A novel route to fully substituted cyanoallenes from three components, ketones, chloromethyl p-tolyl sulfoxide, and nitriles, via α- bromocyclopropyl p-tolyl sulfoxides

Article abstract of DOI:10.1016/j.tetlet.2006.01.161

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chloromethyl p-tolyl sulfoxide in high yields, with lithium α-carbanion of nitriles gave the adducts in quantitative yields. The adducts were converted to α-bromocyclopropy

Full text of DOI:10.1016/j.tetlet.2006.01.161

Tetrahedron Letters 47 (2006) 2835–2838
A novel route to fully substituted cyanoallenes from
three components, ketones, chloromethyl p-tolyl sulfoxide, and
nitriles, via a-bromocyclopropyl p-tolyl sulfoxides
Tsuyoshi Satoh* and Youhei Gouda
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 4 January 2006; revised 23 January 2006; accepted 27 January 2006
Available online 6 March 2006
Abstract—Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chloromethyl p-tolyl sulfoxide in high
yields, with lithium a-carbanion of nitriles gave the adducts in quantitative yields. The adducts were converted to a-bromocyclo-
propyl p-tolyl sulfoxides in two steps in good yields. Finally, the sulfoxides were treated with excess lithium carbanion of isobutyro-
nitrile to afford fully substituted cyanoallenes in high to quantitative yields via sulfoxide–lithium exchange reaction. This
procedure offers a novel synthetic method for fully substituted cyanoallenes with coupling of three components (ketones, chloro-
methyl p-tolyl sulfoxide, and nitriles) in good overall yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Allenes are very interesting and highly important com-
pounds in organic and synthetic organic chemistry.1
Moreover, the allenyl structure is frequently found in
natural products and pharmaceuticals.2 In view of the
importance of allenes, a large number of studies have
been reported on their chemistry and synthesis.1,2 The
general methods for the synthesis of allenes are, for
example, isomerization of acetylenes,3 ring-opening of
cyclopropylidenes,4 the reaction of propargylic deriva-
tives with organocopper reagents,5 and b-elimination
of olefins.6 We recently reported a novel method for syn-
thesis of allenes by the reaction of magnesium alkylidene
carbenoids with lithium a-sulfonyl carbanions.7
Although many methods for the preparation of allenes
have appeared as above, it is still difficult to synthesize
fully substituted (tetra-substituted) allenes having sev-
eral functional groups.
with 1-chlorovinyl p-tolyl sulfoxides with nitriles.9 In
continuation of our interest in the development of new
synthetic method of allenes, we recently studied a com-
bination of our two strategies described above and a no-
vel synthetic method for fully substituted cyanoallenes
from three components, ketones, chloromethyl p-tolyl
sulfoxide, and nitriles was realized. The essence of this
method is shown in Scheme 1.
Thus, 1-chlorovinyl p-tolyl sulfoxides 3 were synthesized
from ketones 1 and chloromethyl p-tolyl sulfoxide 2 in
three steps in over 90% overall yields.10 Reaction of 3
with lithium a-carbanions of nitriles gave the adducts
4 in nearly quantitative yields. Treatment of the adducts
4 with t-BuOK in a mixture of THF–t-BuOH gave
cyclopropyl sulfoxides, which were brominated with
LDA–CBr4 to afford a-bromocyclopropyl p-tolyl sulfox-
ides 5 in over 80% yields. Finally, sulfoxides 5 were trea-
ted with lithium a-carbanion of isobutyronitrile to give
the fully substituted cyanoallenes 7 via lithium cycloprop-
ylidene 6 in high yields.
Previously, we reported a new method for synthesis of
allenes from 1-chlorocyclopropyl phenyl sulfoxides via
magnesium cyclopropylidenes.8 Recently, we have been
investigating the development of new synthetic methods
The details of this investigation are described by using 1-
chlorovinyl p-tolyl sulfoxide 8 as a representative exam-
ple (Scheme 2). 1-Chlorovinyl p-tolyl sulfoxide 8 was
synthesized from cyclopentadecanone in high overall
yield.10,11 Treatment of 8 with 2.5 equiv of lithium a-
carbanion of propionitrile in THF at À78 °C for
Keywords: Allene; Cyanoallene; Sulfoxide; Sulfoxide–lithium exchange;
Lithium cyclopropylidene.
*
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 3235
2214; e-mail: tsatoh@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.161

2836
T. Satoh, Y. Gouda / Tetrahedron Letters 47 (2006) 2835–2838
Li
R3
TolS(O)CH2Cl
R3CHCN
R1
R2
R1
R2
Cl
R1
R2
CN
H
1) t-BuOK
2
O
in three steps
lit. 10
S(O)Tol
2) Bromination
1
S(O)Tol
Cl
3
4
H3C
R3
R3
CN
R1
R2
R3
R1
R2
CN
Br
H3C
R1
R2
CN
Br
Li
-LiBr
Rearrangement
.
CN
Li
7
S(O)Tol
5
6
Scheme 1.
Li
CH3
CN
CH3
CN
2.5 eq CH3CHCN
t-BuOK
Cl
S(O)Tol
15
THF-t-BuOH
-78 ºC ~ r. t.
90%
S(O)Tol
S(O)Tol
THF, -78 ˚C
95%
H
Cl
10
9
8
H3C
H3C
CH3
CN
CN
NCS / THF (99%)
Li
99%
CH3
CN
.
15
S(O)Tol
or
LDA-CBr4 / THF
X
(85%)
11a X=Cl
11b X=Br
12
Scheme 2.
10 min afforded the adduct 9 in 95% yield as a mixture
of two diastereomers. The adduct 9 was then treated
with 5 equiv of t-BuOK in a mixture of THF–t-BuOH.
The intramolecular SN2 reaction took place to give the
desired cyclopropane having p-tolyl sulfinyl group 10
in high yield. The cyclopropyl sulfoxide 10 was chlori-
nated with NCS12 in THF to give the chloride 11a in
quantitative yield.
Grignard reagent,8 11a was treated with PhMgCl at 0 °C
for 1 h (Scheme 3). All the starting materials 11a disap-
peared to give a magnesium cyclopropylidene 13a; how-
ever, no desired allene 12 was observed. Instead,
chlorocyclopropane 14 was obtained in 65% yield.
Treatment of 11a with t-BuLi also gave 14 or a complex
mixture without the desired allene 12 via a lithium cyclo-
propylidene 13b.
First, based on our experience with the synthesis of
The intermediate of these reactions is the magnesium
allenes from a-chlorocyclopropyl phenyl sulfoxides with
cyclopropylidene 13a or lithium cyclopropylidene 13b.
CH3
CH3
CH3
CN
CN
Alkylmetal
THF
CN
15
15
S(O)Tol
Metal
H
Cl
Cl
Cl
11a
13a Metal=MgCl
13b Metal=Li
14
Alkylmetal
Yield of 14
Conditions
-30 ~ 0 ˚C, 0 ˚C, 1 h
65%
PhMgCl (2.5 eq)
t-BuLi (3 eq)
t-BuLi (3 eq)
50%
-80 ˚C, 1 h
complex mixture
-80 ~ 0 ˚C, 0 ˚C, 1 h
Scheme 3. Treatment of a-chlorocyclopropyl p-tolyl sulfoxide 11a with alkylmetals.

T. Satoh, Y. Gouda / Tetrahedron Letters 47 (2006) 2835–2838
2837
In our previous letter,8 magnesium cyclopropylidenes
rearranged to allenes at above À60 °C; however, in this
study, highly substituted cyclopropylidenes having a cy-
ano group (13a and 13b) were found to be quite stable
and no rearrangement occurred.
67% yield. This result implied that both sulfoxide-lith-
ium exchange and bromine–lithium exchange reaction
took place at the same time at À78 °C. Indeed, by treat-
ment of 11b with t-BuLi at À50 °C and À30 °C (entries 5
and 6) the yield of 17 was diminished and the yield of the
desired allene 12 was increased. The yield of 12 was 44%
when the reaction was conducted at room temperature
(entry 7).
Next, the cyclopropyl sulfoxide 10 was brominated by
treatment with LDA followed by carbon tetrabromide
to give the bromide 11b as a mixture of diastereomers
in 85% yield (Scheme 2). This bromide was treated with
Grignard reagent or alkyllithium and the results are
summarized in Table 1. The bromide 11b was treated
with PhMgCl or i-PrMgBr (entries 1–3). Again, the
main product was desulfinylated bromocyclopropane
16. However, in these cases a trace amount of the de-
sired allene 12 was observed. From these results, again,
the magnesium cyclopropylidene 15a appeared to be
unexpectedly stable.
At this stage of our investigation, we thought that if a
nucleophile (alkyllithim) that attacked only sulfoxide
was used in this reaction, the desired allene 12 could
be obtained in high yield. After some investigation we
found that lithium a-carbanion of isobutyronitrile
worked excellently. Excess of the anion, which was pre-
pared from isobutyronitrile with tert-BuLi, was added
to a solution of 11b in THF portionwise at room tem-
perature to give a quite clean reaction mixture, from
which the desired allene 12 was obtained in quantitative
yield (entry 8).13
Next, the bromide 11b was treated with t-BuLi (entries
4–7). The result shown in entry 4 is quite interesting.
Treatment of the bromo-sulfoxide 15b with t-BuLi at
À78 °C gave cyclopropane 17 as a main product in
Finally, generality of this procedure was investigated
and the results are summarized in Table 2. Entry 1
Table 1. Treatment of a-bromocyclopropyl p-tolyl sulfoxide 11b with alkylmetals
CH3
CH3
CN
CH3
CN
Alkylmetal
THF
CN
CH3
CN
.
+
15
Metal
S(O)Tol
H
12
CH3
CN
Br
Br
Br
16
15a Metal=MgCl
15b Metal=Li
11b
+
H
H
17
Entry
Alkylmetal (equiv)
Conditions
12 (%)
16 (%)
17 (%)
1
2
3
4
5
6
7
8
PhMgCl (2.5)
PhMgCl (2.5)
i-PrMgBr (2.5)
t-BuLi (2.5)
t-BuLi (2.5)
t-BuLi (2.5)
t-BuLi (2.5)
À50 to 0 °C, 0 °C, 0.5 h
À50 to rt, rt, 0.5 h
À50 to rt, rt, overnight
À78 to 0 °C, 0 °C, 2 h
À50 to rt, rt, 2 h
À30 to rt, rt, 2 h
rt, 2 h
Trace
Trace
Trace
Trace
16
34
44
99
66
58
84
29
Trace
13
13
0
0
0
67
37
16
10
0
(CH3)2C(Li)CN (10)
rt, overnight
0
Table 2. Synthesis of fully substituted cyanoallenes 19 from 1-chlorovinyl p-tolyl sulfoxides 3 through a-bromocyclopropyl p-tolyl sulfoxides 18 with
lithium a-carbanion of isobutyronitrile
R3
R1
R2
R3CH(Li)CN
R1
R2
18
(CH3)2C(Li)CN
R1
R2
R3
S(O)Tol
Cl
CN
.
CN
S(O)Tol
19
Br
3
Entry
3
R3
18
19
R1
R2
Yielda (%)
Yield (%)
1
2
3
4
5
–(CH2)14
–
CH3
CH2CH2CH2CH3
CH3
CH2CH2CH2CH3
CH2CH2CH2CH3
72
65
67
85
89
12 (99)
–(CH2)14
–
19a (99)
19b (89)
19c (76)
19d (96)
–(CH2)9–
–(CH2)5–
CH3
CH2CH2Ph
a Three-step overall yield from 1-chlorovinyl p-tolyl sulfoxide 3.

2838
T. Satoh, Y. Gouda / Tetrahedron Letters 47 (2006) 2835–2838
Tetrahedron Lett. 1986, 27, 5499; (c) Alexakis, A.; Marek,
I.; Mangeney, P.; Normant, J. F. J. Am. Chem. Soc. 1990,
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showed the result described above with the overall yield
for the synthesis of the bromocyclopropyl p-tolyl sulfox-
ide from 8. Entry 2 shows the result using hexanenitrile
as the nitrile to give the tetra-substituted allene 19a in
good overall yield. The fully substituted cyanoallenes
were synthesized from cyclodecanone (entry 3) and
cyclohexanone (entry 4) with propionitrile or hexanenit-
rile. By using 4-phenyl-2-butanone and hexanenitrile in
this procedure, the fully substituted allene 19d was ob-
tained in high overall yield. It is interesting to note that
all the substituents of the allene 19d are different, butyl,
cyano, methyl, and 2-phenylethyl groups.
6. (a) Nativi, C.; Ricci, A.; Taddei, M. Tetrahedron Lett.
1987, 28, 2751; (b) Konoike, T.; Araki, Y. Tetrahedron
Lett. 1992, 33, 5093; (c) Zhao, Y.; Quayle, P.; Kuo, E. A.
Tetrahedron Lett. 1994, 35, 3797; (d) Araki, Y.; Konoike,
T. J. Synth. Org. Chem. Jpn. 2000, 58, 956; (e) Tius, M. A.;
Pal, S. K. Tetrahedron Lett. 2001, 42, 2605; (f) Satoh, T.;
Hanaki, N.; Kuramochi, Y.; Inoue, Y.; Hosoya, K.; Sakai,
K. Tetrahedron 2002, 58, 2533.
7. (a) Satoh, T.; Sakamoto, T.; Watanabe, M. Tetrahedron
Lett. 2002, 43, 2043; (b) Satoh, T.; Sakamoto, T.;
Watanabe, M.; Takano, K. Chem. Pharm. Bull. 2003, 51,
960.
8. Satoh, T.; Kurihara, T.; Fujita, K. Tetrahedron 2001, 57,
5369.
9. (a) Satoh, T.; Ota, H. Tetrahedron 2000, 56, 5113; (b)
Satoh, T.; Yoshida, M.; Takahashi, Y.; Ota, H. Tetra-
hedron: Asymmetry 2003, 14, 281; (c) Wakasugi, D.;
Satoh, T. Tetrahedron 2005, 66, 1245; (d) Kawashima, T.;
Kashima, H.; Wakasugi, D.; Satoh, T. Tetrahedron Lett.
2005, 46, 3767.
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan to promote
multi-disciplinary research project, which is gratefully
acknowledged.
References and notes
10. Satoh, T.; Kawashima, T.; Takahashi, S.; Sakai, K.
Tetrahedron 2003, 59, 9599.
11. Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda, K.;
Koyama, M. Tetrahedron 1998, 54, 5557.
12. (a) Tsuchihashi, G.; Ogura, K. Bull. Chem. Soc. Jpn. 1971,
44, 1726; (b) Satoh, T.; Kondo, A.; Musashi, J. Tetra-
hedron 2004, 60, 5453.
1. Some monographs and reviews concerning chemistries
and synthesis of allenes: (a) Patai, S. The Chemistry of
Ketenes, Allenes, and Related Compounds; John Wiley and
Sons: Chichester, 1980, Part 1 and 2; (b) Brandsma, L.;
Verkruijsse, H. D. Synthesis of Acetylenes, Allenes, and
Cumulenes; Elsevier: Amsterdam, 1981; (c) Schuster, H.
F.; Coppola, G. M. Allenes in Organic Synthesis; John
Wiley and Sons: New York, 1984; (d) Point, M. A.
Tetrahedron 1980, 36, 331; (e) Pasto, D. J. Tetrahedron
1984, 40, 2805; (f) Zimmer, R. Synthesis 1993, 165; (g)
Miesch, M. Synthesis 2004, 746; (h) Allenes: application in
synthesis (special topic); Synthesis 2004, pp 735–795.
2. Synthesis and properties of allenic natural products and
pharmaceuticals: Hoffmann-Roder, A.; Krause, N.
Angew. Chem., Int. Ed. 2004, 43, 1196, and the references
cited therein.
3. (a) Franck-Neumann, M.; Martina, D.; Neff, D. Tetra-
hedron: Asymmetry 1998, 9, 697; (b) Oku, M.; Arai, S.;
Katayama, K.; Shioiri, T. Synlett 2000, 493.
4. (a) Doering, W. von E.; LaFamme, P. M. Tetrahedron
1958, 2, 75; (b) Moore, W. R.; Ward, H. R. J. Org. Chem.
1960, 25, 2073; (c) Skattebol, L. Tetrahedron Lett. 1961,
167; (d) Moore, W. R.; Ward, H. R. J. Org. Chem. 1962,
27, 4179.
13. Experiment for the synthesis of allene 12: tert-Butyllithium
(0.89 mmol) was added dropwise to a solution of isobu-
tyronitrile (0.07 mL, 0.81 mmol) in 16 mL of dry THF at
À78 °C and the reaction mixture was stirred at the
temperature for 1 h. In another flask at room temperature,
about one-tenth of the solution of lithium a-carbanion of
isobutyronitrile, described above, was added to a solution
of bromide 11b (40 mg, 0.08 mmol) in 16 mL of THF
portionwise in every 10 min. After the addition, the
reaction mixture was stirred at room temperature for
12 h. The reaction was quenched by adding satd aq NH4Cl
solution and the whole was extracted with CH2Cl2. The
product was purified by silica gel column chromatography
to afford 22.2 mg (99%) of allene 12 as a colorless oil. IR
(neat) 2929, 2857, 2217 (CN), 1954 (allene), 1460 cmÀ1; 1H
NMR d 1.26–1.39 (20H, m), 1.45–1.52 (4H, m), 1.89 (3H,
s), 2.08 (4H, m). MS m/z (%) 273 (M+, 51), 146 (25), 120
(53), 107 (100). Calcd for C19H31N: M, 273.2457. Found:
m/z 273.2456.
5. For example: (a) Posner, G. H. Org. React. 1975, 22, 287;
(b) Marek, I.; Mangeney, P.; Alexakis, A.; Normant, J. F.