LDA-mediated selective addition reaction of vinylidenecyclopropanes with aldehydes, ketones, and enones: Facile synthesis of vinylcyclopropenes allenols, and 1,3-enynes

Article abstract of DOI:10.1021/ol800463k

Highly selective addition reaction of vinylidenecyclopropanes 1 was realized by treatment with LDA in THF and quenching with aldehydes, ketones, and enones. A number of vinylcyclopropenes, allenols, and 1.3-enynes were obtained selectively in moderate to good yields depending on the nature of different electrophiles.

Full text of DOI:10.1021/ol800463k

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1943-1946
LDA-Mediated Selective Addition
Reaction of Vinylidenecyclopropanes
with Aldehydes, Ketones, and Enones:
Facile Synthesis of Vinylcyclopropenes,
Allenols, and 1,3-Enynes
Jian-Mei Lu and Min Shi*
State Key Laboratory of Organometallic Chenistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, China 200032
mshi@mail.sioc.ac.cn
Received February 29, 2008
ABSTRACT
Highly selective addition reaction of vinylidenecyclopropanes 1 was realized by treatment with LDA in THF and quenching with aldehydes,
ketones, and enones. A number of vinylcyclopropenes, allenols, and 1,3-enynes were obtained selectively in moderate to good yields depending
on the nature of different electrophiles.
Vinylidenecyclopropanes 11 are one of the most remarkable
known organic compounds. They have an allene moiety
connected by a cyclopropane ring, and yet they are thermally
stable and reactive substances in organic synthesis. Thermal
and photochemical skeletal conversions of vinylidenecyclo-
propanes 1 have attracted much attention from mechanistic
and synthetic viewpoints since the cyclopropanes can gain
additional driving force by the relief of angular strain.2
Recently, numerous palladium-catalyzed3 as well as Lewis
acid or Brønsted acid catalyzed/mediated4 reactions of
vinylidenecyclopropanes 1 have also been disclosed. How-
ever, the Lewis base or Brønsted base catalyzed/mediated
reactions of vinylidenecyclopropanes 1 are rare. Previously,
(2) (a) Poutsma, M. L.; Ibarbia, P. A. J. Am. Chem. Soc. 1971, 93, 440–
450. (b) Smadja, W. Chem. ReV. 1983, 83, 263–320. (c) Hendrick, M. E.;
Hardie, J. A.; Jones, M. J. Org. Chem. 1971, 36, 3061–3062. (d) Sugita,
H.; Mizuno, K.; Saito, T.; Isagawa, K.; Otsuji, Y. Tetrahedron Lett. 1992,
33, 2539–2542. (e) Mizuno, K.; Sugita, H.; Kamada, T.; Otsuji, Y. Chem.
Lett. 1994, 44, 9–452. (f) Sydnes, L. K. Chem. ReV. 2003, 103, 1133–
1150. (g) Mizuno, K.; Sugita, H.; Hirai, T.; Maeda, H.; Otsuji, Y.; Yasuda,
M.; Hashiguchi, M.; Shima, K. Tetrahedron Lett. 2001, 42, 3363–3366.
(h) Mizuno, K.; Nire, K.; Sugita, H.; Otsuji, Y. Tetrahedron Lett. 1993,
34, 6563–6566. (i) Sasaki, T.; Eguchi, S.; Ogawa, T. J. Am. Chem. Soc.
1975, 97, 4413–4414.
(1) For the synthesis of vinylidenecyclopropanes, please see: (a) Isagawa,
K.; Mizuno, K.; Sugita, H.; Otsuji, Y. J. Chem. Soc., Perkin Trans. 1 1991,
228, 3–2285. (b) Al-Dulayymi, J. R.; Baird, M. S. J. Chem. Soc., Perkin
Trans. 1 1994, 154, 7–1548. For some other papers related to vinylidenecy-
clopropanes, see: (c) Maeda, H.; Hirai, T.; Sugimoto, A.; Mizuno, K. J.
Org. Chem. 2003, 68, 7700–7706. (d) Pasto, D. J.; Brophy, J. E. J. Org.
Chem. 1991, 56, 4554–4556. For a recent review, see: (e) Maeda, H.;
Mizuno, K. J. Synth. Org. Chem. Jpn. 2004, 62, 1014–1025.
(3) (a) Lu, J.-M.; Shi, M. Tetrahedron 2006, 62, 9115–9122. (b) Fall,
Y.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2007, 48, 3579–3581.
10.1021/ol800463k CCC: $40.75
Published on Web 04/12/2008
2008 American Chemical Society

we reported the reaction of gem-aryl-disubstituted methyl-
enecyclopropanes with BuLi in tetrahydrofuran (THF) to give
the corresponding addition products in good yields by
quenching with various electrophiles.5,6 In this paper, we
wish to report the addition reaction of vinylidenecyclopro-
panes 1 by treatment with lithium diisopropylamide (LDA)
in THF to give the corresponding vinylcyclopropenes 4,
allenols 6, and 1,3-enynes 8 in moderate to good yields
selectively by quenching with aldehydes, ketones, and
enones.
Table 1. Reaction of Various Aldehydes 3 with Carbanion
Derived from Vinylidenecyclopropanes 1 and LDA
1
3
(R4)
yield
(%)b
entrya
(R1/R2/R3)
In the case of vinylidenecyclopropanes 1, since it is
anticipated that lithiation of the cyclopropane ring could
easily take place to give the corresponding lithiated inter-
mediate A by treatment with LDA at low temperature, the
subsequent quenching with electrophile E+ would similarly
produce the corresponding product 2 (Scheme 1).
1
2
3
4
5
6
7
8
1a (C6H5/C6H5/C6H5)
1a
1b (C6H5/C6H5/p-CIC6H4)
1c (C6H5/C6H5/p-MeC6H4)
3a (p-BrC6H4)
3b (p-CIC6H4)
3c (C6H5)
3c
3c
3a
4a, 86
4b, 82
4c, 62
4d, 84
4e, 84
4f, 77
4g, 64
4h, 80
4i, 68
4j, 76
4k, 88
1d (p-FC6H4/p-FC6H4/C6H5)
1d
1d
1d
1d
3b
3d (p-MeC6H4)
3e (m-FC6H4)
9
10
11
12
13
14
15
16
1e (p-FC6H4/p-FC6H4/p-MeC6H4) 3a
1f (p-CIC6H4/p-CIC6H4/C6H5)
1d
1d
1d
1d
1a
3c
3f (1-naphthaldehyde) 4l, 76
Scheme 1. Proposal on the Lithiation of
3g (2-furaldehyde)
3h (C6H5CH2CH2)
3i (CH3CH2CH2)
4m, 64
4n, 67
4o, 79
Vinylidenecyclopropanes 1
3j (E-C6H5CHdCH) 4p, 43
a After vinylidenecyclopropanes 1 (0.2 mmol) were lithiated by LDA
(0.4 mmol) at -78 °C for 2 h, aldehydes 3 (0.3 mmol) were added. Then
the reactions were quenched by addition of the aqueous solution of
ammonium chloride after 2 h. b Isolated yields.
We first carried out the lithiation reaction of vinylidenecy-
clopropane 1a by using LDA (2.0 equiv) in THF at -78
°C, and the reaction was subsequently quenched by addition
of p-bromobenzaldehyde 3a (1.5 equiv) in a one-pot manner.
Interestingly, we found that vinylcyclopropene 4a was
obtained in 86% yield rather than the expected product 2
More interestingly, when the reaction was carried out using
benzophenone 5a as an electrophile under identical condi-
tions, the allenol derivative 6a was formed in variable yields
ranging from 42 to 83% along with the corresponding
cyclopropene product7 obtained in different ratios with 6a
ranging from 1:4 to 1:50 (Table 2, entry 1). The structure of
6a was unambiguously determined by an X-ray diffraction.8
When the lithiation time was prolonged to 5 h at -78 °C
under identical conditions, 6a was obtained in 77% yield
along with 5% yield of the corresponding cyclopropene
product (Table 2, entry 2). Adding anhydrous cerium(III)
chloride as an additive into the reaction system afforded 6a
in 62% yield (Table 2, entry 3).9 If the temperature of
lithiation was increased to -41 °C, 6a could be obtained in
85% yield under the similar conditions. In addition, when
the reaction temperature was increased to -20 °C, 6a could
also be obtained in 60% yield. Moreover, in both cases, the
corresponding cyclopropene product was obtained in less
1
(Table 1, entry 1). Its structure was determined by H and
13C NMR spectroscopic data and HRMS (see the Supporting
Information). Other lithiation reagents such as n-butyllithium
(BuLi) and lithium bis(dimethylsilyl)amide (LHMDS) were
also examined, but the results were not as good as those
using LDA. We next examined an assortment of starting
materials 1 and aldehydes 3 in order to evaluate the scope
and limitations of this addition reaction. As can be seen from
Table 1, the corresponding vinylcyclopropenes 4 were
obtained in moderate to good yields (Table 1). In the
reactions with arylaldehydes, the corresponding products
4a-4l were obtained in good yields (Table 1, entries 1-12).
In the reactions with aliphatic aldehydes 3h and 3i, the
corresponding products 4n and 4o were obtained in 67 and
79% yields, respectively (Table 1, entries 14 and 15). As
for 2-furaldehyde 3g, the corresponding vinylcyclopropene
4m was obtained in 64% yield (Table 1, entry 13). For R,ꢀ-
unsaturated aldehyde 3j, the corresponding 1,2-addition
product 4p was formed similarly as the sole product in 43%
yield (Table 1, entry 16).
1
than 1% yield on the basis of H NMR spectroscopic data
(Table 2, entries 4 and 5). These results suggest that the
formation of the corresponding cyclopropene product was
facilitated at lower temperature and the subtle change of the
(5) For some selected reviews, see: (a) Brandi, A.; Goti, A. Chem. ReV.
1998, 98, 589–636. (b) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal.
2002, 344, 111–129. (c) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A.
Chem. ReV. 2003, 103, 1213–1270. (d) Shao, L.-X.; Shi, M. Curr. Org.
Chem. 2007, 11, 1135–1153.
(4) (a) Lu, J.-M.; Shi, M. Tetrahedron 2007, 63, 7545–7549. (b) Zhang,
Y.-P.; Lu, J.-M.; Xu, G.-X.; Shi, M. J. Org. Chem. 2007, 72, 509–516. (c)
Shao, L.-X.; Zhang, Y.-P.; Qi, M.-H.; Shi, M. Org. Lett. 2007, 9, 117–120.
(d) Xu, G.-C.; Liu, L.-P.; Lu, J.-M.; Shi, M. J. Am. Chem. Soc. 2005, 127,
14552–14553. (e) Xu, G.-C.; Ma, M.; Liu, L.-P.; Shi, M. Synlett 2005,
1869, 1872. (f) Lu, J.-M.; Shi, M. Org. Lett. 2006, 8, 5317–5320. (g) Lu,
J.-M.; Shi, M Org. Lett. 2007, 9, 1805–1808. (h) Stepakov, A. V.; Larina,
A. G.; Molchanov, A. P.; Stepakova, L. V.; Starova, G. L.; Kostikov, R. R.;
Russ, J. Org. Chem. 2007, 43, 41–49.
(6) Huang, J.-W.; Shi, M. Org. Biomol. Chem. 2005, 3, 399–400.
(7) The structure of this cyclopropene product is similar to the
vinylcyclopropane 4.
(8) The crystal data of 6a have been deposited in CCDC with number
656880 (also see the Supporting Information).
(9) (a) Ahn, Y.; Cohen, T. Tetrahedron Lett. 1994, 35, 203–206. (b)
Imamoto, T.; Kusumoto, T.; Yokoyama, M. Tetrahedron Lett. 1983, 24,
5233–5236.
1944
Org. Lett., Vol. 10, No. 10, 2008

When the addition reaction was carried out using enones
instead of aldehydes and ketones as electrophiles, the
corresponding 1,3-enyne derivatives 8 were obtained rather
than vinylcyclopropene and allenol derivatives. As can been
seen from Table 3, for almost all cases in which R1, R2, and
Table 2. Reaction of Various Ketones 5 with Carbanion
Derived from Vinylidenecyclopropanes 1 and LDA
Table 3. Reaction of Various Enones 7 with Carbanion Derived
from Vinylidenecyclopropanes 1 and LDA
temp
(°C)
yield
entrya
R1/R2/R3
R5
(%)b c
,
1
2
3
4
1a (C6H5/C6H5/C6H5)
1a
1a
1a
5a (C6H5)
-78 6a (42-83)d
-78 6a (77)e
-78 6a (62)f
-41 6a (85)
-20 6a (60)
5a
5a
5a
5a
5
1a
yield
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
5b (p-MeC6H4) -41 6b (73)
5c (p-ClC6H4) -41 6c (77)
entrya
R1/R2/R3
R6/R7
(%)b
5d (Bu)
5a
5a
-41 6d (64)
-41 6e (85)
-41 6f (76)g
-41 6g (84)
-41 6h (53)h
-41 6i (85)
-41 6j (83)i
1b (C6H5/C6H5/p-ClC6H4)
1c (C6H5/C6H5/p-MeC6H4)
1e (p-FC6H4/p-FC6H4/p-MeC6H4) 5a
1f (p-ClC6H4/p-ClC6H4/C6H5) 5a
1g (p-MeC6H4/p-MeC6H4/C6H5) 5a
1h (C6H5/Me/C6H5)
1i (Bu/Bu/C6H5)
1
2
3
4
5
6
7
8
9
1a (C6H5/C6H5/C6H5)
1b (C6H5/C6H5/p-ClC6H4)
1c (C6H5/C6H5/p-MeC6H4)
1e (p-FC6H4/p-FC6H4/p-MeC6H4) 7a
1f (p-ClC6H4/p-ClC6H4/C6H5) 7a
1g (p-MeC6H4/p-MeC6H4/C6H5) 7a
7a (Me/H)
8a, 72
8b, 71
8c, 75
8d, 72
8e, 33
8f, 57
8g, 75c
8h, 64
8i, 31
7a
7a
5a
5a
rt
6k (77)j
a After vinylidenecyclopropanes 1 (0.2 mmol) were lithiated by LDA
(0.4 mmol) for 3 h at the listed temperature, ketone 5 (0.3 mmol) were
added. Reactions were quenched by addition of the aqueous solution of
ammonium chloride after 2 h. b Isolated yields. c Unless otherwise specified,
the ratios of 6 and the cyclopropene were >100:1. d Lithiation time was
2 h. e Lithiation time was 5 h, and 5% of cyclopropene product was obtained.
f Cerium(III) chloride (0.4 mmol) was added. g 5% of cyclopropene product
was obtained. h 3% of cyclopropene product was obtained. i Only one isomer
was obtained. j 14% of 1i was recovered.
1h (C6H5/Me/C6H5)
7a
1a
1a
7b (Et/H)
7c (C6H5/H)
10 1a
11 1a
12 1a
7d [-(CH2)2-] 8j, 83
7e [-(CH2)3-] 8k, 95
7f (Me/Me)
8l, 80
a After vinylidenecyclopropanes 1 (0.2 mmol) were lithiated by LDA
(0.4 mmol) at -78 °C for 2 h, enones 7 (0.3 mmol) were added. Then the
reactions were quenched by addition of the aqueous solution of ammonium
chloride after 1 h. b Isolated yields. c syn:anti or anti:syn ) 14:1.
reaction temperature can significantly effect the ratios of 6
and the cyclopropene.
R3 ) aromatic groups, the lithiation with LDA and quenching
with methyl vinyl ketone 7a could proceed smoothly to give
1,3-enyne derivatives 8 in good yields (Table 3, entries 1-6).
As for unsymmetrical vinylidenecyclopropane 1h (R1 )
C6H5, R2 ) Me), 1,3-enyne derivative 8g was obtained in
75% yield as isomeric mixtures (Table 3, entry 7). As for
ethyl vinyl ketone 7b and phenyl vinyl ketone 7c, the
corresponding 1,3-enynes were obtained in 64 and 31%
yields, respectively (Table 3, entries 8 and 9). When
2-cyclopenten-1-one 7d and 2-cyclohexen-1-one 7e were
used as the electrophiles, the corresponding 1,3-enyne
derivatives 8j and 8k were formed in 83 and 95% yields,
respectively (Table 3, entries 10 and 11). The structure of
8j was further determined by an X-ray diffraction.10 For
ꢀ-methyl-substituted enone 7f, this addition reaction could
also proceed smoothly to afford the corresponding product
8l in 80% yield (Table 3, entry 12). Surprisingly, no reaction
occurred when dialkylvinylidenecyclopropane 1i was used
as the substrate. Adding anhydrous cerium(III) chloride or
copper salts such as CuI, CuBr, CuCl, and CuCN into the
addition reaction system did not improve the yield of 1,3-
enyne under the standard conditions.
Under these optimized reaction conditions, we next
examined an assortment of vinylidenecyclopropanes 1 and
ketones 5 in order to evaluate the scope of this reaction. For
most cases in which R1, R2, R3, and R5 ) aromatic groups,
the corresponding allenol derivatives 6 can be obtained in
good yields (Table 2, entries 4, 6, 7, 9, 11, and 13). As for
dialkylvinylidenecyclopropane 1i, the corresponding allenol
derivative 6k was obtained in 77% yield at room temperature
(Table 2, entry 15). When 5-nonanone 5d (aliphatic ketone)
was used as an electrophile, 6d was formed in 64% yield
(Table 2, entry 8). As for vinylidenecyclopropanes 1c (R1,
R2 ) C6H5, R3 ) p-MeC6H4) and 1f (R1, R2 ) p-ClC6H4,
R3 ) C6H5), the corresponding allenol derivatives 6f and
6h were obtained in 76 and 53% yields along with 5 and
3% yields of the corresponding cyclopropene products,
respectively (Table 2, entries 10 and 12). For unsymmetrical
vinylidenecyclopropane 1h (R1 ) C6H5, R2 ) Me), 6j was
obtained as a sole product in 83% yield (Table 2, entry 14).
Moreover, on the basis of above results, we can conclude
that the aromatic R1 and R2 groups bearing electron-
withdrawing groups or the aromatic R3 group bearing
electron-donating groups will generally result in lower
selectivity in this reaction which can be found in the cases
A plausible mechanism for the formation of 4, 6, and 8 is
outlined in Scheme 2. Initially, the lithiation of the cyclo-
of substrates 1c (R3 ) p-MeC6H4) and 1f (R1, R2
p-ClC6H4) (Table 2, entries 10 and 12).
)
(10) The crystal data of 8j have been deposited in CCDC with number
670799 (also see the Supporting Information).
Org. Lett., Vol. 10, No. 10, 2008
1945

R2 ) Me) and 1i (R1, R2 ) Bu) with benzaldehyde 3c
product mixtures of 1,3-enynes and allenols were both
obtained in good total yields, suggesting that the electronic
nature and steric effect of the employed vinylidenecyclo-
propane 1 also could significantly effect the product outcome
(Scheme 3).
Scheme 2
.
Proposed Mechanism for the Formation of 4, 6, and
8
Scheme 3. Reaction between 1h and 1i with Benzaldehyde 3c
propyl ring of vinylidenecyclopropane 1 gives the corre-
sponding cyclopropyl carbanion intermediate A by treatment
with LDA.6 When aldehyde 3 is used as an electrophile (E+),
anionic intermediate B-1 is formed through 1,3-shift11 via
carbanion A, which reacts with 3 to give intermediate C-1
and subsequently to furnish product 4. Intermediate A can
also undergo a ring-opening reaction to produce allenic
carbanion B-2.12When ketone 5 is used as an electrophile
(E+), allenol 6 is obtained by the reaction of B-2 with 5
through intermediate C-2 (Scheme 2, path a). Furthermore,
intermediate B-2 can also undergo rearrangement to form
propargylic carbanion B-3.13 When enone 7 is used as an
electrophile (E+), intermediate C-3 is formed through 1,4-
addition of B-3 to enone (Scheme 2, path b). Protonation of
intermediate C-3 produces the corresponding 1,3-enyne 8.
This highly selective synthesis of vinylcyclopropenes 4,
allenols 6, and 1,3-enynes 8 by the addition reaction of
lithiated vinylidenecyclopropanes 1 with aldehydes, ketones,
and enones in THF may be due to the electronic nature of
the employed electrophiles as well as the steric effect
between the electrophiles and intermediates A, B-1, B-2, and
B-3. In addition, the reaction temperature may also affect
the stability of intermediates A, B-1, B-2, and B-3. Further
work regarding this interesting selectivity is underway. Since
selective synthesis has been a formidable challenge in organic
chemistry, this work provides an interesting example on the
controlled highly selective synthesis of vinylcyclopropenes,
allenols, and 1,3-enynes beginning from the same starting
materials.
In conclusion, we have developed a highly selective
addition reaction of vinylidenecyclopropanes 1 with LDA
in THF to give vinylcyclopropenes 4, allenols 6, and 1,3-
enynes 8 in moderate to good yields by quenching with
aldehydes, ketones, and enones. Efforts are in progress to
elucidate further mechanistic details of these reactions and
to understand their scope and limitations.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science andTechnology (04JC14083, 06XD-
14005), and the National Natural Science Foundation of
China for financial support (20472096, 203900502, 20672127,
and 20732008).
Supporting Information Available: Spectroscopic data
of all the new compounds, the detailed descriptions of
experimental procedures, and X-ray diffraction data for
compounds 6a and 8j. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL800463K
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As a control experiment, we found that if the reaction was
carried out between vinylidenecyclopropanes 1h (R1 ) C6H5,
1946
Org. Lett., Vol. 10, No. 10, 2008