Lewis Acid-Catalyzed Nucleophilic Substitutions of Benzylic Alcohols with Sulfamides

Article abstract of DOI:10.1002/ejoc.202001320

Nucleophilic substitutions of benzylic alcohols with sulfamides were achieved using an FeCl₃ Lewis acid catalyst in MeNO₂. It was necessary to adjust the reaction conditions to obtain efficient yields depending on the stability of the carbocation intermediates. The reaction could easily be performed, and it was revealed that a variety of diarylmethanols and benzylic alcohols were applicable to the reaction, irrespective of the type and position of the substituents. The sulfamide moieties were easily deprotected and converted into amine groups.

Full text of DOI:10.1002/ejoc.202001320

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Lewis Acid-Catalyzed Nucleophilic Substitutions of Benzylic
Alcohols with Sulfamides
Authors: Ryoga Oda and Kenya Nakata
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01/2020

10.1002/ejoc.202001320
European Journal of Organic Chemistry
FULL PAPER
Lewis Acid-Catalyzed Nucleophilic Substitutions of Benzylic
Alcohols with Sulfamides
Ryoga Oda[a] and Kenya Nakata*[a]
[a]
R. Oda, Prof. Dr. K. Nakata
Department of Chemistry, Graduate School of Natural Science and Technology
Shimane University
1060 Nishikawatsu Matsue, Shimane 690-8504 (Japan)
E-mail: nakata@riko.shimane-u.ac.jp
http://www.ipc.shimane-u.ac.jp/yuuki_lab/
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Nucleophilic substitutions of benzylic alcohols with
sulfamides were achieved using an FeCl3 Lewis acid catalyst in
MeNO2. It was necessary to adjust the reaction conditions to obtain
efficient yields depending on the stability of the carbocation
intermediates. The reaction could easily be performed, and it was
revealed that a variety of diarylmethanols and benzylic alcohols were
applicable to the reaction, irrespective of the type and position of the
substituents. The sulfamide moieties were easily deprotected and
converted into amine groups.
[refs 1b,6b,8]
(a) Transamination with NH2SO2NH2
H2NSO2NH2
O2
R1
1 NH2
S
R
N
NH2
H
(b) Amination with sulfamoyl chloride[refs 1b,6b,9, see also 10]
O2
R2
S
O2
S
Cl
N
R1
R2
R3
N
N
R3
1 NH2
Sulfamides are important functional groups in organic chemistry,
and they are used in various fields.[1] For example, the
hydrogen-bond donating ability of sulfamides has been utilized
for the development of chiral auxiliaries[2] and organocatalyses.[3]
Sulfamides are also used as radical precursors for C–C bond-
forming reactions by heterodimerization[4] and as useful directing
groups for C–H amination.[5] Because sulfamide moieties are
considered as bioisosteres of amides, ureas, carbamates, and
sulfonamides, they are frequently found in biologically active
compounds.[6] Furthermore, sulfamides are utilized in functional
molecules with self-assembling properties.[7] Thus, until now,
numerous efforts have been devoted to developing an efficient
method to produce sulfamides (Scheme 1). Classically, the
transamination of amines with H2NSO2NH2 (Scheme 1, (a))[1b,6b,8]
and the amination of amines with sulfamoyl chloride (Scheme 1,
(b))[1b,6b,9] have been carried out for this purpose. However,
these methods often have problems with reaction efficiency and
the toxicity of hydrogen chloride as a byproduct. Recently, the
synthesis of unsymmetrical sulfamides using sulfamoyl fluorides
has been reported.[10] Alternatively, several useful sulfuryl-
containing reagents bearing designed leaving groups have been
developed for amination reactions to synthesize sulfamides
H
R
(c) Amination with sulfuryl-containing reagents[ref 11]
O2
S
R2
O2
S
LG
N
R1
R2
R3
N
N
R3
1 NH2
R
H
LG = leaving group
[refs 7d,12]
(d) Amination with SO2/I2 or DABCO·(SO2)2/I2
O2
S
SO2/I2 or
R1
R1
1 NH2
R
N
N
DABCO·(SO2)2/I2
H
H
DABCO = 1,4-diazabicyclo[2.2.2]octane
(e) Transition-metal catalyzed coupling reaction[ref 13]
O2
R2
S
NH2
N
R3
O2
S
transition-metal (cat)
X = halogen, B(OH)2
R1
R2
1 X
N
N
R3
R
H
(Scheme 1, (c)).[11] To provide symmetrical N,N’-disubstituted
Scheme 1. Previously reported sulfamidation.
[7d]
sulfamides, amination with SO2/I2
or DABCO·(SO2)2/I2,[12]
which reduced the difficulty of handling harmful SO2 gas, has
also been reported (Scheme 1, (d)). In addition, the transition-
metal catalyzed coupling reaction (Scheme 1, (e)),[13] reductive
amination of aldehydes,[14] and 1,2-diamination of alkenes[15]
have also been performed for the synthesis of sulfamides.
In recent years, nucleophilic substitutions of alcohols
catalyzed by Lewis acids or Brønsted acids have gained
increasing attention as methods with high atom efficiency and
environmental friendliness (Scheme 2, (a)).[16] A number of
nucleophiles have been applied to the reaction system, and
useful characteristic reactions have been reported. Although
there are many reports on the nucleophilic substitutions of
alcohols using sulfonamides as a nucleophile,[17–19] there are few
reported examples of the application of sulfamides for such a
reaction. As such, we have conducted research on Lewis acid-
1
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10.1002/ejoc.202001320
European Journal of Organic Chemistry
FULL PAPER
Table 1. Examination of different Lewis acids in the nucleophilic substitution of
benzhydrol (1a) with sulfamide 3
catalyzed nucleophilic substitutions of diarylmethanols with
several nucleophiles.[17q,20] Herein, we report the first practical
nucleophilic substitution of benzylic alcohols with sulfamides
catalyzed by Lewis acids (Scheme 2, (b)).
H2NSO2NMe2 (3; 1.5 equiv)
Ph
Lewis acid (5 mol %)
O2
S
Ph
Ph
N
NMe2
Ph
OH
MeNO2 (0.1 M)
temp., time
H
(a) General equation for dehydrative nucleophilic substitutions[ref 16]
1a
2a
Lewis acid
or
Brønsted acid
Entry
1[b]
2
Lewis acid
SnBr4
↑
Temp [°C]
Time [h]
Yield of 2a [%][a]
R2
R2
rt
2
55
95
94
96
89
93
42
88
31
92
+ H2O
R1
R1
OH
Nu
NuH
rt
24
2
(b) This study; sulfamidation of benzylic alcohols
3
↑
50
80
50
50
50
50
50
50
O2
S
NR1R2
4
↑
2
H2N
R
O2
S
R
Lewis acid (cat)
R1
5
SnBr2
SnCl4
SnCl2
InCl3
Yb(OTf)3
FeCl3
2
Ar
N
N
Ar
OH
H
R2
sulfamidation
6
2
Scheme 2. Related previous study (a) and present study (b)
7
2
8
2
To optimize the reaction conditions, we examined the effects
of different Lewis acids and reaction temperatures on the
nucleophilic substitution of benzhydrol (1a) with H2NSO2NMe2
(3) in MeNO2 as a model reaction (Table 1). First, we carried out
the reaction at different temperatures in the presence of SnBr4,
which was previously revealed to function as an efficient Lewis
acid catalyst in the reactions of diarylmethanols with various
nucleophiles (entries 1–4).[17q,20] When the reaction was
conducted at room temperature, some of the starting material 1a
and the homoether generated from 2 molecules of 1a remained
after 2 h, and the desired product 2a was produced in 55% yield
(entry 1). However, when the reaction time was increased to 24
h, the reaction proceeded almost completely to afford 2a in 95%
yield (entry 2). When the reaction temperature was increased to
50 and 80 °C, the reaction proceeded smoothly for 2 h to afford
2a in high yields in both cases (entries 3 and 4). Next, the
reaction was examined in the presence of other tin salts, namely
SnBr2, SnCl4, and SnCl2, and other representative Lewis acids,
namely InCl3 and Yb(OTf)3, at 50 °C for 2 h (entries 5–9). The
reaction using SnCl4 yielded almost the same result as the
reaction using SnBr4 (entry 6). For the reactions using SnBr2 and
InCl3, the yields of 2a were slightly lower than those of the
reactions using SnBr4 and SnCl4 (entries 5 and 8, respectively).
In contrast, the reactions using SnCl2 and Yb(OTf)3 did not
proceed well, and the corresponding yields of 2a were moderate
(entries 7 and 9, respectively). Because FeCl3 has been used as
an efficient Lewis acid catalyst for nucleophilic substitutions,[21]
we also carried out the reaction using FeCl3 (entry 10). In this
case, we obtained a good result that was comparable to those of
SnBr4 and SnCl4. Ultimately, SnBr4, SnCl4, and FeCl3 were
determined to be efficient catalysts for the reaction. Considering
the catalyst availability, we decided to use FeCl3 for the
subsequent examinations.
9
2
10
2
[a] Isolated yield. [b] 1a:2a:homoether [bis(diphenyl)methyl ether] = 10:68:22
as determined by 1H NMR spectroscopic analysis.
In order to explore the scope and limitations of the reaction,
we conducted the sulfamidation of a series of diarylmethanols
1a–1n with H2NSO2NMe2 (3) under the optimized reaction
conditions (50 °C, 2 h) (Table 2). The reactions of 1b–1d, each
bearing a Me-group on the aromatic ring of the substrates,
produced the desired sulfamides 2b–2d, respectively, in high
yields, similar to the case of 1a, regardless of the position of the
substituent (entries 2–4 versus entry 1). For the reaction of 1e, it
was anticipated that the diarylmethyl cation intermediate would
be stabilized by the electron-donating property of the MeO-group
and that the reactivity would be increased. Therefore, the
reaction was carried out at room temperature, and the starting
material was consumed immediately. However, a complex
mixture was obtained (entry 5). To control the reactivity, we
lowered the reaction temperature to 0 °C, and good yields were
obtained in the reactions of 1e and 1g (entries 6 and 8,
respectively). However, the reaction of 1f, which contained a
MeO group in the meta-position, at room temperature for 24 h
was somewhat complicated, and a moderate yield was obtained
(entry 7). In contrast, in the reactions of 1h–1j bearing Cl
substituents on the phenyl ring, it was found that a higher
reaction temperature was necessary to enhance the reactivity
(entries 9–12). The reaction of 1h at 50 °C was not completed
even after 24 h, and 2h was obtained in 58% yield (entry 9).
However, a high yield of 2h was obtained after 2 h when the
reaction temperature was increased to 80 °C (entry 10).
Similarly, the reactions of 1i and 1j at 80 °C for 2 h afforded high
yields of the corresponding products (entries 11 and 12,
respectively). The reaction of 1k bearing an ester group afforded
a high yield of the product within a reaction time of 24 h (entry
13). However, no reaction occurred when 1l, bearing a CN
group, was used, even when the temperature and reaction time
2
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10.1002/ejoc.202001320
European Journal of Organic Chemistry
FULL PAPER
were 80 °C and 24 h, respectively. This result might have
occurred because the carbocation intermediate was destabilized
by the strong electron-withdrawing nature of the CN group (entry
could be attributed to the steric repulsion exerted by the
functional groups. The reactivities of hetero-atoms containing
cyclic benzylic alcohols, 5d and 5e, were found to be high; the
14). The reactions of 1m and 1n, which contained naphthyl rings, corresponding reactions performed at 0 °C afforded high yields
proceeded smoothly at 50 °C for 2 h to produce 2m and 2n,
respectively, in high yields, regardless of the position of the
substituent (entries 15 and 16, respectively).
of the respective products. However, no reaction occurred when
5f, bearing a pyridyl ring, was used.
3 (1.5 equiv)
FeCl3 (5 mol %)
SO2NMe2
Table 2. Sulfamidation of a series of diarylmethanols 1 with H2NSO2NMe2 (3)
3 (1.5 equiv)
OH
HN
Ph
MeNO2 (0.1 M)
temp., time
Ph
R
R
6
Ar
FeCl3 (5 mol %)
O2
S
Ar
5
Ar
N
NMe2
Ar
OH
MeNO2 (0.1 M)
temp., time
H
SO2NMe2
SO2NMe2
HN
Ph
1
2
SO2NMe2
HN
Ph
HN
Ph
Entry
1[b]
2
Ar
Ph (a)
Temp [°C]
Time [h]
Yield [%][a]
Me
50
50
50
50
2
92
6a
6b
6c
95% (50 °C, 2 h)
59% (rt, 24 h)
43% (50 °C, 24 h)
trace (50 °C, 24 h)
ND (80 °C, 24 h)
o-MeC6H4 (b)
m-MeC6H4 (c)
p-MeC6H4 (d)
2
98
SO2NMe2
HN
SO2NMe2
HN
3
2
89
SO2NMe2
HN
4
2
88
N
Ph
5
o-MeOC6H4 (e)
↑
rt
0.25
0.5
24
0.5
24
2
ND[c]
76[d]
34[d]
93
O
6d
86% (0 °C, 1 h)
S
6e
6f
6
0
92% (0 °C, 18 h)
no reaction
(50 °C, 24 h)
7
m-MeOC6H4 (f)
p-MeOC6H4 (g)
o-ClC6H4 (h)
↑
rt
Scheme 3. Sulfamidation of various benzylic alcohols 5 with H2NSO2NMe2 (3).
8
0
9
50
80
80
80
80
80
50
50
58
In order to establish the selective synthesis of N-
monosubstituted sulfamide 7 and N,N’-disubstituted sulfamide 8,
we examined the reaction upon changing the nucleophile from
H2NSO2NMe2 (3) to H2NSO2NH2 (9), with the results listed in
Table 3. When the reaction of 1a with 1.5 equiv of 9 was carried
out at room temperature, it was found that the reaction was
faster than that using 3 (see: Table 2, entry 1). Moreover, the
reaction was completed in 1 h and afforded 7 and 8 in 70% and
30% yield, respectively (entry 1). To preferentially synthesize 7
instead of 8, we increased the amount of nucleophile 9 from 1.5
to 3 equiv. The reaction was performed at a concentration of
0.03 M due to the poor solubility of 9 in 0.1 M MeNO2. The
reactivity was relatively unchanged by the increase in reactant
concentration, and the desired product 7 was preferentially
obtained in 81% yield (entry 2). Upon lowering the reaction
temperature to 0 °C, it was found that the reactivity decreased
and prolonging the reaction time was necessary. In this case,
the ratio of 7 to 8 was almost the same as that in entry 2 (entry
3). When the reaction was carried out with an increase in the
amount of nucleophile 9 to 5.0 equiv at room temperature, the
10
11
12
13
14
15
16
93
m-ClC6H4 (i)
p-ClC6H4 (j)
p-EtO2CC6H4 (k)
p-NCC6H4 (l)
a-Np (m)
2
87
2
94
24
24
2
98
NR[e]
82[d]
88
b-Np (n)
2
[a] Isolated yield. [b] Same as in Table 1, entry 10. [c] Not determined. [d]
Recrystallization yield. [e] No reaction.
To further expand the scope of the substrates, various
benzylic alcohols, instead of diarylmethanols, were applied to
the reaction (Scheme 3). When the reactions of benzylic
alcohols 5a–5c having alkyl substituents at C-1position were
examined, it was found that the reactions were strongly
influenced by the steric effect of the substituents. The reaction of
5a, bearing a linear alkyl substituent, at 50 °C for 2 h produced
6a in 95% yield, while it is reported that treatment of 5a under a
Lewis acid catalyst gave styrene as a major product and several
unidentified products.[22] In contrast, the reactions of 5b and 5c,
bearing branched alkyl substituents, afforded moderate and
negligible yields, respectively, along with the unidentified
products[17a,22], a small amount of the corresponding starting
materials, and homoethers, under different conditions; this result
chemoselectivity
was
improved,
and
the
desired
monosubstituted sulfamide 7 was produced in 89% yield (entry
4). Notably, the reaction was applicable for the 1-g scale (please
refer to the experimental section). In contrast, when the same
reaction was carried out using 0.5 equiv of 9 to selectively
synthesize 8, the reaction at room temperature produced 7 and
8 in 18% and 80% yield, respectively (entry 5). However, when
the aforementioned reaction was carried out at 50 °C, a slightly
complex mixture was produced, and the yield of 8 was lower
than that of the same reaction at room temperature (entry 6).
3
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10.1002/ejoc.202001320
European Journal of Organic Chemistry
FULL PAPER
Table 3. Examination of the reaction conditions of the selective synthesis of N-
diphenylmethyl sulfamide 7 and N,N’-Bis(diphenylmethyl)sulfamide 8
SO2NMe2
HN
3 (1.5 equiv)
FeCl3 (5 mol %)
OH
Me
(1)
Ph
Ph
Me
6a
O2
S
MeNO2 (0.1 M)
50 °C, 2 h
(R)-5a, 99% ee
H2N
NH2
94%, 0% ee
9 (n equiv)
FeCl3 (5 mol %)
Ph
Ph
Ph
Ph
O2
3 (3.0 equiv)
FeCl3 (5 mol %)
O2
S
O2
S
Ph
Ph Ph
+
S
Ph
N
NH2 Ph
N
N
Ph
Ph
N
NMe2
(2)
Ph
OH
MeNO2 (0.1 M)
temp., time
Ph
O
Ph
H
H
H
H
MeNO2 (0.05 M)
50 °C, 2 h
1a
7
8
homoether
2a
95%
Entry
n [equiv]
Temp [°C]
Time [h]
Yield of 7
[%][a]
Yield of
[%][a]
8
Scheme 5. Investigation for the reaction pattern and the intermediate.
1
1.5
3.0
3.0
5.0
0.5
0.5
rt
1
70
81
83
89
18
18
30
15
13
7
Based on the above-mentioned results, a plausible catalytic
pathway is shown in Scheme 6. Activation of the hydroxy group
of 1a by coordination with FeCl3 in step (i) affords int-i. In step
(ii), int-ii is generated, along with dehydroxylation. Although
there is an equilibrium between int-ii and homoether, int-ii is re-
generated from the homoether via re-activation of FeCl3. Finally,
nucleophile 3 reacts with int-ii to afford the desired sulfamide 2a.
2[b]
3[b]
4[b]
5
rt
2
0
24
2
rt
rt
24
24
80
59
6
50
Ph
O2
[a] Isolated yield. [b] The reaction concentration was 0.03 M.
S
Ph
N
NMe2
+ H2O
H
Ph
2a
To demonstrate the versatility of the reactions presented
herein, we attempted to deprotect the sulfamides to produce the
corresponding amines (Scheme 4). In accordance with the
literature procedure,[14d] sulfamide 2a was refluxed in a 5% H2O–
pyridine solvent for 24 h to be converted into amine 9 in near
quantitative yield (Scheme 4, (1)). In a similar way, N,N’-
bis(diphenylmethyl)sulfamide 8 could also be converted to
amine 9 in near quantitative yield (Scheme 4, (2)).
Ph
OH
FeCl3
1a
O2
S
(i)
(iii)
H2N
NMe2
3
Ph
Ph
FeCl3
Ph
int-ii
Ph
O
1a
H
int-i
(ii)
Ph Ph
Ph
5% H2O–pyridine
reflux, 24 h
Ph
O2
S
Ph
homoether
O
Ph
(1)
(2)
HOFeCl3
Ph
N
NMe2
Ph
Ph
NH2
H
2a
9
Scheme 6. Plausible catalytic reaction pathway.
quant yield
Ph
5% H2O–pyridine
reflux, 24 h
Ph
O2
S
Conclusion
Ph
N
N
Ph
Ph
NH2
H
H
8
9
In conclusion, we performed the sulfamidation of benzylic
alcohols catalyzed by FeCl3, a Lewis acid, using nucleophilic
quant yield
substitution reactions for the first time.
A
series of
Scheme 4. Deprotection of sulfamides into the amines.
diarylmethanols and several benzylic alcohols were examined
for the reaction, and it was revealed that this protocol could be
applied to a broad range of substrates. This reaction can be
easily performed without requiring the preparation of a reagent.
The sulfamide moieties were converted into amine groups via a
facile procedure. Further studies are now in progress in our
laboratory to expand the substrate scope of this reaction and to
develop useful materials using this protocol.
It is well established that the nucleophilic substitutions of
alcohols, catalyzed by Lewis acids or Brønsted acids, proceed
via carbocations following the SN1 mechanism.[16] However, we
found that the reaction proceeded with difficulty for steric
hindered substrates, such as 6c. Thus, to verify the reaction
pattern, we carried out the reaction using enantiopure (R)-5a as
a starting substrate (Scheme 5, (1)), for which the product 6a
was obtained in 94% yield as a racemate; therefore, the reaction
was found to follow SN1 mechanism in this case as well. In
addition, the homoether was reacted to give the sulfamide 2a in
95% yield (Scheme 5, (2)), thus confirming the homoether as an
intermediate, as observed by TLC analysis.
Experimental Section
General Information. 1H and 13C NMR spectra were recorded with
chloroform (in chloroform-d) or DMSO (in dimethylsulfoxide-d) as the
internal standard. Electrospray ionization mass (ESI-MS) spectra were
4
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10.1002/ejoc.202001320
European Journal of Organic Chemistry
FULL PAPER
= 3286, 1338, 1151 cm–1
7.25 (m, 2H), 5.62 (d, J = 6.5 Hz, 1H), 5.03 (br s, 1H), 2.56 (s, 6H) ppm.
13C NMR (CDCl3) d = 141.3, 128.7, 127.7, 127.4, 61.5, 37.5 ppm. HRMS
calcd for C15H18N2O2S [M + Na]+ 313.0981, found 313.0979.
.
1H NMR (CDCl3) d = 7.37–7.30 (m, 8H), 7.30–
recorded on a Bruker microTOFII-SHIY3 mass spectrometer (Bruker,
Billerica, MA) using the positive mode ESI-TOF method for acetonitrile
solutions and sodium formate as the reference. Thin layer
chromatography was performed on a Wakogel B5F. All reactions were
carried out under a nitrogen atmosphere in dried glassware. FeCl3, SnCl2,
and H2NSO2NMe2 (3) were purchased from Wako Pure Chemical
Industries Ltd. MeNO2 were purchased from Wako Pure Chemical
Industries Ltd. and Kishida Chemical Co., Ltd. SnCl4 (1.0 M in CH2Cl2),
InCl3, Yb(OTf)3, and H2NSO2NH2 (9) were purchased from Tokyo Kasei
Kogyo Co., Ltd (TCI). SnBr4 was purchased from Sigma-Aldrich. All
reagents were purchased from commercial suppliers and used without
further purification unless otherwise noted.
N-[bis(2-methylphenyl)methyl]-N’,N’-dimethylsulfuric diamide (2b)
(Table 2, entry 2). White solid. (71.0 mg, 98% yield). M.p.: 142–144 °C.
IR (KBr): ṽ = 3270, 1334, 1146 cm–1 1H NMR (CDCl3) d = 7.30–7.25 (m,
.
2H), 7.21–7.26 (m, 6H), 6.03 (d, J = 6.0 Hz, 1H), 4.61 (br s, 1H), 2.55 (s,
6H), 2.38 (s, 6H) ppm. 13C NMR (CDCl3) d = 138.7, 136.1, 130.9, 127.7,
127.4, 125.9, 55.0, 37.5, 19.2 ppm. HRMS calcd for C17H22N2O2S [M +
Na]+ 341.1294, found 341.1292.
Typical Procedure for the Sulfamidation of Benzhydrol (1a) with
H2NSO2NMe2 (3) (Table 2, entry 1). H2NSO2NMe2 (3) (50.5 mg, 0.41
mmol) and benzhydrol (1a) (50.0 mg, 0.27 mmol) were successively
added to a solution of FeCl3 (2.2 mg, 14 mmol) in MeNO2 (2.7 mL) at
room temperature. The whole mixture was stirred for 2 h at 50 °C, and
then the mixture was quenched with H2O at 0 °C and diluted with CH2Cl2.
The organic layer was separated, and the aqueous layer was extracted
with EtOAc. The combined organic layer was dried over Na2SO4. After
the filtration of the mixture and evaporation of the solvent, the crude
product was purified by thin layer chromatography on silica
(toluene/EtOAc = 50/1) twice to afford 2a (72.8 mg, 92% yield) as a white
solid.
N-[bis(3-methylphenyl)methyl]-N’,N’-dimethylsulfuric diamide (2c)
(Table 2, entry 3). White solid. (59.0 mg, 89% yield). M.p.: 86–88 °C. IR
(KBr): ṽ = 3294, 1339, 1156 cm–1. 1H NMR (CDCl3) d = 7.23 (t, J = 8.0 Hz,
2H), 7.17–7.06 (m, 6H), 5.54 (d, J = 7.0 Hz, 1H), 4.91 (br s, 1H), 2.56 (s,
6H), 2.34 (s, 6H) ppm. 13C NMR (CDCl3) d = 141.4, 138.4, 128.5, 128.4,
128.0, 124.3, 61.5, 37.6, 21.4 ppm. HRMS calcd for C17H22N2O2S [M +
Na]+ 341.1294, found 341.1294.
N-[bis(4-methylphenyl)methyl]-N’,N’-dimethylsulfuric diamide (2d)
(Table 2, entry 4). White solid. (61.8 mg, 88% yield). M.p.: 134–135 °C.
IR (KBr): ṽ = 3288, 1339, 1154 cm–1. 1H NMR (CDCl3) d = 7.20 (d, J = 8.0
Hz, 4H), 7.14 (d, J = 8.0 Hz, 4H), 5.56 (d, J = 7.0 Hz, 1H), 4.92 (br s, 1H),
2.57 (s, 6H), 2.33 (s, 6H) ppm. 13C NMR (CDCl3) d = 138.6, 137.3, 129.3,
127.2, 61.1, 37.6, 21.0 ppm. HRMS calcd for C17H22N2O2S [M + Na]+
341.1294, found 341.1294.
The 1 Mmol-Scale Synthesis of 2a. H2NSO2NMe2 (3) (186.2 mg, 1.50
mmol) and benzhydrol (1a) (184.5 mg, 1.00 mmol) were successively
added to a solution of FeCl3 (8.2 mg, 51 mmol) in MeNO2 (10 mL) at
room temperature. The whole mixture was stirred for 2 h at 50 °C, and
then the mixture was quenched with H2O at 0 °C and diluted with CH2Cl2.
The organic layer was separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic layer was dried over Na2SO4. After
the filtration of the mixture and evaporation of the solvent, the crude
product was purified by column chromatography on silica (hexane/EtOAc
= 9/1 to 4/1) to afford 2a (281.8 mg, 97% yield) as a white solid.
N-[bis(2-methoxyphenyl)methyl]-N’,N’-dimethylsulfuric diamide (2e)
(Table 2, entry 6). White solid. (47.2 mg, 76% yield). M.p.: 144–145 °C.
IR (KBr): ṽ = 3323, 1329, 1254, 1155 cm–1. 1H NMR (CDCl3) d = 7.45 (dd,
J = 1.5, 7.5 Hz, 2H), 7.21 (dt, J = 2.0, 8.0 Hz, 2H), 6.93 (dt, J = 1.5, 7.5
Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.99 (d, J = 9.5 Hz, 1H), 5.85 (br d, J =
9.0 Hz, 1H), 3.80 (s, 6H), 2.61 (s, 6H) ppm. 13C NMR (CDCl3) d = 156.4,
129.2, 128.7, 128.5, 120.3, 110.8, 55.3, 54.2, 37.7 ppm. HRMS calcd for
C17H22N2O4S [M + Na]+ 373.1192, found 373.1203.
Typical Procedure for the Sulfamidation of Benzhydrol (1a) with
H2NSO2NH2 (9) to Provide 7 (Table 3, entry 5). To a solution of FeCl3
(1.6 mg, 9.9 mmol) in MeNO2 (6.7 mL) at room temperature was
successively added H2NSO2NH2 (9) (96.5 mg, 1.00 mmol) and
benzhydrol (1a) (36.7 mg, 0.20 mmol). The whole mixture was stirred for
2 h at room temperature, and then the mixture was quenched with H2O at
0 °C and diluted with CH2Cl2. The organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined organic layer
was dried over Na2SO4. After the filtration of the mixture and evaporation
of the solvent, the crude product was purified by thin layer
chromatography on silica (toluene/EtOAc = 4/1) to afford 7 (46.3 mg,
89% yield) as a white solid. The crude 8 was repurified by thin layer
chromatography on silica (toluene/EtOAc = 50/1) twice to afford 8 (2.8
mg, 7% yield) as a white solid.
N-[bis(3-methoxyphenyl)methyl]-N’,N’-dimethylsulfuric diamide (2f)
(Table 2, entry 7). White solid. (23.4 mg, 34% yield). M.p.: 114–116 °C.
IR (KBr): ṽ = 3289, 1330, 1278, 1151, 1053 cm–1 1H NMR (CDCl3) d =
.
7.29–7.23 (m, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.89–6.86 (dm, 2H), 6.81 (dd,
J = 2.0, 8.0 Hz, 2H), 5.55 (d, J = 6.5 Hz, 1H), 4.88 (br s, 6H), 3.79 (s, 6H),
2.60 (s, 6H) ppm. 13C NMR (CDCl3) d = 159.8, 142.8, 129.8, 119.6, 113.2,
113.0, 61.4, 55.2, 37.6 ppm. HRMS calcd for C17H22N2O4S [M + Na]+
373.1192, found 373.1202.
N-[bis(4-methoxyphenyl)methyl]-N’,N’-dimethylsulfuric diamide (2g)
(Table 2, entry 8). White solid. (74.5 mg, 93% yield). M.p.: 120–122 °C.
IR (KBr): ṽ = 3285, 1333, 1249, 1154, 1035 cm–1 1H NMR (CDCl3) d =
.
7.24–7.18 (m, 4H), 6.88–6.82 (m, 4H), 5.54 (d, J = 6.5 Hz, 1H), 4.90 (br s,
1H), 3.78 (s, 6H), 2.56 (s, 6H) ppm. 13C NMR (CDCl3) d = 159.0, 133.8,
128.5, 113.9, 60.4, 55.2, 37.6 ppm. HRMS calcd for C17H22N2O4S [M +
Na]+ 373.1192, found 373.1197.
The 1 Gram-Scale Synthesis of 7. A 500-mL two-necked flask was
charged with FeCl3 (48.8 mg, 0.30 mmol) in MeNO2 (15 mL + 5 mL + 5
mL rinse) and MeNO2 (175 mL). Then, H2NSO2NH2 (9) (2.88 g, 30.0
mmol) and benzhydrol (1a) (1.11 g, 6.00 mmol) were added to this
mixture. The whole mixture was stirred for 2 h at room temperature, and
then the mixture was quenched with H2O at 0 °C and diluted with CH2Cl2.
The organic layer was separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic layer was dried over Na2SO4. After
the filtration of the mixture and evaporation of the solvent, the crude
product was purified by column chromatography on silica (toluene/EtOAc
= 3/1) to afford 7 (1.43 g, 91% yield) as a white solid.
N-[bis(2-chlorophenyl)methyl]-N’,N’-dimethylsulfuric diamide (2h)
(Table 2, entry 10). White solid. (50.3 mg, 93% yield). M.p.: 144–145 °C.
IR (KBr): ṽ = 3294, 1343, 1150 cm–1 1H NMR (CDCl3) d = 7.44–7.36 (m,
.
4H), 7.31–7.22 (m, 4H), 6.39 (d, J = 7.0 Hz, 1H), 4.88 (br s, 1H), 2.75 (s,
6H) ppm. 13C NMR (CDCl3) d = 137.4, 133.5, 130.1, 129.2, 129.1, 126.9,
55.9, 37.9 ppm. HRMS (ESI-TOF) m/z: [M
+
Na]+ calcd for
C15H16Cl2N2O2S 381.0202, found 381.0205.
Procedure for the Deprotection of Sulfamides into Amines (Scheme
4, (1)). According to the literature procedure,[14d] a solution of 8a (291.1
mg, 1.00 mmol) in 5% H2O–pyridine (5.0 mL) was refluxed for 24 h. After
the removal of pyridine by evaporation, the crude solid was dissolved in 1
M HCl and diluted with Et2O. The solution was then back-extracted with
Et2O. The aqueous layer was basified with 6 M NaOH and extracted with
Et2O. The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo to afford amine 9 (183.0 mg, quantitative yield)
without requiring further purification. 1H NMR (CDCl3) d = 7.42–7.36 (m,
4H), 7.36–7.29 (m, 4H), 7.27–7.21 (m, 2H), 5.23 (s, 1H), 1.87 (br s, 2H)
ppm. 13C NMR (CDCl3) d = 145.5, 128.4, 126.83, 126.80, 59.6 ppm.
N-[bis(3-chlorophenyl)methyl]-N’,N’-dimethylsulfuric diamide (2i)
(Table 2, entry 11). White solid. (68.0 mg, 87% yield). M.p.: 115–117 °C.
IR (KBr): ṽ = 3269, 1337, 1150 cm–1 1H NMR (CDCl3) d = 7.32–7.26 (m,
.
6H), 7.22–7.18 (m, 2H), 5.55 (d, J = 7.5 Hz, 1H), 5.13 (br s, 1H), 2.59 (s,
6H) ppm. 13C NMR (CDCl3) d = 142.6, 134.8, 130.2, 128.3, 127.4, 125.5,
60.6, 37.6 ppm. HRMS calcd for C15H16Cl2N2O2S [M + Na]+ 381.0202,
found 381.0201.
N-[bis(4-chlorophenyl)methyl]-N’,N’-dimethylsulfuric diamide (2j)
(Table 2, entry 12). White solid. (67.2 mg, 94% yield). M.p.: 164–166 °C.
IR (KBr): ṽ = 3268, 1331, 1148 cm–1. 1H NMR (CDCl3) d = 7.31 (d, J = 8.5
Hz, 4H), 7.23 (d, J = 9.0 Hz, 4H), 5.55 (d, J = 7.0 Hz, 1H), 5.21 (br s, 1H),
2.57 (s, 6H) ppm. 13C NMR (CDCl3) d = 139.4, 133.8, 129.0, 128.7, 60.3,
37.6 ppm. HRMS calcd for C15H16Cl2N2O2S [M + Na]+ 381.0202, found
381.0199.
[Analytical Data of Compounds 2a–2k, 2m, 2n, 6a, 6b, 6d, 6e, 7, and 8]
N-(diphenylmethyl)-N’,N’-dimethylsulfuric diamide (2a) (Table 2,
entry 1). White solid. (72.8 mg, 92% yield). M.p.: 118–119 °C. IR (KBr): ṽ
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001320
European Journal of Organic Chemistry
FULL PAPER
Diethyl 4,4’-{[(N,N-dimethylsulfamoyl)amino]methylene}dibenzoate
(2k) (Table 2, entry 13). White solid. (68.1 mg, 98% yield). M.p.: 120–
This work was supported by JSPS KAKENHI Grant Number
JP20K05495 and
a Research Grant from The Takahashi
121 °C. IR (KBr): ṽ = 3268, 1329, 1279, 1150, 1109 cm–1 1H NMR
.
Industrial and Economic Research Foundation, Japan.
(CDCl3) d = 8.01 (d, J = 7.4 Hz, 4H), 7.38 (d, J = 8.5 Hz, 4H), 5.70 (d, J =
7.0 Hz, 1H), 5.29 (br s, 1H), 4.36 (q, J = 7.0 Hz, 4H), 2.57 (s, 6H), 1.37 (t,
J = 7.0 Hz, 6H) ppm. 13C NMR (CDCl3) d = 166.0, 145.5, 130.1, 127.3,
61.11, 61.06, 37.6, 14.3 ppm. HRMS calcd for C21H26N2O6S [M + Na]+
457.1404, found 457.1406.
Keywords: Sulfamidation
•
Nucleophilic substitutions
•
Carbocations • Lewis acids • Sulfamides
N-[bis(naphthalen-1-yl)methyl]-N’,N’-dimethylsulfuric diamide (2m)
(Table 2, entry 15). White solid. (66.9 mg, 82% yield). M.p.: 233–236 °C.
IR (KBr): ṽ = 3320, 1338, 1142 cm–1. 1H NMR (DMSO-d6) d = 8.41 (d, J =
9.0 Hz, 1H), 8.19–8.14 (m, 2H), 8.01–7.96 (m, 2H), 7.92–7.87 (m, 2H),
7.57–7.51 (m, 4H), 7.51–7.47 (m, 4H), 7.10 (d, J = 9.5 Hz, 1H), 2.46 (s,
6H) ppm. 13C NMR (DMSO-d6) d = 137.2, 133.5, 130.3, 128.9, 128.3,
126.8, 125.9, 125.2, 122.8, 53.6, 37.4 ppm. HRMS calcd for
C23H22N2O2S [M + Na]+ 413.1294, found 413.1297.
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N-[bis(naphthalen-2-yl)methyl]-N’,N’-dimethylsulfuric diamide (2n)
(Table 2, entry 16). White solid. (55.4 mg, 88% yield). M.p.: 169–170 °C.
IR (KBr): ṽ = 3281, 1328, 1151 cm–1 1H NMR (CDCl3) d = 7.86–7.79 (m,
.
8H), 7.52–7.46 (m, 6H), 5.97 (d, J = 7.0 Hz, 1H), 5.28 (d, J = 7.0 Hz, 1H),
2.58 (s, 6H) ppm. 13C NMR (CDCl3) d = 138.6, 133.1, 132.8, 128.7, 128.0,
127.6, 126.4, 126.3, 126.2, 125.4, 61.7, 37.7 ppm. HRMS calcd for
C23H22N2O2S [M + Na]+ 413.1294, found 413.1299.
N-(1-phenylethyl)-N’,N’-dimethylsulfuric diamide (6a) (Scheme 3).
colorless oil. (54.3 mg, 95% yield). IR (neat): ṽ = 3295, 1327, 1150 cm–1
.
1H NMR (CDCl3) d = 7.37–7.31 (m, 4H), 7.30–7.25 (m, 1H), 4.68 (br s,
1H), 4.51 (dq, J = 7.0, 6.5 Hz, 1H), 2.59 (s, 6H), 1.52 (d, J = 7.0 Hz, 3H)
ppm. 13C NMR (CDCl3) d = 143.2, 128.6, 127.6, 126.2, 53.9, 37.6, 23.9
ppm. HRMS calcd for C10H16N2O2S [M + Na]+ 251.0825, found 251.0826.
[4]
[5]
[6]
[7]
a) M. Movassaghi, O. K. Ahmad, S. P. Lathrop, J. Am. Chem. Soc.
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1159−1171.
N-[cyclohexyl(phenyl)methyl]-N’,N’-dimethylsulfuric diamide (6b)
(Scheme 3). White solid. (31.4 mg, 59% yield). M.p.: 93–94 °C. IR (KBr):
ṽ = 3296, 1326, 1152 cm–1 1H NMR (CDCl3) d = 7.36–7.30 (m, 2H),
.
7.28–7.24 (m, 1H), 7.22–7.18 (m, 2H), 4.88 (br s, 1H), 4.07–4.01 (m, 1H),
2.45 (s, 6H), 2.04–1.97 (m, 1H), 1.81–1.75 (m, 1H), 1.69–1.51 (m, 3H),
1.39–1.32 (m, 1H), 1.26–0.99 (m, 4H), 0.97–0.87 (m, 1H) ppm. 13C NMR
(CDCl3) d = 141.5, 128.3, 127.4, 127.2, 63.6, 44.0, 37.5, 29.9, 29.6, 26.1,
25.9 ppm. HRMS calcd for C15H24N2O2S [M + Na]+ 319.1451, found
319.1451.
a) T. Kurokawa, M. Kim, J. D. Bois, Angew. Chem. Int. Ed. 2009, 48,
2777–2779; b) H. Lu, K. Lang, H. Jiang, L. Wojtas, X. P. Zhang, Chem.
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a) For a review, see: A. B. Reitz, G. R. Smith, M. H. Parker, Expert
Opin. Ther. 2009, 19, 1449–1453; b) For a selected example, see: C.
Cano, J. Pavón, A. Serrano, P. Goya, J. A. Paez, F. R. de Fonseca, M.
Macias-Gonzalez, J. Med. Chem. 2007, 50, 389–393.
N-(3,4-dihydro-2H-chromen-4-yl)-N’,N’-dimethylsulfuric diamide (6d)
(Scheme 3). White solid. (57.4 mg, 86% yield). M.p.: 72–74 °C. IR (KBr):
ṽ = 3320, 1346, 1146 cm–1. 1H NMR (CDCl3) d = 7.33 (d, J = 7.5 Hz, 1H),
7.20–7.14 (m, 1H), 6.93–6.87 (m, 1H), 6.80 (d, J = 8.5 Hz, 1H), 4.57–
4.43 (m, 2H), 4.29–4.22 (m, 1H), 4.21–4.15 (m, 1H), 2.85 (s, 6H), 2.25–
2.14 (m, 2H) ppm. 13C NMR (CDCl3) d = 154.9, 129.6, 129.5, 121.1,
120.8, 117.2, 62.4, 47.9, 38.1, 29.6 ppm. HRMS calcd for C11H16N2O3S
[M + Na]+ 279.0774, found 279.0763.
a) B. Gong, C. Zheng, H. Zeng, J. Zhu, J. Am. Chem. Soc. 1999, 121,
9766–9767; b) F. Hof, C. Nuckolls, S. L. Craig, T. Martín, T. J. Rebek, J.
Am. Chem. Soc. 2000, 122, 10991–10996; c) R. C. Mills, P. Doufou, K.
A. Abboud, J. M. Boncella, Polyhedron 2002, 21, 1051–1055; d) A. V.
Leontiev, H. V. R. Dias, D. M. Rudkevich, Chem. Commun. 2006,
2887–2889; e) M. Maeda, K. Masuda, J. Li, S.-i. Kabashima, I.
Yoshikawa, K. Araki, Soft Matter 2010, 6, 5305–5307; f) P. Gopinath, V.
Ramkumar, K. M. Muraleedharan, CrystEngComm 2014, 16, 10371–
10375; g) L. Pantaine, V. Humblot, V. Coeffard, A. Vallée, Beilstein J.
Org. Chem. 2017, 13, 648–658.
N-(3,4-dihydro-2H-thiochromen-4-yl)-N’,N’-dimethylsulfuric diamide
(6e) (Scheme 3). colorless oil. (67.2 mg, 92% yield). IR (neat): ṽ = 3300,
.
1332, 1143 cm–1 1H NMR (CDCl3) d = 7.34 (d, J = 7.5 Hz, 1H), 7.17–
7.03 (m, 3H), 4.59 (s, 1H), 4.45 (br s, 1H), 7.23 (dt, J = 3.0, 12.5 Hz, 1H),
2.99–2.91 (m, 1H), 2.82 (s, 6H), 2.52–2.45 (m, 1H), 2.12–2.01 (m, 1H)
ppm. 13C NMR (CDCl3) d = 133.4, 132.0, 130.5, 128.5, 126.9, 124.5, 51.3,
38.1, 28.6, 21.8 ppm. HRMS calcd for C11H16N2O2S2 [M + Na]+ 295.0545,
found 295.0539.
[8]
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J. M. McManus, J. W McFarland, C. F. Gerber, W. H. McLamore, G. D.
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N-(diphenylmethyl)sulfuric diamide (7) (Table 3, entry 4). White solid.
(46.3 mg, 89% yield). M.p.:144–145 °C. IR (KBr): ṽ = 3347, 3266, 1331,
1163 cm–1 1H NMR (DMSO-d6) d = 7.80 (d, J = 9.5 Hz, 1H), 7.36 (d, J =
.
[11] a) J.-L. Montero, G. Dewynter, B. Agoh, B. Delaunary, J.-L. Imbach,
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Moreau, V. Coeffard, C. Greck, Adv. Synth. Catal. 2016, 358, 2012–
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7.5 Hz, 4H), 7.30 (t, J = 7.5 Hz, 4H), 7.21 (t, J = 7.5 Hz, 2H), 6.61 (br s,
2H), 5.57 (d, J = 9.5 Hz, 1H) ppm. 13C NMR (DMSO-d6) d = 143.1, 128.2,
127.4, 126.8, 60.1 ppm. HRMS calcd for C13H14N2O2S [M
285.0668, found 285.0664.
+
Na]+
N,N’-[bis(diphenylmethyl)]sulfuric diamide (8) (Table 3, entry 5).
White solid. (34.2 mg, 80% yield). M.p.:160–161 °C. IR (KBr): ṽ = 3296,
1322, 1146 cm–1. 1H NMR (CDCl3) d = 7.28–7.21 (m, 12H), 7.19–7.15 (m,
8H), 5.59 (d, J = 6.5 Hz, 2H), 4.90 (br d, J = 6.5 Hz, 2H) ppm. 13C NMR
(CDCl3) d = 141.0, 128.7, 127.6, 127.2, 61.6 ppm. HRMS calcd for
C26H24N2O2S [M + Na]+ 451.1451, found 451.1458.
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Acknowledgements
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001320
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.202001320
European Journal of Organic Chemistry
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Entry for the Table of Contents
Sulfamidation by nucleophilic substitution catalyzed by FeCl3
H2NSO2NR1R2
FeCl3 (5 mol %)
R
O2
S
R
NR1R2
Ar
N
Ar
OH
H
MeNO2 (0.1 M)
up to 98% yield
Key Topic: Sulfamidation Reaction
Sulfamidation of benzylic alcohols was achieved for the first time using nucleophilic substitutions catalyzed by FeCl3, a Lewis acid. A
variety of N-benzyl-substituted sulfamides were produced efficiently via this novel protocol.
Institute and/or researcher Twitter usernames: @Nakata_Lab
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This article is protected by copyright. All rights reserved.