Methylenation for Aldehydes and Ketones Using 1-Methylbenzimidazol-2-yl Methyl Sulfone

Article abstract of DOI:10.1021/acs.joc.0c01227

The methylenation reagent 1-methylbenzimidazol-2-yl methyl sulfone 2 reacts with various aldehydes and ketones in the presence of t-BuOK (room temperature, 1 h) in dimethylformamide to give the corresponding terminal alkenes generally in high yields. For sensitive substrates, the reaction is better carried out at low temperature using sodium hexamethyldisilazide in 1,2-dimethoxyethane. The byproduct is easily removed from the products, and the reaction conditions are mild and practical. Reagent 2 can be easily prepared from commercially available 2-mercaptobenzimidazole 5 in 95% yield without any expensive reagents.

Full text of DOI:10.1021/acs.joc.0c01227

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Article
Methylenation for Aldehydes and Ketones Using
-Methylbenzimidazol-2-yl (MBI) Methyl Sulfone
1
Kaori Ando, Mai Oguchi, Takahisa Kobayashi, Haruka Asano, and Nariaki Uchida
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01227 • Publication Date (Web): 01 Jul 2020
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Methylenation for Aldehydes and Ketones Using
1
-Methylbenzimidazol-2-yl (MBI) Methyl Sulfone
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Kaori Ando,* Mai Oguchi, Takahisa Kobayashi, Haruka Asano, Nariaki Uchida
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University,
Yanagido 1-1, Gifu 501-1193, Japan
ando@gifu-u.ac.jp
Abstract: Methylenation reagent, 1-methylbenzimidazol-2-yl methyl sulfone 2 reacts with various
aldehydes and ketones in the presence of t-BuOK (rt, 1 h) in DMF to give the corresponding
terminal alkenes generally in high yields. For sensitive substrates, the reaction is better carried out
at low temperature using NaHMDS in DME. The byproduct is easily removed from the products
and the reaction conditions are mild
and practical. The reagent 2 can be
easily prepared from commercially
available 2-mercaptobenzimidazole
5
in 95% yield without any
expensive reagents.
Introduction
The synthesis of alkenes from carbonyl compounds is one of the most fundamental reactions
in organic synthesis. Since terminal alkene structures are not only found in many natural products
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but also used as substrates for many synthetic reactions such as olefin metathesis and sigmatropic
1
reactions, their preparation has been studied intensively. Many methylenation reagents such as
2
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Wittig and Peterson reagents were developed by along with gem-dimetallic reagents such as
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Tebbe reagent, Petasis reagent and others. Transition metal-catalyzed methylenation reactions
7
were also reported. These methods are useful and are often used for the synthesis of bioactive
compounds, but the methylenation reactions may give disappointing yields or fail in some cases.8
Because it depends only on subtle substrate differences, new practical reagents for the
methylenation reaction still need to be developed. The Julia-Kocienski reaction (one-pot Julia
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olefination) is a very efficient tool for the synthesis of E-alkenes, and four methylenation reagents
1a-1d of Julia-Kocienski reaction have been reported (Scheme 1). Julia and co-workers studied
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the methylenation reaction briefly with the benzothiazol-2-yl (BT) methyl sulfone 1a and Nájera
1
1
and co-workers studied the reaction of 3,5-bis(trifluoromethyl)phenyl methyl sulfone 1b. These
reagents gave only low to moderate yields. 1-Phenyl-1H-tetrazol-5-yl (PT) methyl sulfone 1c, the
12
methyl version of the Kocienski reagent, has been used in several total syntheses of natural
1
3
products. Aïssa prepared 1-tert-butyl-1H-tetrazol-2-yl (TBT) methyl sulfone 1d which reacted
14
with a variety of aldehydes and ketones to give terminal alkenes in moderate to high yields, and
1
5
1
d was also used in some total syntheses of natural products. Since Kocienski and co-workers
demonstrated that the anions derived from the TBT alkyl sulfones were more stable than the PT
counterparts, 1d was considered better than 1c. However, there is room for improvement in yields
and the high cost is a drawback of using 1d, so we felt the need to develop a more practical reagent
for the methylenation reaction. During our study on the stereoselective Julia-Kocienski reaction,16
17
we prepared 1-methylbenzimidazol-2-yl (MBI) methyl sulfone 2, which reacted with a variety
of aldehydes and ketones in the presence of either NaHMDS (-55 °C to rt) or t-BuOK (rt, 1 h) in
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DMF to give the corresponding terminal alkenes 4 generally more than 90% yield and the
1
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byproducts are easily removed by either basic aqueous work-up or filtration (Scheme 1). In this
paper, we would like to report full details of our study on the methylenation reaction of aldehydes
and ketones with 1-methylbenzimidazol-2-yl (MBI) methyl sulfone 2.
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Scheme 1. Julia-type methylenation reagents 1 and our reagent 2
1
. Results and Discussion
The reagent 2 was prepared by dimethylation of 2-mercaptobenzimidazole 5 using NaH and
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MeI in THF and following oxidation with Oxone in 92% yield. However, the dimethylation of 5
proved difficult to scale up because the sodium salt of 5 is not soluble in THF, so the reaction
conditions were reoptimized. When a THF solution of 5 was treated with NaH (2.6 eq) at 0 ºC,
large amount of white solid formed, and the reaction mixture could not be stirred. After addition
of MeI (3.0 eq) at 0 °C, the white solid was gradually dissolved by the reaction with MeI at room
temperature to give 1-methyl-2-methylthiobenzimidazole 6 in 97% yield (entry 1 in Table 1).
Although the yield of 6 was high, the isolation procedure was cumbersome because the product
became a mixture of solid and oil. Changing the solvent to more polar DMF allowed stirring, but
part of the product was dissolved in water with DMF and the yield decreased to 87% (entry 2).
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When the reaction was carried out using dimethyl sulfate (1.3 eq) and NaOH (3 eq) in DMF, the
reaction was slow, and 6 was obtained in only 26% yield along with the sulfide 6’ (30%) and 5
after 92 h (entry 3). Since 5 is poorly soluble in MeOH, 5 was treated with NaOMe (3.9 eq) in
MeOH-THF (1:1) and reacted with MeI (2.9 eq) at room temperature. Dimethylation reaction
proceeded to give 6 in 83% yield after 2 h (entry 4). When triethylamine (3.0 eq) was used as a
base in THF, only the monomethylation occurred and the sulfide 6’ was obtained in 78% yield
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(entry 5). Finally, water was selected as the solvent and the reaction was carried out using KOH
(2.3 eq) in water-THF (4:1). After 3 h the reaction was completed and 6 was obtained in 96% yield
(entry 6). When MeI (2.3 eq) was added at 0 ºC, the crude yield of 6 improved to 99.7% (entry 7).
Table 1. Dimethylation reaction of 5
entry
base (eq)
NaH (2.6)
NaH (2.4)
NaOH (3.0)
solvent [M]
THF [0.25]
DMF [0.5]
DMF [0.5]
MeI (eq) time 6 (%)
1
2
3
4
5
6
7
2.8
1 h
1 h
92 h
2 h
6 h
3 h
3 h
97
2.4
87
1.3a
26b
NaOMe (3.9) MeOH-THF(1:1) [0.5]
2.9
2.3
2.3
2.3
83
-b,c
3
Et N (3.0)
THF [0.2]
KOH (2.3)
KOH (2.3)
H
H
2
O-THF(4:1) [0.4]
O-THF(4:1) [0.4]
96c
99.7d
2
2
2 4
0 mmol scale except for entries 4 and 5, which were performed in 10 and 2 mmol scale, respectively. [a] Me SO was
used instead of MeI. [b] 6’ was obtained in 30% yield in entry 3 and 78% yield in entry 5. [c] MeI was added at rt. [d]
crude yield.
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The oxidation of sulfide 6 was also reoptimized (Table 2) and the method of work-up proved
to be very important. We reported oxidation of 6 with Oxone (2KHSO
5
·KHSO
O (1:1) gave the MBI-sulfone 2 in 92% yield, but running the reaction again gave 79% yield
on a 20 mmol scale (entry 1). The same reaction gave 76% yield in EtOH-H O (1:1) (entry 2).
Therefore, we decided to reexamine some oxidation reagents. Using KMnO in AcOH-H O, 2 was
obtained in 54% yield (entry 3). Oxidation using m-CPBA (3.0 eq) gave 2 in 62% yield, and H
4
·K
2
SO ) in MeOH-
4
1
8
H
2
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2
O
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oxidation catalyzed by (NH
4
)
6
Mo
7
O
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gave 2 in 14% yield along with 2’ (85% yield) (entries
21
4
-5). As excess H
2
O
2
was used in entry 5, the remaining H
2
O
2
was destroyed with Na
2
S
2
O
3
when
the reaction was complete. The same reaction was carried out in the same procedure and it was
found that 2’ was formed by the addition of aq. Na . Thus, 2’ appears to have been generated
by a nucleophilic attack of Na on the ipso carbon of 2, followed by desulfonylation. To
confirm this, sulfone 2 was treated with sat. aq. Na in EtOH. Unexpectedly, the reaction
proceeded rapidly, giving 7 (80%) as a major product with a small amount of 2’ (12%) (Scheme
). Thus, 7 is formed by the attack of an oxygen nucleophile, and the Mo catalyst may be involved
in the formation of 2’. Upon quenching with aq. Na SO , sulfone 2 was obtained in 94% yield
entry 6). In entry 7, the crude 6 from entry 7 in Table 1 was oxidized on a 20 mmol scale to give
2
S
2
O
3
2
S
2
O
3
2
S
2
O
3
2
2
2
2
3
(
2
in 95% yield from 5 in two steps and one isolation. This procedure is easy and reproducible.
Table 2. Oxidation of the sulfide 6 to the sulfone 2
entry
[O] (eq)
solvent
MeOH-H O (1:1)
EtOH-H O (1:1)
time
5 h
2 (%)
79
1
2
Oxone (3.0)
Oxone (3.0)
2
2
5 h
76
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KMnO
4
(3.6)
AcOH-H
CH
2
O (2:1)
45 h
19 h
17 h
1 h
54
62
m-CPBA (3.0)
2
Cl
2
35% H
35% H
35% H
2
2
2
O
O
O
2
2
2
-cata
-cata
-cata
EtOH
EtOH
EtOH
14bc
94d
95d,e
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1 h
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4
-4 mmol scale except for entries 1 and 7, which were performed in 20 mmol scale. [a] H
O (0.1 eq). [b] 2’ was obtained in 85% yield. [c] The reaction was quenched with aq. Na
SO . [e] Yield from 5 by using 6 (entry 7 in Table 1).
2
O
2
(9 eq) and (NH
4 6 7 24
) Mo O -
H
2
2 2 3
S O . [d] The reaction was
quenched with aq. Na
2
3
Scheme 2. Reaction of 2 with sat. aq. Na
2
S
2
O in EtOH
3
The methylenation reaction using 2 was first carried out with p-methoxyacetophenone 3a.
Since the Julia-Kocienski reactions are generally more efficient using a Barbier-type procedure,
the solution of 2 was treated with base in the presence of 3a. The results are summarized in Table
3. When 1.3 eq of NaHMDS was added to a solution of 3a and 2 (1 eq) in THF at -78 °C and the
resulting mixture was gradually warmed to room temperature over 2 h, 42% yield of the alkene 4a
was obtained along with 2 (34%), 3a (50%), and 7 (entry 1). LiHMDS and KHMDS were less
effective, and 4a was obtained in slightly higher 54% yield using NaHMDS in DME (-55 °C to rt)
(
entries 2-4). Using DMF as solvent increased the yield to 79% and increasing the amount of
NaHMDS (1.7 eq) resulted in 88% yield (entries 5-6). The more practical conditions for the
methylenation reaction of 3a with 2 were further studied. Following the Aïssa’s procedure,14a
a
suspension of Cs
2
CO (3 eq), 2, and 3a in THF-DMF (3:1) was heated at 70 °C for 16 h. Since the
3
reaction hardly progressed, continued heating at 90 °C for another 3 days gave 4a in 38% yield
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(
entry 7). When the DMF solution of 2 and 3a was treated with t-BuOK (1.7 eq) at room
temperature, 4a was obtained in 58% yield (entry 8). Increasing the amount of t-BuOK to 2.5 eq
increased the yield to 79% and increasing both the amount of 2 (1.2 eq) and t-BuOK (3 eq) gave
1
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4
a in 92% yield in 1 h (entries 9-11). This procedure is more convenient and economical, and the
reaction was completed in 1 h at room temperature. To establish scalability, the reaction was run
on a 5 mmol scale to give 4a in 93% yield (entry 12).
Table 3. Methylenation of p-methoxyacetophenone by the sulfone 2
entry
base (eq)
solvent
THF
conditions
-78 °C to rt
-78 °C to rt
-55 °C to rt
-55 °C to rt
-55 °C to rt
-55 °C to rt
90 °C, 3 d
rt, 5 h
4a (%)a
42
1
2
3
4
5
6
7
8
9
NaHMDS (1.3)
LiHMDS (1.3)
KHMDS (1.3)
NaHMDS (1.3)
NaHMDS (1.3)
NaHMDS (1.7)
THF
21
DME
25
DME
54
DMF
79
DMF
88
Cs
2
CO
3
(3.0)
THF/DMFb
DMF
38
t-BuOK (1.7)
t-BuOK (2.5)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
58
DMF
rt, 1.5 h
79
1
0c
11d
2de
DMF
rt, 1 h
87
DMF
rt, 1 h
92
1
DMF
rt, 1 h
93
0.3 mmol of 3a and 0.3 mmol of 2 were used unless otherwise noted. [a] Isolated yield. [b] 3:1 mixture. [c] 1.1 eq of 2
was used. [d] 1.2 eq of 2 was used. [e] 5 mmol scale.
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A plausible reaction mechanism was shown in Scheme 3. The anion obtained from 2 and the
base reacts with 3 to form alkoxide A, from which nucleophilic addition of the oxyanion to the
ipso carbon of benzimidazole ring occurs to form B. Terminal alkene 4 would form by Smiles
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rearrangement along with C and SO
obtained. It seems that SO reacted with the base (NaHMDS or t-BuOK) to form (TMS)
or t-BuOSO K because no bubbles could be detected during the reaction. Moreover, t-BuOK is
2
. After aqueous work-up with aq. NH
4
Cl, alkene 4 and 7 are
2
2
NSO Na
2
2
not basic enough to completely deprotonate 2, and excess t-BuOK is believed to help increase the
amount of anion A and increase the yield of alkenes. For these reasons, it is likely that excess base
was required for high yields.
Scheme 3. A plausible reaction mechanism
The methylenation reactions of various ketones and aldehydes with 2 were performed using
Method A (NaHMDS in DMF at -55 °C to rt) (Table 4). The reactions of p-bromoacetophenone
3b, 2-adamantanone 3c, and N-Boc-4-piperidinone 3d gave the corresponding alkenes in 86-95%
yield using NaHMDS (1.7 eq) in DMF (entries 2-4). Reaction of 3,4-dimethoxybenzaldehyde 3e
with 2 using 1.7 eq of NaHMDS gave 4e in 72% yield, while 4e was obtained in 97% yield using
1.3 eq of NaHMDS (entries 5-6). The extra base is harmful in this reaction, and it seems better to
use 1.3 eq of NaHMDS for aldehydes. Using this procedure, the reaction of 1-naphthaldehyde 3f
gave 4f in 90% yield (entry 7).
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Table 4. Methylenation using 2 and NaHMDS in DMF
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
3
NaHMDS (eq)
4a (%)
88
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3e
3f
1.7
1.7
1.7
1.7
1.7
1.3
1.3
86
95
95
72
97
90
0.3 mmol of 3 and 0.3 mmol of 2 were used and the yields are isolated yields.
Using Method B (t-BuOK in DMF), methylenation reactions of various ketones with 2 were
performed (Table 5). Methylenation of 3b under the standard conditions (t-BuOK (3.0 eq) in DMF
at room temperature for 1 h) gave 4b in 82% yield, while 95% yield was obtained using 4 eq of t-
BuOK (entries 2-3). Methylenations of aliphatic ketones 3c and 3d were also efficient under the
standard conditions. Treatment of a DMF solution of 2 and 3c with t-BuOK (3.0 eq) for 1 h
provided alkene 4c in 89% yield (entry 4). Although the Wittig reagent, CH
3
P(C
6
H ) Br, is the
5
3
most frequently used methylenation reagent, the separation of the product alkene from by-product,
triphenylphosphine oxide (FW 278), is not always easy. In our reaction, the by-product C (FW
1
48) is a small molecule that is easily removed from the reaction mixture by basic aqueous work-
up. In fact, almost pure alkenes 4c and 4d were obtained in 96 and 99% yield, respectively, after
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
diluting the reaction mixture with hexane and washing with 1 M NaOH (entries 5-6). This greatly
simplifies the purification of the product alkenes. 2-Octanone 3g was also converted to 4g in 91%
yield and the reaction of -ionone 3h gave 4h in 91% yield using 3.5 eq of t-BuOK (entries 7-9).
Methylenation of sterically hindered (-)-menthone 3i under the standard conditions gave alkene 4i
in 59% yield along with the recovered 3i (39%) and trace amount of 2 (entry 10). Even using 2 eq
of 2, the yield was only 60% along with recovered 3i (38%) (entry 11). These results indicate that
the yield of alkene 4i is just moderate due to the low reactivity of sterically hindered 3i and the
slow decomposition of 2 in the presence of t-BuOK in DMF. To prevent decomposition of 2, 3i
was first treated with 1 eq of 2 and 3 eq of t-BuOK at 0 °C, followed by the addition of 0.5 eq of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
and 1 eq of t-BuOK at 20 and 40 minutes, respectively (entry 12). The yield of 4i increased to
3% and 3i was recovered in 22%. As the amount of t-BuOK was further increased to total 7 eq,
7
the yield of 4i was further improved to 84% (entry 13). (-)-Menthone 3i used contained 7.7% of
isomenthone, while the product alkene 4i contained only 4.2% of its isomer. Therefore,
stereoselective reaction occurred to give 4i. Since the recovered 3i contained 19% of isomenthone
in entry 11, the total of iso-4i and isomenthone after the reaction is 9.7% (38 x 0.19 + 60 x 0.042).
This means 2% (9.7-7.7) stereoisomerization of ketone 3i occurred during the reaction.
Methylenation of -tetralone 3j using 3 eq of t-BuOK in DMF at room temperature provided
alkene 4j in 73% yield from 1.2 eq of 2, and 77% yield from 1.5 eq of 2 (entries 14-15). From both
reactions, 3j was recovered in 23% yield. Since 3j is an easily enolizable ketone, the CeCl -
3
promoted Julia-Kocienski reaction was attempted according to the Sasaki’s procedure.23,24 When
a THF solution of 2 and LDA (1 eq) was added to a solution of 3j and CeCl (1 eq) in THF at -
3
78 °C and the resulting mixture was warmed to 0 °C, only trace amount of alkene 4j was obtained
and most of ketone 3j was recovered (entry 16). The reaction was carried out using t-BuOK (3 eq)
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in the presence of t-BuOH (2 eq), intended to protonate the enolate from ketone 3j, but the yield
of 4j dropped to 66% (entry 17). The initial treatment of 3j with 1.2 eq of 2 and 3 eq of t-BuOK at
0 °C, followed by the addition of 2 (0.8 eq) and t-BuOK (1.6 eq) after 30 min increased the yield
to 84% (entry 18). The reaction of 1-indanone 3k was also run under the same conditions as entry
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8 to give 4k in 84% yield (entry 19). These results are noteworthy because the Wittig reactions
of these ketones give only moderate to low yields.6c,25 Thus, methylenation of various ketones with
2
using t-BuOK in DMF for 1 h at room temperature generally gave alkenes 4 in high yields. When
the yield is moderate, adding extra t-BuOK generally improves the yield.
Table 5. Methylenation of ketones 3 by 2 using t-BuOK
entry
1
3
2 (eq)
1.2
t-BuOK (eq)
3.0
conditions
rt, 1 h
4 (%)
92
82
95
89
96
99
91
84
91
59
60
73
84
3a
3b
3b
3c
3c
3d
3g
3h
3h
3i
2
1.2
3.0
rt, 1 h
3
1.3
4.0
rt, 1 h
4
1.2
3.0
rt, 1 h
5a
6a
7
1.2
3.0
rt, 1 h
1.2
3.0
rt, 3 h
1.2
3.0
rt, 1 h
8
1.2
3.0
rt, 2 h
9
1.2
3.5
rt, 1 h
10
11
12
1.2
3.0
rt, 1 h
3i
2.0
3.0
rt, 1 h
3i
1+0.5+0.5
1+0.5+0.5
3+1+1
4+1.5+1.5
0 °C, 2 h
0 °C, 2 h
13
3i
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
4a
3j
3j
3j
3j
3j
3k
1.2
1.5
3.0
3.0
rt, 1 h
rt, 1 h
73
77
15
16
1.2
LDA,1.0b
3.0c
-78 to 0 °C
rt, 1.5 h
trace
66
1
1
1
7
8
9
1.2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.2+0.8
1.2+0.8
3+1.6
3+1.6
0 °C, 1.5 h
rt, 1.5 h
84
84
0
.3 mmol of 3 was used and the yields are isolated yields. [a] By basic work-up. [b] In the presence of CeCl
3
(1 eq). [c]
In the presence of t-BuOH (2 eq).
1
3
Since the PT sulfone 1c has been used for many total syntheses, the reactivity of 1c and 2
was compared. When Method B was used to carry out the reaction of 1c and 3d (the same
conditions as entry 6 in Table 5), 4d was obtained in 72% yield along with the recovered 3d (14%).
No sulfone 1c was recovered. The same reaction of 2 with 3d gave 4d in 99% yield (entry 6 in
Table 5). To test the relative stability of the sulfone reagents, DMF solutions of 1c and 2 were
treated with t-BuOK (2.5 eq) at 0 °C for 30 min and quenched with aqueous NH Cl, respectively
4
1
(
Scheme 4). None of the starting sulfone 1c was detected by H NMR, but 2 was recovered in 49%
yield along with a dimeric product 8 (19%), 7 (5%), and tert-butoxybenzimidazole 9. Therefore,
2 is much more stable than 1c in the presence of bases and this seems to be the reason that 2 gave
4
d in much higher yield.
Scheme 4. Stability of 1c and 2 in the presence of t-BuOK in DMF
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1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Methylenation reactions of various aldehydes with 2 were carried out using Method B (t-BuOK
in DMF) (Table 6). The reaction of 3,4-dimethoxybenzaldehyde 3e was carried out using t-BuOK
(2.6 eq) and 2 (1.2 eq) in DMF for 1 h at room temperature to give 4e in 92% yield (entry 1). The
reactions of 1-naphthaldehyde 3f and p-chlorobenzaldehyde 3l gave the alkenes 4f and 4l in 91%
and 93% yields, respectively, using 3.0 eq of t-BuOK. These yields were higher than using 2.6 eq
of t-BuOK (entries 2-5). Methylenation of 1-pyrencarboxaldehyde 3m gave 4m in 95% yield under
the standard conditions (entry 6). The reaction of sterically hindered aldehyde 3n was performed
more efficiently by the sequential addition of reagent 2 and t-BuOK, yielding 4n in 95% yield
(entries 7-8). The reactions of citronellal 3o and cinnamaldehyde 3p were carried out under the
standard conditions to give alkenes 4o and 4p in 97 and 96% yield, respectively (entries 9-10).
The reaction of n-octanal 3q with 1.1 eq of 2 gave 4q in 63% yield and 74% yield with 1.5 eq of
1
2
(entries 11-12). Due to volatility, the yield was calculated by H NMR with methyl benzoate as
the internal standard. When the above reaction was carried out at 0 °C under the same conditions,
the yield decreased to 68% (entry 13). Increasing 2 to 2 eq under the same conditions as entry 12
increased the yield of alkene to 91% (entry 14).
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 6. Methylenation of aldehydes 3 by 2 using t-BuOK
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
1
3
3e
3f
2 (eq)
1.2
t-BuOK (eq)
2.6
conditions
rt, 1 h
4 (%)
92
2
1.1
2.6
rt, 1 h
86
3
3f
1.1
3.0
rt, 1 h
91
4
3l
1.1
2.6
rt, 1 h
88
5a
6
3l
1.1
3.0
rt, 1 h
93
3m
3n
3n
3o
3p
3q
3q
3q
3q
1.2
3.0
rt, 1 h
95
7
1.2
2.6
rt, 3 h
78
8
1+0.5+0.5
1.1
2+1+1
2.6
rt, 2 h
95
9a
rt, 1 h
97
1
0
1
1.2
2.6
rt, 1 h
96
63b
1
1.1
2.6
rt, 1 h
12
1.5
2.6
rt, 0.5 h
0 °C, 2 h
rt, 1 h
74b
68b
91b
1
3
4
1.5
2.6
1
2.0
2.6
0
.3 mmol of 3 was used and the yields are isolated yields. [a] By basic aqueous work-up. [b] The yield was determined
1
by H NMR by using methyl benzoate as an internal standard.
Next, we investigated the chemoselectivity between aldehyde and ketone in the methylenation
with 2 (Scheme 5). Treatment of a mixture of aldehyde 3e and ketone 3h (both 1 eq) with 2 (1 eq)
and t-BuOK (2.6 eq) in DMF at 0 °C resulted in the exclusive formation of alkene 4e in 89% yield
1
(Scheme 3). H NMR of the crude mixture showed 97:3 selectivity between 4e and 4h. Thus,
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selective methylenation of aldehyde 3e occurred in the presence of ketone 3h. A mixture of ketone
3
d and aldehyde 3o (both 1 eq) was treated with 2 (1 eq) and t-BuOK (2.6 eq) in DMF at 0 °C to
1
give 4d as the major product in 62% yield. H NMR of the crude mixture showed a selectivity
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
between 4d and 4o of 88:12. That is, ketone 3d reacted preferentially in the presence of aldehyde
3
4
o. When the same reaction was performed at room temperature, the selectivity between 4d and
o changed to 42:58. Although the selectivity depends on the reaction conditions and the steric
and electronic properties of the carbonyl compounds, chemoselective reactions could occur in
some cases.
Scheme 5. Competitive methylenation of aldehyde and ketone
Methylenation with 2 has already been used in some synthetic studies.26 For example,
Calenbergh and co-workers reported the methylenation of a ketone derived from -D-galactose
was performed smoothly with our reagent 2 to give the exocyclic methylene derivative.26c
However, Mori reported that methylenation of cyclopentanone having a methyl ester group on the
side chain with 2 gave the corresponding alkene in only 27% yield (51% based on the consumed
ketone) using NaHMDS in DMF at -55 °C to rt (method A) and in 28% yield using t-BuOK at rt
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
method B), where the product was t-Bu ester.26b Interestingly, Qin and co-workers reported that
6
a
methylenation of -ketoester 3r via Wittig reaction or Takai olefination resulted in complete
recovery of the starting material from 0 °C to room temperature and decomposition at elevated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8c
temperature (Scheme 6). Similar ketones 3s and 3t were also subjected to the Wittig reaction
conditions (CH
3
P(C
6
H ) Br, t-BuOK in toluene), 4s was not formed while 4t, only one methylene
5
3
8
c
unit short, was isolated in high yield. Since these results are hard to understand, we decided to
carry out methylenation of 3s and 3t.
Scheme 6. The Wittig methylenation of 3r-3t
Methylenations of 3s and 3t were first carried out by Method B (t-BuOK (3 eq), DMF, rt, 2 h).
However, in both reactions, only trace amounts of alkenes 4s and 4t were obtained. Therefore, the
methylenation reactions of these ketones were carried out at low temperature and the reaction
conditions were re-optimized (Table 7). When 1.7 eq of NaHMDS was added to a DMF solution
of 2 and 3t at -55 °C and the mixture was warmed to room temperature (Method A), alkene 4t was
obtained in 29% yield (entry 1). When the solvent was changed to DME and the reaction was
carried out at -80 °C for 1.5 h, the yield increased to 61% (entry 2). Using 1.6 eq of 2 and 2.2 eq
of NaHMDS improve the yield to 84% (entry 3). Under the conditions of entry 3 (Method C), the
reaction of 3s with 2 gave alkene 4s in 78% yield (entry 4). Thus, alkenes 4t and 4s were
successfully obtained in good yields with our methylenation reagent 2, while the Wittig reaction
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of 3s did not give any products. Since the substrate ketones were recovered in 6-13% yield in
entries 3 and 4, the yield might be further improved by increasing 2 or base.
Table 7. Methylenation of ketones 3s and 3t using 2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
3
3t
3t
3t
3s
reagent
2 (1.2 eq)
2 (1.2 eq)
2 (1.6 eq)
2 (1.6 eq)
NaHMDS
1.7 eqa,b
1.7 eq
4 (%)
4 (%) 3 (%)
1
2
3
4
-55 °C to rt
-80 °C, 1.5 h
-80 °C, 1.5 h
-80 °C, 1.5 h
29
61
84
78
17
39
6
2.2 eq
2.2 eq
13
0
.3 mmol of 3 was used. [a] Base was added to a solution of 2 and 3. [b] DMF was used instead of DME.
2. Conclusions
Synthetic method of our methylenation reagent, 1-methylbenzimidazol-2-yl (MBI) methyl
sulfone 2 was re-optimized. Dimethylation of 2-mercaptobenzimidazole 5 was carried out in H
THF using MeI and KOH, and the resulting methyl sulfide 6 was oxidized with H and a
catalytic amount of (NH Mo 24 in EtOH. The yield of 2 is 95% from 5 by two steps and one
2
O-
2
O
2
4
)
6
7
O
isolation and this procedure is easy and reproducible. We found the method of work-up for the
oxidation reaction is very important. Our reagent 2 can react with various aldehydes and ketones
in the presence of t-BuOK in DMF for 1 h at room temperature to give terminal alkenes in generally
high yields. For both sterically hindered substrates and easily enolizable ketones, the yields were
improved by adding an excess 2 and t-BuOK. For n-octanal, which is susceptible to the aldol
reaction under basic conditions, it is recommended to use an excess of 2 and a slightly excess of t-
BuOK. Unfortunately, the methylenation of -keto esters 3s and 3t using t-BuOK in DMF was
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
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unsuccessful. In these cases, methylenation was successfully carried out at low temperature using
NaHMDS in DME. Reagent 2 can be easily prepared without expensive reagents and the reaction
conditions are mild and practical. We believe our methylenation reagent 2 is a useful complement
0
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to the Wittig reagent CH
3
P(C
6
H ) Br and other methylenation reagents. In order to expand the
5
3
scope and utility, further study on this olefination reaction is presently under active investigation
in this laboratory.
3
. Experimental
Commercially available reagents were used without purification. N,N-Dimethylformamide
(DMF), tetrahydrofuran (THF), and dimethoxyethane (DME) were dried using Molecular Sieves
4A. All reactions in dry solvents were carried out under argon atmosphere. Analytical thin-layer
chromatography (TLC) was performed on Merk TLC plates (No.5715) precoated with silica gel
6
0 F254. Silica gel column chromatography was carried out using Kanto silica gel 60N (spherical,
1
13
neutral, 63-210 m). The H NMR (400 MHz) and C NMR (100 MHz) were recorded on a JEOL
-400 in CDCl
3
using tetramethylsilane as an internal standard ( = 0 ppm). All the product alkenes
1
except for 4s are known compounds and H NMR spectra are identical to the reported values.
1
-Methylbenzimidazol-2-yl methyl sulfone (2): To a solution of 86% KOH (3.001 g, 46 mmol)
in H O (40 mL) was added 2-mercaptobenzimidazole 5 (3.004 g, 20 mmol) and THF (10 mL) at
ºC. After the solid had dissolved (7 min later), MeI (2.86 mL, 46 mmol) was added dropwise.
The resulting mixture was stirred at RT for 3 h. The reaction was quenched with aq. NH Cl, and
the mixture was extracted with AcOEt (15 mL x 3). The combined extracts were washed with
brine, dried with MgSO , and concentrated under reduced pressure. The residue was resolved in
EtOH (60 mL), and (NH Mo O (2.470 g, 2.0 mmol) and 35% H (16 mL, 180 mmol)
2
0
4
4
4
)
6
7
O24•H
2
O
2 2
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were added slowly at 0 ºC. After the resulting mixture was stirred at RT for 1 h, aq. Na
2
SO was
3
added slowly at 0 ºC and extracted with AcOEt (15 mL x 3). The combined extracts were washed
with brine, dried with MgSO , and concentrated. Column chromatography (silica gel, hex/AcOEt
4
1
1
1
1
1
1
1
1
1
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9
0
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2
3
4
5
6
7
8
9
0
2
1
:1) provided 2 (3.991 g, 95% yield) as a colorless solid. R
32.5-135.4 °C17a (recrystallized from H
f
= 0.32 (hexane/AcOEt 2:1); mp =
, 400 MHz)  7.84 (dt,
1
2
O-EtOH (2:1)); H NMR (CDCl
3
1H, J = 8.4, 0.8 Hz), 7.43-7.50 (m, 2H), 7.37-7.42 (ddd, 1H, J = 2.0, 6.0, 8.4 Hz), 4.13 (s, 3H),
+
+
3
.55 (s, 3H); HRMS (ESI): m/z calcd for C
9
H
11
N
2
O S [(M + H) ] 211.0536, found 211.0536.
2
Typical experimental procedure for the methylenation (Method A) (entry 6 in Table 4) To a
solution of 2 (0.063 g, 0.30 mmol) and 3,4-dimethoxybenzaldehyde 3e (0.050 g, 0.30 mmol) in
DMF (1.5 mL) under argon was added NaHMDS (1.9 mol/L in THF, 0.206 mL, 0.39 mmol) at -
5
5 °C. The solution was stirred at -55 °C for 5 min, then the mixture was warmed to room
temperature over 2 h and stirred at that temperature for 2 h. The reaction was quenched with
aqueous NH Cl and the mixture was extracted with AcOEt (2 x 10 mL). The combined extracts
were washed with H O (3 x 10 mL), brine, dried (MgSO ), and concentrated. Column
4
2
4
chromatography (silica gel; hexane/AcOEt (5:1)) provided 1,2-dimethoxy-4-vinylbenzene 4e
1
(0.048 g, 97%) as colorless oil; R
f
= 0.54 (hexane/AcOEt 4:1); H NMR (CDCl
3
, 400 MHz)  6.92-
6
5
.99 (m, 2H), 6.83 (d, 1H, J = 8.0 Hz), 6.66 (dd, 1H, J = 10.8, 17.2 Hz), 5.61 (d, 1H, J = 17.2 Hz),
.15 (d, 1H, J = 10.8 Hz), 3.91 (s, 3H), 3.89 (s, 3H).27
Typical experimental procedure for the methylenation (Method B) (entry 12 in Table 3) To a
solution of 2 (1.262 g, 6.00 mmol) and p-methoxyacetophenone 3a (0.751 g, 5.00 mmol) in DMF
(25 mL) under argon was added t-BuOK (97%) (1.735 g, 15.0 mmol) at room temperature. After
stirring for 1 h, the reaction was quenched with aqueous NH Cl and the mixture was extracted with
4
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AcOEt (3 x 30 mL). The combined extracts were washed with H O (3 x 20 mL), brine, dried
2
(
MgSO
4
), and concentrated. Column chromatography (silica gel; hexane/AcOEt (10:1)) provided
= 0.74 (hexane/AcOEt 3:1);
2-(4-methoxyphenyl)propene 4a (0.688 g, 93%) as a colorless oil; R
f
0
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2
3
4
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8
9
0
1H NMR (CDCl
s, 1H), 4.99 (s, 1H), 3.81 (s, 3H), 2.13 (s, 3H).28
3
, 400 MHz)  7.41 (dt, 2H, J = 8.8, 2.4 Hz), 6.86 (dt, 2H, J = 8.8, 2.4 Hz), 5.28
(
Typical experimental procedure for the methylenation (Method B-basic work up) (entry 6 in
Table 5) To a solution of 2 (0.076 g, 0.36 mmol) and N-Boc-4-piperidone 3d (0.060 g, 0.30 mmol)
in DMF (1.5 mL) under argon was added t-BuOK (0.104 g, 0.90 mmol) at room temperature. After
stirring for 1 h, the reaction was diluted with hexane (10 mL) and the mixture was successively
washed with 1M NaOH (2 x 5 mL), H
2
O (5 mL), aq. NH
4
Cl (3 mL), and brine. The organic layer
was dried (MgSO ), and concentrated. Column chromatography (silica gel; hexane/AcOEt (9:1))
4
provided N-Boc-4-methylenepiperidine 4d (0.059 g, 99%) as colorless oil; R = 0.73
f
1
(
hexane/AcOEt 3:1); H NMR (CDCl
3
, 400 MHz)  4.74 (s, 2H), 3.42 (t, 4H, J = 6.0 Hz), 2.18 (t,
4
H, J = 6.0 Hz), 1.47 (s, 9H).14a
Typical experimental procedure for the methylenation (Method B’) (entry 18 in Table 5) To a
solution of 2 (0.076 g, 0.36 mmol) and -tetralone 3j (0.042 mL, 0.30 mmol) in DMF (1.5 mL)
under argon was added t-BuOK (0.104 g, 0.90 mmol) at 0 ºC. After stirring for 30 min at 0 ºC,
both 2 (0.051 g, 0.24 mmol) and t-BuOK (0,056 g, 0.48 mmol) were additionally added and the
mixture was stirred for further 30 min. The reaction was quenched with aq. NH
4
Cl and extracted
with AcOEt (10 mL x 2). The combined extracts were washed with H O (10 mL x 3) and brine (5
2
mL), dried with MgSO
4
, and concentrated. Column chromatography (silica gel, hexane) provided
1
4
j (0.036 g, 84% yield) as a colorless oil; R
f
= 0.83 (hexane/AcOEt 3:1); H NMR (CDCl
3
, 400
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MHz)  7.62-7.65 (m, 1H), 7.08-7.18 (m, 3H), 5.47 (s, 1H), 4.94 (s, 1H), 2.84 (t, 2H, J = 6.0 Hz),
2
.54 (t 2H, J = 6.0 Hz), 1.88 (quin, 2H, J = 6.0 Hz).6c
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Typical experimental procedure for the methylenation (Method C) (entry 5 in Table 7) To a
solution of 2 (0.101 g, 0.48 mmol) in DME (0.8 mL) under argon was added NaHMDS (1.9 mol/L
in THF, 0.35 mL, 0.66 mmol) at -80 ºC. After 10 min, a solution of 3s (0.078 g, 0.30 mmol) in
DME (0.7 mL) was added and the mixture was stirring for 1.5 h at -80 ºC. The reaction was
quenched with aq. NH
4
Cl and extracted with AcOEt (10 mL x 2). The combined extracts were
, and concentrated. Column chromatography (silica gel,
washed with brine, dried with MgSO
4
hexane/AcOEt 30:1) provided 4s (0.061 g, 78% yield) as a colorless oil; R = 0.84 (hexane/AcOEt
f
1
5
:1); H NMR (CDCl
3
, 400 MHz)  7.23-7.30 (m, 2H), 7.15-7.21 (m, 3H), 5.10 (t, 1H, J = 1.8 Hz),
5.04 (d, 1H, J = 1.8 Hz), 4.14 (q, 2H, J = 7.1 Hz), 2.22-2.62 (m, 6H), 1.67-1.88 (m, 4H), 1.27 (t,
13
3
1
H, J = 7.1 Hz); C{H} NMR (100 MHz, CDCl
3
)  174.4, 154.7, 138.2, 129.8, 127.8, 126.1,
07.8, 60.4, 57.1, 43.8, 34.1, 33.6, 23.6, 13.8; HRMS (ESI): m/z calcd for C17
H
22NaO +
[(M +
2
+
Na) ] 281.1512, found 281.1511.
Supporting Information
1
Characterization of 2’, 7, 4b, 4c, 4f-4i, 4k-4q and 4t, references of supplementary data, H NMR
spectra of 6, 2, 2’, 7, 4a-4q, 4s, and 4t.
Acknowledgments
This research was partially supported by the JSPS KAKENHI Grant Number 17K05781.
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References
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[
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[
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[
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Lead. J. Org. Chem. 1994, 59, 2668-2670. (b) Matsubara, S.; Sugihara, M.; Utimoto, K.
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(a) Lebel, H.; Paquet, V. Rhodium-Catalyzed Methylenation of Aldehydes. J. Am. Chem.
Soc. 2004, 126, 320-328. (b) Lebel, H.; Davi, M.; Díez-González, S.; Nolan, S. P. Copper-Carbene
Complexes as Catalysts in the Synthesis of Functionalized Styrenes and Aliphatic Alkenes. J. Org.
Chem. 2007, 72, 144-149. (c) Xu, S.; Gao, Y.; Chen, R.; Wang, K.; Zhang, Y.; Wang, J. Copper(I)-
Catalyzed Olefination of N-Sulfonylhydrazones with Sulfones. Chem. Commun. 2016, 52, 4478-
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480.
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(a) Shishido, K.; Tokunaga, Y.; Omachi, N.; Hiroya, K.; Fukumoto, K.; Kametani, T. Total
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Intramolecular [3+2] Cycloaddition. J. Chem. Soc., Perkin Trans. I 1990, 2481-2486. (b) Kaluza,
N. M.; Schollmeyer, D.; Nubbemeyer, U. Total Synthesis of (-)-C/D-cis-Dehydro-3-O-methyl-
estradiols. Eur. J. Org. Chem. 2016, 357-366. (c) Chen, D.; Liu, H.-M.; Li, M.-M.; Yan, Y.-M.;
Xu, W.-D.; Li, X.-N.; Cheng, Y.-X.; Qin, H.-B. Concise Synthesis of (±)-Lingzhiol via Epoxy-
Arene Cyclization. Chem. Commun. 2015, 51, 14594-14596.
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Julia-Kocienski Reaction. Eur. J. Org. Chem. 2009, 1831-1844. (c) Chatterjee, B.; Bera, S.; Mondal,
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of Carbonyl Compounds with Lithio Derivatives of 2-[Alkyl- or (2’-Alkenyl)- or Benzyl-Sulfonyl]-
Benzothiazoles. Tetrahedron Lett. 1991, 32, 1175-1178.
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[
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trans-1,2-Disubstituted Alkenes Based on the Condensation of Aldehydes with Metallated 1-Phenyl-
H-tetrazol-5-yl Sulfones. Synlett 1998, 26-28.
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[
Formal Total Synthesis of the Tumor and GSK-3 Inhibiting Agelastatin A. Org. Lett. 2003, 5,
2927-2930. (b) Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.; Aliev, A. E.;
Hale, K. J. Enantioselective Formal Synthesis of the Antitumor Macrolide Bryostatin 7. Org. Lett.
2
006, 8, 4477-4480. (c) Davis, F. A.; Zhang, Y.; Li, D. Sulfinimine-Derived 2,3-Diamino Esters
in the Asymmetric Synthesis of Piperidine (2S,3S)-(+)-CP-99,994. Tetrahedron Lett. 2007, 48,
7838-7840. (d) Cheung, L. L.; Marumoto, S.; Anderson, C. D.; Rychnovski, S. D. Assignment of
Absolute Configuration to SCH 351448 via Total Synthesis. Org. Lett. 2008, 10, 3101-3104. (e)
Zhu, K.; Panek, J. S. Total Synthesis of (+)-SCH 351448. Org. Lett. 2011, 13, 4652-4655. (f)
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649-1657. (g) Li, N.-S.; Scharf, L.; Adams, E. J.; Piccirilli, J. A. Highly Stereocontrolled Total
Synthesis of -D-Mannosyl Phosphomycoketide: A Natural Product from Mycobacterium
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A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-
Coupling Protocol. J. Am. Chem. Soc. 2016, 138, 3675-3678.
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Butyl-1H-tetrazole-5-yl Sulfones in the Modified Julia Olefination. Synlett 2000, 365-366.
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of an Intramolecular Cyclopropanation Reaction and Synthesis of (±)-epi-Lindenene and (±)-iso-
Lindenene. Synlett 2007, 2679-2682. (b) Fuwa, H.; Suzuki, T.; Kubo, H.; Yamori, T.; Sasaki, M.
Total Synthesis and Biological Assessment of (-)-Exiguolide and Analogues. Chem. Eur. J. 2011,
1
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7, 2678-2688. (c) Qian, S.; Zhao, G. Total Synthesis of (+)-chloranthalactone F. Chem. Commun.
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[
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[21] Na
2
S
2
3
O is often used to decompose the remaining oxidant after oxidation of sulfides to
sulfones. In fact, the MBI benzyl sulfone was obtained in 89% yield by oxidation of the
corresponding sulfide (H
2
O
2
, (NH
4
)
6
Mo
7
O
24) and work-up with Na
2
S
2
O
3
(unpublished results). It
as the steric hindrance
is reasonable to assume that 2 is susceptible to the ipso attack of Na
2
S
2
O
3
around the carbon bound to the sulfur atom is reduced compared with the benzyl counterpart.
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2
to 2-Benzimidazolones under
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[
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