received April 20, 2007
O
chiral Lewis acid
CH2Cl2
S
S
+
N
N
O
R
R
1c-i
2
up to 97% ee
3c-i
A series of N-sulfinyl dienophiles 1c-i has been screened in asymmetric hetero-Diels-Alder reactions
using chiral bis(oxazoline)copper(II) and –zinc(II) triflates. The survey pointed out N-sulfine 1c (R =
P(=O)(OPh)2) as the most promising N-sulfine regarding yield and stereoselectivity (up to 97% ee). The
relative configurations, and in one case the absolute configuration, of the HDA adducts were established by
X-ray analysis.
J. Heterocyclic Chem., 45, 149 (2008).
and stereoselectivities (63 – 85% yield, 92 – 98% ee)
[1a,1b]. Unfortunately, reactions run with 10 mol % of the
chiral Lewis acid gave poor yields and selectivities.
However, in combination with trimethylsilyl trifluoro-
methanesulfonate (TMSOTf, 100 mol %), high yields (68
– 86%) and enantioselectivities (97 – 98% ee) were
obtained.
INTRODUCTION
The Diels-Alder (DA) and hetero-Diels-Alder (HDA)
reactions constitute an extremely useful set of reactions,
particularly for stereoselective synthesis. We are currently
studying the asymmetric HDA reaction using N-sulfinyl
dienophiles 1 as reagents for stereoselective introduction
of nitrogen into organic compounds [1]. This reaction
affords 1,2-thiazine 1-oxides, which can be further
transformed into synthetically useful derivatives, e.g.
homoallylic amines and vicinal amino alcohols, by well
established techniques [2].
HDA reactions with acyclic dienes were in general less
successful under the catalytic conditions [1a]. For Ts
sulfine 1b, a pronounced competitive uncatalyzed HDA
reaction reduced the impact of the catalyst. For Cbz
sulfine 1a the modest results (30 – 60% ee) were
comparable to the results of reactions promoted by
stoichiometric amounts of 4-Cu(OTf)2. The disturbing
uncatalyzed HDA reaction of Ts sulfine 1b, the low
selectivity observed for 1a in the reactions with acyclic
dienes, and the general need of TMSOTf as an additive in
the catalytic system prompted us to seek more suitable N-
sulfines. Thus, a survey of the N-sulfines 1c – 1i was
undertaken (Scheme 2).
A series of chiral Lewis acids have previously been
tested as promoters for the stereoselective HDA reactions
of N-sulfinyl dienophiles 1a and 1b with 1,3-cyclo-
hexadiene (2) (Scheme 1) [1].
Scheme 1
O
O
R
catalyst
CH2Cl2
S
S
S
+
+
The optimum N-sulfinyl dienophile for the asymmetric
HDA reaction should (i) be moderately reactive in the
N
N
R
N
R
O
2
exo
3a: R = Cbz
3b: R = Ts
endo
uncatalysed reaction, (ii) engage in
a
bidentate
1a: R = Cbz
1b: R = Ts
coordination to the chiral Lewis acid, restricting the
conformational freedom of the complex and thereby
induce high enantiomeric excess in the HDA adduct, and
(iii) release from the Lewis acid immediately after the
HDA product is formed. In addition, the R group at N
(Scheme 2) should be easily cleaved. N-Sulfines 1c – 1f
were chosen since they were assumed to form a bidentate
coordination to the tested Lewis acids. The p-nitrophenyl
sulfine 1g was expected to be less reactive compared to 1c
– 1f, and was therefore included. N-Sulfines 1h and 1i
with the electron donating R groups n-Bu and BnO were
O
O
N
N
Ph
Ph
4
HDA test reactions
The catalyst survey pointed out 4-Cu(OTf)2 and 4-
Zn(OTf)2 as the most suitable catalysts regarding yields

150
M. M. Endeshaw, L. K. Hansen, and O. R. Gautun
Vol 45
selected to elucidate the scope and limitations of the
asymmetric HDA reaction.
The results of the asymmetric HDA reaction of N-
sulfines 1c – 1f with 1,3-cyclohexadiene (2) promoted
either by 4-Cu(OTf)2, 4-Zn(OTf)2) or 5-TiCl2 (Scheme 3)
are presented in Table 1. The survey pointed out 1c as the
most promising N-sulfine regarding yield, diastereomeric
and enantiomeric excess in the 4-Zn(OTf)2 promoted
reaction at -75 ºC (entry 4: 73% yield, endo/exo > 90%,
95% ee). Unfortunately, a distinct drop in ee (45% ee,
entry 5) was observed when the reaction was run with 10
mol % of the catalyst. In combination with TMSOTf (100
mol %), the enantiomeric excess was only slightly
improved (60% ee, entry 6). However, 4-Cu(OTf)2 (10
mol %) and TMSOTf (100 mol %) appeared to be the
optimum combination and gave endo-3c in 51% yield and
97% ee (entry 7).
RESULTS AND DISCUSSION
The N-sulfinyl compounds 1c – 1i were in general
prepared by treating the respective amino precursor with
thionyl chloride, using ether or benzene as solvent.
Occasionally pyridine or triethyl amine was added as base
in accordance with literature procedures (Scheme 2) [3-6].
Scheme 2
O
S
+
+
SOCl2
2 HCl
R
NH2
N
R
1
Attempts to apply N-sulfinyl dienophiles 1e and 1f with
either 4-Cu(OTf)2 or 4-Zn(OTf)2 failed to give any HDA
adduct at all. For 1e, the HDA reaction mediated by the
Lewis acid 5-TiCl2 gave endo-3e in 45% yield and 24%
ee (entry 13). N-Sulfine 1f failed also with 5-TiCl2 as
promoter (entry 15).
O
O
N
O
O
S
S
S
S
O
OPh
N
N
N
N
N
N
P
N
OPh
O
O
O
1c: 86% (crude) 1d: 90%
1e: 66%
1f: 78%
Several attempts have been made at the HDA reactions
of N-sulfines 1g, 1h and 1i with 1,3-cyclohexadiene (2)
under various reaction conditions, in the presence or
absence of the chiral Lewis acids mentioned above. No
HDA adducts were observed in any of the reactions. For
the N-sulfines 1h and 1i with electron donating groups (R
= n-Bu and OBn, respectively) this result was expected.
Attempts to react 1h and 1i in an “inverse electron
demand” HDA reaction with the electron-deficient diene
crotonaldehyde, with and without Lewis acid (BF3 x OEt2,
4-Cu(OTf)2 and 4-Zn(OTf)2), also failed.
O
O
O
O
S
S
S
N
N
N
NO2
1g: 71%
1h: 42%
1i: 74%
Preparation of N-sulfinyl dienophiles 1c-i
Since N-sulfines 1 in general, are known to be highly
reactive towards nucleophilic attack on the electropositive
sulfur atom and moisture sensitive (returning back to the
amino precursor), purification of the crude product was
either performed by distillation (high vacuum) or
crystallization. The products were either stored neat or as
1.0 – 2.5 M solutions in dry dichloromethane in sealed
flasks in the freezer (-20 ºC). Since we were unable to
purify N-sulfinyl 1c the crude product was used as a stock
solution in dry dichloromethane.
Scheme 3
O
O
R
1
2
S
S
Lewis acid
CH2Cl2
S
+
+
2
N
N
N
O
4
R
exo
R
endo
The N-sulfinyl compounds may adopt E and Z
configurations. Structure analyses in the solid or gaseous
state have revealed that N–sulfines generally have a Z-
configuration, while the configuration in solution is more
uncertain [6,7]. The X-ray of the new N-sulfine 1f with Z-
configuration (shown in Figure 1) fits with the general
trend [8].
1c: R = P(=O)(OPh)2
1d: R = 5-Me-isoxazol-3-yl
1e: R = 2-pyrimidyl
3c: R = P(=O)(OPh)2
3d: R = 5-Me-isoxazol-3-yl
3e: R = 2-pyrimidyl
1f: R = phthalimidyl
3f: R = phthalimidyl
Ph
Ph
Ph
O
OH
Ph
OH
Ph
O
H3
O3
5
H4
C3
C1
C8
C4
Screening of N-sulfinyl dienophiles 1 in asymmetric HDA reactions with 2
C2
N2
N1
C5
C7
C6
S1
H5
The different reactivity observed for 1c – 1f and 1g – 1i
in the HDA reaction may be ascribed to their different
ability in forming a chelate ring with the Lewis acid
catalyst. The former dienophiles have in common two
O1
H6
O4
Figure 1. X-ray crystal structure of N-sulfinyl 1f [8].

Jan-Feb 2008
N-Sulfinyl Dienophiles for Asymmetric Hetero-Diels-Alder Reactions
151
Table 1
Screening of N-Sulfinyl Dienophiles 1 in the HDA Test Reaction with 1,3-cyclohexadiene (2) [a].
Entry
N-Sulfine
Lewis acid (mol %)
Temp/°C (time/h)
Yield % [b]
Endo (% ee) : Exo [c]
Configuration of endo-3
1
2
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1f
-
rt (22)
rt (22)
63
60
61
73
67
40
51
82
57
51
33
65
45
30
0
>95 : <5
>95 (46) : <5
>95 (74) : <5
>95 (95) : <5
>95 (45) : <5
>95 (60) : <5
>95 (97) : <5
67 : 33
>95 (68) : <5
>95 (25) : <5
>95 (47) : <5
20 : 80
-
4-Zn(OTf)2 (100)
4-Zn(OTf)2 (100)
4-Zn(OTf)2 (100)
4-Zn(OTf)2 (10)
4-Zn(OTf)2 (10) [d]
4-Cu(OTf)2 (10) [d]
-
4-Zn(OTf)2 (100)
4-Cu(OTf)2 (100)
5-TiCl2 (100)
-
(1S,2R,4R)
(1S,2R,4R)
(1S,2R,4R)
(1S,2R,4R)
(1S,2R,4R)
(1S,2R,4R)
3
4
-40 (22)
-75 (22)
-75 (22)
-75 (22)
-75 (22)
rt (22)
-75 (22)
-75 (22)
-75 (20)
rt (22)
5
6
7
8
9
10
11
12
13
14
15
-
[e]
[e]
[e]
-
5-TiCl2 (100)
-
-75 (20)
rt (22)
>95 (24) : <5
60 : 40
[e]
-
1f
5-TiCl2 (100)
-75 (20)
-
-
[a] All reactions except for the 5-TiCl2 promoted ones were carried out in CH2Cl2. The 5-TiCl2 promoted reactions were carried out in a
mixture of toluene and CH2Cl2 (8:1). [b] Isolated yield of endo- and exo-3. [c] The endo/exo ratio was determined by 1H NMR (400 MHz).
[d] Reaction with 100 mol% TMSOTf. [e] The absolute configuration was not determined.
basic coordination sites that may form either a 6-
membered ring (1c – 1e) or a 7-membered ring (1f) with
the metal. On the contrary, compounds 1g – 1i have only
one basic coordination site (at sulfoxide O) and will
therefore be less activated for the HDA reaction.
by the S=O bond (2.26 - 1.24 ppm), while in the exo
configuration these protons are less shielded (3.0 – 1.5
1
ppm). H NMR data of other endo/exo-3 adducts with
known configurations supported this assignment [1d].
The absolute configuration of endo-3c, from the 4-
Zn(OTf)2 and 4-Cu(OTf)2 catalysed reactions (Table 1,
entries 2 – 7), was determined by X-ray analysis of the
ring opened allylic phenyl sulfoxide [1R,4S,S(S)]-6,
shown in Scheme 4 and Figure 2 [8]. The ring opening
reaction of endo-3c with phenyl magnesium bromide was
expected to proceed with inversion at the sulfoxide group
and thus endo-3c had the (1S,2R,4R)-configuration.
C14
C15
C16
C11
C13
C12
O3
P1
O1
O4
N1
C36
C32
C35
C34
O2
C1
C31
S1
C6
C5
C33
C2
C3
C21
C22
C26
C25
C4
C23
C24
Scheme 4
Figure 2. X-ray structure of [1R,4S,S(S)]-6 [8].
1
2
S
O
P
PhMgBr
THF, -60 oC
(79%)
O
PhO
PhO
N
O
4
N
S
H7
H6
.
.
P
H
Ph
PhO
PhO
O
H92
H101
C5
C7
C9
C6
C8
C10
H8
H5
(1S,2R,4R)-3c
[1R,4S,S(S)]-6
H102
H91
O1
N1
S1
Ring opening of endo-3c to [1R,4S,S(S)]-6
C1
N2
The relative configurations of HDA adducts endo-3d
and exo-3e were determined by X-ray analysis (Fig. 3 and
4) [8]. For endo-3f, the relative configuration was deter-
mined by considering the shielding effect of the “S=O”
group in the 1H NMR spectra, similar to the work
described by Zhang and Flann [9]. In the endo configur-
ation the protons at the 7- and 8-positions are unaffected
C2
O2
C3
H2
C4
H42
H43
H41
Figure 3. X-ray structure of endo-3d [8].

152
M. M. Endeshaw, L. K. Hansen, and O. R. Gautun
Vol 45
and was difficult to purify by vacuum distillation, the crude
product (86% yield) was stored and used as a stock solution in
dry dichloromethane. Analytical data for 1c: Ir (neat): 3056 (w),
H6
C6
H5
C5
H7
1
1592 (s), 1545 (s), 1490 (s), 1264 (s), 1160 (s) cm-1; H nmr: ꢀ
C7
H102
C10
7.41-7.15 (10H, m, Ph); 13C nmr: ꢀ 150.1, 150.0, 130.2 (d, JPC
=
S1
O1
C8
C9
N1
H101
H92
3 Hz), 126.2 (d, JPC = 5.7 Hz), 120.6, 120.5; ms: (chemical
ionization) m/z 296 (0.4, M+1), 295 (0.4, M+), 264 (2), 250 (17),
249 (23), 248 (13), 170 (12), 94 (4), 77 (7), 29 (100).
C1
N2
H8
H91
C2
N3
H2
C4
(Z)-N-Sulfinyl-N-aminophthalimide (1f). A solution of N-
aminophthalimide (3.3 g, 20.4 mmol) in dry benzene (40 ml)
was heated to 40 °C and stirred for 10 min. Thionylchloride (4.6
ml, 63.2 mmol) was then added to the solution via a syringe and
the mixture was refluxed overnight. The product (3.29 g, 77%),
a yellow solid, precipitated from the reaction mixture at room
temperature. Analytical data for 1f: Mp 157-158 °C (from
benzene); ir (potassium bromide): 1709 (s, C=O), 1596 (s), 1463
C3
H3
H4
Figure 4. X-ray structure of exo-3e [8].
In conclusion, a screening of N-sulfinyl dienophiles for
asymmetric hetero-Diels-Alder reactions using chiral
bis(oxazoline)copper(II) and –zinc(II) triflates has been
presented. The survey pointed out P(O)(OPh)2 sulfine 1c
as the most promising N-sulfine regarding yield and
stereoselectivity (up to 97% ee). The result is comparable
with results reported earlier for Cbz sulfine 1a and Ts
sulfine 1b [1].
1
(s), 1370 (m), 1351 (m) cm-1; H nmr: ꢀ 7.98 (2H, dd, J = 5.6,
2.8 Hz, Ar), 7.85 (2H, dd, J = 5.6, 2.8 Hz, Ar); 13C nmr: ꢀ 160.5
(C=O), 135.6, 130.4, 125.0; ms: (70 eV, electron impact) m/z
208 (46, M+), 180 (18), 132 (89), 104 (100), 76 (5); hrms calcd
for C8H4N2O3S 207.9943, found 207.9943. Anal. Calcd for
C8H4N2O3S: C, 46.15; H, 1.94; N, 13.46. Found: 46.21; H, 1.98;
N, 13.41. The (Z)-configuration of 1f was determined by X-ray
crystallographic analysis (Figure 1) [8].
General Procedure for the Uncatalysed HDA Reaction. To
a solution of the N-sulfinyl compound 1 (1.8 mmol) in dry
CH2Cl2 (3 ml) was added 1,3-cyclohexadiene (2) (0.43 ml, 4.5
mmol). The reaction mixture was then stirred at room
temperature for 24 h under N2-atmosphere. The solvent was
evaporated in vacuo, and the crude product analysed by H nmr
to determine the endo/exo ratio. The crude product was purified
by flash chromatography.
Preparation of the Copper(II)-bis(oxazoline) Catalyst, 4-
Cu(OTf)2, and the Zinc(II)-bis(oxazoline) Catalyst, 4-
Zn(OTf)2. An oven dried round bottom flask was charged with
copper(II) triflate or zinc triflate (0.025 mmol) in an argon
atmosphere. Dry CH2Cl2 (2 ml) and a solution of the phenyl box
ligand 4 [15] in CH2Cl2 (0.5 M, 52 μl, 0.026 mmol) were added
and the resulting suspension was stirred for 2 h. At this time
most of the solids had dissolved. A light green solution was
observed in generation of the copper(II) catalyst. No colour was
observed with zinc.
EXPERIMENTAL
General Remarks. N-Sulfines 5-methyl-N-sulfinyl-3-
isoxazolamine (1d) [10], N-sulfinyl-2-pyrimidinamine (1e) [11],
p-nitro-N-sulfinylaniline (1g) [10], N-sulfinyl-1-butanamine (1h)
[12], and O-(phenylmethoxy)-N-sulfinylhydroxylamine (1i)
[13,14] were prepared according to the literature. Ligands 4 [15]
and 5 [16] were prepared as described in the literature. Solvents
were dried according to standard procedures [17]. Tlc was
performed on Merck silica gel 60 F254 plates and visualized with
UV light (254 nm) and phosphomolybdic acid in ethanol
solution. Silica gel for flash chromatography was purchased
from Grace-Amicon (35-70 micron). Optical rotations were
measured with a Perkin Elmer 241 Polarimeter. Enantiomeric
excesses were determined by hplc analysis, using Daicels
columns Chiralpak AD and Chiralcel OJ (250 ꢀ 4.6 mm). 1H and
13C nmr spectra (Bruker Advance DPX instruments 300/75
MHz, 400/100 MHz and 600/150 MHz) were obtained from
solutions of CDCl3, and chemical shifts are in ppm and
referenced to TMS via the lock signal of the solvent. 1H and 13C
nmr signals were assigned by 2D correlation techniques. Ir
1
General Procedure A: Asymmetric HDA Reaction with 10
mol % of 4-Cu(OTf)2 or 4-Zn(OTf)2. A solution of the N-
sulfinyl dienophile 1 (620 μl, 0.4 M in CH2Cl2, 0.248 mmol) was
added into the precooled solution of the catalyst (0.025 mmol) at
-75 °C. A precooled solution of 1,3-cyclohexadiene (2) (0.5
mmol) in CH2Cl2 (0.3 ml) and TMSOTf (0.248 mmol) was
added into the reaction mixture, respectively. The diene solution
was added slowly along the wall of the round bottom flask. The
reaction mixture was stirred for 22 h and quenched by addition
of a phosphate buffer (pH 7, 3 ml), allowed to warm to room
temperature and extracted with CH2Cl2 (3 x 3 ml). The
combined organics were dried (MgSO4), filtered through a short
silica plug and concentrated. The crude product was analysed by
1H nmr to determine the endo/exo ratio and, thereafter purified
by flash chromatography. The enantiomeric composition was
determined by chiral hplc.
spectra were run on
a Thermo Nicolet FT-IR NEXUS
instrument, and only the strongest/structurally most important
peaks are listed. The mass spectra were recorded on a Finnigan
MAT 95XL mass spectrometer. The electron-impact mass
spectra were recorded at 70 eV with a direct inlet and the
chemical ionization mass spectra were obtained using methane
(ionized at 200 eV) as carrier gas. The high resolution mass
spectra (hrms) were obtained by using perfluorokerosene (PFK)
as standard to provide the reference masses. X-rays were
recorded on Enraf-Nonius CAD-4 diffractometer. Elemental
analysis was determined by the Laboratory of Organic
Elemental analysis, Prague Institute of Chemical Technology,
Czech Republic. Melting points are reported uncorrected.
General Procedure B: Asymmetric HDA Reaction with
100 mol % of 4-Cu(OTf)2 or 4-Zn(OTf)2. A solution of the
catalyst (0.40 mmol) was cooled to -75 °C before a solution of
N-sulfinyl compound 1 in dry CH2Cl2 (0.5 -1.0 M, 0.40 mmol)
N-Sulfinylphosphoramidic acid diphenyl ester (1c) [18].
The title compound was prepared according to a general
literature procedure [19]. Since 1c is highly moisture sensitive

Jan-Feb 2008
N-Sulfinyl Dienophiles for Asymmetric Hetero-Diels-Alder Reactions
153
was added. The resulting mixture was stirred for 10 min before a
precooled solution of 1,3-cyclohexadiene (2) (0.80 mmol) in dry
CH2Cl2 (0.5 ml) was added slowly along the wall of the flask.
After 22 hours reaction time, the reaction mixture was quenched
by addition of a phosphate buffer (pH 7, 3 ml), allowed to warm
to room temperature, and worked up as described in general
procedure A.
Asymmetric HDA Reaction with 100 mol % of 5-TiCl2.
The 5-TiCl2 promoted HDA reactions were performed as
described in the literature [1d].
5.3 Hz), 120.4(d, JPC = 5.4 Hz), 60.1 (C-4), 46.9 (C-1), 28.6 (d,
JPC = 3.9 Hz, C-6), 21.1 (C-5); ms: (70 eV, electron impact) m/z
326 (33), 275 (4.6), 250 (57.9), 249 (100), 248 (66.1), 232
(13.9), 218 (10.4), 170 (65.6), 156 (23.3), 126 (14.7), 110 (25.1),
94 (93.6), 78 (89.1), 77 (97.7), 65 (24.5), 51 (24.3). Anal. Calcd
for C24H24NO4PS; C, 63.56; H, 5.33; N, 3.09. Found: C, 63.25;
H, 5.36; N, 2.97. The absolute configuration of [1R,4S,S(S)]-6
was determined by X-ray crystallographic analysis (Figure 2)
[8].
3-(5-Methylisoxazol-3-yl)-2ꢀ4-thia-3-azabicyclo[2.2.2]oct-5-
ene 2-oxide (3d). The uncatalysed reaction between N-sulfine
1d and 2 according to the general procedure afforded a mixture
of endo-3d and exo-3d (2:1). Flash chromatography (EtOAc/
hexane 4/1) of the crude product yielded 259 mg (64% yield) of
endo-3d as a white solid and second fraction containing a
mixture of 5-methyl-3-isoxazolamine and exo-3d. All attempts
to separate 5-methyl-3-isoxazolamine and exo-3d failed.
Analytical data for endo-3d: Tlc Rf 0.15 (EtOAc/hexane 4/1);
mp 126-127 °C; ir (potassium bromide): 3130 (w), 2963 (w),
1616 (s), 1485 (s), 1455 (s), 1433 (s), 1367 (s), 1273 (s), 1163
(s), 1102 (s), 1045 (s), 1009 (s) cm-1; 1H nmr: ꢀ 7.00 (1H, ddd, J
= 7.9, 7.1, 1.5 Hz, H-5), 6.35 (1H, app t, J = 7.49, 7.27 Hz, H-6),
6.02 (1H, s, 4-isoxozol), 5.12-5.09 (1H, m, H-4), 4.35-4.31(1H,
m, H-1), 2.36 (3H, s, CH3), 2.05-1.94 (1H, m, H-8), 1.87-1.79
(1H, m, H-7), 1.58-1.51 (1H, m, H-8), 1.31-1.23 (1H, m, H-7);
13C nmr: ꢀ 170.3 (5-isoxazol), 162.5 (3-isoxazol), 137.6 (C-5),
125.2 (C-6), 94.4 (4-isoxazol), 55.4 (C-1), 50.8 (C-4), 22.4 (C-
8), 15.9 (C-7), 12.8 (CH3); ms: (70 eV, electron impact) m/z 224
(M+, 0.1), 163 (2), 146 (9), 144 (134), 109 (18), 80 (82), 79
(100). Anal. Calcd for C10H12N2O2S: C, 53.55; H, 5.39; N, 12.49;
S, 14.30. Found: C, 53.31; H, 5.43; N, 12.43; S, 14.45. The
relative configuration of (1R*,2S*,4S*)-3d was determined by
X-ray crystallographic analysis (Figure 3) [8]. Data for exo-3d:
(1S,2R,4R)-(2-Oxo-2ꢀ4-thia-3-azabicyclo[2.2.2]oct-5-en-3-
yl)phosphonic acid diphenyl ester ((1S,2R,4R)-3c).
Asymmetric HDA reaction between 1c and 2, catalysed by 4-
Cu(OTf)2 or 4-Zn(OTf)2 according to the general procedures A
and B, afforded only the endo adduct (1S,2R,4R)-3c in 46 – 97%
ee and in 51 – 73% yields (Table 1, entries 2 - 7) as a white
solid. The crude product was in general purified by flash
chromatography (EtOAc/pentane 1/1). Analytical data for
(1S,2R,4R)-3c: Tlc Rf 0.16 (EtOAc/pentane 1/1); mp 101-103
°C; [ꢀ]2D0 -163.5 (c = 1.0, CH2Cl2); hplc: (Chiralpak AD, 2-
propanol/n-hexane 20/80, 1 ml min-1, 230 nm) 88% ee, tR 22.84
(1R,2S,4S) and 27.77 (1S,2R,4R) min; ir (potassium bromide):
3241 (w), 3058 (w), 2967 (w), 1586 (s), 1487 (s), 1373 (s), 1283
(m), 1234 (m) cm-1; 1H nmr: ꢀ 7.38-7.23 (10H, m, Ph), 6.86 (1H,
app t, J = 7.55, 7.45 Hz, H-5), 6.28 (1H, app t, J = 7.4 Hz, H-6),
4.88-4.82 (1H, m, H-4), 4.38-4.32 (1H, m, H-1), 1.80-1.60 (2H,
m, H-7/H-8), 1.48-1.35 (1H, m, H-8), 1.20-1.07 (1H, m, H-7);
13C nmr: ꢀ 150.6 (d, JPC = 4.02 Hz), 150.5 (d, JPC = 4.02 Hz),
137.2 (d, JPC = 5.01 Hz, C-5), 130.0, 129.9, 125.7, 125.6 (d, JPC
= 3.02 Hz, C-6), 120.6 (d, JPC = 5.03 Hz), 120.5 (d, JPC = 5.03
Hz), 56.1 (d, JPC = 5.03 Hz, C-1), 50.9 (d, JPC = 2.01 Hz, C-4),
24.6 (C-7), 14.9 (C-8); ms: (70 eV, electron impact) m/z 375
(0.1, M+), 329 (3), 295 (47), 247 (67), 246 (63), 201 (8), 170
(50), 156 (19), 94 (44), 77 (96), 65 (29), 51 (29). Anal. Calcd for
C18H18NO4PS: C, 57.59; H, 4.83; N, 3.73. Found: C, 57.66; H,
4.81; N, 3.81.
1
Tlc Rf 0.31 (EtOAc/hexane 4/1); H nmr: ꢀ (selected signals)
6.98 (1H, ddd, J = 8.2, 5.8, 1.0 Hz, H-5), 6.30 (1H, app t, J = 7.6
Hz, H-6), 5.95 (1H, s, 4-isoxazol), 5.00-4.97 (1H, m, H-4), 4.13-
4.07 (1H, m, H-1), 2.91-2.85 (1H, m, H-7), 2.34 (3H, s, CH3),
2.44-2.38 (1H, m, H-8), 1.64-1.51 (2H, m, H-7/8); 13C nmr:
170.6 (5-isoxazol), 162.4 (3-isoxazol), 141.4 (C-5), 127.5 (C-6),
94.4 (4-isoxazol), 56.0 (C-1), 50.5 (C-4), 24.7 (C-7), 12.7 (CH3),
11.4 (C-8).
The asymmetric HDA reaction between 1d and 2, promoted
by 4-Zn(OTf)2 according to the general procedure B, afforded
exclusively endo-3d as product (Table 1, entry 9). Analytical
data: [ꢀ]2D0 -230.2 (c = 1.0, CH2Cl2); hplc: (Chiralcel OJ, 2-
propanol/n-hexane 35/65, 0.5 ml min-1, 230 nm) 68% ee, tR
23.69 and 30.59 (major) min. The absolute configuration was
not determined.
[1R,4S,S(S)]-(4-Benzenesulfinylcyclohex-2-enyl)phosphor-
amidic acid diphenyl ester, [1R,4S,S(S)]-6. A solution of
phenyl magnesium bromide in THF (1 M, 604 μl, 0.604 mmol)
was added to a stirred solution of (1S,2R,4R)-3c (88% ee, 201
mg, 0.537 mmol) in dry THF (4 ml) at -60 °C and the mixture
was stirred for 30 min and then hydrolyzed with aqueous NH4Cl
(satd. 8 ml). The layers were separated and the aqueous layer
extracted with Et2O (3 x 4 ml). The combined organics were
washed with brine (5 ml), dried (MgSO4) and concentrated in
vacuo. The crude was purified by flash chromatography
(EtOAc/pentane, gradient 1/1 to 7/3) yielded the allylic
sulfoxide [1R,4S,S(S)]-6 (192.4 mg, 79%) as a white solid.
Analytical data for [1R,4S,S(S)]-6: Mp 140-141 °C (from
CH2Cl2/heptane); [ꢀ]2D0 -222 (c = 1.0, CH2Cl2); hplc: (Chiralpak
AD, 2-propanol/n-hexane 40/60, 1 ml min-1, 230 nm) 77% ee, tR
13.47 [1S,4R,S(R)] and 21.06 [1R,4S,S(S)] min.); ir (potassium
bromide): 3193 (w), 2918 (w), 1589 (m), 1483 (s), 1251 (m),
3-(2-Pyrimidinyl)-2ꢀ4-thia-3-azabicyclo[2.2.2]oct-5-ene 2-
oxide (3e). The uncatalysed reaction between N-sulfine 1e and 2
according to the general procedure afforded a mixture of endo-
3e and exo-3e (1:4). Flash chromatography (EtOAc/hexane 4/1)
of the crude product yielded 155 mg (51% yield) of exo-3e as a
white solid and a second fraction containing a mixture of endo-
3e and 2-pyrimidinamine. Flash chromatography (acetone
/CH2Cl2 1/9) of the latter fraction afforded 43 mg (14% yield) of
endo-3e as a white solid. Analytical data of endo-3e: Tlc Rf 0.13
(EtOAc/hexane 4/1); mp 126-127 °C; ir (potassium bromide):
3074 (w), 2939 (w), 1578 (s), 1556 (s), 1416 (s), 1370 (m), 1349
1
1194 (s) cm-1; H nmr: ꢀ 7.60-7.54 (2H, m, Ph) 7.46-7.43 (3H,
m, Ph), 7.40-7.30 (4H, m, Ph), 7.28-7.21 (4H, m, Ph), 7.20-7.13
(2H, m, Ph), 6.07 (1H, ddd, J = 10.1, 3.4, 1.7 Hz, H-2), 5.50
(1H, ddd, J = 10.1, 3.4, 1.5 Hz, H-3), 3.95 (1H, m, H-1), 3.30
(1H, m, H-4), 3.20 (1H, t, J = 11.6 Hz, NH), 2.12-2.0 (1H, m, H-
5), 1.95-1.84 (1H, m, H-5), 1.83-1.70 (1H, m, H-6), 1.68-1.55
(1H, m, H-6); 13C nmr: ꢀ 151.0 (d, JPC = 4.5 Hz), 150.91 (d, JPC
= 4.5 Hz), 141.9, 137.5 (d, JPC = 6.64 Hz, C-2), 131.4, 129.9,
1
(m), 1109 (m) cm-1; H nmr: ꢀ 8.48 (2H, d, J = 4.8 Hz, 4-pyr/6-
pyr), 7.00 (1H, ddd, J = 8.1, 7.2, 1.6 Hz, H-5), 6.84 (1H, t, J =
4.8 Hz, 5-pyr), 6.44 (1H, app t, J = 7.2 Hz, H-6), 5.75-5.72 (1H,
129.2, 125.2 (app. d, JPC = 2.9 Hz), 124.8, 121.9, 120.5 (d, JPC
=

154
M. M. Endeshaw, L. K. Hansen, and O. R. Gautun
Vol 45
m, H-4), 4.34-4.30 (1H, m, H-1), 1.90-1.77 (2H, m, H-7/8),
1.71-1.63 (1H, m, H-8), 1.38-1.29 (1H, m, H-7); 13C nmr: ꢀ
161.0 (2-pyr), 158.3 (4-pyr/6-pyr), 137.1 (C-5), 126.6 (C-6),
114.2 (5-pyr), 55.3 (C-1), 47.3 (C-4), 23.6 (C-8), 15.9 (C-7); ms:
(70 eV, electron impact) m/z 221 (M+, 5), 173 (49), 172 (96),
143 (46), 142 (14), 125 (27), 95 (20), 80 (100), 79 (93), 77 (18).
Anal. Calcd for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99.
Found: C, 54.01; H, 4.93; N, 18.76. Analytical data of exo-3e:
Tlc Rf 0.27 (EtOAc/hexane 4/1); mp 124-125 °C (from
CH2Cl2/pentane); hplc: (Chiralpak AD, 2-propanol/n-hexane
10/90, 1 ml min-1, 241 nm) tR 18.88 and 23.06 min; ir (potassium
bromide): 3074 (w), 2937 (w), 1578 (s), 1560 (s), 1417 (s), 1366
(m), 1351 (m), 1289 (m), 1233 (m), 1183 (m), 1087 (s), 1055
(18), 104 (33), 80 (100), 79 (39). Anal. Calcd for C14H12N2O3S:
C, 58.32; H, 4.20; N, 9.72. Found: C, 58.14; H, 4.28; N, 9.98.
Acknowledgement. This work was supported by a grant from
the Norwegian Research Council (grant 140593/431 to M.M.E.)
which is gratefully acknowledged. We also thank Mrs. Julie
Jackson and Associate Professor Helge Kjøsen (NTNU) for
performing the mass spectrometric measurements.
REFERENCES
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R. Eur. J. Org. Chem. 2006, 5249. (b) Bayer, A.; Endeshaw, M. M.;
Gautun, O. R. J. Org. Chem. 2004, 69, 7198. (c) Bayer, A.; Gautun, O.
R. Tetrahedron: Asymmetry 2001, 12, 2937. (d) Bayer, A.; Hansen, L.
K.; Gautun, O. R. Tetrahedron: Asymmetry 2002, 13, 2407. (e) Bayer,
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1
(m), 1026 (m) cm-1; H nmr: ꢀ 8.47 (2H, d, J = 4.8 Hz, 4-pyr/6-
pyr), 6.90 (1H, ddd, J = 7.9, 6.2, 0.7 Hz, H-5), 6.84 (1H, t, J =
4.7 Hz, 5-pyr), 6.36 (1H, app t, J = 7.6 Hz, H-6), 5.69-5.66 (1H,
m, H-4), 4.09-4.05 (1H, m, H-1), 3.02-2.92 (1H, m, H-7), 2.41-
2.31 (1H, m, H-8), 1.69-1.54 (2H, m, H-7/8); 13C nmr: ꢀ 161.2
(2-pyr), 158.3 (4-pyr/6-pyr), 140.5 (C-5), 128.2 (C-6), 114.4 (5-
pyr), 56.1 (C-1), 47.2 (C-4), 25.1 (C-7), 12.2 (C-8); ms: (70 eV,
electron impact) m/z 221 (M+, 4), 173 (28), 172 (68), 143 (28),
141 (47), 125 (18), 95 (18), 80 (96), 79 (100), 77 (25). Anal.
Calcd for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99, S, 14.49.
Found: C, 53.97; H, 5.00; N, 18.92; S, 14.45. The relative
configuration of (1R*,2R*,4S*)-3e was corroborated by X-ray
crystallographic analysis (Figure 4) [8].
[7] Romano, R. M.; Della Védova, C. O. J. Mol. Struct. 2000,
522, 1.
The asymmetric HDA reaction between 1e and 2, promoted
by 5-TiCl2 according to literature [1d], afforded exclusively
endo-3e as product (Table 1, entry 13). Analytical data: [ꢀ]D2 0
-55.7 (c = 1.0, CH2Cl2); hplc: (Chiralcel OJ, 2-propanol/n-
hexane 35/65, 0.7 ml min-1, 241 nm) 24% ee tR 19.4 (major) and
23.3 min. The absolute configuration was not determined.
2-(2-Oxo-2ꢀ4-thia-3-azabicyclo[2.2.2]oct-5-en-3-yl)isoin-
dole-1,3-dione (3f). The uncatalysed reaction between N-sulfine
1f and 2 according to the general procedure afforded a mixture
of endo-3f and exo-3f (3:2). Flash chromatography (EtOAc/
hexane 4/1) of the crude product yielded 100.3 mg (17% yield)
of endo-3f as a white solid and a second fraction, tlc Rf 0.28
(EtOAc/hexane 4/1), containing an inseparable mixture assumed
[8] Inquiries concerning X-ray should be addressed to L.K.H. (e-
mail: lars-kristian.hansen@chem.uit.no). Crystallographic data for
structures 1f, (1R,4S,S(S))-6, endo-3d and exo-3e have been deposited in
the Cambridge Crystallographic Data Centre as supplementary
publication nos CCDC 270398, CCDC 270396, CCDC 270399 and
CCDC 270397, respectively. Copies of the data can be obtained free of
charge from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax:
+44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
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1910.
1
to be exo-3f and N-aminophthalimide. Overlap in the H nmr
spectrum of the latter fraction made it difficult to report the exo-
3f data. Analytical data for endo-3f: Tlc Rf 0.15 (EtOAc/hexane
4/1); mp 169-171 °C (Charred at this temperature); ir (potassium
bromide): 3090 (w), 2935 (w), 1727 (s), 1467 (m), 1371 (s),
1199 (s), 1109 (s) cm-1; 1H nmr: ꢀ 7.90 (2H, dd, J = 5.5, 3.1 Hz,
Isoindole), 7.79 (2H, dd, J = 5.5, 3.1 Hz, Isoindole), 7.10 (1H,
ddd, J = 8.1, 7.2, 1.7 Hz, H-5), 6.32 (1H, app t, J = 7.4, 7.2 Hz,
H-6), 4.39-4.35 (1H, m, H-1), 4.19-4.16 (1H, m, H-4), 2.26-2.21
(1H, m, H-7), 2.12-2.06 (1H, m, H-8), 1.95-1.85 (1H, m, H-7),
1.32-1.24 (1H, m, H-8); 13C nmr: ꢀ 166.2 (C=O), 138.3 (C-5),
135.0, 129.9, 124.4, 124.1, 59.1, 57.3, 23.6, 16.7; ms: (chemical
ionization) m/z 289 (M+1, 3), 208 (8), 192 (11), 162 (20), 132
[13] Michaelis, A.; Schröter, G. Ber. Dtsch. Chem. Ges. 1893, 26,
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