A novel and efficient method for the olefination of carbonyl compounds with Grignard reagents in the presence of diethyl phosphite

Article abstract of DOI:10.1039/c001931c

The widely available carbonyl compounds react with Grignard reagents in the presence of diethyl phosphite to give the corresponding olefins in good to excellent yields: A range of conjugated dienes, terminal olefins, multisubstituted-alkenes and conjugated enynes could be readily obtained by the method in mild conditions.

Full text of DOI:10.1039/c001931c

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A novel and efficient method for the olefination of carbonyl compounds with
Grignard reagents in the presence of diethyl phosphite†
Tongqiang Wang, Yuanyuan Hu and Songlin Zhang*
Received 12th February 2010, Accepted 23rd March 2010
First published as an Advance Article on the web 7th April 2010
DOI: 10.1039/c001931c
Table 1 Optimization of reaction conditionsa
The widely available carbonyl compounds react with Grig-
nard reagents in the presence of diethyl phosphite to give the
corresponding olefins in good to excellent yields: A range of
conjugated dienes, terminal olefins, multisubstituted-alkenes
and conjugated enynes could be readily obtained by the
method in mild conditions.
The carbonyl olefination by the Wittig reaction,1 Julia–Lythgoe
olefination and Peterson olefination,2 as well as their variants,
Entry Additive (equiv.)
2a (equiv.) Time/h Yield (%)b
have become invaluable methods in organic synthesis.3 However,
these reactions could not avoid the need for stepwise generation
of ylides under basic conditions. The catalytic alternative to the
classic Wittig reaction has proven to be quite promising, avoiding
the limitation.4 Accordingly, several catalytic aldehyde and ketone
olefination systems have been reported based on Mo,5 Re,6 Fe,7
Ru,8 Co,9 Rh,10 Cu,11 and Ir12 complexes. And these nonbasic
reaction conditions allowed the synthesis of conjugated esters and
ketones in high yields and excellent E-selectivity. However, these
reactions based on a variety of ancillary ligands. Olefination of
dithioacetals with Grignard reagents was reported by Luh.13 In this
reaction, the substrates-dithioacetals were obtained from carbonyl
compounds, and the nickel catalyst was required. Although the
carbonyl olefination has been well explored, the attempt to find
a one-pot synthesis method of olefin from environment-friendly
and inexpensive reagents is meaningful and needed.
1
2
3
4
5
6
7
8
Ph2P(O)H (1.0)
(EtO)3P (1.0)
(EtO)2P(O)CH2COOEt (1.0)
(EtO)3PO (1.0)
Ph3P (1.0)
(EtO)2P(O)H (1.0)
(EtO)2P(O)H (0.8)
(EtO)2P(O)H (1.2)
(EtO)2P(O)H (1.5)
(EtO)2P(O)H (1.2)
(EtO)2P(O)H (1.2)
(EtO)2P(O)H (1.2)
(EtO)2P(O)H (1.2)
(i-PrO)2P(O)H(1.2)
(PhO)2P(O)H(1.2)
3
3
3
3
3
3
3
3
3
4
3
2
1
3
3
24
24
24
24
24
5
5
5
5
5
5
5
5
5
None
None
None
None
None
79
65
85
9
80
10
11
12
13
14
15
67c
90c
86c
32c
82
42
24
a To a solution of 1a (0.5 mmol) in THF (3 mL) was added 2a in THF
(0.5 M, 3 mL, 1.5 mmol) and additive at room temperature. b Isolated yield
based on 1a after silica gel chromatography. c To a solution of 1a (0.5 mmol)
in THF (3 mL) was added 2a in THF (0.5 M) at room temperature, and
the mixture was stirred for 30 min, then the additive (0.6 mmol) was added
to this mixture at room temperature.
Herein, we present our preliminary results, which have led to
the development of a new method for the olefination of carbonyl
compounds with Grignard reagents in the presence of diethyl
phosphite (Scheme 1).
In initial experiments, we investigated the effect of different
additives on the carbonyl olefination with the model reaction
between the benzophenone and allylmagnesium bromide (Table 1).
Treatment of benzophenone with allylmagnesium bromide in
THF at room temperature in the presence of diphenylphosphine
oxide, triethylphosphite, ethyl-2-(diethoxyphosphoryl) acetate, tri-
ethylphosphate or triphenylphosphine did not afford the product
3a (Table 1, entries 1–5). After some investigations, we concluded
that the diethyl phosphite was the effective additive, and when the
1.2 equiv. of it was added to the mixture of benzophenone and
2 equiv. of allylmagnesium bromide affording the product 3a in
86% yield at room temperature (Table 1, entry 12). It is worth
mentioning that the use of (EtO)2P(O)H as the additive is more
advantageous than (i-PrO)2P(O)H and (PhO)2P(O)H in terms of
cheap and readily available considerations. Encouraged by this
efficient experimental results, we examined the scope of carbonyl
compounds and Grignard reagents. The representative examples
are presented in Table 2.
Scheme 1 Olefination of carbonyl compounds with Grignard reagents.
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chem-
istry. Chemical Engineering and Materials Science of Soochow University,
Suzhou, 215123, People’s Republic of China. E-mail: zhangsl@suda.edu.cn
† Electronic supplementary information (ESI) available: General ex-
perimental information, 1H and 13C NMR spectra. See DOI:
10.1039/c001931c
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Table 2 Olefination of carbonyl compounds and Grignard reagentsa
Entry
Carbonyl Compounds
Grignard Reagents
Product
Yield (%)b
1
2
3
Ar = C6H5
90
83
95
Ar = 4-ClC6H4
Ar = 4-MeOC6H4
4
5
Ar–CHO
Ar = 4-MeOC6H4
Ar = 2-furan
82
87
6
7
70
83
8
9
10
11
12
13
14
Ar = C6H5(4a)
Ar = 4-ClC6H4
Ar = 4-MeC6H4
Ar = 2-naphthyl
Ar = 2-thiophene
Ar = 2-furan
91
86
90
81
89
61
92
Ar = C6H5
15
16
17
Ar = 4-BrC6H4
Ar = 4-MeC6H4
94
90
87
18
19
91
84
20
82
21
22
Ar–CHO
Ar = 4-MeOC6H4
90
84
23
43
24
25
Ar = 4-MeOC6H4
90
90
26
27
81
70
28
29
Ar = C6H5
72
83
Ar = 4-MeC6H4
a To a solution of carbonyl compounds (0.5 mmol) in THF (3 mL) was added Grignard reagents in THF (0.5 M, 2.2 mL, 1.1 mmol) at room temperature,
and the mixture was stirred for 30 min, then the diethyl phosphite (0.6 mmol) was added to this mixture at room temperature. b Isolated yield based on
carbonyl compounds after silica gel chromatography.
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Olefination of ketones or aldehydes (Table 2) were achieved in
good to excellent yields at room temperature using 2.2 equiv. of
Grignard reagents and 1.2 equiv. of diethyl phosphite in THF. A
range of conjugated dienes (Table 2, entries 1–6 and 26), terminal
alkenes (Table 2, entries 8–16), multisubstituted-alkenes (Table 2,
entries 17–20, 23–24 and 27) and conjugated enynes (Table 2,
entries 28 and 29) could be readily obtained by the method in mild
conditions.
different from the reaction by the acid-catalyzed dehydration of
hydroxide compounds.15
The reaction of diethyl phosphite with Grignard reagents16
(Scheme 2) indicate that diethyl phosphite, magnesium bromide
diethoxy(oxo)phosphate(III) (7) or dialkylphosphinylmagnesium
bromide (8) may be the accelerant for the olefination. During
the course of our studies on mechanism, we found that the
most diethyl phosphite could be recovered after the reaction. So,
we first exclude the possibility of dialkylphosphinylmagnesium
bromide (8). We re-investigated this reaction employing the 1-
phenyl-1-p-tolylethanol (9a) as substrate to react with the diethyl
phosphite, magnesium bromide diethoxy(oxo)phosphate(III) (7)
or magnesium bromide diethylphosphinite and found that only 7
give the product in medium yield (Scheme 3). Thus, 7 was proposed
as a key intermediate during this transformation. And olefination
was achieved in good yield at room temperature employs 1.2 equiv.
of 5a and 1.2 equiv. of 7 in THF (Table 3, entry 6).
And we were pleased to find that (E)-alkenes could be obtained
as the predominant products by the reaction of aldehydes with
Grignard reagents in high stereoselectivity (Table 2, entries
4–6, 21–22, 25–26), the corresponding (Z)-alkenes were not found
1
from HNMR spectrums. However, when 1,2-diphenylethanone
reacted with benzylmagnesium bromide, the (E)/(Z) mixture as
product was obtained (Table 2, entry 27). When the reaction of
allylmagnesium bromide with acetophenone was investigated, the
mixture of conjugated diene (Table 2, entry 7a) and 1,4-diene
(Table 2, entry 7b) as product was obtained.
The yields both electron-donating (Table 2, entries 3–5, 10, 16
and 29) and electron-withdrawing groups (Table 2, entries 2, 9
and 15) in benzene rings be employed are good to excellent.
Moreover, thiophene and furan heterocycles (Table 2, entries 6,
12–19) participate efficiently in the reaction.
It is worth mentioning that the conjugated enynes were also
obtained from this method (Table 2, entries 28 and 29). Compared
with the recently-developed methods, namely, metal-catalyzed
dimerization/oligomerization of terminal alkynes to afford con-
jugated enynes,14 the advantages of this methodology were worth
notice.
Scheme 2 The reaction of diethyl phosphite with Grignard reagent.
Aliphatic ketones also reacted with aliphatic and heterocycle
Grignard reagents in the presence of diethyl phosphite to give the
corresponding alkenes. But, the reaction yield of 2-adamantanone
with ethylmagnesium bromide was lower (Table 2, entry 23). And
cycloolefins could also be obtained in good to excellent yields
(Table 2, entries 17, 18 and 19).
Scheme 3 The reaction of 1-phenyl-1-p-tolylethanol with diethyl phos-
phite, magnesium bromide diethoxy(oxo)phosphate(III) or magnesium
bromide diethylphosphinite.
Preliminary studies were undertaken to probe the mechanism
for this olefination process. Noticeably, this reaction could not
occur in the absence of diethyl phosphite. To investigate the role
of diethyl phosphite during this transformation, we tested acids as
the additive, the results indicated that no or only trace amounts of
products were observed (Table 3, entries 1–3). Thus, it was clear
that the method we reported in this communication was quite
To further understand the mechanism of this transformation, we
tested other alkalis instead of 7 as an additive, however, there was
no product observed (Table 3, entries 4, 5 and 7). Unfortunately,
we can not use a catalytic amount of diethyl phosphite in this
reaction because diethyl phosphite was also transformed to 8,
shown in Scheme 2. The 8 could not promote the reaction (Table 3,
entry 8).
On the basis of these preliminary results, the mechanism of this
transformation was hypothesized as shown in Scheme 4. It was
revealed that the six-centered transition state for the olefination
reaction 11, It was the P anion that abstracts the H of the methyl
group and the –MgBr of 7 was the assistant.
Table 3 Acids or alkalis as additive in the reactiona
Entry Substrate Additive (equiv.)
5a (equiv.) Time/h Yield (%)b
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
9a
H3PO4(1.2)
AlCl3(1.2)
CF3COOH(1.2)
EtONa(1.2)
NaH(1.2)
(EtO)2P(O)MgBr(1.2) 1.2
(EtO)2P(O)Na(1.2)
Et2P(O)MgBr(2)
3
3
3
2
2
24
24
24
24
24
5
Trace
None
None
None
None
85
1.2
1.2
24
24
None
None
a To a solution of substrates (0.5 mmol) in THF (3 mL) was added 5a in
THF (0.5 M, 2.2 mL, 1.1 mmol) at room temperature, and the mixture was
stirred for 30 min, then the additive (0.6 mmol) was added to this mixture
at room temperature. b Isolated yield based on substrate after silica gel
chromatography.
Scheme 4 Proposed mechanism for olefination of carbonyl.
In summary, we have demonstrated a one-pot manner ole-
fination of carbonyl compounds with Grignard reagents. A
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range of conjugated dienes, terminal alkenes, multisubstituted-
alkenes and conjugated enynes could be readily obtained in
the mild conditions. Further investigation of the usage of other
organometal reagents are in progress in our group.
We gratefully acknowledge the Program for Hi-Tech Re-
search of Jiangsu Science and Technology Department
(BE2008063), Innovation Fund for Small Technology-based
Firms (08C26223201851), Innovator Fund of Suzhou Govern-
ment (ZXJ0726), Suzhou LAC Co., LTD and Suzhou Chiral
Chemistry Co., LTD (www.suzhoulac.com) for financial support.
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Org. Biomol. Chem., 2010, 8, 2312–2315 | 2315
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