New One-pot Cross-coupling Reaction between Grignard Reagents and Alkoxymethyldiphenylphosphonium Iodides in situ-Formed from Alcohols, Chlorodiphenylphosphine and Iodomethane

Article abstract of DOI:10.1246/cl.2003.676

A new one-pot cross-coupling reaction between Grignard reagents and alkoxymethyldiphenylphosphonium iodides, which were in situ-formed from ⁿBuLi-treated alcohols, chlorodiphenylphosphine and iodomethane, proceeded smoothly to afford the corresponding coupling products in good to high yields.

Full text of DOI:10.1246/cl.2003.676

6
76
Chemistry Letters Vol.32, No.8 (2003)
New One-pot Cross-coupling Reaction between Grignard Reagents and
Alkoxymethyldiphenylphosphonium Iodides in situ-Formed from Alcohols,
Chlorodiphenylphosphine and Iodomethane
y;yy
y;yy Ãy;yy
and Teruaki Mukaiyama
Taichi Shintou,
Center for Basic Research, The Kitasato Institute, 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
Wataru Kikuchi,
y
yy
(Received April 30, 2003; CL-030365)
A new one-pot cross-coupling reaction between Grignard
reagents and alkoxymethyldiphenylphosphonium iodides,
which were in situ-formed from BuLi-treated alcohols, chloro-
diphenylphosphine and iodomethane, proceeded smoothly to af-
ford the corresponding coupling products in good to high yields.
tried (Table 1, entry 1). When PhMgBr and the phophonium salt
ꢀ
were allowed to react at 100 C for 0.5 h, the desired 1-benzyl-
n
4-methoxybenzene was obtained in 10% yield along with tri-
phenylphosphine (53% yield) which was formed by direct at-
tack of Grignard reagent on phosphorus atom. Interestingly,
the desired product was obtained in 38% yield when the reac-
ꢀ
tion was carried out using benzyl bromide at 50 C for 2 h
(Table 1, entry 4) while the desired product was not obtained
when mild oxidant such as 2,6-dimethyl-1,4-benzoquinone
There are a number of reactions reported concerning
Grignard reagents and phosphorus compounds such as phospho-
rus trichloride, trialkyl phosphate, triaryl phosphate and alkyl
ꢀ
was used at À78 C for 3 h (Table 1, entry 3).
1,2
diphenylphosphinate etc. Since Grignard reagents generally
attack on phosphorus atom, therefore, phosphine or oxophos-
phorane derivatives are formed in the main. Among the few ex-
amples of C-alkylation reaction with hindered Grignard re-
agents having mesityl or trityl groups and phosphates having
After screening several types of alkylating reagents shown
in Table 2, the desired product was obtained in 59% yield and
no triphenylphosphine was observed when phosphonium salt
formed by treating alkoxydiphenylphosphine with iodomethane
at rt for 1 h was used (Table 2, entry 8). Generally, monoalkyl-
phosphonic esters are known to be formed by the reaction of tri-
alkyl phosphites with alkyl halides (Michaelis–Arbuzov reac-
3
trimethyl or geranyl diethyl groups, no successful C-alkylation
using Grignard reagents and alkoxydiphenylphosphines was re-
4
ported to date. In our previous paper, alkylations of various
8,9
tion). However, the above reaction did not take place in the
case of using alkoxydiphenylphosphine and iodomethane even
5
,6
7
carboxylic acids or phenols with alkoxydiphenylphosphoni-
um salt in situ-formed from alcohols, chlorodiphenylphosphine
and 2,6-dimethyl-1,4-benzoquinone were presented as a new-
type of oxidation–reduction condensation. Alkoxydiphenyl-
phosphines having a primary, secondary or tertiary alkoxy
group, oxidizing agent such as 2,6-dimethyl-1,4-benzoquinone,
and carboxylic acids or phenols afforded the alkylated products
in good to high yields. In our point of view, alkoxydiphenyl-
phosphines behaved more effectively in the formation of impor-
tant intermediate phosphonium salt since the alkoxy part had
been introduced to phosphine in advance. In order to expand
the idea of this type of reaction, C-alkylation reaction using
Grignard reagents and alkoxymethyldiphenylphosphonium io-
ꢀ
when they were heated at 100 C, therefore, higher temperature
ꢀ
(150–250 C) should be needed. Since then, iodomethane was
used as the most preferable reagent for a complete formation
of alkoxyalkyldiphenylphosphonium salts from alkoxydiphe-
nylphosphines and alkylating reagents as shown in Table 2. In
the above reaction, Grignard reagents coupled with iodide anion
of the phosphonium salts forming an intermediate ate complex I
which was in turn decomposed to procedure cross-coupling
product together with Ph2MeP=O and MgXI. Similarly,
alkoxydiphenylphosphonium salts were formed easily in case
À
À
of using anion such as OTf or BF4 while the coupling reac-
tion hardly proceeded because Grignard reagents did not form
the corresponding ate complex I with phosphonium triflate or
tetrafluoroborate. Actually, corresponding alcohol and Ph2Me-
P=O were detected after quenching the reaction with saturated
aq NH4Cl.
n
dides in situ-formed from BuLi-treated alcohols, chlorodiphe-
nylphosphine and iodomethane were tried and the correspond-
ing cross-coupling products were obtained in good to high
yields along with methyl(diphenyl)phosphine oxide (Scheme 1).
In the first place, C-alkylation of 1 equivalent of PhMgBr
When 2.0 or 3.0 equivalents of PhMgBr were allowed to re-
Table 1. Cross-coupling reaction between PhMgBr and alkoxydiphenyl-
2
phosphonium salt in situ-formed from PMBOH, Ph PCl and Additive
with 1 equivalent of p-methoxybenzyloxydiphenylphosphine
n
(Ph2POPMB), in situ formed from BuLi-treated p-methoxy-
benzyl alcohol (PMBOH) and chlorodiphenylphosphine, was
nBuLi
2
PhMgBr
1.0 equiv.)
(
Ph PCl
R'MgX
PMBOH
Ph POPMB
2
n
Me
THF
Additive
THF
1
. BuLi / Ph PCl
MeO
Yield/%
2
ROH
Ph POR
2
2
. MeI
Yield/%a
Entry
1
2
Additive
None
None
Condition
ꢀ
I
100 C, 0.5 h
ꢀ
10
10
53
—
I
b
100 C, 0.5 h
Me
Ph P O R
2
,6-Dimethyl-1,4-
benzoquinone
BnBr
R
R' + Ph MeP=O + MgXI
ꢀ
2
2
3
4
À78 C, 3 h
50 C, 2 h
N.D.
38
R'MgXI
Scheme 1.
ꢀ
Trace
a
b
Yields of by-product (PPh ). 5 equivalent of PhMgBr was used.
3
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.8 (2003)
677
Table 2. Cross-coupling reaction between PhMgBr and p-methoxydiphe-
nylphosphonium salt in situ-formed from PMBOH, Ph2PCl and alkylating
reagents
Table 4. Various cross-coupling reaction between Grignard reagents and
alkoxymethyldiphenylphosphonium iodide in situ-formed from ROH,
Ph2PCl and MeI
nBuLi
2
Me
n
R'MgX
1
2
. BuLi / Ph PCl
RX (1.0 equiv.)
Condition A
PhMgBr
1.0 equiv.)
2
Ph POR
Ph PCl
R R'
ROH
2
PMBOH
Ph POPMB
2
. MeI (1.0 equiv.)
THF, rt, 1 h
THF
R
I
0
Entry
1
ROH
R MgBr
equiv. Yield/%
(
Ph POPMB
2
p-MeO-C6H4CH2OH
PhMgCl
PhMgBr
PhMgl
2
2
2
2
2
2
3
2
3
3
3
3
3
3
3
3
3
3
quant.
quant. (99)
30
THF
Condition B
2a
X
MeO
b
3
a
Entry Alkylating reagents Condition A Condition B
Yield /%
38
4
5
6
7
8
p-MeO-C6H4MgBr
p-CF -C H MgBr
98
96
92
90
30
N.R.
94
89
86
82(81)
76
80
78(79)
N.R.
N.R.
ꢀ
ꢀ
ꢀ
ꢀ
1
2
3
4
5
6
7
8
9
BnBr
BnBr
BnCl
Bnl
50 C, 1 h
rt, 1 h
100 C, 1 h
rt, 1 h
50 C, 1 h
rt, 0.5 h
50 C, 1 h
rt, 1 h
rt, 1 h
rt, 1 h
rt, 1 h
rt, 1 h
rt, 1 h
50 C, 2 h
50 C, 1 h
3
6
4
PhCH MgBr
2
48
19
52
ꢀ
CH (CH ) MgBr
2 5
50 C, 2 h
rt, 1 h
3
cyclohexyl-MgBr
t
b
ꢀ
ꢀ
9
BuMgCl
p-MeO-C6H4MgBr
CH (CH ) MgBr
EtOTs
HBF4
50 C, 1 h
rt, 1 h
22 (22)
N.D.
N.D.
59
32 (3)
29 (12)
17 (19)
6
10
11
BnOH
þ
À
ꢀ
ꢀ
Et3O BF4
50 C, 1 h
rt, 1 h
3
2 5
1
2
p-Cl-C6H4CH2OH
p-MeO-C6H4MgBr
PhCH MgBr
CH (CH ) MgBr
3 2 3
2
PhCH MgBr
PhCH2CH2MgBr
Mel
Etl
a
ꢀ
13
14
15
1
1
50 C, 1 h
2
n
1
0
1
2
3
Bul
tBul
MeOTf
rt, 3 h
rt, 3 h
rt, 1 h
rt, 1 h
CH (CH ) OH
3
CH3(CH2)4OH
2
5
1
1
1
6a
7
i
PrOH
p-MeO-C6H4MgBr
BnB(C6F5)4
N.D.
t
aYields of parenthesis are ones of by-product (Ph3P).
18
BuOH
PhMgBr
aYields in the parenthesis are those carried out by one-pot procedure and
the same results were obtained without removing lithium chloride.
bGrignard reagent in Et2O solution.
act with one molar each of Ph2POPMB and iodomethane at
room temperature, the desired cross-coupling product was ob-
tained in quantitative yields (Table 3, entries 4 and 5).
Next, the cross-coupling reaction by using various Grignard
reagents and alkoxymethyldiphenylphosphonium iodides in
temperature and then was refluxed for 1 h. The dark brown mix-
ture was transferred via cannula to an addition funnel, and was
slowly added at 0 C to a mixture of alkoxydiphenylphosphine
0.6 mmol) and iodomethane (0.6 mmol), and the solution was
ꢀ
10
n
situ-formed from BuLi-treated several alcohols, chlorodiphe-
(
nylphosphine and iodomethane were tried (Table 4). When ben-
zyl alcohols having electron-donating or electron-withdrawing
groups and aliphatic or phenyl Grignard reagents having elec-
tron-donating or electron-withdrawing groups were used, the
corresponding coupling products were obtained in good to high
yields (Table 4, entries 1–14). On the other hand, the desired
product was obtained in 30% yield when secondary Grignard
reagent such as cyclohexylmagnesium bromide was used
stirred for 1 h at room temperature. After completion of the re-
action (detected by TLC), it was quenched with saturated aq
NH4Cl and the mixture was extracted with Et2O. The organic
layers were dried over anhydrous sodium sulfate, filtered and
concentrated. The crude product was purified by preparative
TLC to afford the desired products.
Thus, a new and efficient method for one-pot cross-cou-
pling reaction by using Grignard reagents and alkoxymethyldi-
phenylphosphonium iodides, in situ formed from alcohols,
chlorodiphenylphosphine and iodomethane, proceeded smooth-
ly to afford the corresponding cross-coupling products in good
to high yields. Further study on this type of condensation reac-
tion is now in progress.
(
t
Table 4, entry 8). When tertiary Grignard reagent such as
BuMgCl was treated with the phosphonium salt formed from
Ph2POPMB and iodomethane, the desired product was not
formed. Also, in the case of using primary alcohols such as hex-
yl alcohol or pentanol, the reaction proceeded smoothly to af-
ford the cross-coupling products in good yields. When isopropyl
alcohol or tert-butyl alcohol was used, no C-alkylation reaction
took place at all.
Typical experimental procedure is as follows: under argon
atmosphere, a solution of magnesium (0.9 mmol) and bromo-
benzene (0.9 mmol) in THF (3 mL) was stirred for 1 h at room
This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science, and Technology (MEXT).
References and Notes
1
2
3
K. D. Berlin and M. E. Peterson, J. Org. Chem., 32, 125 (1967).
K. D. Barlin and R. U. Pagilagan, J. Org. Chem., 32, 129 (1967).
a) S. Araki, T. Sato, and Y. Butsugan, J. Chem. Soc., Chem. Commun.,
Table 3. Cross-coupling reaction between PhMgBr and p-methoxyben-
zyloxymethyldiphenylphosphonium iodide in situ-formed from PMBOH,
Ph2PCl and MeI
1
982, 285. b) H. Gilman and B. J. Gai, J. Am. Chem. Soc., 82, 6326 (1960).
4
T. Shintou, W. Kikuchi, and T. Mukaiyama, Bull. Chem. Soc. Jpn., in
press, (2003).
T. Mukaiyama, T. Shintou, and W. Kikuchi, Chem. Lett., 2002, 1126.
T. Mukaiyama, W. Kikuchi, and T. Shintou, Chem. Lett., 32, 300 (2003).
T. Shintou, W. Kikuchi, and T. Mukaiyama, Chem. Lett., 32, 22 (2003).
G. M. Kosolapoff, in ‘‘Organic Reactions,’’ ed. by R. Adams, John Wiley
Me
n
1
2
. BuLi / Ph PCl
PhMgBr
2
Ph POPMB
2
PMB Ph
5
6
7
8
PMBOH
. MeI (1.0 equiv.)
THF, rt, 1 h
I
Entry PhMgBr/equiv. Yield/% Entry PhMgBr/equiv. Yield/%
&
Sons, New York (1951), Vol. 6, p 273.
H. R. Hudson, A. Kow, and J. C. Roberts, J. Chem. Soc., Perkin Trans. 2,
983, 1363.
Preparation of various alkoxydiphenylphosphines. See ref. 4 or 6.
1
2
3
1.0
1.3
1.5
59
75
97
4
5
2.0
3.0
quant.
quant.
9
1
1
0
Published on the web (Advance View) July 7, 2003; DOI 10.1246/cl.2003.676