Highly Diastereoselective and Irreversible Aldol Reactions of N -Sulfonylimidates

Article abstract of DOI:10.1055/s-0035-1562785

A mild method for the aldolization of N-sulfonylimidates was developed. The reaction proceeds in excellent diastereoselectivity to provide a range of useful β-hydroxyimidates in high yield. The innate reversibility of the reaction is suppressed by the use of a titanium complex as a Lewis acid.

Full text of DOI:10.1055/s-0035-1562785

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 3413–3419
paper
3413
H. E. Bartrum et al.
Paper
Synthesis
Highly Diastereoselective and Irreversible Aldol Reactions of
N-Sulfonylimidates
Hannah E. Bartruma,b
Sébastien Carreta,b
Jean-François Poisson*a,b
Et3N
R3CHO
NTs
OR2
OH
NTs
OR2
TiCl2(Oi-Pr)2
R1
R3
R1
a Univ. Grenoble Alpes, Département de Chimie Moléculaire
(DCM), 38000 Grenoble, France
b CNRS, Département de Chimie Moléculaire (DCM), 38000
Grenoble, France
76–98%
21 examples
anti/syn up to 99:1
jean-francois.poisson@univ-grenoble-alpes.fr
Dedicated to the memory of Prof. Jean Normant, an exceptional
and inspiring supervisor
Received: 26.05.2016
Accepted after revision: 29.06.2016
Published online: 30.08.2016
show a similar pattern of reactivity. We report herein the
successful aldol reaction of sulfonylimidates under mild ba-
sic conditions, with the aid of titanium salts to stabilize the
products and prevent retro-aldolization.5
DOI: 10.1055/s-0035-1562785; Art ID: ss-2016-c0384-op
Abstract A mild method for the aldolization of N-sulfonylimidates was
developed. The reaction proceeds in excellent diastereoselectivity to
provide a range of useful β-hydroxyimidates in high yield. The innate re-
versibility of the reaction is suppressed by the use of a titanium com-
plex as a Lewis acid.
NTs
OR2
NTs
OR2
DBU or
strong base
Previous work R1
R1
R3
imine
NHR4
Key words aldolization, imidates, titanium, stereoselectivity, sulfonyl
NTs
OR2
NTs
weak base
R1
R1
R3
N-Sulfonylimidates represent an important class of or-
ganic derivatives with a large variety of applications: they
have received interest as pro-drug candidates and pharma-
cophores and been employed as precursors to active drug
molecules featuring ester or sulfonamide functional
groups.1 They also represent versatile synthetic building
blocks and are widely utilized as intermediates for the syn-
thesis of heterocycles.2
Despite this synthetic utility and the variety of existing
methods for the formation of N-sulfonylimidates, limited
attention has been devoted to their functionalization, par-
ticularly at the α-position. Kobayashi et al. have investigat-
ed the catalytic Mannich-type reaction of alkyl N-sulfo-
nylimidates with imines to give β-amino imidates in good
to excellent yields and with good diastereocontrol.3 Subse-
quently, Barbas III et al. developed an organocatalytic enan-
tioselective Michael addition reaction of N-sulfonylimidates
to α,β-unsaturated aldehydes: the reaction proceeded with
low diastereoselectivity and in moderate yield.4 Strikingly,
the more obvious and synthetically useful direct reaction
with an aldehyde has not been reported to date (Scheme 1).
We have recently studied the aldolization of sulfinylimi-
dates, and found that the high reversibility of the reaction
could be overcome by using a titanium Lewis acid.5 We
wondered whether the parent sulfonylimidates would
This work
OR2
OH
R3CHO
additive
Scheme 1 Context of this work
The required N-sulfonylimidates 1a–f were synthesized
from the corresponding imidate hydrochloride salts.6 In
general, synthesis via the ortho ester intermediate6b,7 gave
higher yields of the desired sulfonylimidate than direct con-
version from the imidate hydrochloride.3a However, the di-
rect method was necessary to provide access to the bulkier
isopropyl sulfonylimidate 1c, for which the ortho ester in-
termediate could not be formed, presumably as a result of
steric congestion.
The reaction of methyl 2-phenyl-N-tosylacetimidate
(1a) with benzaldehyde was first studied (Table 1). Treat-
ment of N-sulfonylimidate 1a with various bases including
triethylamine (entry 1), followed by addition of benzalde-
hyde resulted only in recovery of unreacted starting materi-
al, even after prolonged reaction times.8 These results were
comparable to those obtained during previous studies of
the aldolization of N-sulfinylimidates and highlight the in-
herent reversibility of the reaction.9 Subsequently, the
treatment of N-sulfonylimidate 1a and benzaldehyde with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 3413–3419

3414
H. E. Bartrum et al.
Paper
Synthesis
three equivalents of TiCl2(Oi-Pr)2 in combination with tri-
ethylamine pleasingly afforded the product 2a in excellent
yield and as a single diastereoisomer (entry 2). Further opti-
mization showed that the amount of base and TiCl2(Oi-Pr)2
utilized could be reduced to three and two equivalents, re-
spectively, without any detrimental effect on either the
yield or selectivity of the reaction (entry 4). However, at-
tempts to further reduce the amount of TiCl2(Oi-Pr)2 result-
ed in incomplete conversion, lower diastereoselectivity (en-
try 5), and eventually complete retardation of the reaction
(entry 6). In addition, quite disappointingly, attempts to
change the isopropoxy group on titanium by various chiral
diols failed to produce the desired product.
high diastereoselectivity, although the yields of the aldol
products were slightly lower due to the presence of an un-
identified byproduct (entries 20 and 21). A range of aro-
matic, heteroaromatic, unsaturated and tertiary alkyl alde-
hydes were well tolerated by the reaction conditions. The
reaction of aldehydes bearing electron withdrawing or elec-
tron donating groups on the aromatic ring were equally ef-
ficient providing the corresponding products in high yields
(entries 7 and 8).
In addition, more sterically hindered aromatic alde-
hydes, including those bearing ortho substituents on the ar-
omatic ring, reacted well under these conditions (Table 2,
entry 14), as did those bearing meta or para substituents.
Aromatic aldehydes containing halide substituents (F, Br)
on the ring were also well tolerated and no erosion of the
Table 1 Optimization of Conditions for the Aldolization Reactiona
Ts
Ts
Ts
N
N
N
Table 2 Scope of the Sulfonylimidate Aldolizationa,b
Et3N
Ph
Ph
Ph
Ph
Ph
OMe
+
OMe
OMe
Ts
PhCHO
TiCl2(Oi-Pr)2
Ts
1a
N
N
OH
OH
Et3N
R1
R3
R1
OR2
2a
2a'
OR2
R3CHO
1a–f
OH
TiCl2(Oi-Pr)2
Entry
Et3N (equiv) [Ti] (equiv)b Time (h) Conv. (%)c,d
dr (2a/2a′)
2a–u
1
4
4
3
3
3
3
0
18
2
0
–
100 (95)d
100 (95)d
100 (95)d
70
>99:1
>99:1
>99:1
96:4
–
Entry
2
R1
Ph
R2
Me
R3
Ph
dr
Yield (%)c
2
3
3
2.5
2
2
1
2
2a
2b
2c
2d
2e
2f
>99:1
>99:1
>99:1
93:7
96:4
93:7
99:1
99:1
99:1
98:2
83:17
>99:1
99:1
>99:1
98:2
96:4
99:1
98:2
>99:1
99:1
99:1
95
96
93
94d
96d
94d
97
98
95
93
76
96
98
97
95
95d
97
94
96
81
79
4
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Ph
Ph
5e
6
1.5
0.5
24
48
3
i-Pr
Me
Et
0
4
2-thienyl
2-thienyl
2-thienyl
a Reaction conditions: PhCHO (1.5 equiv), CH2Cl2.
5
b [Ti] = TiCl2(Oi-Pr)2.
c Conversion determined by 1H NMR analysis of the crude reaction mixture.
d Yield given in parentheses.
6
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
e PhCHO (1.2 equiv) used.
7
2g
2h
2i
p-NO2C6H4
m-MeOC6H4
m-FC6H4
2-furyl
8
9
The scope of the reaction was next investigated (Table
2). To determine the influence of the OR2 group of the imi-
date on the diastereoselectivity of the reaction, the reactivi-
ties of methyl, ethyl, and isopropyl imidates (1a, 1b, and 1c,
respectively) were compared. Reaction with benzaldehyde
was highly selective, in all cases yielding a single diastereo-
isomer in excellent yield (entries 1–3). The reactions utiliz-
ing 2-thiophenecarboxaldehyde were slightly less selective
and indicated that there was no significant difference in the
diastereoselectivity observed for the three imidates (entries
4–6). This suggests that the steric bulk of the OR2 group is
not a determining factor in the stereochemical outcome of
the reaction. Variation of the other substituent on the imi-
date (R1) was successfully tolerated, and reactions with imi-
dates 1d (R1 = p-MeOC6H4) and 1e (R1 = p-FC6H4) proceeded
with diastereoselectivities and efficiencies comparable to
the reactions with imidate 1a (R1 = Ph), to give similar
yields of the desired products 2 (entries 13–19). The chlo-
roalkyl-substituted imidate 1f (R1 = Cl) also reacted with
10
11
12
13
14
15
16
17
18
19
20
21
2j
2k
2l
PhCH=CH
t-Bu
2m
2n
2o
2p
2q
2r
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-FC6H4
p-FC6H4
p-FC6H4
Cl
Ph
o-MeC6H4
p-BrC6H4
1-naphthyl
Ph
m-MeOC6H4
t-Bu
2s
2t
Ph
2u
Cl
m-FC6H
4
a Reaction conditions: 1 (1 equiv), R3CHO (1.5 equiv), Et3N (3 equiv), CH2Cl2,
TiCl2(Oi-Pr)2 (2 equiv), r.t., 1–2 h.
b Only the major diastereoisomer is depicted.
c Yield of a single isolated diastereoisomer (>99:1).
d Yield of the mixture of diastereoisomers.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 3413–3419

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H. E. Bartrum et al.
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Synthesis
high diastereoselectivity was observed (entries 9, 15 and
21). Heterocyclic aldehydes were compatible with the reac-
tion conditions, as were α,β-unsaturated aldehydes and
naphthaldehyde (entries 4–6, 10, 11, and 16). The aldoliza-
tion was also successful when using pivaldehyde, which
gave the corresponding product in excellent yield and ex-
cellent diastereoselectivity (entries 12 and 19), but not
with enolizable aldehydes.
The relative anti configuration of the major diastereo-
isomer was secured by X-ray crystallographic analysis of
crystalline 2a.10 This anti configuration is in agreement
with previous reports on α-functionalization of sulfonylim-
idates.3a,4 This structure also confirmed the E geometry of
the N-tosylimidates that we previously observed in the N-
sulfinylimidate series.5 A rationalization of this stereo-
chemical outcome is that the deprotonation of the N-sulfo-
nylimidate occurs selectively to form the preferred E-eno-
late (with the bulky N–Ts group and the R1 group on oppo-
site sides of the C–C bond).3a Due to the steric repulsions
between the R3 group of the aldehyde and both the R1 and
the OR2 group of the imidate in transition state B, it is en-
visaged that the reaction occurs via transition state A to
give the anti product (Scheme 2). In analogy to work con-
ducted with the N-sulfinylimidate,5 it is likely that titanium
plays an important role not only in templating the reaction,
but also in remaining coordinated to the final product, thus
preventing the retro-aldolization.
obtained by filtration through activated alumina. A 1 M solution of
TiCl2(Oi-Pr)2 in anhydrous CH2Cl2 was made directly prior to use
(from freshly distilled TiCl4 and Ti(Oi-Pr)4).11 Et3N was distilled from
CaH2 and stored over KOH. All aldehydes were distilled before use.
TLC was performed on (0.2 mm) silica gel aluminum backed plates,
which were visualized by exposure to UV light followed by staining
with basic KMnO4 solution. Silica gel (0.040–0.063 mm) was em-
ployed for flash column chromatography. Melting points are uncor-
rected. An FT-IR spectrometer was used to record IR spectra. NMR
spectra were recorded at 298 K, at the frequency stated; samples were
prepared as dilute solutions in CDCl3. Chemical shifts are expressed in
ppm; the solvent residual peaks are used as the internal standard
(CDCl3: δH = 7.26, δC = 77.16). Assignments of 13C NMR spectra were
made with the aid of DEPT experiments. Mass spectra were recorded
by using ESI techniques. HRMS was carried out on an Orbitrap appa-
ratus (ESI).
3-Hydroxy-N-tosylimidates 2 by Aldol Reaction of N-Tosylimidates
1; General Procedure
Et3N (49 μL, 0.354 mmol, 3 equiv) was added dropwise to a stirred
solution of one of the N-sulfonylimidates 1a–f (0.118 mmol, 1 equiv)
in CH2Cl2 (1.5 mL) under argon at r.t. A preformed solution of alde-
hyde R3CHO (0.177 mmol, 1.5 equiv) and TiCl2(Oi-Pr)2 (0.236 mL,
0.236 mmol, 2 equiv, 1 M solution in CH2Cl2) was then added drop-
wise via a cannula or syringe over approximately 10 min, and the re-
sulting solution was stirred at r.t. until TLC analysis indicated the ab-
sence of starting material (typically 1–2 h). The reaction mixture was
poured into a mixture of ice and sat. aq NaCl and the organic layer
was separated. The aqueous layer was extracted (3 × CH2Cl2) and the
combined organic extracts were dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The crude product was purified by
column chromatography to give the corresponding pure β-hydroxy-
imidate 2a–u.
Tol
S
Tol
S
Ti
Ti
O
O
N
H
N
O
O
O
O
Methyl 3-Hydroxy-2,3-diphenyl-N-tosylpropanimidate (2a)
H
H
H
OMe
OMe
Yield: 46 mg (95%); colorless solid; mp 185–186 °C; Rf = 0.3 (EtOAc–
pentane, 3:7).
R3
R3
R1
R1
IR (neat): 3478, 3029, 3010, 2955, 2928, 1611, 1596, 1492, 1451,
A, favored
B, disfavored
1438, 1284, 1248, 1161, 1146, 1086, 1042, 1018 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.4 Hz, 2 H), 7.31–7.17 (m,
12 H), 5.35 (d, J = 10.4 Hz, 1 H), 5.23 (d, J = 10.4 Hz, 1 H), 3.86 (s, 3 H),
3.07 (br s, 1 H), 2.43 (s, 3 H).
Ts
Ts
13C NMR (100 MHz, CDCl3): δ = 174.9 (C=N), 143.5 (C), 141.3 (C), 139.1
(C), 134.2 (C), 129.7 (CH), 129.5 (CH), 128.6 (CH), 128.5 (CH), 128.3
(CH), 128.1 (CH), 127.0 (CH), 126.8 (CH), 76.9 (CH), 58.4 (CH), 56.2
(CH3), 21.7 (CH3).
OH
N
OH
N
R3
OMe
R3
OMe
R1
R1
anti-product
syn-product
ESI-MS: m/z = 409.9 [M + H]+
Scheme 2 Stereochemical rationalization
ESI-HRMS: m/z [M + H]+ calcd for C23H24NO4S: 410.1420; found:
410.1420; m/z [M + Na]+ calcd for C23H22NNaO4S: 432.1240; found:
432.1240.
In summary, we have successfully developed a mild and
efficient method for the previously unreported and chal-
lenging aldolization of N-sulfonylimidates. The reaction
was found to be highly efficient and in most cases proceed-
ed with high levels of stereocontrol to give diastereomeri-
cally pure products.
Ethyl 3-Hydroxy-2,3-diphenyl-N-tosylpropanimidate (2b)
Yield: 48 mg (96%); colorless needles; mp 156–157 °C; Rf = 0.3
(EtOAc–pentane, 3:7).
IR (neat): 3501, 3067, 2996, 2939, 1610, 1594, 1572, 1312, 1278,
1248, 1143, 1090, 1020 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.4 Hz, 2 H), 7.22–7.09 (m,
12 H), 5.24 (d, J = 10.2 Hz, 1 H), 5.13 (d, J = 10.2 Hz, 1 H), 4.27–4.10 (m,
2 H), 3.08 (br s, 1 H), 2.34 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H).
Reactions were carried out under argon in glassware flame-dried un-
der vacuum. Standard inert atmosphere techniques were used in han-
dling all air- and moisture-sensitive reagents. Anhydrous CH2Cl2 was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 3413–3419

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H. E. Bartrum et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 174.3 (C=N), 143.4 (C), 141.4 (C), 139.2
(C), 134.4 (C), 129.7 (CH), 129.5 (CH), 128.5 (CH), 128.4 (CH), 128.2
(CH), 127.9 (CH), 126.8 (CH), 126.7 (CH), 77.0 (CH), 65.4 (CH2), 58.5
(CH), 21.7 (CH3), 13.7 (CH3).
13C NMR (100 MHz, CDCl3): δ = 173.6 (C=N), 145.2 (C), 143.5 (C), 139.1
(C), 134.4 (C), 129.5 (CH), 128.7 (CH), 128.2 (CH), 126.9 (CH), 126.8
(CH), 125.2 (CH), 125.1 (CH), 72.2 (CH), 65.4 (CH2), 58.5 (CH), 21.7
(CH3), 13.6 (CH3).
ESI-MS: m/z = 446.2 [M + Na]+.
ESI-MS: m/z = 452.2 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C24H26NO4S: 424.1577; found:
424.1576; m/z [M + Na]+ calcd for C24H25NNaO4S: 446.1396; found:
446.1395.
ESI-HRMS: m/z [M + H]+ calcd for C22H24NO4S2: 430.1141; found:
430.1140; m/z [M + Na]+ calcd for C22H23NNaO4S2: 452.0960; found:
452.0961.
Isopropyl 3-Hydroxy-2,3-diphenyl-N-tosylpropanimidate (2c)
Isopropyl 3-Hydroxy-2-phenyl-3-(2-thienyl)-N-tosylpropan-
imidate (2f)
Yield: 48 mg (93%); colorless needles; mp 113–114 °C; Rf = 0.2 (EtO-
Ac–pentane, 2:8)
Yield: 49 mg (94%); isolated as a 93:7 mixture of diastereoisomers;
colorless needles; Rf = 0.2 (EtOAc–pentane, 2:8).
IR (neat): 3482, 3031, 2989, 2911, 1589, 1497, 1454, 1295, 1282,
1149, 1090, 1051, 1037 cm–1
.
IR (neat): 3471, 3067, 3027, 2953, 2928, 1615, 1597, 1508, 1442,
1285, 1248, 1226, 1147, 1089, 1019 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.0 Hz, 2 H), 7.30–7.24 (m, 4
H), 7.23–7.16 (m, 8 H), 5.30 (d, J = 10.4 Hz, 1 H), 5.19 (d, J = 10.4 Hz, 1
H), 5.16–5.10 (m, 1 H), 3.10 (br s, 1 H), 2.42 (s, 3 H), 1.39 (d, J = 6.0 Hz,
3 H), 1.24 (d, J = 6.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.7 (C=N), 143.3 (C), 141.5 (C), 139.4
(C), 134.5 (C), 129.6 (CH), 129.5 (CH), 128.4 (CH), 128.1 (CH), 127.8
(CH), 126.7 (CH), 77.0 (CH), 73.2 (CH), 58.5 (CH3), 21.6 (CH3), 21.3
(CH3), 21.2 (CH3).
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.0 Hz, 2 H), 7.30–7.27 (m, 2
H), 7.22–7.12 (m, 5 H), 7.06–7.04 (m, 1 H), 6.74–6.70 (m, 2 H), 5.39 (d,
J = 10.2 Hz, 1 H), 5.26 (d, J = 10.2 Hz, 1 H), 5.02 (app pent., J = 6.2 Hz, 1
H), 3.00 (br s, 1 H), 2.34 (s, 3 H), 1.26 (d, J = 6.2 Hz, 3 H), 1.20 (d, J = 6.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.0 (C=N), 145.3 (C), 143.3 (C), 139.3
(C), 134.5 (C), 129.6 (CH), 129.5 (CH), 128.6 (CH), 128.1 (CH), 126.8
(CH), 126.7 (CH), 125.1 (CH), 125.0 (CH), 73.2 (CH), 72.2 (CH), 58.5
(CH), 21.6 (CH3), 21.2 (CH3), 21.1 (CH3).
ESI-MS: m/z = 437.9 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C25H28NO4S: 438.1733; found:
438.1735; m/z [M + Na]+ calcd for C25H27NNaO4S: 460.1553; found:
460.1555.
ESI-MS: m/z = 443.8 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C23H26NO4S2: 444.1297; found:
444.1294; m/z [M + Na]+ calcd for C23H25NNaO4S2: 466.1117; found:
466.1116.
Methyl 3-Hydroxy-2-phenyl-3-(2-thienyl)-N-tosylpropanimidate
(2d)
Methyl 3-Hydroxy-3-(4-nitrophenyl)-2-phenyl-N-tosylpropan-
imidate (2g)
Yield: 46 mg (94%); colorless needles; Rf = 0.2 (EtOAc–pentane, 3:7).
IR (neat): 3497, 3452, 2954, 2923, 1610, 1436, 1284, 1255, 1148,
Yield: 52 mg (97%); colorless needles; mp 184–185 °C; Rf = 0.15
(EtOAc–pentane, 3:7).
1090, 1039, 1016 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.2 Hz, 2 H), 7.56–7.49 (m, 2
H), 7.31–7.20 (m, 5 H), 7.06 (dd, J = 4.4, 1.6 Hz, 1 H), 6.74–6.72 (m, 2
H), 5.44 (d, J = 10.4 Hz, 1 H), 5.31 (d, J = 10.4 Hz, 1 H), 3.75 (s, 3 H),
2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.2 (C=N), 145.0 (C), 143.6 (C), 139.0
(C), 134.2 (C), 129.5 (CH), 128.7 (CH), 128.2 (CH), 127.0 (CH), 126.8
(CH), 125.3 (CH), 125.2 (CH), 72.0 (CH), 58.5 (CH), 56.2 (CH3), 21.7
(CH3).
IR (neat): 3483, 2955, 2918, 1594, 1519, 1496, 1436, 1348, 1310,
1288, 1246, 1188, 1091, 1055, 1018 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.8 Hz, 2 H), 7.76 (d, J = 8.0
Hz, 2 H), 7.29–7.19 (m, 6 H), 7.15–7.14 (m, 3 H), 5.26 (d, J = 10.6 Hz, 1
H), 5.18 (d, J = 10.6 Hz, 1 H), 3.80 (s, 3 H), 3.47 (br s, 1 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.0 (C=N), 148.6 (C), 147.7 (C), 143.8
(C), 138.6 (C), 133.3 (C), 129.7 (CH), 129.6 (CH), 128.9 (CH), 128.6
(CH), 127.7 (CH), 126.9 (CH), 123.6 (CH), 76.0 (CH), 58.5 (CH), 56.4
(CH3), 21.7 (CH3).
ESI-MS: m/z = 437.8 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C21H22NO4S2: 416.0984; found:
416.0983; m/z [M + Na]+ calcd for C21H21NNaO4S2: 438.0804; found:
438.0805.
ESI-MS: m/z =454.8 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C23H23N2O6S: 455.1271; found:
455.1269; m/z [M + Na]+ calcd for C23H22N2NaO6S: 477.1090; found:
477.1089.
Ethyl 3-Hydroxy-2-phenyl-3-(2-thienyl)-N-tosylpropanimidate
(2e)
Methyl 3-Hydroxy-3-(3-methoxyphenyl)-2-phenyl-N-tosylpropan-
imidate (2h)
Yield: 48 mg (96%); isolated as a 96:4 mixture of diastereoisomers;
colorless needles; Rf = 0.4 (EtOAc–pentane, 3:7).
Yield: 51 mg (98%); colorless needles; mp 155–156 °C; Rf = 0.3
(EtOAc–pentane, 3:7).
IR (neat): 3465, 2992, 2953, 2922, 1590, 1285, 1256, 1117, 1090, 1019
cm–1
.
IR (neat): 3470, 3021, 2958, 2904, 1608, 1594, 1493, 1455, 1437,
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, 2 H), 7.31–7.30 (m, 2
H), 7.29–7.16 (m, 5 H), 7.05 (dd, J = 4.4, 1.2 Hz, 1 H), 6.74–6.73 (m, 2
H), 5.43 (d, J = 10.6 Hz, 1 H), 5.28 (d, J = 10.6 Hz, 1 H), 4.26–4.00 (m, 2
H), 2.34 (s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H).
1329, 1285, 1266, 1246, 1148, 1087, 1037, 1016 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 2 H), 7.24–7.22 (m, 4
H), 7.15–7.10 (m, 3 H), 7.05 (t, J = 8.0 Hz, 1 H), 6.76 (d, J = 7.6 Hz, 1 H),
6.68–6.63 (m, 2 H), 5.26 (d, J = 10.4 Hz, 1 H), 5.12 (d, J = 10.4 Hz, 1 H),
3.78 (s, 3 H), 3.62 (s, 3 H), 2.93 (br s, 1 H), 2.35 (s, 3 H).
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13C NMR (100 MHz, CDCl3): δ = 174.9 (C=N), 159.7 (C), 143.5 (C), 142.9
(C), 139.1 (C), 134.3 (C), 129.8 (CH), 129.6 (CH), 129.5 (CH), 128.6
(CH), 128.0 (CH), 126.9 (CH), 119.0 (CH), 114.0 (CH), 112.2 (CH), 76.8
(CH), 58.3 (CH), 56.2 (CH3), 55.3 (CH3), 21.7 (CH3).
13C NMR (100 MHz, CDCl3): δ = 174.6 (C=N), 143.5 (C), 139.0 (C), 136.4
(C), 132.2 (C), 129.6 (CH), 129.5 (CH), 129.1 (CH), 128.9 (CH), 128.6
(CH), 128.2 (CH), 127.9 (CH), 126.9 (CH), 74.3 (CH), 57.6 (CH), 56.1
(CH3), 21.6 (CH3).
ESI-MS: m/z = 439.9 [M + H]+.
ESI-MS: m/z = 458.3 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C24H26NO5S: 440.1526; found:
440.1527; m/z [M + Na]+ calcd for C24H25NNaO5S: 462.1345; found:
462.1347.
ESI-HRMS: m/z [M + H]+ calcd for C25H26NO4S: 436.1577; found:
436.1574; m/z [M + Na]+ calcd for C25H25NNaO4S: 458.1396; found:
458.1395.
Methyl 3-(3-Fluorophenyl)-3-hydroxy-2-phenyl-N-tosylpropan-
Methyl 3-Hydroxy-4,4-dimethyl-2-phenyl-N-tosylpentanimidate
imidate (2i)
(2l)
Yield: 48 mg (95%); colorless needles; mp 180–181 °C; Rf = 0.3
Yield: 44 mg (96%); colorless needles; mp 121–122 °C; Rf = 0.4
(EtOAc–pentane, 3:7)
(EtOAc–pentane, 3:7).
IR (neat): 3467, 2953, 2927, 1595, 1490, 1451, 1438, 1284, 1267,
IR (neat): 3512, 2973, 2955, 2911, 2867, 1609, 1583, 1444, 1362,
1256, 1148, 1118, 1045, 1019 cm–1
.
1344, 1297, 1285, 1255, 1147, 1092, 1009 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.0 Hz, 2 H), 7.23–7.18 (m, 4
H), 7.15–7.05 (m, 4 H), 6.91–6.80 (m, 2 H), 6.79–6.76 (m, 1 H), 5.21 (d,
J = 10.4 Hz, 1 H), 5.13 (d, J = 10.4 Hz, 1 H), 3.77 (s, 3 H), 3.07 (br s, 1 H),
2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.5 (C=N), 164.0 (C), 150.2 (C, d, J =
226), 144.0 (C, d, J = 7), 143.6 (C), 133.8 (C), 130.0 (CH, d, J = 8), 129.7
(CH), 129.5 (CH), 128.7 (CH), 128.2 (CH), 126.9 (CH), 122.4 (CH, d, J =
3), 115.1 (CH, d, J = 21), 113.8 (CH, d, J = 21.8), 76.2 (CH, d, J = 2), 58.3
(CH), 56.2 (CH3), 21.7 (CH3)
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.2 Hz, 2 H), 7.39 (d, J = 8.2
Hz, 2 H), 7.23–7.18 (m, 5 H), 5.11 (d, J = 10.0 Hz, 1 H), 3.96 (br d, J =
10.0 Hz, 1 H), 3.65 (s, 3 H), 2.73 (br s, 1 H), 2.35 (s, 3 H), 0.74 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 176.0 (C=N), 143.4 (C), 139.2 (C), 136.2
(C), 130.0 (CH), 129.5 (CH), 128.6 (CH), 128.0 (CH), 126.8 (CH), 80.4
(CH), 56.0 (CH), 54.7 (CH3), 36.8 (C), 26.8 (CH3), 21.7 (CH3).
ESI-MS: m/z = 390.0 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C21H28NO4S: 390.1733; found:
390.1736; m/z [M + Na]+ calcd for C21H27NNaO4S: 412.1553; found:
412.1556.
19F NMR (377 MHz, CDCl3): δ = –112.7.
ESI-MS: m/z = 427.9 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C23H23FNO4S: 428.1326; found:
428.1328; m/z [M + Na]+ calcd for C23H22FNNaO4S: 450.1145; found:
450.1149.
Methyl 3-Hydroxy-2-(4-methoxyphenyl)-3-phenyl-N-tosylpropan-
imidate (2m)
Yield: 51 mg (98%); colorless needles; mp 134–135 °C; Rf = 0.3
(EtOAc–pentane, 3:7).
Methyl 3-(2-Furyl)-3-hydroxy-2-phenyl-N-tosylpropanimidate
(2j)
IR (neat): 3540, 3068, 3028, 3006, 2952, 1581, 1514, 1443, 1260,
1251, 1171, 1091, 1046 cm–1
.
Yield: 44 mg (93%); colorless needles; mp 189–190 °C; Rf = 0.3
(EtOAc–pentane, 3:7).
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 8.4
Hz, 2 H), 7.26–7.18 (m, 7 H), 6.72 (d, J = 8.4 Hz, 2 H), 5.29 (d, J = 10.6
Hz, 1 H), 5.18 (d, J = 10.6 Hz, 1 H), 3.85 (s, 3 H), 3.72 (s, 3 H), 2.95 (br s,
1 H), 2.43 (s, 3 H).
IR (neat): 3472, 3033, 2953, 2932, 1610, 1595, 1496, 1439, 1310,
1283, 1254, 1149, 1139, 1087, 1017 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.0 Hz, 2 H), 7.30–7.13 (m, 8
H), 6.09 (dd, J = 3.2, 2.0 Hz, 1 H), 6.01 (d, J = 3.2 Hz, 1 H), 5.49 (d, J =
11.0 Hz, 1 H), 5.21 (d, J = 11.0 Hz, 1 H), 3.75 (3 H, s), 2.84 (1 H, br s),
2.35 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 175.3 (C=N), 159.3 (C), 143.5 (C), 141.5
(C), 139.2 (C), 130.8 (CH), 129.5 (CH), 128.6 (CH), 128.2 (CH), 126.9
(CH), 126.8 (CH), 126.2 (C), 114.0 (CH), 76.9 (CH), 57.6 (CH), 56.1
(CH3), 55.3 (CH3), 21.7 (CH3).
13C NMR (100 MHz, CDCl3): δ = 174.2 (C=N), 153.2 (C), 143.6 (C), 142.6
(CH), 139.0 (C), 134.1 (C), 129.5 (CH), 129.3 (CH), 128.7 (CH), 128.1
(CH), 127.0 (CH), 110.3 (CH), 108.3 (CH), 69.6 (CH), 56.2 (CH), 55.7
(CH3), 21.7 (CH3).
ESI-MS: m/z = 439.9 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C24H26NO5S: 440.1526; found:
440.1525; m/z [M + Na]+ calcd for C24H25NNaO5S: 462.1345; found:
462.1346.
ESI-MS: m/z = 421.8 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C21H22NO5S: 400.1213; found:
400.1213; m/z [M + Na]+ calcd for C21H21NNaO5S: 422.1032; found:
422.1033.
Methyl 3-Hydroxy-2-(4-methoxyphenyl)-3-(2-tolyl)-N-tosylpropan-
imidate (2n)
Yield: 52 mg (97%); colorless needles; mp 172–173 °C; Rf = 0.3
(EtOAc–pentane, 3:7).
Methyl 3-Hydroxy-2,5-diphenyl-N-tosylpent-4-enimidate (2k)
Yield: 38 mg (76%); pale yellow oil; Rf = 0.4 (EtOAc–pentane, 3:7).
IR (neat): 3487, 3059, 3029, 2951, 1593, 1495, 1440, 1288, 1265,
IR (neat): 3483, 3022, 2949, 2832, 1604, 1511, 1442, 1308, 1296,
1287, 1258, 1244, 1150, 1118 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 7.6
Hz, 1 H), 7.30–7.26 (m, 2 H), 7.23–7.18 (m, 3 H), 7.10 (td, J = 7.6, 1.2
Hz, 1 H), 6.97 (d, J = 7.6 Hz, 1 H), 6.69 (dd, J = 6.4, 2.0 Hz, 2 H), 5.49 (d,
J = 10.4 Hz, 1 H), 5.44 (d, J = 10.4 Hz, 1 H), 3.89 (s, 3 H), 3.71 (s, 3 H),
2.42 (s, 3 H), 2.15 (s, 3 H).
1150, 1090, 1017 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, 2 H), 7.38–7.36 (m, 2
H), 7.25–7.10 (m, 10 H), 6.49 (dd, J = 16.0, 0.4 Hz, 1 H), 5.98 (dd, J =
16.0, 6.0 Hz, 1 H), 5.00 (d, J = 10.0 Hz, 1 H), 4.87–4.83 (m, 1 H), 3.72 (s,
3 H), 2.84 (br s, 1 H), 2.33 (s, 3 H).
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13C NMR (100 MHz, CDCl3): δ = 175.3 (C=N), 159.3 (C), 143.4 (C), 139.5
(C), 139.2 (C), 136.1 (C), 130.6 (CH), 130.5 (CH), 129.5 (CH), 128.1
(CH), 126.9 (CH), 126.8 (CH), 126.0 (CH), 113.9 (CH), 72.3 (CH), 56.9
(CH), 56.1 (CH3), 55.2 (CH3), 21.7 (CH3), 19.4 (CH3).
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 2 H), 7.23–7.11 (m, 9
H), 6.80 (t, J = 8.4 Hz, 2 H), 5.26 (d, J = 10.4 Hz, 1 H), 5.09 (d, J = 10.4
Hz, 1 H), 3.78 (s, 3 H), 2.99 (br s, 1 H), 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.6 (C=N), 161.2 (C), 152.3 (C, d, J =
247), 143.6 (C), 141.1 (C), 131.3 (CH, d, J = 8), 130.0 (C, d, J = 3), 129.5
(CH), 128.6 (CH), 128.4 (CH), 126.9 (CH), 126.8 (CH), 115.5 (CH, d, J =
21), 76.9 (CH), 57.6 (CH), 56.2 (CH3), 21.7 (CH3).
ESI-MS: m/z = 453.8 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C25H28NO5S: 454.1682; found:
454.1682; m/z [M + Na]+ calcd for C25H27NNaO5S: 476.1502; found:
476.1503.
19F NMR (377 MHz, CDCl3): δ = –114.1.
ESI-MS: m/z = 427.8 [M + Na]+.
Methyl 3-(4-Bromophenyl)-3-hydroxy-2-(4-methoxyphenyl)-N-
tosylpropanimidate (2o)
ESI-HRMS: m/z [M + H]+ calcd for C23H23FNO4S: 428.1326; found:
428.1326; m/z [M + Na]+ calcd for C23H22FNNaO4S: 450.1145; found:
450.1146.
Yield: 58 mg (95%); colorless needles; mp 158–159 °C; Rf = 0.3
(EtOAc–pentane, 3:7).
IR (neat): 3518, 2990, 2951, 1595, 1511, 1325, 1299, 1287, 1259,
Methyl 2-(4-Fluorophenyl)-3-hydroxy-3-(3-methoxyphenyl)-N-to-
sylpropanimidate (2r)
1248, 1148, 1074, 1048, 1030, 1011 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.4 Hz, 2 H), 7.34–7.31 (m, 4
H), 7.19 (d, J = 8.8 Hz, 2 H), 7.09 (d, J = 8.4 Hz, 2 H), 6.73 (d, J = 8.8 Hz,
2 H), 6.70 (d, J = 10.8 Hz, 1 H), 5.14 (d, J = 10.8 Hz, 1 H), 3.84 (s, 3 H),
3.73 (s, 3 H), 3.10 (br s, 1 H), 2.43 (s, 3 H).
Yield: 51 mg (94%); colorless needles; mp 131–132 °C; Rf = 0.2
(EtOAc–pentane, 2:8).
IR (neat): 3484, 3012, 2955, 2897, 1609, 1597, 1507, 1494, 1439,
1321, 1286, 1267, 1247, 1222, 1153, 1118, 1090, 1053, 1017 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 174.9 (C=N), 159.4 (C), 143.6 (C), 140.6
(C), 139.0 (C), 131.6 (CH), 130.9 (CH), 129.5 (CH), 128.5 (CH), 126.9
(CH), 125.8 (C), 122.1 (C), 114.1 (CH), 76.2 (CH), 57.6 (CH), 56.2 (CH3),
55.3 (CH3), 21.7 (CH3).
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.0 Hz, 2 H), 7.31–7.15 (m, 4
H), 7.13 (t, J = 8.0 Hz, 1 H), 6.90 (t, J = 8.6 Hz, 2 H), 6.81–9.72 (m, 3 H),
5.32 (d, J = 10.4 Hz, 1 H), 5.14 (d, J = 10.4 Hz, 1 H), 3.85 (s, 3 H), 3.71 (s,
3 H), 2.94 (br s, 1 H), 2.42 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.5 (C=N), 161.2 (C), 159.7 (C), 151.3
(C, d, J = 247), 143.6 (C), 142.7 (C), 131.3 (CH, d, J = 8), 130.0 (C, d, J =
3), 129.7 (CH), 129.5 (CH), 126.9 (CH), 119.0 (CH), 115.5 (CH, d, J =
21), 114.0 (CH), 112.3 (CH), 76.8 (CH), 57.5 (CH), 56.2 (CH3), 55.3
(CH3), 21.7 (CH3).
ESI-MS: m/z = 517.8 and 519.8 (1:1) [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C24H25BrNO5S: 518.0631; found:
518.0626; m/z [M + Na]+ calcd for C24H24BrNNaO5S: 540.0450; found:
540.0448.
19F NMR (377 MHz, CDCl3): δ = –114.1.
ESI-MS: m/z = 480.2 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C24H25FNO5S: 458.1431; found:
458.1430; m/z [M + Na]+ calcd for C24H24FNNaO5S: 480.1251; found:
480.1251.
Methyl 3-Hydroxy-2-(4-methoxyphenyl)-3-(1-naphthyl)-N-tosyl-
propanimidate (2p)
Yield: 55 mg (95%); isolated as a 96:4 mixture of diastereoisomers;
colorless needles; Rf = 0.4 (EtOAc–pentane, 3:7).
IR (neat): 3527, 3036, 2949, 2835, 1591, 1511, 1438, 1287, 1251,
1183, 1154, 1091, 1031, 1021 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4
Hz, 2 H), 7.79 (d, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.56–7.51 (m,
2 H), 7.50–7.43 (m, 1 H), 7.38–7.34 (m, 1 H), 7.30–7.26 (m, 2 H), 7.23–
7.19 (m, 2 H), 6.69 (d, J = 8.4 Hz, 2 H), 6.05 (d, J = 10.6 Hz, 1 H), 5.83 (d,
J = 10.6 Hz, 1 H), 3.91 (s, 3 H), 3.64 (s, 3 H), 2.43 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.2 (C=N), 159.1 (C), 143.4 (C), 139.2
(C), 136.5 (C), 134.0 (C), 131.5 (C), 130.4 (CH), 129.5 (CH), 129.1 (CH),
128.9 (CH), 126.9 (CH), 126.4 (CH), 126.3 (C), 125.8 (CH), 125.4 (CH),
124.8 (CH), 123.7 (CH), 114.0 (CH), 72.7 (CH), 56.2 (CH), 55.8 (CH3),
55.2 (CH3), 21.7 (CH3).
Methyl 2-(4-Fluorophenyl)-3-hydroxy-4,4-dimethyl-N-tosylpen-
tanimidate (2s)
Yield: 46 mg (96%); colorless needles; mp 116–117 °C; Rf = 0.4
(EtOAc–pentane, 3:7).
IR (neat): 3499, 2956, 2905, 2869, 1610, 1505, 1444, 1296, 1223,
1090, 1036, 1013 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.4 Hz, 2 H), 7.46–7.43 (m, 2
H), 7.30 (d, J = 8.0 Hz, 2 H), 7.01–6.97 (m, 2 H), 5.19 (d, J = 10.8 Hz, 1
H), 3.98 (t, J = 10.8 Hz, 1 H), 3.73 (s, 3 H), 2.761 (d, J = 10.8 Hz, 1 H),
2.43 (s, 3 H), 0.82 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 175.7 (C=N), 163.8 (C), 150.2 (C, d, J =
223), 143.6 (C), 132.0 (C, d, J = 4), 131.5 (CH, d, J = 8), 129.5 (CH), 126.8
(CH), 115.6 (CH, d, J = 21), 80.5 (CH), 56.1 (CH3), 53.8 (CH), 36.8 (C),
26.8 (CH3), 21.7 (CH3).
ESI-MS: m/z = 511.9 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C28H28NO5S: 490.1682; found:
490.1680; m/z [M + Na]+ calcd for C28H27NNaO5S: 512.1502; found:
512.1501.
19F NMR (377 MHz, CDCl3): δ = –114.2.
ESI-MS: m/z = 407.9 [M + H]+.
Methyl 2-(4-Fluorophenyl)-3-hydroxy-3-phenyl-N-tosylpropan-
imidate (2q)
ESI-HRMS: m/z [M + H]+ calcd for C21H27FNO4S: 408.1639; found:
408.1643; m/z [M + Na]+ calcd for C21H26FNNaO4S: 430.1458; found:
430.1461.
Yield: 49 mg (97%); colorless needles; mp 148–149 °C; Rf = 0.3
(EtOAc–pentane, 3:7).
IR (neat): 3470, 3027, 2953, 2927, 1615, 1598, 1508, 1495, 1455,
1442, 1284, 1248, 1225, 1147, 1088, 1019 cm–1
.
Methyl 2-Chloro-3-hydroxy-3-phenyl-N-tosylpropanimidate (2t)
Yield: 35 mg (81%); colorless needles; mp 153–154 °C; Rf = 0.2
(EtOAc–pentane, 2:8).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 3413–3419

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IR (neat): 3427, 3033, 2952, 2913, 1610, 1434, 1302, 1289, 1245,
1145, 1084, 1040, 1014 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.4 Hz, 2 H), 7.50–7.32 (m, 7
H), 5.82 (d, J = 8.6 Hz, 1 H), 4.90 (t, J = 8.6 Hz, 1 H), 3.89 (s, 3 H), 3.08
(d, J = 8.6 Hz, 1 H), 2.44 (s, 3 H).
Supporting Information
.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562785.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
13C NMR (100 MHz, CDCl3): δ = 169.8 (C=N), 144.1 (C), 139.3 (C), 138.2
(C), 129.7 (CH), 129.3 (CH), 129.0 (CH), 127.2 (CH), 127.1 (CH), 76.6
(CH), 56.6 (CH), 56.5 (CH3), 21.7 (CH3).
References
(1) Bundgaard, H.; Larsen, J. D. J. Med. Chem. 1988, 31, 2066.
(2) (a) Griffiths, G. J.; Hauck, M. B.; Imwinkelried, R.; Kohr, J.; Roten,
C. A.; Stucky, G. C. J. Org. Chem. 1999, 64, 8084. (b) Connolly, D.
J.; Lacey, P. M.; McCarthy, M.; Saunders, C. P.; Carroll, A. M.;
Goddard, R.; Guiry, P. J. J. Org. Chem. 2004, 69, 6572. (c) Iso, Y.;
Kozikowski, A. P. Synthesis 2006, 243. (d) Smith, T. E.; Kuo, W.
H.; Balskus, E. P.; Bock, V. D.; Roizen, J. L.; Theberge, A. B.;
Carroll, K. A.; Kurihara, T.; Wessler, J. D. J. Org. Chem. 2008, 73,
142. (e) Cannon, J. S.; Olson, A. C.; Overman, L. A.; Solomon, N. S.
J. Org. Chem. 2012, 77, 1961.
ESI-MS: m/z = 390.2 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C17H19ClNO4S: 368.0717; found:
368.0719; m/z [M + Na]+ calcd for C17H18ClNNaO4S: 390.0537; found:
390.0540.
Methyl 2-Chloro-3-(3-fluorophenyl)-3-hydroxy-N-tosylpropan-
imidate (2u)
Yield: 36 mg (79%); colorless needles; mp 141–142 °C; Rf = 0.2
(3) (a) Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 1804. (b) Matsubara, R.; Kobayashi, S. Synthesis 2008,
3009. (c) Matsubara, R.; Berthiol, F.; Nguyen, H. V.; Kobayashi, S.
Bull. Chem. Soc. Jpn. 2009, 82, 1083. (d) Nguyen, H. V.;
Matsubara, R.; Kobayashi, S. Angew. Chem. Int. Ed. 2009, 48,
5927. (e) Nakano, J.; Masuda, K.; Yamashita, Y.; Kobayashi, S.
Angew. Chem. Int. Ed. 2012, 51, 9525.
(4) Massa, A.; Utsumi, N.; Barbas, C. F. Tetrahedron Lett. 2009, 50,
145.
(5) Bartrum, H. E.; Viceriat, A.; Carret, S.; Poisson, J.-F. Org. Lett.
2014, 16, 1972.
(EtOAc–pentane, 2:8).
IR (neat): 3421, 2952, 1613, 1596, 1456, 1433, 1304, 1291, 1268,
1241, 1147, 1085, 1041, 1015 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.0 Hz, 2 H), 7.43–7.28 (m, 4
H), 7.23–7.20 (m, 1 H), 7.11–7.07 (m, 1 H), 5.78 (d, J = 9.6 Hz, 1 H),
4.92 (d, J = 9.6 Hz, 1 H), 3.90 (s, 3 H), 3.28 (br s, 1 H), 2.47 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.4 (C=N), 164.2 (C), 149.9 (C, d, J =
237), 144.2 (C), 141.8 (C, d, J = 7), 130.5 (CH, d, J = 8), 129.7 (CH), 127.1
(CH), 122.8 (CH, d, J = 3), 116.2 (CH, d, J = 21), 114.4 (CH, d, J = 22),
76.0 (CH, d, J = 2), 56.7 (CH), 56.4 (CH3), 21.7 (CH3).
19F NMR (377 MHz, CDCl3): δ = –112.0.
ESI-MS: m/z = 408.2 [M + Na]+.
ESI-HRMS: m/z [M + H]+ calcd for C17H18ClFNO4S: 386.0623; found:
386.0628; m/z [M + Na]+ calcd for C17H17ClFNNaO4S: 408.0443; found:
408.0446.
(6) (a) McElvain, S. M.; Stevens, C. L. J. Am. Chem. Soc. 1946, 68,
1917. (b) Yadav, V. K.; Babu, K. G. Eur. J. Org. Chem. 2005, 452.
(7) McElvain, S. M.; Venerable, J. T. J. Am. Chem. Soc. 1950, 72, 1661.
(8) Reaction of 1a under analogous conditions to those utilized by
Kobayashi for the Mannich-type reaction3 resulted in complete
recovery of the starting material.
(9) Treatment of product 2a with triethylamine in dichlorometh-
ane at room temperature resulted in complete retro-aldoliza-
tion yielding the starting material N-sulfonylimidate 1a and
benzaldehyde.
(10) CCDC 1481884 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
Acknowledgment
We thank the ANR (project Lycomet ANR-11-JS-07-006-01) for finan-
cial support. H. E. B. acknowledges the Marie Curie program for a
postdoctoral fellowship (project Metalk - 301130). We also acknowl-
edge support from ICMG FR 2607, Grenoble, through which NMR and
MS analyses have been performed, and Dr. Christian Philouze (DCM,
Grenoble) for X-ray measurements.
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures. The ORTEP representation
is included in the Supporting Information.
(11) This procedure is adapted from: Reetz, M. T.; Westermann, J.;
Steinbach, R.; Wenderoth, B.; Peter, R.; Ostarek, R.; Maus, S.
Chem. Ber. 1985, 118, 1421.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 3413–3419