A Convenient Stereoselective Reduction of Gem-Dibromides with a Combination of Dimethyl Phosphite and Potassium Carbonate

Article abstract of DOI:10.1080/10426507.2015.1024786

An efficient and highly stereoselective reduction of a gem-dibromocyclopropane to the corresponding monobromocyclopropane under mild reaction conditions was developed using a combination of dimethyl phosphite and potassium carbonate. This reaction provided a simple and practical way for the synthesis of the valuable monobromocyclopropanes and β-monobromoalkenes.

Full text of DOI:10.1080/10426507.2015.1024786

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A Convenient Stereoselective Reduction of gem-
Dibromides with a Combination of Dimethyl Phosphite
and Potassium Carbonate
a
a
b
ab
Yalei Zhao , Tieqiao Chen , Xiang-Bo Wang & Li-Biao Han
a 1
College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082,
China
b 2
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki
05-8565, Japan
Accepted author version posted online: 18 Mar 2015.
3
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To cite this article: Yalei Zhao, Tieqiao Chen, Xiang-Bo Wang & Li-Biao Han (2015): A Convenient Stereoselective Reduction of
gem-Dibromides with a Combination of Dimethyl Phosphite and Potassium Carbonate, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2015.1024786
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A Convenient Stereoselective Reduction of gem-Dibromides with a Combination of Dimethyl
Phosphite and Potassium Carbonate
1
*1
2
*1,2
Yalei Zhao, Tieqiao Chen, Xiang-Bo Wang, and Li-Biao Han
1
2
College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8565,
Japan
Received xxxx; accepted xxxx.
Address correspondence to Prof. Li-Biao Han, National Institute of Advanced Industrial Science and
Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan. E-mail: libiao-han@aist.go.jp; and Dr. Tieqiao
Chen, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China.
E-mail: chentieqiao@hnu.edu.cn
Abstract: An efficient and highly stereoselective reduction of a gem-dibromocyclopropane to the
corresponding monobromocyclopropane under mild reaction conditions was developed using a
combination of dimethyl phosphite and potassium carbonate. This reaction provided a simple and
practical way for the synthesis of the valuable monobromocyclopropanes and β-monobromoalkenes.
1
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Key words: Reduction; stereoselective; gem-dibromides; dimethyl phosphite; potassium carbonate
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INTRODUCTION
The stereoselective reduction of a gem-dibromocyclopropane to a monobromocyclopropane is an
1
,2
important reaction in organic synthesis. This transformation is closely related to the preparation of
agrochemicals, pharmaceuticals and natural products, since many of these molecules hold cyclopropyl
1
,2
groups with defined cis or trans configurations. Traditionally, such a stereoselective reduction was
achieved by using metallic reagents. However, the hazardous condition, complicated manipulation and
3
low functional-group tolerance limited the applications. In 1981, Hirao et al. disclosed that a gem-
dibromocyclopropane could be efficiently reduced to the corresponding bromocyclopropane with up
4
to 88:12 (cis/trans) selectivity by using a combination of diethyl phosphite and triethylamine.
5
-8
This reduction system was later modified. Meijs achieved up to >99:1 stereoselectivity with the
reduction of dibromocyclopropyl compounds using an excess potassium dimethyl phosphate (6 eqs) in
6
liquid NH
3
. A similar reduction was also observed by using a VCl
3
-Zn-a secondary phosphite system
7
(
reaction time: 60h). By applying the microwave irradiation technology, Tokuda et al. developed an
efficient reduction of gem-dibromoalkenes using a combination of diethyl phosphite and EtONa in EtOH,
8
but they did not tested the reactivity of dibromocyclopropyl compounds.
An ongoing project on the study of biological activity of phosphorus compounds in this laboratory
needs a rapid access to bromocyclopropanes. Although they had been prepared by the literature`s
methods as mentioned above, the selectivity of the products was either not satisfactory or the reaction
3
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required complicated manipulation. So we decided to reinvestigate Hirao`s method, in order to find out
an easy-operating highly efficient practical reduction system.
Herein, we report a highly stereoselective reduction of gem-dibromocyclopropanes to the
corresponding monobromocyclopropanes under mild reaction conditions using the readily available
dimethylphosphite and potassium carbonate (Scheme 1). Monobromoalkenes could also be obtained
similarly from the corresponding dibromoalkenes. Compared to the literature`s procedures, the present
method does not use hazardous chemicals, and thus is simpler and more practical.
RESULTS AND DISCUSSION
As shown in Table 1, an extensive screening on the reaction conditions revealed that 2,2-
dibromocyclopropylbenzene 1a could be efficiently reduced to the corresponding
monobromocyclopropane 2a by a combination of dimethyl phosphite and potassium carbonate. Thus, it
ο
was found that heating a mixture of 1a, (MeO)
2
P(O)H and K
2
CO
3
in DMF at 100 C overnight produced
8
9% yield of 2a with 84% selectivity to the cis-isomer (Table 1, entry 1). The reduction also proceeded
efficiently in propylene carbonate and acetonitrile with a slightly improved selectivity (entries 2 and 3).
The selectivity could be improved to 97% when the reaction was conducted in toluene (entry 4), and a
quantitative yield of 2a was obtained in dioxane and THF (entries 5 and 6) with 96% selectivity to the
cis-product. In addition to potassium carbonate, cesium carbonate also produced 2a in an almost
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quantitative yield with very high selectivity (entry 7). However, other bases such as Na
2
CO , CsOAc,
3
NaOAc, Na
2
SiF did not give satisfactory results (entries 7-11). As demonstrated by entry 12, this
6
ο
reaction also took place smoothly at 80 C with two equivalents of (MeO)
2
P(O)H and 1 equivalent of
K
2
CO to quantitatively produce 2a highly selectively. Finally, even a stoichiometric amount of the
3
chemicals could produce a good yield (75% yield) of the reduced product 2a (entry 13).
By using the optimized reaction conditions described in Table 1, a variety of gem-dibromides
could be stereoselectively reduced to the corresponding monobromides 2 in high yields. As shown in
Table 2, all of the aromatic dibromocyclopropanes investigated could be converted stereoselectively to
the corresponding monobromocyclopropanes in high yields under the reaction conditions (Table 2,
entries 1-3). It is worth noting that the bromo atom bonded to benzene (entry 2) and the chloro atom at
the benzyl position (entry 3) remained intact during the reduction. However, compared to the high
reactivity of dibromocycopropanes, an analogue dichlorocyclopropane could not be reduced under the
reaction conditions (entry 4). In addition to aromatic dibromocyclopropanes, aliphatic
dibromocyclopropanes also served as good substrates in this reduction to produce the corresponding
products in high yields with high cis-stereoselectivity (entries 5 and 6).
In addition to gem-dibromocyclopropyl compounds, the current reduction system could also be
applicable to the selective reduction of gem-dibromoalkenes to produce the corresponding bromoalkenes
selectively (entries 7-13). Thus, 83% yield of β-bromostyrene 2g was obtained with 95% selectivity to
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the trans form from β-dibromostyrene 1g (entry 7). Similarly, both gem-dibromoalkenes with 1-naphthyl
and 2-naphthyl substituent also served as good substrates in this reaction to produce the corresponding
trans-β-monobromoalkenes in 92% and 86% yields, respectively (entries 8 and 9). Substrates bearing
either an electron-donating group (MeO) or an electron-withdrawing group (NO
were all applicable to this reaction to give the expected products in high yields with high trans-
stereoselectivity (entries 10 and 11). Worth noting again is that even the easily reducible NO group
2
) on the benzene ring
2
is tolerable under the current reduction conditions. Similarly, aliphatic gem-dibromoalkenes were
efficiently reduced to the corresponding monobromoalkenes with a moderate stereoselectivity (entries
1
2 and 13).
On the basis of the experimental results and literature`s reports, possible mechanisms were
proposed as shown in Schemes 2 and 3. As shown in Table 1, the use of an alkali metal carbonate with a
5
-8
higher basicity is necessary for efficiently promoting the reaction (Cs
2
CO
3
= K
2
CO
3
> Na
2
CO ). In
3
addition, it was known that an alkali metal phosphonate MOP(OR)
2
could reduce the
6
dibromocompounds. Therefore, it is rationally assumed that a potassium phosphonate KOP(OMe)
2
is
involved in the current (MeO)
2
P(O)H/K
2
CO
3
system as shown in eq 1.
OMe)2 (1)
(
MeO 2
)
P
(
O
)
H  → KOP
(
−
KHCO
3
5
,6
As for the reduction of dibromocyclopropyl compounds, it was assumed that the halophilic
attack of the resulting dimethyl phosphonate anion on the gem-dibromocylopropanes occurred
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subsequently at the less hindered trans-site (Scheme 2). As a result, the cis- monobromocyclopropane
6
was formed selectively.
5
,8
As for the reduction of gem-dibromoalkenes, the addition of the resulting dimethyl phosphonate
anion to the gem-dibromoalkene might take place first, generating anions 4 and 4’. Protonation of 4 and
4
’ afforded intermediates 5 and 5’. The reduction product monobromides were produced by elimination
of (MeO) P(O)Br from 5 and 5’ (Scheme 3). It was proposed that the interaction of Br with the
2
phosphoryl group generating four-membered rings in 5 and 5’ is the key factor determining the
8
stereoselectivity. Because of the repulsion between Br and the R group, the formation of 5 is more
8
favorable than 5’. Therefore, the formation of trans-monobromides is favored.
CONCLUSION
In summary, by employing a combination of dimethyl phosphite with potassium carbonate, we
have developed a very simple and practical system for the selectively reduction of gem-dibromides to
the corresponding monobromides under mild reaction conditions. This reaction is applicable to the
synthesis of a wide range of monobromocyclopropanes and β-monobromoalkenes in high yields with
high stereoselectivity.
EXPERIMENTAL SECTION
General Information. Except where otherwise noted, all reactions were carried out in oven-dried
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glass tubes under N atmosphere with dry solvents under anhydrous conditions. Dry solvents were
2
obtained by purification according to standard methods. Reagents were used as received unless
otherwise noted. Column chromatography was performed using Silica Gel 60 (particle size 40-50 μm)
purchased from Kanto Chemical Co. Inc. All solvents and reagents were purchased from Wako Pure
Chemical Industries Ltd. (Japan), Tokyo Chemical Industry Co. (Japan), and Aldrich Chemical Co.
(
USA) .The pure products were obtained by column chromatography or GPC (LC-908). NMR spectra
1
13
were obtained on a JEOL ECX-400 instrument (400 MHz for H, 100 MHz for C NMR spectroscopy).
1
CDCl
3
, or C
6
D
6
was used as the solvent. Chemical shifts for H NMR are referred to internal Me
4
Si (0
ppm) and reported as follows: chemical shift (δ ppm), multiplicity, integration and coupling constant
1
3
(
Hz). Data for C NMR are reported in ppm relative to the center line of a triplet at 77.0 ppm for
1
13
chloroform-d). H and C multiplicities are reported as follows: singlet (s), doublet (d), doublet of
doublets (dd), quartet (q), multiplet (m), and broad resonance (br). Gas chromatographic (GC) analysis
was acquired on a Shimadzu GC-2010 Series GC System equipped with a flame-ionization detector. The
Supplemental Materials file contains characterization data of the known products, together with sample
1
13
H and C NMR spectra for compounds 2a-2m (Figures S 1 – S 24).
Typical Experimental Procedure
General procedure for Synthesis of gem-dibromocyclopropanes:
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In a 100-mL three-necked round-bottomed flask equipped with a teflon-coated magnetic stir bar
and a condenser, alkene (10 mmol), bromoform (40 mmol), and benzyltriethylammonium chloride
(
TEBA) (0.1 mmol) was added. The result mixture was placed in an ice bath, then, 2.4 g of a 50%
aqueous solution of sodium hydroxide (NaOH) (1.2 g, 30 mmol in 1.2 mL of H O) was added dropwise
2
by a syringe in 10 min. The reaction mixture is stirred vigorously at bath temperature (approximately
°C) for 2 h and at room temperature for 22 h, then cooled in an ice bath again and quenched by
0
injecting 6 M hydrochloric acid (3 mL) dropwise over a 10 min period. The result mixture was extracted
with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure, then distilled to afford the products.
General procedure for Synthesis of gem-dibromoalkenes:
To a solution of PPh
3
(20 mmol) and CBr
4
(10 mmol) in CH
2
Cl
2
(20 mL) under N atmosphere in
2
ο
1
00mL round-bottomed flask at 0 C was added R-CHO (10 mmol) dropwise, the result mixture was
allowed to warm to room temperature and stirred for another 1h, then water (50 mL) was added and
extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The products were purified by silica gel used hexane as eluent.
General Procedure for Reduction of gem-Dibromides with Dimethyl Phosphite and
Potassium Carbonate:
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General procedure: An oven-dried glass tube containing an Teflon-coated stir bar was charged
with a mixture of dibromide (0.2 mmol), (MeO)
2
P(O)H (0.4 mmol), and K
2
CO (0.2 mmol) in 0.4 mL of
3
ο
dioxane under N
1 mL) was added to the reaction mixture, and extracted with ethyl acetate. The combined organic
extracts were dried over anhydrous Na SO , concentrated in vacuum, and the resulting residue was
2
atmosphere and stirred at 80 C for 13h. After the reaction, Na
2
CO
3
saturated solution
(
2
4
purified by GPC to afford the pure products.
ACKNOWLEDGMENT
The authors are grateful for financial supports from NFSC 21373080, the Fundamental Research
Funds for the Central Universities (Hunan University) and Canon Foundation.
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a
Table 1. Optimization of reaction conditions
a
A mixture of 1a (0.2 mmol), (MeO)
2
P(O)H and a base in a solvent (0.4 mL) was heated in a 10
b
mL glass tube. GC yield using dodecane as an internal standard.
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a
Table 2. Reduction of gem-Dibromides with Dimethylphosphite and Carbonates.
a
Reaction conditions: gem-dibromide (0.2 mmol), (MeO)
2
P(O)H (2 equiv), K
2
CO
3
(1 equiv), dioxane
O
b
(
0.4 mL), 80 C, 13 h. Isolated yield.
15
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Scheme 1. Selective reduction of gem-dibromides with dimethylphosphite and potassium carbonate.
16
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Scheme 2. A proposed mechanism for the reduction of gem-dibromocyclopropanes.
17
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Scheme 3. A proposed mechanism for the reduction of gem-dibromoalkenes.
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