An efficient CuCN-catalyzed synthesis of optically active 2,3-allenols from optically active 1-substituted 4-chloro-2-butyn-1-ols

Article abstract of DOI:10.1021/jo900710e

(Chemical Equation Presented) The sequential treatment of optically active terminal propargylic alcohols with n-BuLi/(HCHO)_n and regioselective chlorination afforded the corresponding optically active 4-chloro-2-butyn-1-ols. With R¹

Full text of DOI:10.1021/jo900710e

2-halo-1,3(Z)-dienes,8 and allylic alcohols.9 Thus, it is highly
desirable to develop efficient methodologies for the synthesis
of optically active 2,3-allenols with high ee value. Usually,
optically active 2,3-allenols are prepared by the enantioselective
reduction of 1,2-allenyl ketones,10 the reaction of optically active
propargylic/allenic metallic reagents with carbonyl groups,11
Crabbe´ reaction of optically active terminal propargylic alco-
hols,12 the cross-coupling reaction with optically active alkynyl
oxiranes13 and the kinetic resolution of racemic 2,3-allenols.14
However, there are still some difficulties: some of the reagents
or catalysts for these known methods are not easily available
or the enantioselectivities are not satisfactory and the kinetic
resolution of racemic 2,3-allenols is restricted to one or two
carbon 1,2-allenyl carbinols.14 In our previous report, we
disclosed a synthesis of optically active 2,3-allenols from the
reaction of easily available propargylic methyl ethers with
Grignard reagents in moderate yield with up to 99% ee, but in
some cases the yield is not satisfactory, and the 1-substituent
group is limited to an aryl group.15 Herein, we wish to report
a more efficient and general synthesis of optically active 2,3-
allenols from optically active 1-substituted 4-chloro-2-butyn-
1-ols of high ee value in moderate to high yields by using CuCN
as the catalyst.
An Efficient CuCN-Catalyzed Synthesis of
Optically Active 2,3-Allenols from Optically
Active 1-Substituted 4-Chloro-2-butyn-1-ols
Jing Li, Wangqing Kong, Chunling Fu, and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis,
Department of Chemistry, Zhejiang UniVersity,
Hangzhou 310027, Zhejiang, People’s Republic of China
masm@mail.sioc.ac.cn
ReceiVed April 4, 2009
Synthesis of the Starting Materials. The racemic starting
materials 3a-e can be prepared by treating propargylic chloride
with n-BuLi and subsequent reaction with the corresponding
aldehydes16 (Scheme 1).
The sequential treatment of optically active terminal prop-
argylic alcohols with n-BuLi/(HCHO)n and regioselective
chlorination afforded the corresponding optically active
4-chloro-2-butyn-1-ols. With R1 being a methyl or an ethyl
group, an alternative for the synthesis of the corresponding
optically active propargylic alcohols is the Novozym 435-
catalyzed kinetic resolution of these racemic 4-chloro-2-
butyn-1-ols. The subsequent reaction of these optically active
4-chloro-2-butyn-1-ols with the corresponding Grignard
reagents under the catalysis of 5 mol % of CuCN afforded
the optically active secondary 2,3-allenols in good yields with
up to >99% ee.
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Allenes are a class of compounds with two orthogonal
π-bonds and have proven to be useful intermediates in organic
synthesis.1,2 Of particular interest is 2,3-allenols, which can be
used for the synthesis of 2,5-dihydrofurans,3 2(5H)-furanones,4
vinylic epoxides,5 ꢀ-halo-ꢀ,γ-alkenals,3l,6 ꢀ-halo-ꢀ,γ-alkenones,3l,7
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* To whom correspondence should be addressed. Fax: (+86) 021-62609305.
(1) (a) Patai, S. The Chemistry of Ketenes, Allenes, and Related Compounds;
John Wiley & Sons: New York, 1980; Part 1. (b) Landor, S. R. The Chemistry
of The Allenes; Academic Press: London, UK, 1982; Vols. 1-3. (c) Schuster,
H. F.; Coppola, G. M. Allenes in Organic Synthesis; John Wiley & Sons: New
York, 1984. (d) Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry; Wiley-
VCH: Weinheim, Germany, 2004; Vols. 1 and 2.
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C. U.; Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100, 3067. (b) Marshall,
J. A. Chem. ReV. 2000, 100, 3163. (c) Hashmi, A. S. K. Angew. Chem., Int. Ed.
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(e) Bates, R.; Satcharoen, V. Chem. Soc. ReV. 2002, 31, 12. (f) Sydnes, L. K.
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2009, 42, 45.
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10.1021/jo900710e CCC: $40.75  2009 American Chemical Society
Published on Web 05/28/2009

TABLE 1. CuBr-Catalyzed Reaction of 4-Chloro-2-butyn-1-ol 5
with Alkyl or Phenyl Grignard Reagents
SCHEME 1
entry
R
t (h)
yield (%)
1
2
3
4
n-C4H9
n-C7H15
n-C10H21
Ph
4.7
3.0
3.3
5.4
79 (6a)
59 (6b)
63 (6c)
46 (6d)
SCHEME 2
TABLE 2. Cu(I)-Catalyzed Reaction of Racemic 3a with
C2H5MgBra
C2H5MgBr
(equiv)
catalyst
(mol %)
yield of
7a (%)
recovery
of 3a (%)
entry
t (h)
1
2
3
4
5
6
7
8
4
4
4
4
4
3
3
3
3
3
3
16
16
16
16
16
19
12.5
19
12
0
38
54
24
75
74
71 (63)
55
61
84
8
8
43
2
5
CuCl (20)
CuBr (20)
CuI (20)
CuCN (20)
CuCN (10)
CuCN (5)
CuCN (2)
CuCN (5)
CuCN (5)
CuCN (5)
SCHEME 3
2
26
13
6
9b
10c
11d
3.5
3.5
46
21
0
a NMR yields determined by using 1,3,5-trimethyl benzene as the
internal standard. The isolated yield is given in parentheses; b Reaction
temperature: -50 °C; c Reaction temperature: -40 °C; d Reaction temper-
ature: rt.
79% yield (entry 1, Table 1). With these results in hand, we
studied the scope of this reaction with some typical results being
summarized in Table 1.
Then the racemic 4-chloro-1-phenyl-2-butyn-1-ol 3a was used
as the model substrate to optimize the conditions for the reaction
with C2H5MgBr to prepare secondary 2,3-allenols in ether (Table
2). First, different Cu(I) salts were screened as the catalyst with
4.0 equiv of C2H5MgBr in ether (entries 2-5, Table 2); it turned
out that CuCN was found to be the best catalyst affording the
product 7a in 75% NMR yield with 2% of the reactant being
recovered (entry 5, Table 2). Then the effect of the amount of
the catalyst on the reaction was studied (entries 6-8, Table 2):
5 mol % was found to be the best catalyst affording the product
7a in 71% NMR yield (63% isolated yield) with a trace amount
of reactant 3a being recovered (2%); the effect of reaction
temperature was also screened (entries 9-11, Table 2). When
the reaction was conducted at rt, it was not clean: 2-ethyl-1-
phenyl-2-hexen-1-ol was formed in 18% NMR yield based on
the analysis of the 1H NMR spectra of the crude product. This
compound was formed by the carbometalation of the 2,3-allenol
7a with EtMgBr (entry 11, Table 2).9 Finally, the best results
were obtained when the reaction was conducted at -60 °C with
5 mol % of CuCN as the catalyst, using 3.0 equiv of Grignard
reagent to afford the target product 7a in 71% NMR yield (entry
7, Table 2).
It is known that optically active terminal propargylic alcohols
1 can be easily prepared from racemic propargylic alcohols 1
through Novozym 435-catalyzed kinetic resolution17 with R
being an Ar group or an alkyl group beyond C5 unit connected
to the hydroxylated carbon atom. By treating the optically active
propargylic alcohols 1a-c with n-BuLi and the subsequent
reaction with (HCHO)n, optically active 1-substituted 2-butyn-
1,4-diols 2a-c may be formed. Subsequent selective chlorina-
tion of the primary hydroxyl group afforded the optically active
1-substituted 4-chloro-2-butyn-1-ols 3a-c (Scheme 2).
For the substrates with R being a methyl or an ethyl group,
we tried the kinetic resolution of racemic 1-substituted 4-chloro-
2-butyn-1-ols 3d or 3e to afford the required optically active
1-substituted 4-chloro-2-butyn-1-ols 3d and 3e in high enan-
tiopurity17 (Scheme 3).
At first we tried the reaction of 4-chloro-2-butyn-1-ol 5 with
n-C4H9MgBr in Et2O without any catalyst but only a trace
amount of product was afforded. However, when 20 mol % of
CuBr was used, luckily, 2-butyl-2,3-butadienol was formed in
With the optimized reaction condition in hand (entry 7, Table
2), the scope of the CuCN-catalyzed reaction of 1-substituted
4-chloro-2-butyn-1-ols 3 with Grignard reagents was studied
(Table 3). It can be concluded that the reaction can be used to
(17) Xu, D.; Li, Z.; Ma, S. Tetrahedron Lett. 2003, 44, 6343.
J. Org. Chem. Vol. 74, No. 14, 2009 5105

TABLE 3. CuCN-Catalyzed Reaction of Racemic 1-Substituted
4-Chloro-2-butyn-1-ols 3 with Alkyl Grignard Reagents
SCHEME 4
entry
R1
Ph (3a)
Ph (3a)
Ph (3a)
R2
t (h)
yield of 7 (%)
when 10.0 mmol of (S)-3e was used as compared to a 0.5 mmol
scale reaction (70%) (Scheme 4).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C2H5
12.5
10
18
17
11
18
17
17
11
5
17
17
17
17
11
13
63 (7a)
92 (7b)
61 (7c)
76 (7d)
53 (7e)
63 (7f)
71 (7g)
79 (7h)
61 (7i)
69 (7j)
67 (7k)
63 (7l)
70 (7m)
98 (7n)
71 (7o)
74 (7p)
i-C3H7
n-C4H9
n-C5H11
C2H5
n-C4H9
n-C5H11
n-C7H15
C2H5
n-C4H9
n-C5H11
n-C7H15
n-C4H9
n-C7H15
n-C4H9
n-C5H11
In conclusion, we have developed an efficient CuCN-
catalyzed synthesis of optically active 2,3-allenols from optically
active 1-substituted 4-chloro-2-butyn-1-ols with up to >99% ee.
Due to the easy availability of the starting materials17 and the
synthetic potential of the products,3j,k,m this method may be
useful in organic synthesis. Further studies in this area are
currently under investigation in our laboratory.
Ph (3a)
p-CH3C6H4 (3b)
p-CH3C6H4 (3b)
p-CH3C6H4 (3b)
p-CH3C6H4 (3b)
n-C5H11 (3c)
n-C5H11 (3c)
n-C5H11 (3c)
n-C5H11 (3c)
CH3 (3d)
a
a
a
Experimental Section
1H NMR and 13C NMR were recorded on instruments operated
at 300 and 75 MHz, respectively. Deuteriochloroform (CDCl3) was
used as solvent in all NMR experiments. Chemical shifts (δ) are
given in parts per million (ppm). Infrared spectra were recorded
on a FT-IR spectrometer. Mass spectra were carried out in EI or
ESI mode. HRMS spectra were carried out in EI and ESI mode.
The enantiomeric excess values (ee) were determined by HPLC or
GC analysis with chiral columns. Flash column chromatography
was performed on silica gel (10-40 µ).
CH3 (3d)
C2H5 (3e)
C2H5 (3e)
a Grigard reagent (4 equiv) was used.
TABLE 4. CuCN-Catalyzed Reaction of Optically Active
1-Substituted 4-Chloro-2-butyn-1-ols 3 with Grignard Reagents
Synthesis of (R)-(-)-2-Ethyl-1-phenyl-2,3-butadien-1-ol ((R)-
(-)-7a): Typical Procedure. To a dried Schlenk vessel were added
anhydrous Et2O (2.1 mL), CuCN (1.4 mg, 0.016 mmol), and (R)-
(+)-4-chloro-1-phenyl-2-butyn-1-ol ((R)-(+)-3a) (54.4 mg, 0.30
mmol, 97.7% ee) at room temperature. A solution of C2H5MgBr
in Et2O (0.9 mL, 1 M in Et2O, 0.9 mmol) was then added dropwise
to the resulting mixture at -60 °C under nitrogen in 5 min. After
the addition was over, the reaction mixture was stirred for 13 h as
monitored by TLC, quenched with saturated ammonium chloride
solution (1 mL), extracted with ether (10 mL × 3), washed with
brine (10 mL), and dried over anhydrous sodium sulfate. Evapora-
tion and column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate ) 10/1) afforded (R)-(-)-7a15 (34.9 mg, 67%)
with 97.7% ee as determined by HPLC analysis (Chiralcel OD-H,
3
7
entry
R1
ee (%)
R2
t (h) yield (%) ee (%)
1
2
3
4
5
6
7
8
9
Ph (R-3a)
Ph (R-3a)
Ph (R-3a)
97.7
97.7
96.8
96.8
99.9
98.9
99.9
98.3
98.3
C2H5
13
10
13
5
11
11
9
67 (R-7a)
89 (R-7b)
60 (R-7c)
73 (R-7j)
69 (S-7m)
69 (R-7m)
79 (S-7n)
70 (S-7o)
79 (S-7p)
97.7
97.2
96.2
i-C3H7
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C7H15
n-C4H9
n-C5H11
a
n-C5H11 (R-3c)
CH3 (S-3d)
CH3 (R-3d)
CH3 (S-3d)
C2H5 (S-3e)
C2H5 (S-3e)
-
99.9
99.0
99.9
98.1
98.2
11
7
n-hexane/i-PrOH ) 90/10, 0.8 mL/min, λ ) 230 nm, tR ) 7.6 min
a Unable to determine.
1
(major), 7.0 min (minor)): [R]20 -137.8 (c 1.13, CHCl3); oil; H
D
NMR (300 MHz, CDCl3) δ 7.40-7.24 (m, 5 H), 5.14-5.07 (m, 1
H), 5.07-4.97 (m, 2 H), 2.32 (d, J ) 4.5 Hz, 1 H), 1.93-1.71 (m,
2 H), 0.97 (t, J ) 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
203.8, 142.1, 128.3, 127.7, 126.6, 109.9, 80.2, 74.1, 20.9, 11.9.
prepare differently substituted 2,3-allenols in moderate to good
yields. It should be noted that when R2 is a secondary alkyl
group, i.e., an isopropyl group, the reaction afforded the
1-phenyl-2-(isopropyl)-2,3-butdienol 7b in 92% yield (entry 2,
Table 3). It should be noted that no reaction was observed when
4-hydroxy-4-aryl-2-butynyl methyl ethers were treated with
secondary alkyl Grignard reagent in our previous report.15 R1
not only can be an aryl group (entries 1-8, Table 3), but also
an alkyl group (entries 9-16, Table 3). It should also be pointed
out that when n-C7H15MgBr was used, 4 equiv of Grignard
reagent were necessary to have a complete consumption of the
substrates 3 (entries 8, 12, and 14, Table 3).
Under the optimized conditions, the reaction of optically
active 1-substituted 4-chloro-2-butyn-1-ols 3 with Grignard
reagents shows no obvious racemization (Table 4).
The reaction of (S)-6-chloro-4-hexyn-3-ol (S)-3e afforded (S)-
4-butylhexa-4,5-dien-3-ol (S)-7o in almost the same yield (71%)
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20732005) and the State
Basic and Development Research Program (2006CB806105) is
greatly appreciated. Shengming Ma is a Qiu Shi Adjunct
Professor at Zhejiang University. We thank Mr. Xinpeng Jiang
in our group for reproducing the results presented in entries 1
and 2 of Table 3 and entries 1 and 2 of Table 4.
Supporting Information Available: Detailed experimental
procedures and analytical data for all new products not listed
in the text and 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO900710E
5106 J. Org. Chem. Vol. 74, No. 14, 2009