Palladium-catalyzed C-N cross coupling of sulfinamides and aryl halides

Article abstract of DOI:10.1021/jo3003584

The palladium-catalyzed C-N cross coupling of sulfinamides and aryl halides is reported. In the presence of Pd₂(dba)₃, tBuXPhos, NaOH, and a small amount of water, the C-N cross coupling of chiral tert-butanesulfinamide and aryl halides was accomplished to give N-aryl tert-butanesulfinamide without racemization, and the coupling of racemic p-toluenesulfinamide smoothly afforded N-aryl p-toluenesulfinamides. 2-Bromopyridine was also suitable for the coupling. Addition of a small amount of water to the catalytic system was of importance to obtain high yields.

Full text of DOI:10.1021/jo3003584

Note
pubs.acs.org/joc
Palladium-Catalyzed C−N Cross Coupling of Sulfinamides
and Aryl Halides
Xiaofei Sun, Xingzhao Tu, Chuan Dai, Xiaoping Zhang, Binbin Zhang, and Qingle Zeng*
Institute of Green Catalysis and Synthesis, College of Materials and Chemistry & Chemical Engineering,
Chengdu University of Technology, Chengdu 610059, China
S
* Supporting Information
ABSTRACT: The palladium-catalyzed C−N cross coupling
of sulfinamides and aryl halides is reported. In the presence of
Pd2(dba)3, tBuXPhos, NaOH, and a small amount of water,
the C−N cross coupling of chiral tert-butanesulfinamide and
aryl halides was accomplished to give N-aryl tert-butanesulfi-
namide without racemization, and the coupling of racemic
p-toluenesulfinamide smoothly afforded N-aryl p-toluenesulfina-
mides. 2-Bromopyridine was also suitable for the coupling. Addition of a small amount of water to the catalytic system was of
importance to obtain high yields.
ulfinamides, especially chiral sulfinamides, are an important
class of organic compounds in modern organic chemistry.1
Enantiomer-pure tert-butanesulfinamide, p-toluenesulfinamide,
etc., and their derivatives are extensively used as chiral auxilia-
ries in the synthesis of chiral drugs and natural products1 and as
chiral ligands in catalytically asymmetric reactions.2
A number of approaches have been developed for the syn-
thesis of racemic N-aryl arenesulfinamides3 from thionylani-
line,3a benzenesulfinylazide,3b nitrosobenzenes,3c sulfonyl chlo-
rides,3d methyl sulfinates,3e and for the synthesis of racemic
N-aryl alkanesulfinamides from the reaction of thionylaniline
and organomagnesium halides,3a,4 or of tert-butanesulfinyl
chloride and amines.5
finamide under a harsh reaction condition (heating for 5 days
at 120 °C) for preparation of chiral β-diketiminato-type
ligands containing oxazoline moiety (no chiral HPLC was
run to testify the stability of chirality of the sulfinyl moiety),6d
and Selvakumar and his co-workers developed a protocol of Pd-
catalyzed C−N coupling of racemic tert-butanesulfinamide and
substituted aryl bromides and chlorides with at least an
electron-withdrawing group with extremely high yields, even for
ortho-substituted aryl halides.6e Here we disclosed our protocol
of Pd-catalyzed C−N cross coupling of racemic as well as
optically active sulfinamides.
S
As part of our continuous studies on C−N cross coupling8
and metal-catalyzed organic reactions,9 we tried to discover a
general protocol for copper-catalyzed C−N cross coupling of
tert-butanesulfinamide and aryl halides under similar reaction
But synthetic methods of chiral N-aryl sulfinamides are
scarce.6 Cram described the synthesis of N-phenyl
p-toluenesulfinamide from in situ formed lithium anilinide
and menthyl p-toluenesulfinate.6a Ellman found a synthetic
method of N-phenyl tert-butanesulfinamide by reaction of in
situ formed lithium anilinide and tert-butanethiosulfinate at
−78 °C.6b But in Cram and Ellman’s protocols, partial
racemization, harsh reaction conditions, and complex manip-
ulation are flaws.2d,6a,b
́
conditions to Toure’s protocol. Unfortunately, only low yields
(<30%) were obtained in dozens of trials, although high
conversions of iodobenzene and bromobenzene were observed.
So we had to resort to palladium-catalyzed C−N cross coupling
of sulfinamides and aryl halides (Scheme 1).
Scheme 1. Palladium-Catalyzed C−N Cross Coupling of
Sulfinamides 1 and Aryl Halides 2
In the area of palladium-catalyzed C−N cross coupling,7
amines,7c,d amides,7e imines,7f ureas,7g ammonia,7h hydrazines,7i
sulfonamides,7j sulfoximines,7k sulfamide,7l nitrite,7m and so on
as the nitrogen sources have been well developed. In contrast,
analogous C−N cross coupling of tert-butanesulfinamide and
aryl halides are rare.6c−e
́
Toure reported copper-catalyzed C−N cross coupling of
tert-butanesulfinamide and 2-bromopyridine to give N-(2-pyridyl)
tert-butanesulfinamide with >90% conversion (but no isolated
yield and no characterization data were given).6c
During our research on palladium-catalyzed C−N coupling
of chiral tert-butanesulfinamide and racemic p-toluenesulfina-
mide and aryl halides, Du reported Pd-catalyzed C−N coupling
of chiral 2-(2′-bromophenyl)oxazolines and (S)-tert-butanesul-
As a beginning, a common catalytic system of palladium-
catalyzed C−N cross coupling was adopted for this coupling, i.e.,
1 mol % Pd2(dba)3, 5 mol % (2-biphenyl)di-tert-butylphosphine
Received: March 3, 2012
Published: March 29, 2012
© 2012 American Chemical Society
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Note
(Johnphos), 2 equiv of sodium tert-butoxide, and 6 mL of
dioxane at 90 °C for 20 h.
Under these conditions, the C−N cross coupling of
tert-butanesulfinamide and bromobenzene really worked, but
the yield of N-phenyl tert-butanesulfinamide 1a was low (only
10%) (Table 1, entry 1). Toluene in place of dioxane as a
as Pd(dba)2, PdCl2, and Pd(OAc)2, afforded no better results.
Some more conditions about temperature and time were
examined, but no better results were obtained (for the details,
see the Supporting Information). In a word, the optimized
reaction conditions are 2 mol % Pd2(dba)3 as the palladium
source, tBuXPhos as the ligand, NaOH as the base, and toluene
with 5% water as the solvent at 90 °C for 20 h.
In view of the importance of chirality, (R) form, (S) form,
and racemic tert-butanesulfinamides were first investigated
under the optimized reaction conditions. Palladium-catalyzed
C−N cross coupling of bromobenzene and (R) form, (S) form,
and racemic tert-butanesulfinamides gave the corresponding
N-phenyl tert-butanesulfinamides 3a−3c with high yields,
respectively (Table 2, entries 1 to 3). Commercial 98% ee
Table 1. Optimization of Conditions of Palladium-Catalyzed
C−N Cross Coupling
a
b
entry
Pd source
ligand
base
H2O (mL) yield (%)
c
1
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
tBuXPhos
tBuXPhos
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOH
KOH
0
10
26
84
88
83
89
86
<5
91
76
Table 2. Palladium-Catalyzed C−N Cross Coupling of Aryl
2
0
a
c
Bromides and Sulfinamides
3
0.3
0.3
0.6
0.3
0.3
0
4
5
6
7
8
NaOH
NaOH
NaOH
entry
R
config.
ArX
product
yield (%)
9
0.3
0.3
b
1
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
4-Tol
4-Tol
R
S
PhBr
PhBr
PhBr
3a
3b
3c
3d
3e
3f
91
86
84
89
77
53
82
95
92
67
52
82
73
20
13
41
92
71
75
70
60
10
c
a
2
Unless otherwise noted, all reactions were performed by heating (R)-
tert-butanesulfinamide (1 mmol), bromobenzene (1.3 mmol),
Pd2(dba)3 (0.02 mmol), monophosphine ligand (0.05 mmol),
inorganic base (2.4 mmol), degassed water (indicated volume), and
3
4
5
6
7
8
9
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
4-MeC6H4Br
3-MeC6H4Br
2-MeC6H4Br
3-MeOC6H4Br
4-NO2C6H4Br
4-AcC6H4Br
4-COOHC6H4Br
4-FC6H4Br
4-PhC6H4Br
2-C10H7Br
b
toluene (6 mL) in a sealed tube for 20 h at 90 °C. Isolated yield.
c
Dioxane was used.
3g
3h
3i
solvent gave a little higher yield (26%) (Table 1, entry 2).
Other common solvents, such as THF, dimethoxyethane, and
benzene gave poorer yields than that of toluene.
d
10
3j
11
12
13
14
15
16
17
18
19
20
21
3k
3l
When we screened mixed solvents, occasionally we found
that a little degassed water (0.3 mL) in dioxane (6 mL) made a
sharp increase of yield of the desired N-phenyl tert-butane-
sulfinamide (Table 1, entry 3). Toluene with 0.3 mL of
degassed water gave up to 88% yield (Table 1, entry 4). When a
little more degassed water (0.6 mL) was added in toluene, the
yield decreased slightly (Table 1, entry 5). We thought that
sodium tert-butoxide would turn into sodium hydroxide and
tert-butanol once sodium tert-butoxide met water. Really, when
much cheaper sodium hydroxide and potassium hydroxide was
used instead of sodium tert-butoxide, comparable yields were
obtained (Table 1, entries 6 and 7). If water has no other
function but transforms sodium tert-butoxide into sodium
hydroxide, the degassed water was not necessary any more for a
catalytic system with sodium hydroxide as a base. But in fact,
sodium hydroxide and dry toluene gave hardly anything without
addition of water (Table 1, entry 8). The essential reason of the
huge promotion of water is still unknown. Perhaps the facile
dissolution of inorganic base sodium hydroxide in water should
be partially responsible for the promotion. Similar to the C−N
coupling, water accelerating N-arylation of heteroarylamines and
amines were reported by Hartwig10 and Yin.11
3m
3n
3a
3a
3h
3o
3p
3q
3r
1-C10H7Br
PhI
PhCl
4-NO2C6H4Cl
3-NO2C6H4Cl
2-C5H4NBr
PhBr
4-MeC6H4Br
a
Unless otherwise noted, all reactions were performed by heating (R)-
tert-butanesulfinamide (1 mmol), aryl halide (1.3 mmol), Pd2(dba)3
(0.02 mmol), tBuXPhos (0.05 mmol), NaOH (2.4 mmol), degassed
b
water (0.3 mL), and toluene (6 mL) for 20 h at 90 °C. 98.7% ee.
c
d
97.3% ee. NaOH (3.4 mmol) is used.
(R)- and (S)-tert-butanesulfinamide gave 98.7% ee (R)- and
97.3% ee (S)-N-phenyl tert-butanesulfinamide, respectively,
which implies that no racemization occurred during the alkaline
C−N cross coupling (Table 2, entries 1 and 2). Because of the
alkali resistance of tert-butanesulfinamide and the excellent
chiral induction ability, enantiomer-pure (R)- and (S)-tert-
butanesulfinamides are extensively used as chiral auxiliaries in
synthesis of chiral amines. Alkali-resistant chiral N-aryl
tert-butanesulfinamides 3 possess chiral tert-butanesulfinamide
moiety, so it is expected to be extensively used in synthesis of
chiral drugs and chiral chemicals in the near future.1,6
Encouraged by the good results, some more ligands were
screened. To our surprise, 2-di-tert-butylphosphino-2′,4′,6′-
triisopropylbiphenyl (tBuXPhos) with more steric hindrance
gave the highest yield up to 91% (Table 1, entry 9). A smaller
amount of Pd2(dba)3 (1 mol %) resulted in a lower yield
(Table 1, entry 10). Other palladium sources (4 mol %), such
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Once the stability of chirality in the transformation of the C−
N cross coupling was confirmed, other aryl bromides were
investigated further under the optimized reaction conditions.
Palladium-catalyzed C−N cross coupling of 4-bromotoluene
and (R)-tert-butanesulfinamide gave nearly the same yield as
that of bromobenzene (Table 2, entry 4 vs entry 1). 3-
Bromotoluene gave a bit lower yield (Table 2, entry 5).
ortho-Bromotoluene gave much lower yield than para- and
meta-substituted tolyl bromides (Table 2, entries 6 vs 4 and 5).
Since tert-butanesulfinamide possesses a bulky tert-butyl group,
probably the high steric hindrance 2-methylphenyl and
tert-butanesulfinamide in a palladium complex of the transitional
state decreases the efficiency of the coordination of the substrates
and palladium.12
Toure
́
reported the first synthesis of chiral N-(2-pyridyl)
́
tert-butanesulfinamide 3p. But in Toure’s paper there is no yield
and no characterization data.6b We found that our palladium
catalytic protocol could efficiently finish the C−N cross cou-
pling with 75% isolated yield (Table 2, entry 19), and chiral
N-(2-pyridyl) tert-butanesulfinamide 3p was fully characterized.
In addition to tert-butanesulfinamide, racemic p-toluenesulfi-
namide reacted with aryl bromides under the similar reaction
conditions to afford N-aryl p-toluenesulfinamides 3q−3r with
moderate yields (Table 2, entries 20 and 21).
N-Aryl tert-butanesulfinamides are readily derived into other
compounds. The hydrogen on nitrogen atom in an N-aryl
tert-butanesulfinamide has higher acidity due to the electron-
drawing effect of aryl and sulfinyl groups. So N-methylation and
N-allylation of (R)-N-phenyl tert-butanesulfinamide were
smoothly performed with sodium hydride as a base to give
N-methyl-N-phenyl tert-butanesulfinamide 4 and N-allyl-N-
phenyl tert-butanesulfinamide 5 with high yields, respectively
(Scheme 2). Those compounds will find their applications in
The coupling of aryl bromides with electron-donating groups
carried out well. The coupling of 3-methoxyphenyl bromide
with an electron-donating group carried out smoothly to afford
a good yield of 82% (Table 2, entry 7), and the product 3g is
facile to form a single crystal.13
In contrast, 4-nitrobromobenzene with a strong electron-
withdrawing nitro group achieved extremely high yield up to
95% (Table 2, entry 8). 4-Bromoacetophenone with an
electron-withdrawing acetyl group also gave high yield (Table 2,
entry 9). It demonstrates that electron-withdrawing groups in aryl
halides promote the coupling of sulfinamides.
Scheme 2. Methylation and Allylation on Nitrogen Atom of
N-Phenyl tert-Butanesulfinamide
4-Bromobenzoic acid with an electron-withdrawing carboxyl
group afforded a moderate yield (Table 2, entry 10), so the fact
seems contradictory to the above rule. But the coupling reac-
tion conducted under strongly alkaline condition, so the
substrate 4-bromobenzoic acid must have formed a salt, i.e.,
sodium 4-bromobenzoate. The negative ion of 4-bromoben-
zoate and the low solubility in organic solvent possibly are
responsible for the mild yield. The yield of N-(4-fluorophenyl)
tert-butanesulfinamide 3k was moderate (Table 2, entry 11).
Perhaps the fluoro group participated in the C−N coupling,
which produced complex byproducts.
The yield of C−N cross coupling of 4-bromobiphenyl and
tert-butanesulfinamide was fairly good (Table 2, entry 12).
2-Bromonaphthalene also afforded good results (Table 2, entry
13), but 1-bromonaphthalene gave much lower yield (Table 2,
entry 14). Perhaps the reason is the same as that of
ortho-bromotoluene, i.e., the huge steric hindrance between
tert-butanesulfinamide and 1-bromonaphthalene.
Aryl iodides often demonstrate much higher reactivity than
aryl chlorides and bromides in copper-catalyzed carbon-hetero-
atom cross coupling7c but are poor substrates for palladium-
catalyzed cross coupling.14 Palladium-catalyzed C−N cross
coupling of tert-butanesulfinamide and iodobenzene gave an
extremely poor result, only 13% yield (Table 2, entry 15).
Fortunately, aryl bromides and chlorides usually are much
cheaper, more readily available, and more diverse than aryl
iodides, so the poor reactivity of aryl iodides will not demolish
this coupling protocol’s applications.
Chlorobenzene showed higher reactivity than iodobenzene
but much poorer reactivity than bromobenzene (Table 2, entry
16 vs entries 15 and 1). It is obvious that strong electron-
withdrawing groups greatly promote palladium-catalyzed C−N
cross coupling of aryl chlorides and tert-butanesulfinamide
(Table 2, entries 17−19). para-Chloronitrobenzene gave a
fairly high yield up to 92% (Table 2, entry 17). meta-Chloro-
nitrobenzene gave good yield (Table 2, entry 18). Because of a
steric group on the ortho position, ortho-chloronitrobenzene did
not react.
organic synthesis and medicine synthesis, for example, in syn-
thesis similar compounds to tetrahydroquinoline-based
PPARα/γ agonists.15
In summary, we have developed an efficient palladium-
catalyzed C−N cross coupling of sulfinamides and aryl halides.
Application of Pd2(dba)3 as the palladium source, tBuXPhos as
the ligand, cheap sodium hydroxide as the base, and a little
degassed water as the additive is both convenient and cost-
effective. Probably because of the acceleration of the dissolution
of inorganic base, the addition of a small amount of water is the
key to promote the reaction. The chirality of (R)- and (S)-tert-
butanesulfinamides is preserved in N-aryl tert-butanesulfina-
mides without racemization during the coupling.
EXPERIMENTAL SECTION
■
General Experimental Procedure of Pd-Catalyzed C−N Cross
Coupling of Sulfinamides and Aryl Halides. An oven-dried
ground test tube, which was equipped with a magnetic stir bar and
fitted with a rubber septum, was charged with (R)-, (S)-, or racemic
tert-butanesulfinamide (0.121 g, 1.0 mmol), Pd2(dba)3 (0.018 g,
0.02 mmol), tBu-XPhos (0.0212 g, 0.05 mmol), and NaOH (0.08 g,
2 mmol). The vessel was evacuated and backfilled with argon (this
process was repeated a total of 3 times), and then the aryl halide
(1.3 mmol), toluene (10 mL), and degassed water (0.3 mL) were
added via syringe (aryl chlorides or amines that were solids at room
temperature were added with the catalyst and base). The solution was
stirred at 90 °C for 20 h. The reaction mixture was then cooled to
room temperature, quenched by water, and extracted with ethyl
acetate (20 mL) twice. The organic layer was combined, dried over
anhydrous sodium sulfate, and filtrated. The filterate was condensed
under vacuum. The residual was purified with silica gel column
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Note
chromatography with a solution of petroleum ether and ethyl acetate
(5:1 (vol:vol)) as an eluent to afford the N-aryl tert-butanesulfinamide.
(R)-N-Phenyl tert-Butanesulfinamide 3a (Table 2, Entries 1,
15, 16).6b White crystalline solid (0.179 g, 91% yield) with 98.1% ee
(HPLC, Diacel Chiralcel OD-H column, 90:10 hexanes/2-propanol,
1 mL/min, 254 nm; (R)-N-phenyl tert-butanesulfinamide, tR = 4.8 min;
(S)-N-phenyl tert-butanesulfinamide, tR = 9.2 min): mp 111−114 °C;
[α]D22 = −182° (c 0.3, CHCl3) (lit [α]D23 −181° (c 1.0, CHCl3)); 1H
NMR (300 MHz, CDCl3) δ (ppm) 7.25−7.24 (m, 2H), 7.01 (t, J =
6.3 Hz, 3H), 5.41 (d, J = 11.1 Hz, 1H), 1.33 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 142.1, 129.1, 122.4, 117.9, 56.3, 22.3;
IR (KBr) ν (cm−1) 3452, 3145, 2961, 2889, 1598, 1495, 1412, 1363,
1287, 1236, 1053, 887, 751; ESI-MS (negative mode), m/z = 196
[M − H]−.
m/z = 241 [M − H]−. Anal. Calcd for C10H14N2O3S: C, 49.57; H,
5.82; N, 11.56. Found: C, 49.65; H, 5.93; N 11.45.
(R)-N-(4-Acetylphenyl) tert-Butanesulfinamide 3i (Table 2,
Entry 9). Yellow solid (0.220 g, 92%): mp 110.5−111.4 °C; 1H NMR
(300 MHz, CDCl3) δ (ppm) 7.67 (d, J = 8.6 Hz, 2H), 6.94 (d, J =
8.7 Hz, 2H), 2.43 (s, 3H), 1.30(s, 9H); 13C NMR (300 MHz, CDCl3)
δ (ppm) 196.6, 147.2, 130.7, 129.9, 115.9, 56.8, 26.1, 22.3; IR (KBr) ν
(cm−1) 3456, 3276, 2961, 1693, 1611, 1509, 1475, 1356, 1182, 1119,
21
1056, 861, 840, 712; [α]D = −69.6° (c 0.05, ethyl acetate); ESI-MS
(negative mode), m/z = 238 [M − H]−. Anal. Calcd for C12H17NO2S:
C, 60.22; H, 7.16; N, 5.85. Found: C, 60.31; H, 7.26; N 5.92.
(R)-N-(4-Carboxyphenyl) tert-Butanesulfinamide 3j (Table 2,
1
Entry 10). White solid (0.161 g, 67%): mp 164.2 °C; H NMR (300
MHz, CD3OD) δ (ppm) 7.94 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz,
2H), 1.32 (s, 9H); 13C NMR (75 MHz, CD3OD) δ (ppm) 168.5,
147.9, 131.5, 124.2, 116.4, 56.9, 21.7; IR (KBr) ν (cm−1) 3481, 3186,
2985, 1703, 1671, 1608, 1461, 1425, 1286, 1238, 1172, 1056, 8801,
(S)-N-Phenyl tert-Butanesulfinamide 3b (Table 2, Entry 2).
White crystalline solid (0.167 g, 86% yield) with 97.3% ee (HPLC,
Diacel Chiralcel OD-H column, 90:10 hexanes/2-propanol, 1 mL/min,
21
768; [α]D = −63.3° (c 0.078, ethyl acetate); ESI-MS (negative
254 nm; (R)-N-phenyl tert-butanesulfinamide, tR = 4.8 min; (S)-N-
mode), m/z = 240 [M − H]−. Anal. Calcd for C11H15NO3S: C, 54.75;
H, 6.27; N, 5.80. Found: C, 54.87; H, 6.41; N 5.74.
21
phenyl tert-butanesulfinamide, tR = 9.2 min): mp 110−113 °C; [α]D
=
+179.2 (c 0.075, ethyl acetate). Other data are the same as those of
(Table 2, entry 1).
(R)-N-(4-Fluorophenyl) tert-Butanesulfinamide 3k (Table 2,
1
Entry 11). Yellow solid (0.112 g, 52%): mp 59.2 °C; H NMR (300
( )-N-Phenyl tert-Butanesulfinamide 3c (Table 2, Entry 3).
White crystalline solid (0.166 g, 84% yield): mp 103−105 °C. Other
data are the same as those of (Table 2, entry 1).
MHz, CDCl3) δ (ppm) 6.96 (d, J = 6.4 Hz, 4H), 5.36 (s, 1H), 1.33
(s, 9H); 13C NMR (75 MHz, CDCl3) δ (ppm) 160.6, 138.0, 120.5 (d,
J = 31.8 Hz, 2C), 115.9 (d, J = 90.3 Hz, 2C), 56.5, 22.4; IR (KBr) ν
(cm−1) 3448, 3227, 2963, 2926, 2612, 1607, 1506, 1473, 1367, 1336,
1273, 1209, 1157, 1135, 1100, 1069, 886, 833, 776; [α]D21 = −73.0° (c
0.01, ethyl acetate); ESI-MS (negative mode), m/z = 214 [M − H]−.
Anal. Calcd for C10H14FNOS: C, 55.79; H, 6.55; N, 6.51. Found:
C, 55.92; H, 6.70; N 6.44.
(R)-N-(4-Tolyl) tert-Butanesulfinamide 3d (Table 2, Entry 4).
1
Yellow solid (0.187 g, 89%): mp 82−83 °C; H NMR (300 MHz,
CDCl3) δ (ppm) 7.06 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H),
5.33 (s, 1H), 2.28 (s, 3H), 1.32 (s, 9H); 13C NMR (300 MHz, CDCl3)
δ (ppm) 139.4, 132.3, 129.7, 118.7, 56.2, 22.4, 20.5; IR (KBr) ν
(cm−1) 3445, 3242, 2957, 2922, 2864, 1613, 1513, 1472, 1382, 1275,
(R)-N-(4-Biphenyl) tert-Butanesulfinamide 3l (Table 2, Entry
21
1228, 1177, 1050, 881, 810; [α]D = −114.0° (c 0.01, ethyl acetate);
1
12). Yellow solid (0.224 g, 82%): mp 153−156 °C; H NMR (300
ESI-MS (negative mode), m/z = 210 [M − H]−. Anal. Calcd for
C11H17NOS: C, 62.52; H, 8.11; N, 6.63. Found: C, 62.58; H, 8.17; N
6.59.
MHz, CDCl3) δ (ppm) 7.49−7.29 (m, 7H), 7.06 (d, J = 8.5 Hz, 2H),
6.03 (d, J = 3.9 Hz, 1H), 1.37 (s, 9H); 13C NMR (300 MHz, CDCl3) δ
(ppm) 114.6, 140.4, 135.6, 128.6, 127.9, 126.8, 126.6, 118.4, 56.5,
(R)-N-(3-Tolyl) tert-Butanesulfinamide 3e (Table 2, Entry 5).
22.4; IR (KBr) ν (cm−1) 3453, 3252, 2926, 1610, 1519, 1485, 1386,
1
White solid (0.162 g, 77%): mp 84−85 °C; H NMR (300 MHz,
21
1305, 1286, 1268, 1228, 1191, 1057, 912, 880, 838, 767; [α]D
=
CDCl3) δ (ppm) 7.15 (t, J = 7.9 Hz, 1H), 6.84−6.79 (m, 3H), 5.30
(s, 1H), 2.30 (s, 3H), 1.33 (s, 9H); 13C NMR (300 MHz, CDCl3) δ
(ppm) 142.0, 139.1, 129.0, 123.4, 118.8, 115.2, 56.3, 22.4, 21.3; IR
(KBr) ν (cm−1) 3451, 3246, 2965, 1605, 1474, 1368, 1289, 1165,
−110.8° (c 0.15, ethyl acetate); ESI-MS (negative mode), m/z = 272
[M − H]−. Anal. Calcd for C16H19NOS: C, 70.29; H, 7.00; N, 5.12.
Found: C, 70.43; H, 7.16; N 5.01.
(R)-N-(2-Naphthyl) tert-Butanesulfinamide 3m (Table 2,
21
1
1047, 937, 874, 829, 776; [α]D = −127.5° (c 0.06, ethyl acetate);
Entry 13). White solid (0.181 g, 73%): mp 122−124 °C; H NMR
ESI-MS (negative mode), m/z = 210 [M − H]−. Anal. Calcd for
C11H17NOS: C, 62.52; H, 8.11; N, 6.63. Found: C, 62.61; H, 8.20;
N 6.56.
(300 MHz, CDCl3) δ (ppm) 1.37 (s, 9 H), 6.08 (s, 1 H), 7.15 (d, J =
8.7 Hz, 1H), 7.27−7.39 (m, 3 H), 7.58−7.66 (m, 3 H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 139.7, 133.9, 129.7, 129.1, 127.5, 126.6,
126.4, 124.1, 119.0, 113.5, 56.5, 22.4; IR (KBr) ν (cm−1) 3454, 3202,
2961, 1628, 1599, 1511, 1464, 1386, 1364, 1340, 1247, 1210, 1177,
(R)-N-(2-Tolyl) tert-Butanesulfinamide 3f (Table 2, Entry 6).
1
Yellow solid (0.112 g, 53%): mp 62−64 °C; H NMR (300 MHz,
21
CDCl3) δ (ppm) 7.18−7.11 (m, 3H), 7.00−6.93 (m, 1H), 5.25 (s,
1H), 2.29 (s, 3H), 1.34 (s, 9H); 13C NMR (300 MHz, CDCl3)
δ(ppm) 139.8, 130.7, 127.5, 127.0, 123.3, 119.1, 56.4, 22.4, 17.6; IR
(KBr) ν (cm−1) 3452, 3248, 2959, 1589, 1492, 1373, 1277, 1238,
1177, 1062, 871, 748; [α]D21 = −67.3° (c 0.03, ethyl acetate); ESI-MS
(negative mode), m/z = 210 [M − H]−. Anal. Calcd for C11H17NOS:
C, 62.52; H, 8.11; N, 6.63. Found: C, 62.45; H, 8.23; N 6.68.
(R)-N-(3-Methoxyphenyl) tert-Butanesulfinamide 3g (Table 2,
1067, 961, 918, 850, 820, 742; [α]D = −134.2° (c 0.10, ethyl
acetate); ESI-MS (negative mode), m/z = 246 [M − H]−. Anal. Calcd
for C14H17NOS: C, 67.98; H, 6.93; N, 5.66. Found: C, 67.87; H, 6.98;
N 5.82.
(R)-N-(1-Naphthyl) tert-Butanesulfinamide 3n (Table 2, Entry
14). Brown oil (0.052 g, 20%): 1H NMR (300 MHz, CDCl3) δ (ppm)
7.96 (s, 1H), 7.83 (t, J = 5.0 Hz, 1H), 7.60 (d, J = 2.2, 1H), 7.51−7.48
(m, 2H), 7.36 (t, J = 5.4 Hz, 2H), 5.84 (s, 1H), 1.42 (s, 9H); 13C
NMR (75 MHz, CD3OD) δ (ppm) 136.9, 134.2, 128.5, 127.3, 126.1,
125.9, 125.6, 124.6, 121.2, 117.4, 66.9, 22.6; IR (KBr) ν (cm−1) 2973,
2868, 1580, 1513, 1459, 1396, 1320, 1266, 1174, 1057, 1057, 891, 771;
[α]D21 = −43.5° (c 0.04, ethyl acetate); ESI-MS (negative mode), m/z
= 246 [M − H]−. Anal. Calcd for C14H17NOS: C, 67.98; H, 6.93; N,
5.66. Found: C, 68.05; H, 6.83; N 5.54.
1
Entry 7). White solid (0.186 g, 82%): mp 111−112 °C; H NMR
(300 MHz, CDCl3) δ (ppm) 7.16 (t, J = 8.2 Hz, 1H), 5.60−5.55 (m,
3H), 5.34 (s, 1H), 3.78(s, 3H), 1.33 (s, 9H); 13C NMR (300 MHz,
CD3OD) δ (ppm) 160.2, 143.5, 129.8, 110.1, 107.9, 103.5, 56.3, 54.9,
22.3; IR (KBr) ν (cm−1) 3456, 3273, 3112, 3076, 2966, 1584, 1519,
21
1246, 1186, 1113, 1068, 875, 795, 751; [α]D = −2.6° (c 0.05, ethyl
acetate); ESI-MS (negative mode), m/z = 226 [M − H]−. Anal. Calcd
for C11H17NO2S: C, 58.12; H, 7.54; N, 6.16. Found: C, 58.23; H, 7.61;
N 6.25.
(R)-N-(4-Nitrophenyl) tert-Butanesulfinamide 3h (Table 2,
Entry 17). Yellow solid (0.223 g, 92%). Other data are the same as
those of (Table 2, entry 8).
(R)-N-(4-Nitrophenyl) tert-Butanesulfinamide 3h (Table 2,
(R)-N-(3-Nitrophenyl) tert-Butanesulfinamide 3o (Table 2,
1
1
Entry 8). Yellow solid (0.227 g, 95%): mp 133−136 °C; H NMR
Entry 18). Yellow solid (0.168 g, 71%): mp 147−149 °C; H NMR
(300 MHz, CDCl3) δ (ppm) 8.11 (d, J = 9.1 Hz, 2H), 7.04 (d, J =
9.1 Hz, 2H), 6.32 (s, 1H), 1.35 (s, 9H); 13C NMR (75 MHz, CD3OD)
δ (ppm) 148.9, 141.6, 125.2, 115.7, 57.3, 22.1; IR (KBr) ν (cm−1)
3453, 3265, 2964, 1596, 1508, 1470, 1336, 1298, 1058, 869, 794,
(300 MHz, CDCl3) δ (ppm) 7.79 (s, 1H), 7.69 (dd, J1 = 1.68 Hz, J2 =
4.45 Hz, 1H), 7.27 (d, J = 5.2 Hz, 2H), 6.66 (s, 1H), 1.36 (s, 9H); 13C
NMR (300 MHz, CDCl3) δ (ppm) 148.7, 143.9, 129.9, 123.0, 116.9,
111.9, 57.1, 22.4; IR (KBr) ν (cm−1) 3453, 3076, 2965, 2861, 1619,
1527, 1476, 1401, 1349, 1293, 1238, 1055, 996, 948, 884, 826, 801,
21
751; [α]D = −44 (c 0.01, ethyl acetate); ESI-MS (negative mode),
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dx.doi.org/10.1021/jo3003584 | J. Org. Chem. 2012, 77, 4454−4459

The Journal of Organic Chemistry
Note
737; [α]D21 = −2.1° (c 0.024, ethyl acetate); ESI-MS (negative mode),
m/z = 241 [M − H]−. Anal. Calcd for C10H14N2O3S: C, 49.57; H,
5.82; N, 11.56. Found: C, 49.46; H, 5.97; N 11.72.
ASSOCIATED CONTENT
* Supporting Information
Complete spectral data for all compounds, chiral HPLC for
racemic, (R)- and (S)-N-phenyl tert-butanesulfinamides, and
single crystal X-ray data for (R)-N-(3-methoxyphenyl)
tert-butanesulfinamide (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
(R)-N-(2-Pyridyl) tert-Butanesulfinamide 3p (Table 2, Entry
1
19). Pale yellow solid (0.149 g, 75%): mp 137−139 °C; H NMR
(300 MHz, CDCl3) δ (ppm) 8.22 (d, J = 4.3 Hz, 1H), 7.61 (dt, J1 =
1.8 Hz, J2 = 8.3 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.91 (q, J = 5.2 Hz,
1H), 1.35 (s, 9H); 13C NMR (300 MHz, CDCl3) δ (ppm) 155.2,
148.0, 138.2, 117.4, 110.2, 56.5, 22.4; IR (KBr) ν (cm−1) 3452, 3081,
2973, 1605, 1535, 1476, 1364, 1275, 1052, 884, 743; [α]D21 = −147.3°
(c 0.037, ethyl acetate); ESI-MS (negative mode), m/z = 197 [M −
H]−. Anal. Calcd for C9H14N2OS: C, 54.52; H, 7.12; N, 14.13. Found:
C, 54.65; H, 7.26; N 14.26.
AUTHOR INFORMATION
Corresponding Author
*E-mail: qinglezeng@hotmail.com.
Notes
■
( )-N-Phenyl p-Toluenesulfinamide 3q (Table 2, Entry 20).3d
1
The authors declare no competing financial interest.
White solid (0.163 g, 70%): mp 110−112 °C; H NMR (300 MHz,
CDCl3) δ (ppm) 7.63 (t, J = 6.2 Hz, 2H), 7.30−7.22 (m, 4H), 7.09−
7.00 (m, 3H), 6.55 (s, 1H), 2.42 (s, 3H); 13C NMR (300 MHz,
CDCl3) δ (ppm) 141.7, 141.4, 140.7, 129.7, 129.4, 125.4, 123.3, 118.7,
21.3; IR (KBr) ν (cm−1) 3452, 3099, 2861, 2791, 1641, 1599, 1488,
1400, 1225, 1171, 1088, 1052, 893, 814, 758; ESI-MS (negative
mode), m/z = 230 [M − H]−.
ACKNOWLEDGMENTS
■
We appreciate the National Science Foundation of China
(Grant No. 20672088), the Science and Technology Bureau of
Sichuan (Grant No. 2011HH0016), and the Cultivating
Program for Excellent Innovation Team of Chengdu University
of Technology (No. HY0084) for financial support.
( )-N-(p-Tolyl) p-Toluenesulfinamide 3r (Table 2, Entry
21).3d Pale yellow solid (0.148 g, 60%): mp 114−116 °C; H NMR
1
(300 MHz, CDCl3) δ (ppm) 7.64 (d, J = 7.7 Hz, 2H), 7.28 (t, J = 7.8
Hz, 2H), 7.02 (dd, J1 = 24.6 Hz, J2 = 8.6 Hz, 4H), 6.32 (s, 1H), 2.42 (s,
3H), 2.29 (s, 3H); 13C NMR (300 MHz, CDCl3) δ (ppm) 141.6,
141.5, 137.9, 133.2, 129.8, 129.6, 125.5, 119.4, 21.3, 20.7; IR (KBr) ν
(cm−1) 3452, 3145, 2917, 2316, 1613, 1512, 1397, 1281, 1228, 1176,
1088, 1051, 892, 804; ESI-MS (negative mode), m/z = 244 [M − H]−.
Synthetic Procedure of (R)-N-Methyl-N-phenyl tert-Butane-
sulfinamide 4 (Scheme 2). N-Phenyl (R)-tert-butanesulfinamide
(1 mmol, 0.1970 g), 80% NaH in mineral oil (2 mmol, 0.0629 g), and
THF (10 mL) were added to an oven-dried flask equipped with a
magnetic stirring bar. The mixture was stirred in an ice water bath for
1 h, and then methyl iodide (0.3 mmol, 0.18 g) was added by syringe
to the flask. The reaction mixture was stirred overnight. After being
quenched by saturated NH4Cl solution, the reaction mixture was
extracted with ethyl acetate (20 mL) three times. The combined
organic layer was washed with saturated NaCl solution and then dried
over anhydrous sodium sulfate. The filtrate was condensed under
vacuum. The residual was purified with a silica gel column chroma-
tography with a mixed solution of petroleum ether and ethyl acetate (5:1
(v:v)) as an eluent to give a pale yellow oil. (R)-N-Methyl-N-phenyl
tert-butanesulfinamide (0.1712 g, 81%): 1H NMR (300 MHz, CDCl3)
δ (ppm) 7.28 (dd, J1 = 8.2 Hz, J2 = 7.7 Hz, 2H), 7.14 (d, J = 8.0 Hz,
2H), 6.99 (t, J = 7.2 Hz, 1H), 3.05 (s, 3H), 1.25 (s, 9H); 13C NMR
(300 MHz, CDCl3) δ (ppm) 147.3, 129.1, 122.3, 118.3, 60.1, 29.7,
23.7; IR (KBr) ν (cm−1) 2958, 1597, 1495, 1362, 1277, 1216, 1175,
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mide (0.2036 g, 86%): H NMR (300 MHz, CDCl3) δ (ppm) 7.31−
7.26 (m, 2H), 7.18 (t, J = 1.2 Hz, 2H), 7.07 (dd, J1 = 7.3 Hz, J2 =
1.0 Hz, 1H), 5.78 (t, J = 6.5 Hz, 1H), 5.17−5.10 (m, 2H), 4.04 (dq,
J1 = 2.2 Hz, J2 = 1.5 Hz, 2H), 1.23 (s, 9H); 13C NMR (75 MHz,
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23.4; IR (KBr) ν (cm−1) 3013, 2954, 1615, 1595, 1501, 1365, 1280,
21
1219, 1085, 1026, 842, 754; [α]D = +108.5 (c 0.376, CHCl3);
ESI-MS (negative mode), m/z = 236 [M − H]−. Anal. Calcd for
C13H19NOS: C, 65.78; H, 8.07; N, 5.90. Found: C, 65.67; H, 8.19;
N 5.78.
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