Practical Methylenation Reaction for Aldehydes and Ketones Using New Julia-Type Reagents

Article abstract of DOI:10.1021/acs.orglett.5b01049

A new Julia-type methylenation reagent, 1-methyl-2-(methylsulfonyl)benzimidazole (1e), reacts with a variety of aldehydes and ketones in the presence of either NaHMDS (-55 °C to rt) or t-BuOK (rt, 1 h) in DMF to give the corresponding terminal alkenes in high yields. The byproducts are easily removed, and the reaction conditions are mild and practical.

Full text of DOI:10.1021/acs.orglett.5b01049

Letter
pubs.acs.org/OrgLett
Practical Methylenation Reaction for Aldehydes and Ketones Using
New Julia-Type Reagents
Kaori Ando,* Takahisa Kobayashi, and Nariaki Uchida
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
*
S Supporting Information
ABSTRACT: A new Julia-type methylenation reagent, 1-methyl-2-
methylsulfonyl)benzimidazole (1e), reacts with a variety of aldehydes
and ketones in the presence of either NaHMDS (−55 °C to rt) or t-BuOK
rt, 1 h) in DMF to give the corresponding terminal alkenes in high yields.
The byproducts are easily removed, and the reaction conditions are mild and practical.
(
(
1
1
he synthesis of alkenes from carbonyl compounds is one of
the most fundamental reactions in organic synthesis. Since
−78 °C to rt, and Cs CO in THF/DMF(3:1) at 70 °C), and
2
3
T
1d was successfully used in the syntheses of some natural
products. Since Kocienski and co-workers demonstrated that
the anions derived from TBT alkyl sulfones are more stable than
12
terminal alkene structures are frequently observed in natural
products and terminal alkenes are often used as the substrates for
many synthetic reactions such as olefin metathesis and
sigmatropic reactions, their preparation has been studied
intensively. Many methylenation reagents were developed by
9b
the PT and BT counterparts, 1d seems to be the best
methylenation reagent. However, since the starting material for
the preparation of 1d is expensive, the metalation reaction
requires rather expensive bases such as NaHMDS or Cs CO ,
1
2
3
Wittig, Peterson, and Johnson, along with gem-dimetallic
2
3
4
reagents such as Tebbe’s reagent and Nysted reagent. Recently,
and there is some room for improvement of the yields, we felt the
need to develop a more practical route to the methylenation
reaction. Kende and Mendoza reported that the imidazolyl
sulfones 4 react with aldehydes to give β-hydroxy imidazolyl
transition-metal-catalyzed methylenation reactions have also
5
been reported. The Julia−Kocienski reactions (one-pot Julia
olefination) are a very efficient tool for direct alkene synthesis via
6
1
3
metalated heteroarylsulfones with carbonyl compounds. The
sulfones, which can be transformed to alkenes using SmI2. We
had a working hypothesis that the benzo-fused imidazolyl sulfone
four methylenation reagents of Julia−Kocienski-type reagents
have been reported (Scheme 1). Julia and co-workers studied the
14
1e
can react with carbonyl compounds to afford alkenes
directly. New reagent 1e can be prepared from cheap 2-
mercaptobenzimidazole 5 by dimethylation and oxidation. Here,
we report the methylenation reaction of various aldehydes and
ketones using 1e.
Scheme 1. Julia-Type Methylenation Reagents
The dimethylation of 5 gave a quantitative yield of 6 by using
NaH and MeI in THF (Scheme 2). The oxidation of 6 was first
performed using m-CPBA to give 1e in 62% yield. The oxidation
Scheme 2. Preparation of the Benzoimidazolyl Sulfone 1e
methylenation reaction briefly with the benzothiazol-2-yl (BT)
7
methyl sulfone 1a. Naj
́
era and co-workers studied the reaction
8
of 3,5-bis(trifluoromethyl)phenyl methyl sulfone 1b. 1-Phenyl-
H-tetrazol-5-yl (PT) methyl sulfone 1c, the methyl version of
1
9
the Kocienski reagent, has been used in several total syntheses of
1
0
natural products. Ais
H-tetrazol-5-yl (TBT) methyl sulfone 1d with a variety of
̈
sa reported the reaction of 1-tert-butyl-
1
aldehydes and ketones to give terminal alkenes in moderate to
Received: April 20, 2015
high yields using two efficient procedures (NaHMDS in THF at
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01049
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with hydrogen peroxide catalyzed by ammonium molybdate gave
only 14% yield of 1e, and the main product was 7 (yield 85%),
Table 2. Methylenation of Ketones and Aldehydes with 1e by
NaHMDS
15
a
which seemed to be produced by the Pummerer-type rearrange-
ment of the corresponding sulfoxide. When Oxone was used,
92% yield of 1e (BI sulfone) was obtained after 5 h. Longer
reaction time was harmful and caused some hydrolysis of 1e.
Since the Julia−Kocienski reactions are generally more
efficient when the Barbier-type procedure was used, a solution
of 1e was treated with base in the presence of either aldehyde or
ketone. The methylenation reaction using 1e was first carried out
with p-methoxyacetophenone 2a. The results are summarized in
Table 1. When 1.3 equiv of NaHMDS was added to a THF
entry
2
NaHMDS (equiv)
1e (equiv)
yield (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2j
1.7
1.7
1.7
1.7
1.7
1.3
1.3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
88
86
95
95
72
97
90
a
2j
Table 1. Methylenation of p-Methoxyacetophenone with 1e
2k
a
0
.3 mmol of 2 and 0.3 mmol of 1e were used.
entry
base (equiv)
solvent
THF
conditions
yield (%)
1
2
3
4
5
6
7
8
NaHMDS (1.3)
LiHMDS (1.3)
NaHMDS (1.3)
KHMDS (1.3)
NaHMDS (1.3)
NaHMDS (1.7)
Cs CO (3)
−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
42
21
54
25
79
88
38
58
79
87
92
THF
DME
DME
DMF
DMF
THF/DMF
DMF
DMF
DMF
DMF
DMF
obtained by using 1.3 equiv of NaHMDS. Therefore,
methylenation reactions of aldehydes should be performed by
using 1.3 equiv of NaHMDS as a standard procedure. The
reaction of aldehyde 2k gave 3k in 90% yield using this
procedure.
b
2
3
t-BuOK (1.7)
t-BuOK (2.5)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
9
rt, 1.5 h
c
10
11
12
rt, 1 h
d
d
rt, 1 h
The methylenation reactions of 1e with a variety of ketones
and aldehydes were performed using method B (t-BuOK in
DMF, Table 3). The methylenation reaction of 2b using the
standard conditions gave 3b in 82% yield, while 95% yield was
obtained by using 4 equiv of t-BuOK (entries 2 and 3). The
reactions of aliphatic ketones were also efficient, and not only 2c
and 2d but also α,β-unsaturated ketone 2e were transformed to
the corresponding alkenes in high yields (91−99%, entries 5, 6,
and 8). Although the Wittig reagent CH P(C H ) Br is the most
,
e
rt, 1 h
93
a
b
c
0
.3 mmol of 2a and 0.3 mmol of 1e were used. 3:1 mixture. 1.1
d
e
equiv of 1e was used. 1.2 equiv of 1e was used. 5 mmol scale.
solution of 1e and 2a at −78 °C and the mixture was gradually
warmed to room temperature, 42% yield of the alkene 3a was
obtained along with 34% of 1e, 50% of 2a, and 8 (entry 1).
LiHMDS was less effective, and NaHMDS in DME (−55 °C to
rt) gave 3a in slightly higher 54% yield (entries 2 and 3). The use
of DMF as solvent increased the yield to 79%, and 88% yield was
obtained by increasing the quantity of NaHMDS (1.7 equiv)
16
3
6
5 3
often used methylenation reagent, problems occur in the
separation of triphenylphosphine oxide (FW 278) from the
products in a large scale. In our reaction, the anion derived from
1e and base reacts with 2 to give the alkoxide A, from which
nucleophilic addition to the benzimidazole part occurs to give B
(
entry 6) (method A). More practical conditions for the
methylenation reaction of 2a using 1e were further studied.
11
6
Following Ais
equiv), 2a, and 1e in THF−DMF (3:1) was heated at 70 °C for
6 h. However, the reaction hardly proceeded. Therefore, further
heating was continued at 90 °C for 3 days to give 3a in 38% yield
entry 7). When the DMF solution of 1e and 2a was treated with
t-BuOK (1.7 equiv) at room temperature, 3a was obtained in
8% yield (entry 8). Increasing the quantity of t-BuOK to 2.5
equiv gave a higher 79% yield, and both increasing the quantity of
e (1.2 equiv) and t-BuOK (3 equiv) gave 3a in 92% yield in 1 h
entry 11) (method B). This procedure is more convenient and
̈
sa’s procedure, the suspension of Cs CO (3
(Scheme 3). Terminal alkene 3 would be formed by Smiles
2
3
rearrangement along with C and SO . Since we could not detect
2
1
any gas bubble even in a 5 mmol scale reaction, SO probably
2
reacts with t-BuOK to form t-BuOSO K. After aqueous workup
2
(
with aq NH Cl, 3 and 8 were obtained. The byproduct 8 (FW
4
148) is a small molecule and was easily removed from the
reaction mixture by either filtration or column chromatography.
When the reaction mixture of 1e and 2c was diluted with hexane
and washed with 1 M NaOH, the usual workup gave almost pure
3c. The alkene 3c was obtained in 96% yield after column
chromatography (entry 5). This method greatly simplifies
purifications of the product alkenes, and the crude mixture is
almost pure. The reaction of aliphatic ketone 2d and aldehydes 2i
and 2l was performed in the same way to give the corresponding
alkenes in 93−99% yields (entries 6, 15, and 19). For the
methylenation of aldehydes, 2.6 equiv of t-BuOK is enough
except for some improvement of yields were observed for 2i and
2k by using 3.0 equiv of t-BuOK (entries15 and 18). Although it
was reported that treatment of α-tetralone 2g with methylene-
5
1
(
economical and the reaction proceeded in 1 h at room
temperature. To establish scalability, the reaction was also run
at the 5 mmol scale to give 3a in 93% yield (entry 12).
The methylenation reactions of 1e with a variety of ketones
and aldehydes were performed using method A (NaHMDS in
DMF, Table 2). The reactions of p-bromoacetophenone 2b and
aliphatic ketones 2c and 2d gave the corresponding alkenes in
8
6−95% yield. When aldehyde 2j was reacted with 1e using 1.7
equiv of NaHMDS, 3j was obtained in 72%, while 97% yield was
B
DOI: 10.1021/acs.orglett.5b01049
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Methylenation of Ketones and Aldehydes with 1e by
t-BuOK
isopropylation following by oxidation with Oxone (Scheme 4).
The compound 9 was obtained in 64% yield (not optimized)
a
Scheme 4. Preparation of 1f and the Reaction of 1f with 2a, 2g,
2h, and 2m
entry
2
t-BuOK (equiv)
1e (equiv)
yield (%)
1
2
3
4
2a
2b
2b
2c
2c
2d
2e
2e
3.0
3.0
4.0
3.0
3.0
3.0
3.0
3.5
3.0
3.0
3.0
3.0
3.0
2.6
3.0
2.6
2.6
3.0
2.6
2.6
2.6
1.2
1.2
1.3
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.2
2.0
1.1
1.1
1.2
1.1
1.1
1.1
1.1
1.5
92
82
95
89
96
99
84
91
91
71
77
59
60
88
93
92
86
91
97
63
74
b
5
b
6
7
8
c
9
2-octanone 2f
b
10
11
12
13
14
15
16
17
18
19
20
21
2g
along with the S-methyl compound (22%) and the dimethyl 6
(4%). When the reaction of 1f with 2h was performed using t-
BuOK in DMF, 3h was obtained in 76% yield (16% higher yield).
When the reactions of 1f with 2a, 2g, and 2m were performed,
the yields were almost same as with the reaction of 1e.
2g
2h
2h
2i
b
2i
Since the PT sulfone 1c have been used for many total
10
2j
syntheses, the comparison of the reactivity of 1c and 1e was
studied next. When the reaction of 1c with 2d was performed by
using method B, 72% yield of 3d was obtained along with the
recovered 2d (14%). The sulfone 1c was not recovered at all. The
same reaction of 1e with 2d gave 99% yield of 3d (entry 6 in
Table 3). In order to test the relative stability of the metalated
sulfones, the DMF solutions of 1c, 1e, and 1f were treated with t-
BuOK (2.5 equiv) at 0 °C for 30 min and quenched with aq
2k
2k
b
c
2l
n-octanal 2m
c,d
2m
a
0
.3 mmol of 2 was used, and the yield shows isolated yields except for
b c
entries 9, 20, and 21. By basic aqueous workup. NMR yield was
determined by using methyl benzoate as an internal standard. 30 min
instead of 1 h.
d
NH Cl solution, respectively. None of the starting sulfone 1c was
4
1
17
detected by H NMR, while 1e and 1f were recovered in 49%
and 79% yield, respectively. Thus, both 1e and 1f are much more
stable than 1c in the presence of base, and this seems to be the
reason that 1e gave much higher yield of 3d.
Scheme 3. Plausible Reaction Mechanism
Next, we tested the chemoselectivity between aldehydes and
ketones in the methylenation with 1e (Scheme 5). When a
Scheme 5. Competitive Methylenation of Aldehyde and
Ketone
triphenylphosphorane gave its enolate instead of leading to any
4
e
alkene product, the reaction of 1e with 2g gave 3g in 71% yield
entry 10). The yield was slightly improved to 77% by using 1.5
(
equiv of 1e along with the recovered 2g (23%) (entry 11). The
reactions of 2-octanone 2f and n-octanal 2m were performed in a
similar way to give the alkenes in 91 and 74% yields, respectively
(
entries 9 and 21). Furthermore, we tested the reaction of 1e
with the sterically hindered (−)-menthone 2h (entries 12 and
3). The alkene 3h was obtained in 59% yield along with the
1
recovered 2h (39%) and trace amount of 1e. The yield was only
slightly improved to 60% by using 2 equiv of 1e. These results
show that 1e decomposes slowly in the presence of t-BuOK in
DMF, and the yield of alkene 3h was just moderate because of the
low reactivity of sterically hindered 2h. Generally, the combined
yields of the product 3 and the recovered 2 were nearly equal to
mixture of aldehyde 2j and ketone 2e (both 1 equiv) were treated
with 1e (1 equiv) and t-BuOK (2.6 equiv) in DMF at 0 °C, the
exclusive formation of alkene 3j in 89% yield was observed
1
(Scheme 3). The H NMR of the crude mixture showed the
selectivity between 3j and 3e was 97:3. Thus, selective
methylenation of aldehyde 2j occurred in the presence of ketone
2e. When a mixture of ketone 2d and aldehyde 2l (both 1 equiv)
was treated with 1e (1 equiv) and t-BuOK (2.6 equiv) in DMF at
1
00% except for the reaction with n-octanal 2m, where 2m was
not detected at all in the reaction mixture (entry 21).
In order to improve the stability of the reagent, we prepared
the N-isopropyl reagent 1f by successive methylation and
1
0 °C, 3d was obtained in 62% yield as a main product. The H
C
DOI: 10.1021/acs.orglett.5b01049
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
NMR of the crude mixture showed the selectivity between 3d
and 3l was 88:12. That is, ketone 2d reacted preferentially in the
presence of aldehyde 2l. When the same reaction was performed
at room temperature, the selectivity between 3d and 3l changed
to 42:58. Although the selectivity depends on the reaction
conditions and the steric and electronic character of carbonyl
compounds, chemoselective reactions could occur in some cases.
When the reaction of 1f with 2d and 2l was performed at 0 °C,
the yield of 3d was improved to 66% with the same 88:12
selectivity.
In summary, we found that new methylenation reagents 1e
and 1f react with a variety of aldehydes and ketones in the
presence of t-BuOK in DMF at room temperature in 1 h to give
terminal alkenes in high yields. The reagents can be prepared
easily without any expensive reagents and the reaction conditions
are mild and practical. We believe our new methylenation
reagents are useful complements to the Wittig reagent
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CH P(C H ) Br and other methylenation procedures. In order
3
6
5 3
to expand the scope and utility, further study on this olefination
reaction is presently under active investigation in this laboratory.
1
176. (b) Dastbaravardeh, N.; Kirchner, K.; Schnu
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ASSOCIATED CONTENT
■
(
́
́
ez-Mulia,
*
S
Supporting Information
́
́
́
Castillo, R.; Hernan
16) Yu, B.; Zhang, H.; Zhao, Y.; Chen, S.; Xu, J.; Hao, L.; Liu, Z.
Catalysis 2013, 3, 2076.
17) A dimeric product was isolated in 19% from the reaction mixture
́
dez-Luis, F. Eur. J. Med. Chem. 2012, 52, 193.
Typical experimental procedures, compound characterization
data, and the NMR spectra of compounds 1e, 1f, 6−9, and 3a−
m. The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01049.
(
(
along with 1e (49%) and 8 (5%). Furthermore, tert-butoxybenzimida-
zole was detected in the crude mixture. See the Supporting Information
for the proposed structures.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ando@gifu-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by the JSPS KAKENHI
Grant No. 25410111.
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DOI: 10.1021/acs.orglett.5b01049
Org. Lett. XXXX, XXX, XXX−XXX