Catalytic C-N bond alkynylation of N-benzylic sulfonamides with terminal alkynes

Article abstract of DOI:10.1002/cjoc.201400194

A new cross-coupling reaction of N-benzylic sulfonamides with terminal alkynes for the synthesis of internal alkynes is reported. In the presence of 5 mol% of (Tf)₂NH/Bi(OTf)₃ (1:1), a broad range of N-benzylic sulfonamides react smoothly with arylacetylenes to afford structurally diverse internal alkynes in moderate to excellent yields. We reasoned that vinyl cations could be formed by the regioselective attack of terminal alkynes with benzyl cations generated in situ from N-benzylic sulfonamides under acidic conditions, which then eliminated to form a carbon-carbon triple bond. An unprecedented synthesis of internal alkynes from N-benzylic sulfonamides and terminal alkynes has been developed through TfOH/Fe(OTf)₃-catalyzed cleavage of C(sp³)-N bonds and C(sp)-H bonds. This protocol is compatible with a broad range of N-benzylic sulfonamides and arylacetylenes. Copyright

Full text of DOI:10.1002/cjoc.201400194

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DOI: 10.1002/cjoc.201400194
Catalytic C－N Bond Alkynylation of N-Benzylic Sulfonamides
with Terminal Alkynes
Congrong Liu,*,a,b Fulai Yang,b and Tingting Wangb
a School of Environment Engineering, Nanjing Institute of Technology, Nanjing, Jiangsu 211167, China
b Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
A new cross-coupling reaction of N-benzylic sulfonamides with terminal alkynes for the synthesis of internal
alkynes is reported. In the presence of 5 mol% of (Tf)2NH/Bi(OTf)3 (1∶1), a broad range of N-benzylic sulfona-
mides react smoothly with arylacetylenes to afford structurally diverse internal alkynes in moderate to excellent
yields. We reasoned that vinyl cations could be formed by the regioselective attack of terminal alkynes with benzyl
cations generated in situ from N-benzylic sulfonamides under acidic conditions, which then eliminated to form a
carbon-carbon triple bond.
Keywords benzylic amines, alkynylation, internal alkynes, carbon nucleophiles, cross-coupling
Introduction
Scheme 1 Coupling of activated primary benzylic amines with
different C－H bonds (EWG＝electron-withdrawing group)
While primary benzylic amines are readily accessi-
ble, they do not serve as useful carbon electrophiles in
chemical synthesis owing to the poor leaving ability of
their amino groups. In this regard, it is necessary to ac-
tivate primary benzylic amines to enhance electrophilic-
ity by modifying their amino groups. A number of stud-
ies show that the C(sp3)－N bonds of primary benzylic
amines are significantly activated by introducing elec-
tron-withdrawing groups to the amine nitrogen atoms
and undergo cleavage when further promoted with ei-
ther Brønsted acids[1-5] or Lewis acids.[6-10] This double
activation approach allows primary benzylic amines to
emerge as useful carbon electrophiles to couple with
C(sp3)－H bonds[9,10a] and C(sp2)－H bonds[1-4,6-8,10a]
under various acidic conditions (Scheme 1). To our
knowledge, there has been no report on the coupling of
C(sp) － H bonds with activated primary benzylic
amines.
C(sp3)
ref. 9 and 10a
H
R
C(sp3)
C(sp2)
C(sp)
Ar
EWG
C(sp2)
ref. 1－4, 6－8, and 10a
H
R
R
H
H
R
N
N
Ar
Ar
Ar
H
C(sp)
H
R
This work
Ar
intramolecular Friedel-Crafts reaction (Scheme 2).[11] In
this context, switching reaction conditions might result
in deprotonation of the vinyl cations to give internal
alkyne.[12]
Recently we discovered a FeCl3-catalyzed [3＋2]
annulation reaction of sulfonyl-activated primary ben-
zylic amines (N-benzylic sulfonamides) with disubsti-
tuted alkynes for the synthesis of indene derivatives.[10b]
However, this protocol was not applicable at all to ter-
minal alkynes. We reasoned that analogous vinyl
cations could be formed by the regioselective attack of
terminal alkynes with benzyl cations generated in situ
from N-benzylic sulfonamides through C(sp3)－N bond
cleavage under acidic conditions, but they would prefer
to stay farther away from the internal aromatic rings and
consequently, ring closure could not occur through an
Herein, we wish to report a new coupling reaction of
activated primary benzylic amines with terminal alkynes
for the synthesis of internal alkynes through the cleav-
age of C(sp3)－N bonds and C(sp)－H bonds in the
presence of acidic catalysts (Scheme 1).
To test our hypothesis, we evaluated a number of
Brønsted acids and Lewis acids (5 mol%) in the model
reaction of p-toluenesulfonyl-activated benzhydryl-
amine (sulfonamide 1aa) with phenylacetylene (2a) in 1,
2-dichloroethane at 90 ℃ (Table 1, Entries 1－8). The
best catalytic activity was observed with (Tf)2NH,
which promoted the reaction to afford internal alkyne 3a
*
E-mail: congrong@njit.edu.cn; Tel: 0086-025-86118974; Fax: 0086-025-86118972
Received March 30, 2014; accepted May 2, 2014; published online May 22, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400194 or from the author.
Chin. J. Chem. 2014, 32, 387—390
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Liu, Yang & Wang
COMMUNICATION
Scheme 2 Possible reaction pathway for the formation of inter-
nal alkynes (for simplicity, proton represents an acidic catalyst)
p-toluenesulfonyl-activated primary benzylic amines. In
the presence of 5 mol% of (Tf)2NH/Bi(OTf)3 (1∶1), a
range of N-diarylmethyl sulfonamides smoothly coupled
with terminal alkyne 2a to afford structurally diverse
internal alkynes in good yields (Table 2, 3a－3f). This
cross-coupling reaction allowed the synthesis of skipped
enynes and diynes from the corresponding N-arylvinyl-
methyl and N-alkynylarylmethyl sulfonamides, respec-
tively, and no rearrangement was observed for the car-
bon-carbon multiple bonds in the reaction (Table 2, 3g
and 3h). Moreover, the C(sp3)－N bonds of N-mono-
benzylic sulfonamides were also able to be cleaved un-
der the same reaction conditions and underwent cross-
coupling reaction with terminal alkyne 2a to afford the
desired alkyne products in moderate yields (Table 2, 3i
－3m). This cross-coupling reaction was not applicable
to less reactive N-benzylic sulfonamides such as
N-benzyl-p-toluenesulfonamide.[13]
R1
R1
H+
Ts
N
R2
R2
H
R3
TsNH2
R1
R1
H
R3
R2
R2
R3
R1
H
H+
R1
R2
H
R2
R3
R3
in 54% yield (Table 1, Entry 4). Doubling the amount of
(Tf)2NH improved the yield to 70% (Table 1, Entry 8)
and more excitingly, significantly higher yield (85%)
was obtained by combined use of (Tf)2NH and Bi(OTf)3
in a 1∶1 ratio (Table 1, Entry 9). The yield was found
to decrease dramatically when replacig 1,2-dichloro-
ethane with a few other organic solvents (Table 1, En-
tries 10－12). Moreover, the efforts to enhance yield
proved fruitless by activating benzhydrylamine with
several other electron-withdrawing groups such as Ms,
POPh2, COPh, and Cbz (Table 1, Entries 13－16).
Table 2 Cross-coupling of N-benzylic sulfonamides with al-
kyne 2aa,b
(Tf)2NH/Bi(OTf)3
Ts
R1
R2
Cl
R1
R2
(1:1, 5 mol%)
+
Ph
3a - 3m
N
Ph
DCE, 90 oC, 1 d
H
1
2a
Ph
Ph
Cl
Ph
Ph
The substrate scope is broad with respect to
3a, 85%
Ph
3b, 70%
Ph
Ph
Ph
3c, 77%
Table 1 Optimization of reaction conditionsa
Me
EWG
H
Ph
Ph
Ph
Ph
Ph
catalyst, solvent
90 oC, 24 h
Ph
+
N
Ph
Ph
S
Ph
1a
2a
3a
3d, 80%
3e, 84%
Yieldb/
%
Ph
3f, 71%
Entry
a
EWG
Catalyst/mol%
Solvent
Ph
1
2
3
4
5
6
7
8
9
1aa Ts
1aa Ts
1aa Ts
1aa Ts
1aa Ts
1aa Ts
1aa Ts
1aa Ts
1aa Ts
TsOH (5)
H2SO4 (5)
TfOH (5)
(Tf)2NH (5)
Sc(OTf)3 (5)
Fe(OTf)3 (5)
Bi(OTf)3 (5)
(Tf)2NH (10)
DCE trace
Ph
Me
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10
43
54
27
45
52
70
85
Ph
Ph
Ph
3g, 66%
Ph
Me
3h, 61%
R
3i, 55%
MeO
Ph
Me
3j, R = Me, 60%
3k, R = OMe, 53%
Ph
(Tf)2NH/Bi(OTf)3 (1∶1, 5) DCE
Ph
10 1aa Ts
11 1aa Ts
12 1aa Ts
13 1ab Ms
(Tf)2NH/Bi(OTf)3 (1∶1, 5) MeNO2 48
(Tf)2NH/Bi(OTf)3 (1∶1, 5) dioxane 39
(Tf)2NH/Bi(OTf)3 (1∶1, 5) DMF trace
3l, 64%
3m, 40%
a
Reaction conditions: sulfonamide 1 (0.20 mmol), alkyne 2a
(0.30 mmol), (Tf)2NH/Bi(OTf)3 (1∶1, 5 mol%), 1,2-dichloro-
ethane (2.0 mL), 90 ℃ (oil bath), 1 d. Isolated yields are
(Tf)2NH/Bi(OTf)3 (1∶1, 5) DCE
72
b
14 1ac POPh2 (Tf)2NH/Bi(OTf)3 (1∶1, 5) DCE trace
15 1ad POPh (Tf)2NH/Bi(OTf)3 (1∶1, 5) DCE 25
shown.
16 1ae Cbz (Tf)2NH/Bi(OTf)3 (1∶1, 5) DCE trace
Reaction conditions: benzhydrylamine derivative 1a (0.20
mmol), alkyne 2a (0.30 mmol), catalyst, solvent (2.0 mL), 90 ℃
(oil bath), 24 h. b Isolated yield.
a
The cross-coupling reaction was found to occur
smoothly between terminal alkyne 2a and a p-toluene-
sulfonyl-activated secondary benzylic amine. For ex-
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Chin. J. Chem. 2014, 32, 387—390

Catalytic C－N Bond Alkynylation of N-Benzylic Sulfonamides with Terminal Alkynes
ample, internal alkyne 3a was obtained in 89% yield
from the reaction of sulfonamide 4 with terminal alkyne
2a in the presence of 5 mol% of (Tf)2NH/Bi(OTf)3 (1∶
1) (Equation 1). It is noteworthy that the monobenzylic
C(sp3)－N bond of sulfonamide 4 was not cleaved at all,
which is consistent with our aforementioned observation
with the reaction of N-benzyl-p-toluenesulfonamide
under the same conditions.
cals were purchased from the Sinopharm Chemical Re-
agent Co., Meryer, Acros, Alfa Aesar, and AstaTech
Pharmaceutical Co., and used as received. All the sol-
vents were freshly distilled over CaH2 before use.
Table 3 Cross-coupling of sulfonamide 1aa with terminal al-
kynesa,b
Ts
+
Ph
Ph
Ph
Ph
(Tf)2NH/Bi(OTf)3 (1:1, 5 mol%)
DCE, 90 oC, 1d
3
R3
N
R
Ts
Ph
Ph
(Tf)2NH/Bi(OTf)3 (1:1, 5 mol%)
DCE, 90 oC, 1 d
H
1aa
2
3n - 3s
(1)
+
2a
3a
N
Ph
89%
Ph
Ph
Ph
4
Br
F
Ph
3o, 88%
3n, 91%
3p, 63%
We also examined the reaction of terminal alkyne 2a
with an optically active N-benzylic sulfonamide. As
demonstrated by Equation 2, the reaction of sulfona-
mide (R)-1ka (95% ee) with terminal alkyne 2a pro-
ceeded smoothly in the presence of 5 mol% of (Tf)2NH/
Bi(OTf)3 (1∶1) to afford internal alkyne 3k in nearly
racemic form (6% ee). This result substantially supports
our proposed reaction pathway depicted in Scheme 2,
wherein a benzyl cation is involved at an early stage of
the reaction.
Ph
Ph
Ph
Me
Me
Me
Me
Ph
3q, 75%
Cl
F
Ph
Ph
Ph
Ph
3r, 70%
3s, 69%
a Reaction conditions: sulfonamide 1aa (0.20 mmol), alkyne 2
(0.30 mmol), (Tf)2NH/Bi(OTf)3 (1∶1, 5 mol%), 1,2-dichloroeth-
ane (2.0 mL), 90 ℃ (oil bath), 1 d. b Isolated yields are shown.
Ts
H
Me
N
(Tf)2NH/Bi(OTf)3 (1:1, 5 mol%)
DCE, 90 oC, 1 d
(2)
3k
+ 2a
50%
6% ee
General procedure for the cross-coupling of N-ben-
zylic sulfonamides with terminal alkynes (Tables 2
and 3)
MeO
(R)-1ka (95% ee)
To a solution of N-benzylic sulfonamide 1 (0.20
mmol) in dry 1,2-dichloroethane (2.0 mL) under nitro-
gen were successively added terminal alkyne 2 (0.30
mmol), Bi(OTf)3 (13.1 mg, 0.020 mmol), and (Tf)2NH
(5.6 mg, 0.020 mmol, dissolved in 0.20 mL of DMF).
The mixture was heated at 90 ℃ (oil bath) for 24 h,
cooled to room temperature, and purified by column
chromatography on silica gel, eluting with petroleum
ether, to give product 3 (Tables 2 and 3).
Finally, a range of arylacetylenes were found to be
able to couple with sulfonamide 1aa in the presence of 5
mol% of (Tf)2NH/Bi(OTf)3 (1∶1) to afford the corre-
sponding internal alkynes in good to excellent yields
(Table 3). By contrast, no reactivity was observed with
alkylacetylenes such as 1-hexyne. As demonstrated by
the results summarized in Tables 2 and 3, a variety of
heteroatoms and alkyl groups were successfully intro-
duced into the internal alkynes by employing function-
alized N-benzylic sulfonamides and terminal alkynes.
Conclusions
Experimental
In summary, we have developed a new cross-
coupling reaction of N-benzylic sulfonamides with ter-
minal alkynes for the synthesis of internal alkynes
through the cleavage of C(sp3)－N bonds and C(sp)－H
bonds under acidic conditions. In the presence of 5
mol% of (Tf)2NH/Bi(OTf)3 (1∶1), a broad range of
N-benzylic sulfonamides react smoothly with arylacety-
lenes to afford structurally diverse internal alkynes in
moderate to excellent yields. Current efforts are directed
toward further synthetic applications of activated ben-
zylic amines as carbon electrophiles.
General information
1H and 13C NMR spectra were recorded on a Bruker
AC-300 FT spectrometer (300 and 75 MHz, respec-
tively) or a Bruker AC-400 FT spectrometer (400 and
100 MHz, respectively) using tetramethylsilane as an
internal reference. High pressure liquid chromatography
(HPLC) analyses were performed on a Hewlett-Packard
1200 Series instrument equipped with an isostatic pump
and a Daicel Chiralpak AS column (250 mm×4.6 mm),
and the UV detection was monitored at 254 nm. Melting
points were uncorrected. N-Benzylic sulfonamides and
other benzhydrylamine derivatives were prepared ac-
cording to literature procedures.[14] The rest of chemi-
Acknowledgement
We are grateful for the financial support from the
Chin. J. Chem. 2014, 32, 387—390
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
389

Liu, Yang & Wang
COMMUNICATION
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 387—390