Study on the coupling of acyclic esters with alkenes - The synthesis of 2-(2-hydroxyalkyl)cyclopropanols via cascade cyclization using allylsamarium bromide

Article abstract of DOI:10.1039/c2cc34630c

The radical cyclization between aliphatic acyclic esters and alkenes was achieved unprecedentedly in the presence of allylsamarium bromide with HMPA and H₂O as additives. The cascade radical cyclization-ring-opening- anionic cyclization allowed facile and efficient access to 2-(2-hydroxyalkyl) cyclopropanols from readily available materials.

Full text of DOI:10.1039/c2cc34630c

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COMMUNICATION
Study on the coupling of acyclic esters with alkenes – the synthesis
of 2-(2-hydroxyalkyl)cyclopropanols via cascade cyclization using
allylsamarium bromidew
Yawei Tu,a Liejin Zhou,a Ruifeng Yin,a Xin Lv,*a Robert A. Flowers II,b
Kimberly A. Choquette,b Huili Liu,a Qingsheng Niua and Xiaoxia Wang*a
Received 28th June 2012, Accepted 18th September 2012
DOI: 10.1039/c2cc34630c
The radical cyclization between aliphatic acyclic esters and alkenes
was achieved unprecedentedly in the presence of allylsamarium
bromide with HMPA and H2O as additives. The cascade radical
cyclization–ring-opening–anionic cyclization allowed facile and
efficient access to 2-(2-hydroxyalkyl)cyclopropanols from readily
available materials.
until very recently.7 Zhang and co-workers reported that
allylSmBr acted as a nucleophile and a SET reagent simulta-
neously when it reacted with g-halo-a,b-unsaturated carbonyl
compounds.7a And we unexpectedly found that 3-aryl-1,2,4-
benzotrizines could be generated from 1,1-bis(benzotriazo1-1-yl)-
methylarenes by treatment of allylSmBr via cascade reductive
debenzotriazoylation and radical rearrangement.7b The divalent
samarium in allylSmBr can rationally account for its SET
reactivity. The potential of allylSmBr to act as a good SET agent
is worth studying since it is an organometallic divalent samarium
agent and may exhibit unique advantages.
Carbonyl–alkene (ketyl–olefin) coupling1 promoted by SmI2 has
found broad applications as the key step in the construction of a
range of important intermediates. In contrast, ester–alkene radical
cyclizations received little attention until 2009, when the Procter
group first reported that the radical intermediates, formed during
lactone reduction with SmI2–H2O, underwent addition to alkenes.2
The success of ester–alkene radial cyclization was based on the
unusual radical anions formed by electron transfer from Sm(II) to
the ester carbonyl.2 Cyclization cascades were also possible when
two unsaturated carbon–carbon bonds were present in the starting
cyclic diester and thus led to the formation of two rings and four
stereocenters with excellent stereocontrol.3 Very recently, the
Procter group also reported that the cascade radical reactions of
unsaturated Meldrum’s acid derivatives allowed complex carbo-
cyclic motifs to be assembled in a single step.4 Nevertheless, the
ester–alkene coupling is at present only limited to cyclic esters
(lactones). Although the reduction of unactivated alkyl esters using
SmI2–H2O–Et3N has been reported for the first time in 2011, the
coupling between aliphatic acyclic esters and alkenes remains a
challenge since it was noticed that the optimal conditions for the
efficient reduction of lactones and cyclic 1,3-esters with SmI2–H2O
did not promote the reduction of aliphatic acyclic esters.5
In this communication, we wish to report the allylSmBr
promoted ester–alkene radical cyclization of the aliphatic esters of
homoallylic alcohols. It provided a facile and diastereoselective
synthesis of 2-(2-hydroxyalkyl)-cyclopropanols from readily
available materials.
During the preliminary investigation, homoallylic alcohol
acetate 1a was employed as the model substrate. However, by
treatment of 1a with 2.2 equiv. of allylSmBr in THF, 1-phenylbut-
3-en-1-ol 2a was obtained in 86% yield (Scheme 1).
We proposed that 2a might be liberated from 1a by the
nucleophilic allylation of the ester moiety. Thus, allylSmBr
acted as a nucleophilic agent in this case. Effective measures
should be taken to inhibit the nucleophilicity of allylSmBr and
enhance its SET ability. Illuminated by the fact that the
addition of HMPA could increase the reducing ability of SmI2,
10 equiv. of HMPA was utilized as an additive.8 However, it
was surprising to find that complex reaction mixtures resulted
from the addition of HMPA (for details, see Table S1, ESIw).
Nevertheless, these results did identify that the addition of
HMPA was able to hinder the nucleophilicity of allylSmBr,
observed through the suppressed formation of 2a. Also,
increasing the amount of allylSmBr and HMPA did not
change this result significantly. Gratifyingly, with HMPA
(10 equiv.) and water (0.5 equiv.) as the co-additives, allylSmBr
did afford 3a in 55% yield. The reaction failed to occur when
AllylSmBr is known as a traditional C-nucleophilic reagent
used for allylation reaction.6 Its potential to act as a single-
electron-transfer (SET) agent has not received much attention
a Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces,
College of Chemistry and Life Sciences, Zhejiang Normal University,
Jinhua 321004, People’s Republic of China.
E-mail: wangxiaoxia@zjnu.cn, lvxin@zjnu.cn
b Department of Chemistry, Lehigh University, Bethlehem, PA 18015,
USA
w Electronic supplementary information (ESI) available: Experimental
details including general procedures, optimization, product character-
ization, NMR spectra, and X-ray crystallographic information. See
DOI: 10.1039/c2cc34630c
Scheme 1 The reaction of 1a with allylSmBr without additives.
c
11026 Chem. Commun., 2012, 48, 11026–11028
This journal is The Royal Society of Chemistry 2012

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water alone was used as the additive. The result improved
further by using a slightly larger amount of additives. How-
ever, further increase in the amount of the promoters hardly
brought about any change. To our delight, the combination of
allylSmBr (2.2 equiv.), HMPA (10 equiv.) and H2O (1.0 equiv.)
afforded satisfactory efficiency (73% yield). The use of excess
H2O seemed to be unfavorable for this reaction. In fact, no
desired 3a was detected when 3.0 equiv. of water was utilized
as the co-additive.
It was worth pointing out that the reaction exhibited high
stereoselectivity and only two pairs (the cis- and trans-) of
diastereoisomers were obtained despite the theoretical existence
of four pairs (three stereocenters) of diastereoisomers for 2-(2-
hydroxyalkyl)cyclopropanols 3. The ratios of the cis- and trans-
isomers range from 6.7 : 1 (Table 1, entry 11) to 0.5 : 1
(Table 1, entry 16). In most cases, the cis-isomer was isolated
as the major product, however, the reaction of 1l, 1n and 1p
afforded the trans-isomer as the major product (Table 1, entries
12, 14 and 16).
With these optimized reaction conditions in hand, the scope
of the reaction was explored, and the results are summarized in
Table 1.
Acetate 1l derived from the tertiary alcohol could also
successfully give the 2-(2-hydroxyalkyl)-cyclopropanol in
excellent yield (Table 1, entry 12). The cascade process seemed
not to be affected by the steric hindrance on the 2-position
(Table 1, entry 13) and was also applicable to the acetates
derived from cyclic ketone and heteroaromatic aldehyde
(Table 1, entries 12 and 14). Besides acetates, other aliphatic
esters of the homoallylic alcohols also worked (Table 1, entries 15
and 16). The homoallylic ester derived from acetophenone (1q),
however, afforded four pairs of diastereoisomers and showed
poor stereoselectivity (see ESIw).
As shown in Table 1, both the 1-aryl and 1-alkyl homoallylic
alcohol esters underwent the cascade ester–alkene radical cyclization
smoothly and the desired 2-(2-hydroxyalkyl)cyclopropanols 3
were prepared in moderate to excellent yields. Generally,
1-alkyl homoallylic acetates afforded better yields of 3 than
1-aryl homoallyl esters.
Table 1 The allylSmBr–HMPA–H2O promoted cascade synthesis of
various 2-(2-hydroxyalkyl)cyclopropanolsa
The structure of 3m (both the cis- and trans-isomers) was
ascertained unambiguously by the X-ray crystal diffraction
analysis (Fig. 1).
The reaction of 1h bearing p-Br on the phenyl ring afforded
1a in 28% yield and also trace amounts of product 3a in
addition to 3h (Scheme 2). The unexpected formation of 1a
and 3a resulting from debromination indicated the powerful
reducing ability of the allylSmBr–HMPA–H2O system.
The reaction of allylic ester 1r and substrate 1t with the
unsaturation nearer or farer than the homoallylic position, however,
resulted in deprotection of the acetyl group (Scheme 3).
Deprotection of esters with other Sm(II) species was also known9
and the mechanism for the deprotection here should be analogous.
Although the ester–alkene coupling seems to be limited only to the
homoallylic esters, it did show high regioselectivity when substrate
1s was examined, where the appropriately located CQC bond
reacted smoothly while the other remained intact (Scheme 3).
In view of the above experiments and the previous reports,2,3,10
a probable single electron transfer (SET) mechanism for the
allylSmBr-promoted cascade intramolecular cyclopropanation
was proposed as shown in Scheme 4. The coordination of
samarium in VII is essential to ensure the high diastereoselectivity.
Yieldb
Entry R1
R2 R3 R4
R
Substrate Product (dr)c
1
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me la
Me lb
Me lc
Me 1d
Me le
Me 1f
Me lg
Me lh
Me li
Me lj
Me 1k
Me 11
3a
3b
3c
3d
3e
3f
73%
(1.5 : 1)
73%
(2.1 : 1)
90%
(1.6 : 1)
55%
(2.3 : 1)
39%
(1.7 : 1)
77%
(2.2 : 1)
40%
(3.8 : 1)
39%
(3.0 : 1)
67%
(1.4 : 1)
86%
(1.6 : 1)
88%
(6.7 : 1)
90%
(0.7 : 1)
82%
(3.2 : 1)
51%
(0.7 : 1)
57%
(1.1 : 1)
65%
(0.5 : 1)
56%
(1.5 : 1)
2
4-CH3C6H4
4-MeOC6H4
2-MeOC6H4
3,4-(MeO)2C6H3
4-FC6H4
4-ClC6H4
4-BrC6H4
n-Pr
3
4
5
6
7
3g
3h
3i
8
9
10
11
12
13
14
15
16
17
i-Pr
3j
Cyclopropyl
–(CH2)5–
C6H5
3k
31
3m
3n
3o
3p
3q
H
H
H
H
Me Me Me lm
2-Furyl
H
H
H
H
H
H
H
Me 1n
Et lo
i-Pr lp
Me lq
Fig. 1 The X-ray crystal structure of 3m.
C6H5
4-CH3C6H4
C6H5
Me H
a
Reaction conditions: a mixture of substrate 1 (1 mmol), allylSmBr
(2.2 eq.), HMPA (10 eq.) and H2O (1 eq.) in dry THF (20 mL) was
b
stirred at rt for 3 h under N2. Isolated yield. The molar ratio of
c
cis : trans based on isolated yields.
Scheme 2 The reaction of 1h under the optimized conditions.
Chem. Commun., 2012, 48, 11026–11028 11027
c
This journal is The Royal Society of Chemistry 2012

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We are grateful to the National Natural Science Foundation
of China (20802070), the Zhejiang Provincial Natural Science
Foundation (Y4110044) and the Research foundation from
Key Laboratory of Synthetic Organic Chemistry of Natural
Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences. RAF is grateful to the National Science
Foundation (CHE-0844946) for support of the work at Lehigh
University. We are thankful to Prof. Gangguo Zhu for helpful
discussion.
Scheme 3 The reactions of the substrates with different location of
the CQC bond.
Notes and references
1 For selected recent reviews of SmI2-mediated carbonyl–alkene
reactions, see: (a) H. Y. Harb and D. J. Procter, Synlett, 2012, 6;
(b) D. J. Procter, R. A. Flowers and T. Skrydstrup, Organic
Synthesis Using Samarium Diiodide: A Practical Guide, Royal
Society of Chemistry, London, 2010, ch. 5; (c) K. C. Nicolau,
S. P. Ellery and J. S. Chen, Angew. Chem., Int. Ed., 2009, 48, 7140;
(d) K. Gopalaiah and H. B. Kagan, New J. Chem., 2008, 32, 607;
(e) D. J. Edmonds, D. Johnston and D. J. Procter, Chem. Rev.,
2004, 104, 3371; (f) P. G. Steel, J. Chem. Soc., Perkin Trans. 1,
2001, 2727; (g) A. Krief and A.-M. Laval, Chem. Rev., 1999,
99, 745; (h) G. A. Molander and C. R. Harris, Tetrahedron,
1998, 54, 3321.
2 D. Parmar, L. A. Duffy, D. V. Sadasivam, H. Matsubara,
P. A. Bradley, R. A. Flowers II and D. J. Procter, J. Am. Chem.
Soc., 2009, 131, 15467.
3 (a) D. Parmar, K. Price, M. Spain, H. Matsubara, P. A. Bradley
and D. J. Procter, J. Am. Chem. Soc., 2011, 133, 2418;
(b) K. D. Collins, J. M. Oliveira, G. Guazzelli, B. Sautier, S. De
Grazia, H. Matsubara, M. Helliwell and D. J. Procter, Chem.–Eur.
J., 2010, 16, 10240.
4 B. Sautier, S. E. Lyons, M. R. Webb and D. J. Procter, Org. Lett.,
2012, 14, 146.
5 M. Szostak, M. Spain and D. J. Procter, Chem. Commun., 2011,
47, 10254.
6 (a) X. D. Liu, S. L. Zhang and J. C. Di, Synthesis, 2009, 2749;
(b) J. C. Di and S. L. Zhang, Synlett, 2008, 1491; (c) Z. F. Li,
X. J. Cao, G. Q. Lai, J. H. Liu, Y. Ni, J. R. Wu and H. Y. Qiu,
J. Organomet. Chem., 2006, 691, 4740; (d) X. S. Fan and
Y. M. Zhang, Tetrahedron Lett., 2002, 43, 5475; (e) Z. F. Li and
Y. M. Zhang, Tetrahedron, 2002, 58, 5301; (f) J. Q. Wang,
J. Q. Zhou and Y. M. Zhang, Synth. Commun., 1996, 26, 3395.
7 (a) Y. Y. Hu, T. Zhao and S. L. Zhang, Chem.–Eur. J., 2010,
16, 1697; (b) Z. Y. Zhong, R. Hong and X. X. Wang, Tetrahedron
Lett., 2010, 51, 6763.
8 (a) M. Shabangi and R. A. II Flowers, Tetrahedron Lett., 1997,
38, 1137; (b) J. B. Shotwell, J. M. Sealy and R. A. II Flowers,
J. Org. Chem., 1999, 64, 5251; (c) E. Prasad and R. A. II Flowers,
J. Am. Chem. Soc., 2002, 124, 6895; (d) E. Prasad, B. W. Knettle
and R. A. II Flowers, J. Am. Chem. Soc., 2004, 126, 6891;
(e) D. V. Sadasivam, P. K. S. Antharjanam and R. A. II Flowers,
J. Am. Chem. Soc., 2008, 130, 7228; (f) K. A. Choquette,
D. V. Sadasivam and R. A. II Flowers, J. Am. Chem. Soc., 2010,
132, 17396.
Scheme 4 A probable mechanism.
In the case of substrate 1q (R1 = Ph, R2 = Me), steric
hindrance may occur and the formation of VII was thus not as
favored, accounting for the poor stereoselectivity observed therein.
The proposed mechanism could further be rationalized by
the isolation of by-product 5a (Scheme 4). Compound 4,
however, could not be obtained by either decreasing the
amount of reducing agent or introducing 1,4-cyclohexadiene11
as the H-donor, indicating a very high efficiency for the
transformation of V into VI.
The reductive potentials of allylSmBr and allylSmBr–HMPA
in THF were determined using cyclic voltammetry (see ESIw).12
The addition of HMPA shifts the reductive peak potential
approximately 760 mV to more negative values, indicating that
HMPA enhances the reducing ability of allylSmBr significantly.
Redox potentials can be estimated from the oxidation and
reduction peaks of the quasi-reversible voltammograms of
Sm-allylBr and were found to be À1.84 Æ 0.01 V in THF.
For Sm-allylBr–HMPA the potential was found to be À2.60 Æ
0.01 V. These values are close (but not identical) to those
determined for SmBr2 and SmBr2–HMPA.13
9 K. Lam and I. E. Marko, Org. Lett., 2009, 11, 2752.
´
10 (a) M. Szostak, M. Spain, D. Parmar and D. J. Procter, Chem.
Commun., 2012, 48, 330; (b) G. Guazzelli, S. D. Grazia,
K. D. Collins, H. Matsubara, M. Spain and D. J. Procter,
J. Am. Chem. Soc., 2009, 131, 7214.
11 Y. Miller, L. Miao, A. S. Hosseini and S. R. Chemler, J. Am.
Chem. Soc., 2012, 134, 12149.
12 (a) M. Shabangi, M. L. Kuhlman and R. A. II Flowers, Org. Lett.,
1999, 1, 2133; (b) R. J. Enemaerke, T. Hertz, T. Skrydstrup and
K. Daasbjerg, Chem.–Eur. J., 2000, 6, 3747.
In summary, we have achieved the first example of aliphatic
acyclic ester–alkene radical cyclization promoted by allylSmBr
with HMPA and H2O as the co-additives. The additives were
found to have inhibited the nucleophilicity and enhanced the
SET ability of allylSmBr. Besides, the reaction provides a facile
and diastereoselective synthesis of cis-2-(2-hydroxyalkyl)cyclo-
propanols14 from the readily available homoallyl esters.
Further investigation of the reductive species present in the
allylSmBr–HMPA system, the exact role of HMPA and H2O,
the use of various additives to tune the SET ability and more
synthetic applications of the allylsamarium–additive system is
currently underway and will be reported in due course.
13 B. W. Knettle and R. A. II Flowers, Org. Lett., 2001, 3, 2321.
14 (a) H. G. Lee, I. L. Lysenko and J. K. Cha, ARKIVOC, 2008, 133;
(b) L. G. Quan, S.-H. Kim, J. C. Lee and J. K. Cha, Angew. Chem.,
Int. Ed., 2002, 41, 2160; (c) J. Lee, C. H. Kang, H. Kim and
J. K. Cha, J. Am. Chem. Soc., 1996, 118, 291; (d) A. Kasatkin and
F. Sato, Tetrahedron Lett., 1995, 36, 6079.
c
11028 Chem. Commun., 2012, 48, 11026–11028
This journal is The Royal Society of Chemistry 2012