Organic Letters
Letter
proceeds efficiently with naphthyl-substituted sulfenamide 1j,
giving sulfinimidate ester 3q in 89% isolated yield, and with
aliphatic sulfenamide 1j, leading to derivatives 3r and 3s in
good yields (Scheme 3). It should be noted that the reaction
proceeds with piperidine-, pyrrolidine-, and morpholine-
substituted sulfenamides, and several primary and secondary
alcohols can proceed toward the formation of the correspond-
ing sulfinimidate esters. The structures of these unusual sulfur
derivatives were assigned on the basis of NMR and HMRS
analysis, and in the case of 3j the structure was confirmed by
X-ray analysis. Interestingly, the crystal structure of sulfinimi-
date ester 3j revealed an almost pyramidal sulfur atom, with
bond angles in the range 99°−111° and bond lengths of 1.78 Å
temperature up to 60 °C resulted in decomposition of the
reactants (Table 1, entry 2). Assuming that a base would have
been required in this process, we ran the reaction in the
presence of 1.5 equiv of aqueous K CO3 or DIPEA
2
(diisopropylethylamine). Under these conditions (Table 1,
entries 3−4), 4a was obtained in 35% and 38% yield,
respectively. The yield of 4a improved up to 53%, using 1.2
equiv of 2a at 50 °C in toluene (Table 1, entry 5). Similar
results were obtained for the reaction in CH Cl (Table 1,
2
2
entries 6−9), while complex mixtures were observed in polar
solvents such as 2-MeTHF or MeOH (Table 1, entries 10−
11). With the aim to improve yields of 4a and accelerate the
optimization study, a Design of Experiment (DoE) approach
was applied to this process. The equivalents of 2a and the
temperature were selected as the main variables, since such
factors appeared to be critical for the reaction. Therefore, a full
18
(
C−S), 1.62 Å (S−O), and 1.59 Å (SN) respectively.
However, the reaction must comply with steric requirements,
since the use of tert-amyl alcohol did not allow for the
preparation of the corresponding sulfinimidate ester 3t from
sulfenamide 1a even in traces (Scheme 4). Much to our
2
factorial 2 design (see SI. for details) was selected, and the
reactions were performed in toluene in the presence of 1.5
equiv of DIPEA (Table 2).
Scheme 4. First Evidence for Sulfinamidine
Table 2. DoE Optimization Study for the Preparation of 4a
a
Entry
2a (equiv)
T (°C)
4a yield
surprise, we were able to isolate the benzyl-(phenyl(piperidin-
1
2
3
4
1.6
1.9
1.6
0
0
25
25
45%
53%
73%
95%
4
1
-yl)-λ -sulfanylidene)carbamate 4a in 15% yield. The
structure of 4a was initially assessed based on NMR, IR, and
HRMS analysis.
Encouraged by this preliminary result, we persevered in our
search for an efficient synthetic strategy for the preparation of
sulfinamidines. First, we initiated an optimization study for the
reaction of sulfenamide 1a with 2a as the nitrogen source
1.9
a
1
Yields calculated by H NMR analysis of the crude reaction mixture
in the presence of internal standard.
Remarkably, sulfinamidine 4a could be obtained in 95%
yield carrying out the reaction at 25 °C, and with the use of 1.9
equiv of 2a. With the optimal conditions in hand, the scope of
the reaction was explored (Scheme 5). Sulfenamides 1a−k
were reacted with N-sources 2a and 2b under the optimized
conditions resulting in the formation of the corresponding
sulfinamidines 4a−m in good to excellent yields. The reaction
leading to 4a was scaled to 2 mmol, and the corresponding
sulfinamidine crystallized. With our delight, X-ray analysis
confirmed the structure of 4a and revealed a pyramidal sulfur
atom with angles in the range 99°−111° and bond lengths of
(
Table 1).
Sulfinamidine 4a was obtained in 20% yield when equimolar
quantities of 1a and 2a were stirred in toluene at room
temperature for 2 h (Table 1, entry 1). However, raising the
Table 1. Optimization Study for the Preparation of 4a
1.62 and 1.68 Å for S−N double and single bonds respectively,
19
a
and 1.78 Å for the C−S bond. The reaction tolerated both
electron-withdrawing (i.e., 4d,f, 4g,h) and electron-donating
groups (i.e., 4c, 4i,j) as well as the naphthyl group (4k) and
aliphatic S-substituents (4l,m). However, the transformation of
Entry
Solvent
T (°C)
Base (equiv)
2a (equiv) 4a yield
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
CH Cl2
CH Cl2
CH Cl2
CH Cl2
25
60
25
25
50
0
25
0
25
25
25
−
1.0
1.0
1.0
1.0
1.2
1.0
1.0
1.3
1.3
1.0
1.0
20%
−
−
b
K CO (1.5)
2
35%
38%
53%
21%
35%
29%
43%
−
3
(
(cyclohexyl)thio)morpholine 1j required longer reaction
DIPEA (1.5)
DIPEA (1.5)
times (24 h), affording the products in excellent yields.
Similarly, when 1-((4-nitrophenyl)thio)piperidine 1f was
reacted, the reaction mixture was stirred for 24 h before the
total consumption of sufenamide was observed. Remarkably,
the use of commercially available NH-sulfenamide 1k returned
the corresponding sulfinamidines 4n and 4o in good yields.
However, the preparation of this kind of scaffold would require
b
K CO (1.5)
2 3
2
b
b
b
b
b
K CO (1.5)
2 3
2
K CO (1.5)
2 3
2
K CO (1.5)
2 3
2
1
1
0
1
2-MeTHF
MeOH
K CO (1.5)
2 3
K CO (1.5)
traces
2
3
20
multistep synthesis.
a
1
After assessing the methods for the preparation of either
sulfinimidate esters 3 and sulfinamidines 4, we turned our
attention to the mechanism of the reaction. To this end, we
Yields calculated by H NMR analysis of the crude reaction mixture
b
in the presence of internal standard. An aqueous solution of K CO
was employed.
2
3
C
Org. Lett. XXXX, XXX, XXX−XXX
Andresini, Michael
