Nickel-catalyzed α-benzylation of sulfones with esters: Via C-O activation

Article abstract of DOI:10.1039/c6ra07130a

The nickel-catalyzed α-benzylation of sulfones with readily available benzylic alcohol derivatives was achieved via C-O activation. The transformation was complete in 30 minutes using a simple Ni(COD)₂ as a catalyst without any additional ligan

Full text of DOI:10.1039/c6ra07130a

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Nickel-Catalyzed α-Benzylation of Sulfones with Esters via C-O
Activation
Jing Xiao,a Jia Yang,a Tieqiao Chena* and Li-Biao Hana,b*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The nickel-catalyzed α-benzylation of sulfones with readily
In recent years, C-O compounds such as benzyl alcohols
available benzylic alcohol derivatives was achieved via C-O and phenol derivatives have attracted much attention as the
activation. The transformation was complete in 30 minutes using a green and inexpensive coupling reagents replacing the
simple Ni(COD)2 as a catalyst without any additional ligands. A halocompounds in metal-mediated coupling reactions.4,5 It
variety of substituted sulfones including the building block for would be appealing to achieve the α-benzylation of simple
bioactive compound eletriptan were synthesized by using the sulfones for the preparation of substituted sulfones by cross-
strategy.
coupling of hydrocarbons with C-O compounds via C-O
activation. Herein, we report a Ni-catalyzed α-benzylation of
Sulfones are valuable common intermediates in organic
synthesis.1 They are also key motifs in many biologically active
compounds as exemplified by amisulpride, dapsone, casodex
and eletriptan (Figure 1).2 The α-alkylation of simple sulfones is
one of the most useful methods to access these functional
sulfones.2 This process traditionally uses nucleophilic
substitution reactions (the couplings of sulfones with alkyl
halides in the presence of a stoichiometric amount of base
such as n-BuLi and LiN(SiMe3)2), in which other functionalities
could be damaged.3
Table 1. Ni-catalyzed cross coupling of benzylic pivalate with methyl phenyl sulfone.a
Run
1
Ligand
PCy3
Base (equiv)
t-BuONa (1.5)
t-BuONa (1.5)
t-BuONa (1.5)
t-BuONa (1.5)
t-BuONa (1.5)
t-BuONa (1.5)
t-BuONa (1.5)
t-BuONa (2.0)
t-BuONa (2.0)
t-BuONa (2.0)
t-BuONa (2.0)
t-BuONa (2.0)
t-BuOLi (2.0)
t-BuOK (2.0)
2a (equiv)
1.2
T (min)
60
60
60
60
60
60
60
60
60
30
15
5
Yieldb
55%
40%
28%
17%
38%
52%
63%
74%
73%
75%
71%
36%
N.D.
trace
52%
N.D.
59%
53%
N.D.
2
dcype
dppp
binap
xantphos
none
none
none
none
none
none
none
none
none
none
none
none
none
none
1.2
3
1.2
4
1.2
5
1.2
6
1.2
7
1.5
8
2.0
9
2.5
10
11
12
13
14
15c
16d
17e
18f
19g
2.0
2.0
2.0
2.0
30
30
30
30
30
30
30
2.0
t-BuONa (2.0)
t-BuONa (2.0)
t-BuONa (2.0)
t-BuONa (2.0)
t-BuONa (2.0)
2.0
2.0
2.0
Figure 1. Selected examples of bioactive aryl sulfones
.
2.0
2.0
aConditions: a mixture of 1a (0.2 mmol), 2a, Ni(COD)2 (0.02 mmol), a phosphine
ligand (P/Ni = 2:1) and a base in toluene (0.5 mL) was stirred at 100 oC for the
time indicated. bGC yield using tridecane as an internal standard. cIn dioxane. dIn
DMF. e80 oC. f120 oC. gIn the absence of nickel catalyst.
a.State Key Laboratory of Chemo/Biosensing and Chemo metrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
E-mail: chentieqiao@hnu.edu.cn
b.National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba,
Ibaraki 305-8565, Japan. E-mail: libiao-han@aist.go.jp
simple sulfones with the readily available benzylic alcohol
derivatives. This transformation is complete in 30 minutes with
Electronic Supplementary Information (ESI) available: [General information, typical
procedure, characterized data, copies of 1H and 13C NMR spectra]. See
DOI: 10.1039/x0xx00000x
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high selectivity for the mono-benzylation product. Moreover, cross-coupling between 1a and 2a took place smoothly in
o
unlike C-O functionalization where phosphine ligands or toluene at 100 C to produce the corresponding product 3a in
carbene ligands are usually required, this reaction can occur 52% yield (entry 6). When 2.0 equiv t-BuONa and 2.0 equiv 2a
efficiently in the presence of Ni(COD)2 without any additional were loaded, 74% yield of 3a was generated (entry 8). Further
ligands. This transformation provides an alternative method increasing the amount of 2a to 2.5 equiv did not improve the
for the α-benzylation of simple sulfones.
reaction efficiency (entry 9). The cross-coupling reaction
proceeded fast and could be complete in 30 minutes (entries
10-12). t-BuONa was essential for this reaction, as none or only
a trace amount of 3a was detected under similar reaction
conditions when t-BuOK or t-BuOLi was used (entries 13 and
14). As for the solvent, the transformation also proceeded
readily in dioxane, but poorly in DMF (entries 15 and 16).
Whether elevating or lowering the reaction temperature
would reduce the yield of the product (entries 17 and 18). The
nickel catalyst was also essential. In the absence of Ni(COD)2,
no trace amount of product could be detected (entry 19).
Worth noting is that no dibenzylated by-product was detected
during the reaction. The main side-product of this reaction is
3,3-dimethyl-1-(phenylsulfonyl)butan-2-one via acylation,
which may also act as the ligand in the catalytic system.6
Table 2. Scope in sulfone compounds.a
O
S
O
3
O
OPiv
+
cat. Ni
Ar
S
Ar
O
1
2
O
S
O
O
S
Ph
Ph
Ph
S
O
O
O
R
R = o-OMe, 3c: 61%
R = m-OMe, 3d: 77%
R = p-OMe, 3e: 75%
3a: 71%
3b: 74%
O
S
O
Table 3. Scope in benzylic alcohol derivatives.a
Ph
Ph
S
O
O
O
S
O
3
(Me)2N
O
S
OR1
+
Ph
N
3g: 69%
cat. Ni
3f: 41%
Ar
O
S
O
Ph
Ar
O
Ph
S
1
2
O
O
O
O
3i: 83%
N
3h: 81%
N
N
S
O
S
O
S
O
S
Ph
Ph
Ph
Ph
O
3a: R1=OC(O)(OPr-i), 63%
3o: 73%
O
O
F
OMe
N
N
O
O
S
3k: 32%
S
3j: 53%
N
S
Ph
O
O
S
Ph
O
t-Bu
O
Ph
Ph
S
3q: 62%
3p: 76%
t-Bu
OPh
O
O
O
O
S
O
S
3m: 71%
t-Bu
3l: 67%
O
Ph
Ph
O
Ph
3r: 84%
3s: 65%
S
CF3
O
O
O
S
O
S
3n: 66%
Ph
Ph
O
3tb: 31%
trace
R
aConditions: 1 (0.2 mmol), 2 (0.4 mmol), Ni(COD)2 (10 mol%), t-BuONa (0.4
mmol), toluene (0.5 mL), 100 oC, 0.5 h. Isolated yield.
3ub
O
R = H,
: 46%
R = Me, 3vb: 67%
R = F, 3wb: 56%
S
Ph
We chose benzyl pivalate 1a and methyl phenyl sulfone
2a as the model reaction and the obtained results were
compiled in Table 1. Phosphine ligands or carbene ligands
O
aConditions: 1 (0.2 mmol), 2 (0.4 mmol), Ni(COD)2 (10 mol%), t-BuONa (2.0 equiv),
toluene (0.5 mL), 100 oC, 0.5 h. Unless otherwise noted, R1 = C(O)Bu-t. Isolated
yield. b80 oC.
showed
a
dramatic effect in nickel-catalyzed C-O
functionalization,4,5 however it was found that this
transformation could take place in the presence of the simple
Ni(COD)2 without any additional ligands (entries 1-6). Thus, in
the presence of 10 mol% Ni(COD)2 and 1.5 equiv t-BuONa, the
This transformation is applicable to other substrates. As
shown in Table 2, a variety of sulfones coupled with benzylic
esters produced the corresponding products in good yields
2 | J. Name., 2012, 00, 1-3
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under the present reaction conditions. Thus, substrates 2, 3a was obtained in 65% isolated yield in 7 mmol scale under
bearing functional groups such as methyl, methoxy (o, m, p- the standard reaction conditions.
position), phenyl and amine on the benzene ring could all
readily couple with benzyl pivalate, giving the corresponding
substituted sulfones in moderate to good yields (3a-3g).
Heterocylic-containing sulfones such as pyridine, pyrimidine,
tetrazole and thiophene also served well and the
corresponding substituted sulfones were generated
successfully (3h–3k). Alkenyl and alkynyl groups survived in the
current catalytic system, facilitating further functionalization
of the coupling products. 2-(Methylsulfonyl)naphthalene 2n
was also converted to the corresponding sulfones in 66% yield
under the standard reaction conditions.
The substrate scope of benzylic alcohol derivatives was
further explored. As shown in Table 3, a carbonate coupled
with 2a smoothly, giving the corresponding sulfone 3a in 63%
yield. Benzylic alcohol pivalates containing methyl, methoxy,
fluorine and t-Bu groups performed well in this catalytic
system. Derivative with an easily hydrogenolytic group
phenoxy was also proved to be a good coupling partner under
the present reaction conditions and the corresponding
coupling product 3s was produced in 65% yield.7 However,
substrate bearing electron-withdrawing group CF3 gave only a
trace amount of product. Naphthylmethyl pivalates all went
through this transformation to give the corresponding
products in moderate to good yields (3t-3w). No trace amount
of product was detected when phenyl pivalate was used as
substrate in the catalytic system.
Scheme 3. KIE experiments.
In order to gain insight into the reaction mechanism, two
separate kinetic isotope effect (KIE) experiments were carried
out. A kinetic isotope effect (kH/kD = 1.08) was obtained,
indicating that the C-H cleavage perhaps was not the rate-
determining step in the reaction (scheme 3).
Scheme 1. Synthesis of building block for bioactive molecule eletriptan.
Scheme 4. Proposed mechanism for the Ni-catalyzed cross-coupling between sulfones
The building block for the bioactive molecule eletriptan
was synthesized successfully by using the present cross-
coupling strategy (Scheme 1). Pivalate 1l generated via
methylation and esterification of the commercially available
indole-5-methanol readily reacted with methyl phenylsulfone,
producing the corresponding product 3x in 73% yield. Sulfone
3x could be converted to N-methylated eletriptan using
literature methods.8 Thus, our method could be a new
alternative method for the synthesis of eletriptan.9
and benzylic alcohol derivatives.
Although the mechanism is not fully understood yet, on
the basis of the above results and previous investigations,5,10-12
a plausible mechanism is proposed in Scheme 4. Ni(0) complex
A
firstly adds to benzylic alcohol derivatives via oxidative
addition,10 generating complex
, followed by ligand exchange
with sulfone by the aid of a base to yield . Reductive
elimination of produces the corresponding coupling product
and regenerates Ni(0) complex
B
C
C
3
A.
Conclusions
In summary, we have achieved the α-benzylation of
sulfones using the readily available benzylic alcohol derivatives
(ester, carbonate) as the alkylating reagent. The simple
Ni(COD)2 without any additional ligands enables this
transformation to complete in half an hour, providing an
alternative practical method for the synthesis of various
Scheme 2. Gram-scale synthesis of 3a.
It should be noted in the present catalytic system, 3a
could be readily prepared in gram scales. As shown in Scheme
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6
Under the standard conditions, the model reaction
proceeded readily to generate the product 3a and side-
product 4a in 75% and 21% GC yield, respectively (eq 1).
After purification of 4a, we performed a control experiment
(eq 2). We found the yield of product 3a was increased from
75% to 89% by addition of 10 mol% 4a. It is reasonable to
deduce that 4a may act as the internal ligand.
valuable sulfones including the building block of bioactive
compound eletriptan.
Acknowledgment
Partial financial supports from NSFC (21373080, 21573064,
21403062), HNNSF 2015JJ3039, the Fundamental Research
Funds for the Central Universities (Hunan University) are
gratefully acknowledged.
1)
OPiv
+
O
O
O
S
O
S
S
10 mol% Ni(COD)2, 2eq. t-BuONa
0.5 mL toluene, 100 o
+
O
O
O
C
2a
4a:
21% GC yield
3a
: 75% GC yield
1a
2)
OPiv
+
4a
: 10 mol%
O
O
S
S
10 mol% Ni(cod)2, 2eq. t-BuONa
O
Notes and references
O
0.5 mL toluene, 100 o
C
3a
: 89% GC yield
1
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4 | J. Name., 2012, 00, 1-3
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Nickel-Catalyzed α-Benzylation of Sulfones with Esters via C-O Activation
Jing Xiao, Jia Yang, Tieqiao Chen and Li-Biao Han
The nickel-catalyzed α-benzylation of sulfones with readily available benzylic alcohol
derivatives was achieved via C-O activation. The transformation was complete in 30 minutes
using a simple Ni(COD)2 as a catalyst without any additional ligands. A variety of substituted
sulfones including the building block for bioactive compound eletriptan were synthesized by
using the strategy.