Sulfuryl chloride as an efficient initiator for the metal-free aerobic cross-dehydrogenative coupling reaction of tertiary amines

Article abstract of DOI:10.1021/ol500661t

A metal-free cross-dehydrogenative (CDC) reaction of tertiary amines was developed using a catalytic amount of sulfuryl chloride (SO₂Cl ₂) under mild aerobic conditions. On the basis of the nature of SO₂Cl₂, it

Full text of DOI:10.1021/ol500661t

Letter
pubs.acs.org/OrgLett
Sulfuryl Chloride as an Efficient Initiator for the Metal-Free Aerobic
Cross-Dehydrogenative Coupling Reaction of Tertiary Amines
Arata Tanoue, Woo-Jin Yoo, and Shu Kobayashi*
̅
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
S
* Supporting Information
ABSTRACT: A metal-free cross-dehydrogenative (CDC) re-
action of tertiary amines was developed using a catalytic amount
of sulfuryl chloride (SO2Cl2) under mild aerobic conditions. On
the basis of the nature of SO2Cl2, it was assumed that the reagent
acts as a radical initiator to induce the metal-free CDC reaction
via a radical-initiated autoxidation mechanism.
ith increased awareness of the environmental impact of
current chemical process, the development of new green
tetrahydroisoquinoline (1a) and nitromethane in the presence
of catalytic amounts of various electrophilic halogenating
reagents (Table 1, Figure 1).
W
and sustainable synthetic methodologies has grown substan-
tially.1 In this context, the direct use of carbon−hydrogen (C−
H) bonds in cross-coupling reactions has emerged as a
potentially powerful strategy to streamline synthetic methods
by bypassing the necessity of synthesizing activated nucleo-
philes and/or electrophiles prior to the coupling event. A
successful class of C−H functionalization reactions is the cross-
dehydrogenative (CDC) reaction of the α-C−H bond of
tertiary amines.2 Pioneered by Murahashi3 and Li,4 who
employed ruthenium and copper catalysts, respectively, using
peroxides as oxidants, rapid improvement upon the original
conditions has led to a CDC reaction that can be performed
under mild aerobic conditions.5 Despite the progress made thus
far, most protocols rely upon the use of toxic metal salts as
catalysts, and examples of metal-free aerobic CDC reactions are
relatively scarce.6
a
Table 1. Investigation of Electrophilic Halogen Sources
b
b
entry
X+ source
conv (%)
yield (%)
1
2
3
4
5
6
7
8
9
NCS
68
>95
9
60
75
10
8
SO2Cl2
tBuOCl
chloramine T
5
dichloramine T
5
4
trichloroisocyanuric acid
<5
5
4
NBS
3
During the course of our investigations to develop a metal-
free CDC reaction in air by using aminium radical cations as
NIS
18
15
>95
>95
<5
11
15
93
90
1
I2
−
redox-active organocatalysts, we found that the SbCl6
c
10
SO2Cl2
SO2Cl2
SO2Cl2
counteranion was the active catalyst. On the basis of this
discovery, we recently reported a unique catalytic system
composed of NaSbCl6 and N-hydroxyphthalimide (NHPI) that
enabled the CDC reaction of N-aryl tetrahydroisoquinolines
with various pronucleophiles under mild aerobic conditions.7
Although the exact nature of the active catalytic species and its
mode of activation are unknown at this stage, one working
hypothesis is that the SbCl6− acts as a reservoir of SbCl5.8 Since
SbCl5 is a well-known strong oxidant and an excellent
electrophilic chlorinating reagent,9 we assumed that a metal-
free aerobic CDC reaction with tertiary amines could be
realized with the catalytic use of organo-based electrophilic
halogenating reagents.
c
,
,
d
e
11
c
12
a
Reaction conditions: amine 1a (0.25 mmol), X+ source (0.025 mmol,
10 mol %), MS 4 Å (50 mg) in MeNO2 (0.6 mL) at 30 °C for 18 h
b
c
1
under a balloon of dry oxygen. Determined by H NMR analysis. 6
d
e
mol % catalyst was used. Protected from light. Under argon
atmosphere.
When we utilized a catalytic amount of N-chlorosuccinimide
(NCS), the desired CDC adduct 2a was obtained in a moderate
yield (entry 1). Surprisingly, in contrast to our previously
reported NaSbCl6/NHPI system, the addition of NHPI was
found to slightly suppress the reaction. We examined various
electrophilic chlorinating reagents and found that SO2Cl2,
which is known as a surrogate of chlorine gas, provided the
In this communication, we wish to report the use of sulfuryl
chloride (SO2Cl2) as a metal-free initiator for the CDC reaction
of tertiary amines and various pronucleophiles under mild
conditions with oxygen gas as the terminal oxidant.
On the basis of our working hypothesis, we examined the
oxidative nitro-Mannich reaction between N-phenyl-1,2,3,4-
Received: March 3, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Letter
yield (entry 5). In addition to the electron-rich N-aryl amines,
an electron-deficient 4-chlorophenyl substrate 1f reacted slowly,
but the desired CDC adduct 2f was obtained in a relatively high
yield (entry 6). We also examined different nitroalkanes and
found that nitroethane and nitropropane were applicable
nucleophiles that provided the expected CDC products 2g,h
in good yields, despite the fact that the reactions proceeded
more slowly (entries 7 and 8). In contrast to the N-aryl
tetrahydroisoquinolines, other tertiary amines such as N,N-
dimethyl-p-toluidine (3) and N-benzyl tetrahydroisoquinoline
were found to be unreactive in our metal-free system.
Next, other pronucleophiles were examined as substrates
(Table 3). After further optimization using dimethyl malonate
as a model substrate, we found that only 2 mol % of SO2Cl2
and 1 equiv of the nucleophile were required when the reaction
was performed in acetonitrile. Similarly, when diethyl malonate
was utilized as a substrate, the desired product 2i was obtained
Figure 1. Electrophilic halogen sources.
desired product in 75% yield (entry 2). On the other hand,
various electrophilic chlorinating sources were screened, but the
results for the CDC reaction was quite poor (entries 3−6). In
addition, other electrophilic halogen reagents, such as N-
bromosuccinimide (NBS), N-iodosuccinimide (NIS), and
iodine, were examined, but in all cases the reaction hardly
proceeded (entries 7−9). On the basis of these results, we
determined SO2Cl2 as the optimal catalyst and examined other
conditions to improve the yield of 2a. Since SO2Cl2 fully
converted the N-aryl amine 1a to provide the CDC adduct 2a
in a good yield, we assumed that the electrophilic chlorinating
reagent may cause some decomposition of the starting material
and/or product to decrease the overall yield. To our delight,
when we lowered the catalyst loading to 6 mol %, the oxidative
nitro-Mannich product 2a was obtained in an excellent yield
(entry 10). In addition, we examined the possibilty of light
being involved in the CDC reaction and found that by
protecting the reaction vessel from ambient light, the reaction
proceeded smoothly (entry 11). We also performed the
reaction in the absence of O2 gas and found the reaction
hardly proceeded (entry 12).
a
Table 3. Substrate Scope of Nucleophiles
With the optimized conditions in hand, the substrate
generality was investigated (Table 2). In addition to simple
a
Table 2. Substrate Scope of Amines and Nitroalkanes
b
entry
Ar
nitroalkane
time (h)
yield (%)
1
2
3
4
5
6
7
8
Ph (1a)
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
EtNO2
18
18
18
72
18
53
48
54
93 (80)
88 (84)
86 (70)
12 (4)
4-Me-C6H4 (1b)
3-Me-C6H4 (1c)
2-Me-C6H4 (1d)
4-MeO-C6H4 (1e)
4-Cl-C6H4 (1f)
Ph (1a)
60 (44)
90 (75)
c
82 (71)
d
Ph (1a)
nPrNO2
70 (62)
a
Reaction conditions: amine 1a-f (0.25 mmol), SO2Cl2 (0.015 mmol,
6 mol %), MS 4 Å (50 mg) in nitroalkenes (0.6 mL) at 30 °C under a
b
balloon of dry oxygen. Determined by 1H NMR analysis; the isolated
c
d
yields are shown in parentheses. dr = 1.8:1. dr = 1.5:1.
N-phenyl-substituted tetrahydroisoquinoline 1a (entry 1),
other N-aryl tetrahydroisoquinolines 1b−f were examined
(entries 2−6). When various tolyl-substituted tetrahydroiso-
quinolines 1b−d were subjected to our optimized catalyst
system, the para- and meta-substituted tolyl substrates 1b,c
underwent the CDC reaction smoothly (entries 2 and 3). On
the other hand, ortho-substituted tertiary amine 1d reacted
sluggishly, and CDC product 2d was obtained in a low yield
(entry 4).10 When a 4-methoxylphenyl substrate 1e was
employed, the desired product 2e was obtained in a moderate
a
Reaction conditions: N-phenyl tetrahydroquinoline 1a (0.25 mmol),
nucleophiles (0.25 mmol), SO2Cl2 (0.005 mmol, 2 mol %), MS 4 Å
(50 mg) in acetonitrile (0.6 mL) at 30 °C under a balloon of dry
oxygen. Determined by H NMR analysis; the isolated yields are
shown in parentheses. dr = 1.6:1. 10 equiv of the nucleophile was
used. 5 equiv of the nucleophile and 6 mol % SO2Cl2 were used.
b
1
c
d
e
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Letter
in a good yield. When methyl acetoacetate was employed, the
CDC adduct 2j was obtained in a good yield with a modest
diastereoselectivity. We also examined the oxidative nitro-
Mannich reaction and found that with an excess of nitro-
methane the desired product 2a was formed in a high yield.
With increased amounts of both SO2Cl2 and the nucleophile,
the oxidative cyanation with trimethylsilyl cyanide was also
successful. In addition to carbon-based nucleophiles, a
phosphine-based nucleophile, such as dimethyl phosphite, was
found to react smoothly to furnish α-amino phosphonate 2m
with an excellent yield. To further broaden the substrate scope,
the oxidative cyanation reaction was attempted with N,N-
dimethyl-p-toluidine (3), and the desired CDC product was
obtained in a modest yield (Scheme 1).
examined the oxidative coupling reaction using a catalytic
amount of a 1:1 SO2Cl2/H2SO4 mixture (entries 4 and 5).
Although the CDC adduct was obtained in a good yield
using only 3 mol % of SO2Cl2 (entry 4), the addition of sulfuric
acid inhibited the oxidative aza-Mannich reaction, and the
possibility of a synergistic effect was ruled out (entry 5). Thus,
we assume that the CDC reaction proceeds through a radical-
initiated autoxidation mechanism. To confirm the radical-
initiated mechanism, we introduced a stoichiometric amount of
a radical inhibitor, 3,5-di-tert-butyl-4-hydroxytoluene (BHT),
and found that the oxidative nitromethylation reaction was
significantly suppressed (entry 6).12
Based on our control studies, our proposed reaction
mechanism is depicted in Scheme 2. Although a radical-
Scheme 2. Proposed Reaction Mechanism
Scheme 1. Oxidative Cyanation of N,N-Dimethyl-p-
Toluidine
To elucidate the role of SO2Cl2 for the metal-free CDC
reaction with N-aryl tetrahydroisoquinolines, we conducted
additional experiments (Table 4). Although most metal-
a
Table 4. Comparison of Catalysts
b
b
entry
initiator (mol %)
MeSO3H (6)
conv (%)
yield (%)
1
2
3
4
5
6
43
45
7
40
38
7
V-70 (6)
H2SO4 (6)
initiated autoxidation mechanism is most probable, the
mechanism of the initiation step still remains unclear. Initially,
we speculated that SO2Cl2 undergoes homolytic cleavage to
generate chlorine radicals to initiate the CDC reaction.
However, based on the bond dissociation energy of ClSO2−
Cl (46 4 kcal/mol),13 it is highly unlikely that the homolytic
cleavage occurs at room temperature. In addition, the
possibility of a light-mediated chlorine radical formation is
denied since the SO2Cl2-initiated CDC reaction occurs in the
absence of light (Table 1, entry 11). One plausible pathway to
generate the radical initiator is through the chlorination
reaction of tertiary N-aryl amines to form the ammonium
cation A, followed by the homolytic cleavage of the N−Cl bond
to generate aminium cation B and the chlorine radical.14 Once
the chlorine radical is formed, it can abstract the hydrogen atom
from 1 to generate the carbon-centered radical intermediate
C,15 and this radical intermediate can react with molecular
oxygen to provide the oxygen-centered radical D. Subsequently,
intermediate D can abstract the hydrogen atom from 1 to form
alkyl hydroperoxide E and intermediate C to propagate the
autoxidation. Elimination of the hydroperoxide anion, followed
by the nucleophilic addition to iminium intermediate F, would
furnish the desired CDC adduct.16
SO2Cl2 (3)
93
33
30
73
10
22
H2SO4 (3), SO2Cl2 (3)
SO2Cl2 (6), BHT (100)
a
Reaction conditions: amine 1a (0.25 mmol), initiator (0.015 mmol,
10 mol %), MS 4 Å (50 mg) in MeNO2 (0.6 mL) at 30 °C for 18 h
b
1
under a balloon of dry oxygen. Determined by H NMR analysis.
catalyzed aerobic CDC reactions occur through the reoxidation
of the catalyst by oxygen gas, such a scenario is improbable for
SO2Cl2 due to the high oxidation potential of electrophilic
chlorine.11 Thus, we assume that the CDC reaction occurs
through an autoxidation mechanism initiated by either an acid6a
or a radical species.6f Indeed, when we utilized methanesulfonic
acid (entry 1) and 2,2′-azobis(4-methoxy-2,4-dimethyl valer-
onitrile) (V-70) (entry 2) as initiators, the oxidative aza-
Mannich reaction proceeded in moderate yields. Since sulfuric
acid could be generated from the hydrolysis of SO2Cl2, we
examined the possibility of an acid-initiated mechanism by
performing the CDC reaction using a catalytic amount of
sulfuric acid (entry 3). On the basis of the poor conversion, we
believe that the CDC reaction with SO2Cl2 does not proceed
through the acid-initiated pathway. To exclude the possibility of
a synergistic effect between SO2Cl2 and sulfuric acid, we
In summary, we developed a metal-free CDC reaction of
tertiary amines that could proceed under very mild aerobic
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Letter
(i) Alagiri, K.; Prabhu, K. R. Org. Biomol. Catal. 2012, 10, 835. (j) Xie,
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conditions. On the basis of our control studies, we assume that
the SO2Cl2-initiated CDC reaction occurs through a radical-
initiated autoxidation mechanism. Although the reaction
mechanism is classic and simple, the SO2Cl2-initiated aerobic
CDC reaction represents one of the most efficient and green
C−H bond functionalization reactions since a catalytic amount
(2−6 mol %) of an inexpensive reagent is required and the
decomposition products of SO2Cl2 (HCl, SO2, and H2SO4) can
be easily removed by evaporation or aqueous workup.
(6) Catalytic metal-free CDC reactions of tertiary amines using
́
́
oxygen as a terminal oxidant: (a) Pinter, A.; Sud, A.; Sureshkumar, D.;
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
Klussmann, M. Angew. Chem., Int. Ed. 2010, 49, 5004. (b) Pan, Y.;
Wang, S.; Kee, C. W.; Dubuisson, E.; Yang, Y.; Loh, K. P.; Tan, C.-H.
Green Chem. 2011, 13, 334. (c) Pan, Y.; Kee, C. W.; Chen, L.; Tan, C.-
S
H. Green Chem. 2011, 13, 2682. (d) Hari, D. P.; Konig, B. Org. Lett.
̈
2011, 13, 3852. (e) Alagiri, K.; Devadig, P.; Prabhu, K. R. Chem.Eur.
J. 2012, 18, 5160. (f) Liu, L.; Wang, Z.; Fu, X.; Yan, C.-H. Org. Lett.
2012, 14, 5692. (g) Dhineshkumar, J.; Lamani, M.; Alagiri, K.; Prabhu,
K. R. Org. Lett. 2013, 15, 1092. (h) Nobuta, T.; Fujiya, A.; Yamaguchi,
T.; Tada, N.; Miura, T.; Itoh, A. RSC Adv. 2013, 3, 10189.
(7) Tanoue, A.; Yoo, W.-J.; Kobayashi, S. Adv. Synth. Catal. 2013,
355, 269.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp.
Notes
(8) Ciminale, F.; Lopez, L.; Forinola, G. M.; Sportelli, S. Tetrahedron
Lett. 2001, 42, 5689.
The authors declare no competing financial interest.
(9) Kovacic, P.; Sparks, A. K. J. Org. Chem. 1961, 26, 1310.
(10) A plausible explanation for the poor reactivity of the ortho-
substituted N-aryl amine 1d could be due to the inability of the N-aryl
amine to adopt a planar structure necessary to stabilize the radical
intermediate. We thank a reviewer for this suggestion.
(11) The oxidation potential of chlorine is reported to be 1.40 V:
Chow, B. F. J. Am. Chem. Soc. 1935, 57, 1440.
(12) We also examined vitamin E (DL- α-tocopherol) as an
antioxidant (1 equiv) and found that the CDC reaction could not
be suppressed completely (39% of 2a was obtained).
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS), the Global COE Program (Chemistry Innovation
through Cooperation of Science and Engineering), The
University of Tokyo, the Japan Science and Technology
Agency (JST), and the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
(13) Takacs, G. A. J. Chem. Eng. Data 1978, 23, 174.
(14) When a catalytic amount of sulfuryl chloride was added to the
solution of 1a in MeCN, the colorless solution immediately turned
yellow (the solution of N,N-dimethyl-p-toluidine (3) turned blue),
although it turned colorless again when a nucleophile or a
stoichiometric amount of sulfuryl chloride was added. These color
changes may suggest the facile formation of radical species such as the
intermediate B shown in Scheme 2. An alternative pathway to generate
chlorine radicals could be through the direct electron transfer between
the electron-rich N-aryl amine and sulfuryl chloride, followed by the
decomposition of sulfuryl chloride radical anion. We thank a reviewer
for this suggestion.
(15) An alternative mechanistic pathway to access intermediate C is
through the deprotonation of aminium radical B with 1a.
(16) 1H NMR spectra of the crude reaction mixture of 1a and
SO2Cl2 in MeCN under an atmosphere of O2 suggests the presence of
alkyl peroxide intermediate E. Please see the Supporting Information
for additional details.
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