Prenyl and geranyl phenyl sulfone, a new carbon nucleophile for Mitsunobu-type alkylation

Article abstract of DOI:10.1016/S0040-4039(00)02129-8

Cyanomethylenetrimethylphosphorane (CMMP), a new Mitsunobu reagent developed recently by the authors, mediated the alkylation of prenyl and geranyl phenyl sulfone with primary and secondary alcohols quite efficiently. Utilizing geranyl phenyl sulfone, norfaranal, an analog of the unique trail pheromone produced by Pharaoh's ant, was synthesized in a short number of steps.

Full text of DOI:10.1016/S0040-4039(00)02129-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 905–907
Prenyl and geranyl phenyl sulfone, a new carbon nucleophile for
Mitsunobu-type alkylation
Kaori Uemoto, Atsuko Kawahito, Noriko Matsushita, Izumi Sakamoto, Hiroto Kaku and
Tetsuto Tsunoda*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
Received 21 September 2000; revised 30 October 2000; accepted 17 November 2000
Abstract—Cyanomethylenetrimethylphosphorane (CMMP), a new Mitsunobu reagent developed recently by the authors, medi-
ated the alkylation of prenyl and geranyl phenyl sulfone with primary and secondary alcohols quite efficiently. Utilizing geranyl
phenyl sulfone, norfaranal, an analog of the unique trail pheromone produced by Pharaoh’s ant, was synthesized in a short
number of steps. © 2001 Elsevier Science Ltd. All rights reserved.
Recently, we demonstrated that cyanomethylene-
trimethylphosphorane (CMMP)1 mediated the C-alky-
lation of some doubly activated methylene and methine
compounds, such as phenylsulfonylacetonitrile (1a), 2-
(phenylsulfonyl)hexanenitrile (1b), (methylthiomethyl)-
tolylsulfone (2), and arylmethyl phenyl sulfones 3, in a
Mitsunobu-type reaction (Scheme 1).2 The traditional
Mitsunobu reagent (DEAD–PPh3) barely promotes the
reaction of these carbon nucleophiles with alcohols.3
Therefore, CMMP augments the synthetic value of the
Mitsunobu reaction and it provides now a very attrac-
tive versatile methodology for CꢀC bond formation.
In our continuing efforts to know the scope and limi-
tations of the synthetic value of this mediator, we
found that allylic phenyl sulfones 5 and 64 were alkyl-
ated effectively. In this paper, we describe the results
of these reactions and an application to a synthesis
of (+)-norfaranal [(+)-(7)],5 which is an analog of
NC
PMe3
(CMMP)
Y
SO2R''
R'
Y
SO2R''
R
OH
+
R
R'
1a: Y = CN, R' = H, R'' = Ph
1b: Y = CN, R' = butyl, R'' = Ph
2: Y = SMe, R' = H, R'' = p-Tol.
3: Y = Ar, R' = H, R'' = Ph
Scheme 1.
Ph
Ph
SO2Ph
CMMP (1.5 equiv.)
Tol., 100°C, 24 h
SO2Ph
+
+
+
Ph
OH
SO2Ph
SO2Ph
(1.5 equiv.)
4
9
10
8
51%
37%
Scheme 2.
Keywords: Mitsunobu reactions; phosphorane; sulfones; pheromone.
* Corresponding author. Fax: +81-88-655-3051; e-mail: tsunoda@ph.bunri-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02129-8

906
K. Uemoto et al. / Tetrahedron Letters 42 (2001) 905–907
(+)-faranal,6,7 the unique trail pheromone produced by
Pharaoh’s ant (Monomorium pharanis, L.).
presence of CMMP to afford the nitrile 12 satisfactorily
with Walden inversion of the carbinyl carbon on 11
(Scheme 3). The acetal-alcohol 13 was obtained by
desulfurization of 12 with SmI2 followed by reduction
of the nitrile with DIBAL, protection of the resulting
formyl group, and removal of the MPM group. The
usual Mitsunobu reaction with benzoic acid and subse-
quent hydrolysis was employed to invert the hydroxy
group on 13 to give the alcohol 14. The geranyl sulfone
6 (3.0 equiv.) was subjected to the present CMMP (3.0
equiv.) alkylation with the alcohol 14 to give the sul-
fone 15. Palladium-catalyzed reaction (10 mol% of
PdCl2(dppp) and 4.0 equiv. of LiHBEt3)10 induced the
cleavage of the CꢀS bond to give acetal 16. Quick
hydrolysis (30 min) of the acetal with 3 equiv. of
p-TsOH in THF–H2O led to (+)-norfaranal [(+)-7] as a
colorless oil, [h]2D2+21.9 (c 1.00, CHCl3), in addition to
21% of the starting material being recovered. Physical
properties of (+)-7 are well compared with those in the
literature7c [h]D22 +17.5 (c 4.46, CHCl3)].
With 1.5 equiv. of CMMP at 100°C in toluene,8 methal-
lyl phenyl sulfone (4) was converted to the benzylated
compound 8 in 51% yield (Scheme 2). However, a
considerable amount of vinyl sulfones 9 and 10 was
also obtained. Since the tendency of double bond
migration was dominated by the thermodynamical sta-
bility of olefin, the reactions of trisubstituted allylic
sulfones 5 and 6, more stable olefins, were carried out
using alcohols of different structure types. The results
are listed in the Table 1.
The alkylation of sulfones 5 and 6 proceeded smoothly
at 100°C to afford the corresponding product without
olefin migration according to expectation. For the reac-
tion of both sulfones, a 1:3 mixture of hexane–benzene
was the best solvent. 1,2-Dimethoxyethane (DME)
could also be used for the reaction of 6. Although a
higher temperature was needed (120°C) for the reaction
of 2-octanol, a secondary alcohol, all types of alcohols
tested condensed with 5 and 6 quite efficiently.
Thus, we have demonstrated that trisubstituted allylic
phenyl sulfones of pKa up to 22.5 can be utilized in the
CMMP mediated Mitsunobu reaction. The CꢀC bond
formation reaction, being much more versatile than
ever, should find much wider application in organic
syntheses.
In order to demonstrate the usefulness of the reaction,
norfaranal was synthesized. The mono-MPM ether of
(2S,3S)-2,3-butanediol (11) was reacted with 1a9 in the
Table 1. Alkylation of allylic sulfones (% yield)
CMMP (1.5 equiv.)
solv., 100°C, 24 h
R'
R
R
R'-OH
+
SO2Ph
(1.5 equiv.)
5: R = H
SO2Ph
6: R = Me2C=CHCH2-
5
6
R'-OH
in Hex. / PhH
(1 / 3)
in Hex. / PhH
in DME
(1 / 3)
89
87
98
Ph
OH
89
93
86
87
92
OH
100
OH
nC16H33OH
89
82
96
78
a
a
76
Hex
OH
a: The reaction was carried out at 120°C .

K. Uemoto et al. / Tetrahedron Letters 42 (2001) 905–907
907
1) SmI2, THF, MeOH, H2O
SO2Ph
2) DIBAL
(1.5 equiv.)
1a
O O
MPMO
CMMP (1.5 equiv.)
Tol., 100 °C, 24h
79 %
MPMO
HO
OH
H
OH
TsOH, CuSO4
4) DDQ, CH2Cl2, H2O
3)
HO
CN
13
11
12
55 %
(3.0 equiv.)
CMMP (3.0 equiv.)
6
O O
H
O
O
1) PhCOOH, DEAD-PPh3
HO
H
Hex. / PhH (1 / 3)
2) 1N NaOH, MeOH
98 %
100 °C, 24 h
54 %
SO2Ph
15
14
LiBHEt3
p-TsOH (3 equiv.)
O
O
Pd(dppp)Cl2
O
H
H
THF, H2O
r.t., 30 min
THF
74 %
16
(+)-7
42 %
Scheme 3.
Rotgans, I. E. M.; Vrielink, A. Naturwissenschaften 1983,
70, 469.
Acknowledgements
6. Ritter, F. J.; Brggemann-Rotgans, I. E. M.; Verwiel, P.
E. J.; Persoons, C. J.; Talman, E. Tetrahedron Lett. 1977,
2617–2618 and Ref. 5a.
This work was supported partially by a Grant-in-Aid
for Scientific Research (C) from the Ministry of Educa-
tion, Science, Sports, and Culture of Japan. A Sunbor
Grant from the Suntory Institute for Bioorganic
Research is also gratefully acknowledged.
7. (+)-Faranal and (+)-7 have been attractive targets of
synthetic efforts and total syntheses have been accom-
plished. In these syntheses, however, the introduction of
dimethyl groups in 3S,4R configuration required multi-
step processes, because of the lack of convenient method
for the construction of dimethyl groups in anti-1,2 posi-
tion. See: (a) Mori, K.; Ueda, H. Tetrahedron Lett. 1981,
22, 461–464. (b) Mori, K.; Ueda, H. Tetrahedron 1983,
38, 1227–1233. (c) Poppe, L.; Novk, L.; Kolonits, P.;
Bata; Szntay, C. Tetrahedron 1988, 44, 1477–1487.
8. In a typical experiment, an Ace pressure tube (max. 200
psi) was used as a sealed reactor at higher temperature.
CMMP (1.5ꢀ3.0 mmol) was added to a dry solvent
solution of an alcohol (1 mmol) and allylic sulfone (1.5
mmol) with stirring under argon atmosphere. The mix-
ture was heating at 100ꢀ120°C for 24 h in the sealed
tube. The product was purified by silica gel column
chromatography after evaporation of the solvent in
vacuo. All new compounds were characterized by IR,
1H-NMR, MS, analysis or High-MS.
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