Unprecedented consecutive, competitive nucleophilic addition to construct densely functionalized propargylic alcohols

Article abstract of DOI:10.1002/chem.200801452

An efficient one-pot process to construct a series of polyfunctionalized propargylic alcohol derivatives from the simple materials without functional protection was investigated. A solution of nBuLi in hexane was added into dry THF by syringe the resulting solution was then maintained at RT for 3 hours. the freshly prepared lithium enolate of acetaldehyde was used directly in the reaction. The nBuLi was added over a period of 30 minutes by syringe to a solution of terminal alkyne in THF at -30°C. The scope and limitations of the reaction was explored by examining other terminal alkynes. A number of different carbonyl-containing substrates were also examined. It was observed that propargylic alcohol derivatives are important synthetic intermediates in organic synthesis.

Full text of DOI:10.1002/chem.200801452

COMMUNICATION
DOI: 10.1002/chem.200801452
Unprecedented Consecutive,
U
G
Jie Liu, Yan An, Ya-Hui Wang, Hai-Ying Jiang, Yu-Xin Zhang, and Zili Chen*[a]
À
Tandem C C bond formation through consecutive nucleo-
philic addition to construct organic compounds is one of the
most attractive strategies in organic synthesis.[1] The classical
route, as exemplified by the reaction shown in Scheme 1
While investigating the reaction of the new cyclopropa-
none surrogate 1-(benzenesulfonyl) cyclopropanol 1,[5a] with
lithium phenyl ethynilide in THF at low temperature to con-
struct 1-alkynyl cyclopropanol 4a,[5b] we accidentally ob-
tained an unexpected product 5a in 5% yield. The structure
of compound 5a was identified to be 1-(2-hydroxy-4-phenyl-
but-3-ynyl)cyclopropanol, which has a -CH2CH(OH)- subu-
nit between the cyclopropanol and the alkynyl functionali-
ties, indicating the participation of the lithium enolate of
acetaldehyde in the reaction. Ring-opening and decomposi-
tion of THF with various organometallic reagents to gener-
ate acetaldehyde enolates have been reported,[6] but little
study of its reactivity and synthetic utility has ever been un-
dertaken.[6c] Meanwhile, this reaction is unprecedented with
a consecutive, competitive nucleophilic addition process to
construct densely functionalized propargylic alcohol deriva-
tives from simple reactants, and would be worthy of further
study.
À
Scheme 1. Tandem C C bond formation by consecutive nucleophilic
additions.
(top), provides an efficient approach to introduce both a,b
substituents at the enone or at an a,b-unsaturated ester. The
key intermediate (enolate A) acts as the new nucleophile in
the last step.[2] Herein we described a new tandem reaction
involving two consecutive nucleophilic additions to succes-
sively introduce two substituents on acetaldehyde,[3] leading
to a series of propargylic alcohol derivatives with multiple
functionalities that are malleable for further transformation
and modification. In this process, the in-situ-generated inter-
mediate (aldehyde B) was used as the new electrophile in
the last step (Scheme 1, bottom). This is the first report, to
the best of our knowledge, of a process involving two con-
The proposed mechanism for the preparation of 5a
(shown in Scheme 2) starts from the nucleophilic addition of
the enolate 2 to the cylopropanone intermediate (route a),
giving a new aldehyde intermediate 3, which was then selec-
tively trapped by lithium alkynilide to provide product 5a
(route b). However, there are two other competitive process
existed, either to construct 1-alkynyl cyclopropanol
4
(route c) or to give oligomerized products (route d). There-
fore, an efficient method should be devised in which the
secutive, competitive nucleophilic addition reactions to es-
[4]
À
tablish two C C bonds in one-pot reaction.
[a] J. Liu, Y. An, Y.-H. Wang, H.-Y. Jiang, Y.-X. Zhang, Dr. Z. Chen
Department of Chemistry, Renmin University of China
Beijing 100872 (China)
Fax : (+86)10-62516660
E-mail: zilichen@ruc.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801452.
Scheme 2. Proposed mechanism to synthesize compound 5a.
Chem. Eur. J. 2008, 14, 9131 – 9134
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9131

Table 2. Preparation of a series of 3-alkynyl-2-hydroxy cyclopropanol
derivatives 5.[a]
first competitive nucleophilic attack must be controlled to
favor the addition of lithium enolate 2 to the ketone (route
a), and the second nucleophilic attack to favor the addition
of lithium alkynylide (route b) to the intermediate 3. We en-
visioned that the difference of nucleophilicity between lithi-
um enolate 2 (sp3 or sp2 carbon) and lithium alkynylide (sp
carbon)[7,8] would leave some space for us to tune the reac-
tion factors to get optimal conditions for the formation of 1-
(2-hydroxy-but-3-ynyl)cyclopropanol (5).
The reaction of compound 1, lithium enolate 2, and phe-
nylacetylene (6a) was chosen as the model system for our
initial investigation. In the event, the consecutive nucleo-
philic addition of enolate 2 (1.1 equiv) and lithium phenyl
ethynylide (2.1 equiv) to compound 1 (0.5 mmol, 1 equiv) in
THF at À408C (2 h) afforded a mixture of 1-phenylethynyl
cyclopropanol (4a) in 16% yield and diol 5a in 39% yield
(Table 1, entry 1). The effect of different ratios of 2/6a on
AHCTREUNG
Alkyne (6)
PhCꢀCH
Product 5
Yield [%][b]
77 (22 )
1
2
3
4
5
p-MeOPhCꢀCH
p-MePhCꢀCH
p-BrPhCꢀCH
m-ClPhCꢀCH
81 (18)
77 (22)
64 (26)
70 (18)
Table 1. Examination of the reaction of compound 1, enolate 2 and lithi-
um phenyl ethynylide 6a.[a]
6a
[equiv]
2
t
Yield
[%] of 4a
Yield
[%] of 5a
N
[equiv]
[h]
6
7
8
9
55 (7)
1
2
3
4
2.1
2.1
2.1
2.1
2.1
4.2
3.5
3.0
1.1
2.2
2.7
3.0
2.7
5.4
5.4
5.4
2
2
2
2
2
4
4
4
16
14
9
11
20
37
22
18
39
49
54
52
49
62
77
73
5[b]
6
72 (11)
64 (18)
7
8
[a] Unless otherwise noted, all reactions were carried out at the 0.5 mmol
scale in THF at À408C. [b] 1 equivalent of HMPA was added.
PhCH2CH2CꢀCH
60 (7)
the yield of the two products was then examined. A relative-
ly good result (54% yield of 5a with 9% yield of 4, Table 1,
entry 3) was obtained when the ratio of 2/6a was adjusted to
2.7:2.1. Increasing the amount of enolate 2 and lithium alky-
nylide enhanced the reaction yield greatly (Table 1, entry 6).
Rational examination then identified a set of best conditions
(1 (1 equiv), 6a (3.5 equiv), 2 (5.4 equiv) in THF (10 mL) at
À408C for 4 h, Table 1, entry 7) to give the desired product
5a in 77% yield. The use of other additive, such as hexa-
10
1-hexyne
63 (15)
[a] Unless otherwise noted, all reactions were carried out at the 0.5 mmol
scale in THF at À408C for 4 h, with the ratio of 1/6/2=1:3.5:5.4. [b] The
figure in the parentheses is the % yield of compound 4.
A
lene underwent the consecutive nucleophilic addition to
give the product 5b in highest yield (81%). Electron-defi-
cient terminal aromatic alkynes exhibited relatively low re-
activity (Table 2, entries 4–6). Alkene-substituted and ali-
phatic alkynes, such as 4-phenyl-1-butyne and 1-hexyne, also
worked effectively in the reaction (Table 2, entries 8–10). It
is notable that the reactivity of electron-rich and electron-
deficient aryl aldehyde exhibited similar reactivity in the re-
action.
this reaction (Table 1, entry 5).[9]
With this standard procedure in hand, we explored the
scope and limitations of the reaction by examining other ter-
minal alkynes. As shown in Table 2, a range of 3-alkynyl-2-
hydroxy cyclopropanols were readily obtained. Both aro-
matic and aliphatic terminal alkynes were able to undergo
the corresponding consecutive nucleophilic addition. Elec-
tron-rich aromatic or heteroaromatic terminal alkynes dis-
played relatively high reactivity and gave higher conversion
(Table 2, Entries 2, 3, and 7). The p-methoxy phenylacety-
To further evaluate this methodology, a number of differ-
ent carbonyl-containing substrates, including aromatic alde-
9132
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Chem. Eur. J. 2008, 14, 9131 – 9134

Nucleophilic Addition Reactions
COMMUNICATION
Table 3. The reaction of different aldehydes, ketone with enolate 2 and
tive nucleophilic addition to give the desired product with
the highest yield (Table 3, entry 10). Coupling of aromatic
ketone or aliphatic aldehyde with enolate 2 and lithium al-
kynilide provided the corresponding diols in relatively low
yields (table 3, entries 13 and 14).
lithium alkynilide.[a]
Propargylic alcohol derivatives are important synthetic in-
termediates in organic synthesis. Multiple functionalities in
compound 5 and 9 would make them even more versatile as
structural motifs for further elaboration. As shown in
Scheme 3 (top), reduction of the triple bond in 5a by Pd/C
hydrogenation, followed by Lewis acid induced cyclopro-
pane fragmentation, provides a keto–oxepane product 11 in
40% yield (Equation c).[11] Meanwhile, 9 f was treated with
AuCl3 in CH2Cl2 at room temperature to yield a dienone
product 12 in 45% yield, which can be used to construct di-
hydropyridine and pyridine derivatives. (Scheme 3,
bottom).[12]
In conclusion, we have developed an efficient one-pot
process to construct a series of polyfunctionalized propargyl-
ic alcohol derivatives from the simple materials without
functional protection. A variety of electrophiles including
cyclopropanone, and aromatic aldehydes have been success-
fully employed in the reaction. Further study to broaden the
applicability of the new methodology and to explore its syn-
thetic utility is in progress.
Reactant 7 Product 9
syn/anti
Yield [%][b]
1
2
3
4
2.3:1[c] (9a) 63 (21)
2.3:1[c] (9b) 69 (26)
2.3:1[c] (9c) 65 (22)
1.9:1[c] (9d) 53 (13)
5
6
2.3:1[d] (9e) 65 (16)
2:1[d] (9 f)
66 (18)
7
8
2.3:1[c] (9g) 63 (22)
1.5:1[c] (9h) 67 (16)
9
10
2:1[d] (9i)
74 (17)
1.8:1[d] (9j) 77 (16)
11
12
1.5:1[d] (9k) 57 (25)
1.5:1[d] (9l) 60 (28)
Experimental Section
Preparation of the solution of the lithium enolate of acetaldehyde (2) in
THF: A solution of nBuLi in hexane (1.93 mL, 2.8m) was added into dry
THF (6 mL) by syringe; the resulting solution was then maintained at
RT for 3 h. After the brown color disappeared, the freshly prepared lithi-
um enolate of acetaldehyde (2) was used directly in the following reac-
tion.
13[e]
14[f]
9m
40 (50)
20 (53)
2:1[d] (9n)
General procedure for the preparation of 1-(2-hydroxy-but-3-ynyl) cyclo-
propanol (5): nBuLi (1.25 mL, 2.8m) was added over a period of 30 min
by syringe to a solution of terminal alkyne (3.5 mmol) in THF (10 mL) at
À308C. The freshly prepared enolate 2 and a solution of 1-(benzenesufo-
nyl)cyclopropanol 1 (99 mg, 0.5 mmol) in THF (5 mL) was then added
successively at À708C. After the reaction was stirred for 4 h at a temper-
ature below À408C, saturated NH4Cl (10 mL) was added slowly to
quench the reaction. Usual workup followed by flash chromatography
[a] Unless otherwise noted, all reactions were carried out at the 0.5 mmol
scale in THF at À408C for 4 h, with the ratio of 7/6/2=1:2.4:3.4. [b] The
figure in the parentheses is the % yield of compound 8. [c] The syn/anti
ratio was determined by 1H NMR spectroscopy. [d] The syn/anti ratio
was determined by the separated yields. [e] The ratio of 7/6/2=1:2.1:8.0.
[f] The ratio of 7/6/2=1:1.2:4.8.
over silica gel gave compound
4 (petroleum ether(PE)/ethyl aceta-
te(EA)=30:1) and diol derivative 5 (PE/EA=20:1).
hydes, ketones, and aliphatic aldehydes, were also exam-
ined.[9] The optimal reaction conditions were slightly modi-
fied according to different sub-
General procedure for the preparation of alkynyl-substituted 1,3-diol
A
strates to get a higher conver-
sion.[9] All these results are
summarized in Table 3. While
utilizing various aromatic alde-
hydes as electrophile, as shown,
almost all of the alkynyl-substi-
tuted 1,3-diol products were ob-
tained in a moderate to good
yield with the syn/anti ratio
ranging from 1.5:1 to 2.5:1.[10]
The heterocyclic furan-2-carbal-
dehyde underwent the consecu- Scheme 3. Further transformation of compound 5a and 9 f
Chem. Eur. J. 2008, 14, 9131 – 9134
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9133

Z. Chen et al.
of 30 min by syringe to a solution of terminal alkyne (1.05 mmol) in THF
(10 mL) at À308C. The freshly prepared enolate 2 and a solution of the
phenylacetaldehyde 7a (0.5 mmol) in THF (5 mL) was then added suc-
cessively at À708C. The reaction was maintained below À408C for 4 h.
Then, saturated NH4Cl (10 mL) was added slowly to quench the reaction.
The usual workup and removal of solvents, followed by flash chromatog-
raphy over silica gel gave 8 (PE/EA=30:1) and the desired 1,3-diols
compound 9 (PE/EA=10:1).
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Acknowledgements
Support of this work by a starter grant from Renmin University of China
and the grant from National Sciences Foundation of China (No.
20502033) are gratefully acknowledged.
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Keywords: cyclopropanone
propargylic alcohol · tandem reactions
·
nucleophilic addition
·
[9] Optimization of the reaction conditions is summarized in the Sup-
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[10] The “1,3-syn dihydroxy” stereochemistry of the product 9aa (major
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the details.
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Received: July 18, 2008
Published online: September 9, 2008
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Chem. Eur. J. 2008, 14, 9131 – 9134