Donor cyclopropanes in synthesis: Utilising silylmethylcyclopropanes to prepare 2,5-disubstituted tetrahydrofurans

Article abstract of DOI:10.1016/j.tetlet.2011.10.091

The use of donor-only silylmethylcyclopropanes in the Lewis acid promoted reaction with aldehydes to generate 2,5-disubstituted tetrahydrofurans is described. The diastereoselectivity obtained in the product is very much dependent upon the temperature of

Full text of DOI:10.1016/j.tetlet.2011.10.091

Tetrahedron Letters 52 (2011) 6974–6977
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Donor cyclopropanes in synthesis: utilising silylmethylcyclopropanes to
prepare 2,5-disubstituted tetrahydrofurans
⇑
Jonathan Dunn, Majid Motevalli, Adrian P. Dobbs
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of donor-only silylmethylcyclopropanes in the Lewis acid promoted reaction with aldehydes to
generate 2,5-disubstituted tetrahydrofurans is described. The diastereoselectivity obtained in the product
is very dependent upon the temperature of the reaction.
Received 12 August 2011
Revised 30 September 2011
Accepted 17 October 2011
Available online 20 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Silylmethylcyclopropane
Donor cyclopropane
2,5-Disubstituted tetrahydrofuran
The use of donor–acceptor (D–A) cyclopropanes in synthesis is
well documented,1,2 and more recently, acceptor-cyclopropanes
have also been utilised in a number of transformations.2 Herein,
we report one of the first applications of donor cyclopropanes—
silylmethylcyclopropanes—in the synthesis of substituted
tetrahydrofurans.
The use of silylmethylcyclopropanes as part of D–A cyclopro-
panes has been widely reported, where the silicon group aids sta-
bilisation of a b-carbocation, via the b-effect, while an anion
stabilising group—most frequently a carbonyl or dicarbonyl func-
tion—is used to stabilise a carbanion (Scheme 1A).3–7 Recent stud-
ies have suggested that the role of this group, frequently malonate,
may be more subtle, including complexation of the Lewis acid be-
tween the 1,3-dicarbonyl groups.8 However, very little has been re-
ported on the use of donor-only cyclopropanes (Scheme 1B), where
there is no anion stabilising group.9 As part of our ongoing interest
in the use of silyl groups to stabilise cationic intermediates,10–12
herein we report the use of acceptor-free silylmethylcyclopropanes
in [3+2] cycloaddition reactions.
Attempts to form the prerequisite silylmethylcyclopropanes by
reaction of cyclopropylmagnesium bromide with either chloro- or
iodomethylsilanes were unsuccessful, as was the ‘reverse’ reaction
of a Grignard reagent derived from a chloromethylsilane with
bromocyclopropane. It should be noted that a very recent publica-
tion suggests that this transformation is possible when using an
organolithium species.13 In our approach, however, a wide variety
of allylsilanes could be prepared from allylmagnesium bromide
with a chlorosilane. These then readily underwent Simmons–
Smith or related reactions to give the desired silylmethylcyclopro-
panes (Table 1).
The cyclopropanes were then employed in [3+2] cycloaddition
reactions. There has only been one previous report attempting
these, with no published experimental details.9 Therefore, it was
considered important to define the scope of the reaction, both in
terms of reaction partner for the donor and also optimising the
reaction conditions. A range of aromatic and aliphatic aldehydes
were reacted with each of the silylmethylcyclopropanes prepared,
in the presence of a Lewis acid (either TiCl4, SnCl4, BF3ÁOEt2 or
InCl3) at either À78 °C, room temperature or reflux, but all failed
to give any tetrahydrofuran product. One feature of these reactions
was that the silylmethylcyclopropane was never recovered, but of-
ten a mixture of the chlorosilane 1, the hydroxysilane 2 or the dis-
iloxane 3 were obtained. When using tin tetrachloride as the Lewis
acid, the homoallylstannane 414 was often obtained in high yields
if an aqueous work-up was avoided (Scheme 2).
To improve the likelihood that the silylmethylcyclopropane
would react with the aldehyde rather than the Lewis acid, more
reactive aldehydes—glyoxals—were investigated. Again, initial tri-
als employing phenyl glyoxal with phenyldimethylsilylmethylcy-
clopropane failed to give any tetrahydrofuran. However, Yadav3
CO2Et
CO2Et
A:
R3Si
R3Si
CO2Et
CO2Et
R3Si
R3Si
D
D
A
B:
⇑
Corresponding author.
E-mail address: a.dobbs@qmul.ac.uk (A.P. Dobbs).
Scheme 1. (A) Donor–acceptor and (B) donor-cyclopropanes.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.091

J. Dunn et al. / Tetrahedron Letters 52 (2011) 6974–6977
6975
Table 1
Table 3
Preparation of silylmethylcyclopropanes
Effect of the size of the silyl substituents and temperature on product distribution
R1R2R3SiCl
Method
Ph
SiR1R2R3
SiR1R2R3
SiR1R2R3
MgCl
O
cis
THF
H
H
SnCl4
O
O
reflux, 6 h
CH2Cl2
Ph
SiR1R2R3
R1
Et
R2
Et
R3
% Yield allylsilane Cyclopropanation methoda % Yield
H
A or B
SiR1R2R3
O
Ph
Et
90
Simmons–Smith
Simmons–Smith
Simmons–Smith
Yamamoto
Simmons–Smith
Simmons–Smith
Simmons–Smith
Furukawa
42
65
77
56
71
86
82
61
63
A: −78 oC, 2 h
nBu nBu nBu 88
O
B: −78 oC to 0 oC, 2 h
H
H
O
iPr
iPr
iPr
81
trans
R1
R2
R3
Conditionsa
% Yield
Ratio cis:trans
Me
tBu
Me
Ph
Ph
Me
Ph
Ph
Ph
59
92
86
iPr
iPr
iPr
A
B
A
B
A
B
A
B
A
B
A
B
81
85b
53
71b
50
48
66
72
43
26
21
53
2:1
trans
2:1
trans
2:1
1:3
2:1
1:1
1:1
1:5
Me
Me
tBu
nBu
Et
Me
Ph
Ph
nBu
Et
Ph
Ph
Ph
nBu
Et
Yamamoto
a
Simmons–Smith: copper chloride (5 equiv)/Zn powder (5 equiv), CH2I2
(2 equiv), Et2O, reflux, 24 h; Yamamoto: AlMe3 (2 equiv), CH2I2 (2 equiv), CH2Cl2,
r.t., 2 h; Furukawa: ZnEt2 (5 equiv), CH2I2 (5 equiv), CH2Cl2, r.t., 6 h.
O
2:1
1:10
conditions
X
SiR1R2R3
SiR1R2R3
R
R
H
O
H
H
a
All reactions performed in the ratio cyclopropane (1 equiv):Lewis acid
(1.1 equiv):aldehyde (1.5 equiv). Conditions A: À78 °C, 2 h; Conditions B: À78 °C–
Si Cl
Si OH
0 °C, 2–3 h.
PhMe2Si
O
SiMe2Ph
Cl3Sn
b
Reaction performed in the ratio cyclopropane (1 equiv):Lewis acid
4
3
2
1
(0.7 equiv):aldehyde (1.5 equiv).
Scheme 2. Attempted [3+2] cycloadditions to give 2,5-disubstituted
tetrahydrofurans.
O
Lewis acid
R
SiiPr3
R
SiiPr3
H
O
H
H
O
CH2Cl2
−78 oC to 0 o
2-3 h
Table 2
O
Lewis acid screening for the reaction of phenyl glyoxal with triisopropylsilylmeth-
ylcyclopropane
C
R = Ph
73%
CO2Et 52%
O
Lewis acid
tBu
22%
14%
Ph
SiiPr3
SiiPr3
Ph
nBu
H
O
CH2Cl2
O
5
O
conditions
Scheme 3. Preparation of silylmethylcyclopropanes.
Lewis acid
Conditionsa
% Yield THF
% Recovered 5
SnCl4
SnBr4
AlCl3
TiCl4
À78 °C, 3 h
À78 °C, 5 h
À78 °C, 4 h
À78 °C, 3 h
Reflux 48 h
0 °C—reflux, 6 d, DCE
Reflux 96 h
0 °C—Reflux, 6 d
81
37
9
0
led to homoallylstannane formation. It was also found that the
more dilute the reaction, the higher the yield of THF, with 0.06 M
(with respect to the cyclopropane) being optimal. Many Lewis
acids were re-screened, and it was found that both tin and zinc ha-
lides were efficient at promoting the reaction but that most other
Lewis acids were very poor at promotion. The effect of temperature
on the reaction was intriguing. During the optimisation reactions,
when the reaction was run at temperatures below 0 °C, two com-
pounds were always obtained which were inseparable by column
chromatography. The compounds had the same molecular mass
(but slightly different retention times by GCMS), Rf values and sim-
ilar NMR signals, that is, the same number of carbon environments
and a duplication of proton signals. The compounds were assigned
as diastereoisomers of the THF arising from the cis/trans relative
stereochemical substitution patterns across the oxygen in the ring.
It was found that performing the reaction at 0 °C gave the trans ste-
reoisomer exclusively, and this could be isolated and characterised.
However, when the reaction was performed at À78 °C and also
quenched at À78 °C, a mixture of diastereomers was obtained,
but with the cis-isomer being the major (but never exclusive)
one. Assignments of stereochemistry were initially based upon
NOE observations.
42
20
11
0
14
0
24
47
6
1
ZnBr2
15
12
63
31
34
2
ZnBr2 (2 equiv)
ZnCl2
0 °C—Reflux, 6 d, DCE
0 °C—Reflux, 6 d, DCE
ZnI2
a
All reactions performed in the ratio cyclopropane (1 equiv):Lewis acid
(1.1 equiv):aldehyde (1.5 equiv).
has proposed that the best method to prevent nucleophilic attack
at silicon during reactions is to incorporate bulky substituents on
the silicon, the tert-butyldiphenylsilyl group in their case. Reaction
of tert-butyldiphenylsilylmethylcyclopropane with freshly distilled
phenyl glyoxal and tin tetrachloride in dichloromethane at À78 °C
gave a moderate 31% yield of a 2,5-disubstituted tetrahydrofuran.
This was our starting point for optimisation studies. It was found
that the similarly bulky triisopropylsilyl group could also be suc-
cessfully employed in the cycloaddition reaction, and the products
were easier to purify by chromatography. First, a range of Lewis
acids was screened for the reaction of triisopropylsilylmethylcyclo-
propane (5) with phenyl glyoxal (Table 2).
Therefore we returned to investigate the combination of the ef-
fect of the size of the silyl group together with the observed tem-
perature effect (Table 3).
Many other aldehydes were reacted employing the optimised
reaction conditions, mostly with those bearing electron-withdraw-
Optimum conditions were found to be combining the SnCl4 and
phenyl glyoxal in CH2Cl2 at À78 °C, followed by dropwise addition
of the cyclopropane via syringe pump at 24 ml/h; rapid addition

6976
J. Dunn et al. / Tetrahedron Letters 52 (2011) 6974–6977
O
Cl
NaBH4
Ph
SiiPr3
MeOH
Ph
SiiPr3
Ph
HO
SiiPr3
O2N
O
O
O
O
H
H
DMAP
NEt3, CH2Cl2
H
H
H
H
0
oC, 15 h
O
O
6
7
O2N
Scheme 4. Reduction of the
a-carbonyl group and subsequent esterification.
Ph
SiiPr3
O
H
H
HO
Figure 1. ORTEP X-ray crystallographic structure of phenyl-{( )-5-[(triisopropylsilyl)methyl]tetrahydrofuran-2-yl}methanol 6.
7. Gupta, A.; Yadav, V. K. Tetrahedron Lett. 2006, 47, 8043.
ing groups in an attempt to increase the reactivity of the aldehyde.
Unfortunately, these were unsuccessful, and tetrahydrofurans
were only obtained when various glyoxals were the reaction part-
ner (Scheme 3).
8. Zhang, J. S.; Shen, W.; Li, M. Eur. J. Org. Chem. 2007, 4855.
9. Fuchibe, K.; Aoki, Y.; Akiyama, T. Chem. Lett. 2005, 34, 538.
10. Dobbs, A. P.; Martinovic, S. A. Tetrahedron Lett. 2002, 43, 7055.
11. Dobbs, A. P.; Guesne, S. J. J.; Martinovic, S.; Coles, S. J.; Hursthouse, M. B. J. Org.
Chem. 2003, 68, 7880.
Finally, it was possible to reduce the carbonyl function in the
product THFs to the alcohol using sodium borohydride in methanol
at room temperature. Starting with a single trans THF gave the re-
duced product 6 as a 2.6:1 mixture of diastereoisomers, presumably
through a low level of chelation control: sodium borohydride is
known to be a weak chelator.15 The alcohol was converted into its
p-nitrobenzoate derivative 7 (72%) in an attempt to crystallise it
(Scheme 4). The crystallisation was unsuccessful. However, on pro-
longed storage, the alcohol was found to crystallise and demon-
strated the trans-relationship of substituents across the oxygen
atom of the ring (Fig. 1).
In summary, we have reported preliminary results and optimi-
sation studies for the reaction of donor silylmethylcyclopropanes
with aldehydes in the presence of a Lewis acid. 16 The temperature
controlled outcome of the reaction offers scope for obtaining either
the cis- or trans-THF products and the relative stereochemistry of
the products was proven by NOE measurements and X-ray crystal-
lography. 16 The latent functionality incorporated into the product
THFs offers considerable scope for these compounds to be useful
scaffolds for further functionalisation. This is currently under
investigation and will be reported in due course.
12. Dobbs, A. P.; Guesne, S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett 2003, 1740.
13. Penafiel, I.; Pastor, I. M.; Yus, M. Tetrahedron 2010, 66, 2928.
14. Ryu, I.; Surukl, H.; Mural, S.; Sonoda, N. Organometallics 1987, 6, 212.
15. Calo, V.; Nacci, A. Tetrahedron Lett. 1998, 39, 3825.
16. Representative
procedure:
preparation
of
trans-( )-(phenyl-(2-
((triisopropylsilyl)methyl)tetrahydrofuran-5-yl)methanone: To a stirred solution
of freshly distilled phenyl glyoxal (0.12 g, 0.90 mmol) in anhydrous CH2Cl2
(2 mL) at À78 °C and under an atmosphere of argon was added, dropwise, a
solution of SnCl4 (0.17 g, 0.08 mL, 0.66 mmol) in anhydrous CH2Cl2 (2 mL). The
resulting mixture was stirred at À78 °C for 5 min followed by the dropwise
addition of
a solution of (cyclopropylmethyl)triisopropylsilane (0.13 g,
0.6 mmol) in anhydrous CH2Cl2 (3 mL). The reaction was stirred at À78 °C
and monitored by TLC, after 1 h the reaction was allowed to warm to 0 °C and
stirred at 0 °C for 1 h. The reaction was quenched by the addition of H2O
(10 mL), the organic layer was separated and the aqueous layer further
extracted with CH2Cl2 (3 Â 10 mL). The combined organic phase was washed
with brine (10 mL), separated, dried (MgSO4), filtered and concentrated in
vacuo to give the impure product (0.25 g) as a yellow oil. Purification by flash
column chromatography [silica gel, gradient elution 100% hexane—20%
Et2O:hexane] afforded the desired product as the trans diastereoisomer
(0.15 g, 73%) as a colourless oil; Rf 0.63 [20% Et2O:hexane]; m
max(film)/cmÀ1
2947 (C–H), 1690 (C@O), 1430 (C–H), 1230 (Si–C), 1115 (C–O), 885; trans-
diastereoisomer: dH (400 MHz; CDCl3) 0.96 (1H, dd, J 14.4 and 7.5, SiCHaHb),
1.02–1.04 (21H, m, overlapping signals 3 Â CH and 6 Â CH3), 1.20 (1H, dd, J
14.4 and 6.6, SiCHaHb), 1.53-1.64 (1H, m, C-3 THF), 2.09–2.23 (2H, m,
overlapping signals C-3 and C-4 THF), 2.27–2.37 (1H, m, C-4 THF), 4.23–4.30
(1H, m, C-2 THF), 5.31 (1H, dd, J 8.3 and 6.1, C-5 THF), 7.45 (2H, app t, J 7.7,
2 Â m-CH Ph), 7.55 (1H, app tt, J 7.4 and 1.4, p-CH Ph), 7.99 (2H, dd, J 8.3 and
i
1.4, 2 Â o-CH Ph); dC (100.6 MHz; CDCl3) 11.4 (3 Â CH, Pr), 16.9 (SiCH2), 19.0
Acknowledgements
i
(6 Â CH3, Pr), 29.3 (C-4 THF), 35.1 (C-3 THF), 78.7 (CH C-2 THF), 79.3 (CH C-5
THF), 128.6 (2 Â m-CH, Ph), 129.0 (2 Â o-CH, Ph), 133.2 (p-CH, Ph), 135.4 (C,
i
Ph), 199.5 (C@O); LRMS (EI+, m/z): M+ not visible, 303 ([MÀ Pr]+, 14%), 261
We wish to thank the following: EPSRC (studentship to J.D.) and
the EPSRC National Mass Spectrometry Service, Swansea, UK for
running all high resolution mass spectra.
(100), 241 (7), 157 (22), 105 (30), 77 (22); HRMS (CI+, m/z) 347.2405 [M+H]+,
C
21H35O2Si requires 347.2401.
( )-Phenyl(2-((triisopropylsilyl)methyl)tetrahydrofuran-5-yl)methanol:
To
a
stirred solution of phenyl(2-((triisopropylsilyl)methyl)tetrahydrofuran-5-
yl)methanone (0.40 g, 1.16 mmol) in HPLC grade MeOH (7.0 mL) at 0 °C was
added in one portion NaBH4 (0.11 g, 2.90 mmol). The mixture was stirred at
0 °C until effervescence had ceased and then warmed to room temperature and
stirred for a further 15 h. The reaction was quenched by the addition of AcOH
(0.1 mL), concentrated to approximately one quarter of the volume under
reduced pressure and partitioned between CH2Cl2 (10 mL) and H2O (10 mL).
The organic phase was separated and the aqueous phase extracted with CH2Cl2
(3 Â 10 mL). The combined organic layer was washed with brine (10 mL), dried
(MgSO4), filtered and concentrated in vacuo to give the impure product (0.33 g)
References and notes
1. Reissig, H. U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
2. Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051.
3. Yadav, V. K.; Balamurugan, R. Org. Lett. 2001, 3, 2717.
4. Yadav, V. K.; Kumar, N. V. J. Am. Chem. Soc. 2004, 126, 8652.
5. Yadav, V. K.; Sriramurthy, V. Angew. Chem., Int. Ed. 2004, 43, 2669.
6. Yadav, V. K.; Sriramurthy, V. Org. Lett. 2004, 6, 4495.

J. Dunn et al. / Tetrahedron Letters 52 (2011) 6974–6977
6977
as a cloudy colourless oil. Purification by flash column chromatography [silica
gel, gradient elution 100% hexane—20% Et2O:hexane] afforded the title
compound as an inseparable mixture of the two diastereoisomers (combined
dddd, J 12.2, 10.8, 9.1 and 7.6, C-3 THF), 2.03–2.15 (1H, m, C-4 THF), 2.59 (1H, d,
J 2.5, OH), 4.19–4.29 (2H, m, overlapping signals C-5 and C-2 THF), 4.91 (1H, dd
appearing as br t, J 2.5, HCOH), 7.24–7.39 (5H, m, Ph); dC (100.6 MHz; CDCl3)
i
yield 0.31 g, 0.89 mmol, 77%, dr 2.6:1) as
a
colourless oil; Rf 0.29 [20%
11.4 (3 Â CH SiiPr3), 17.1 (CH2, Pr3SiCH2), 19.0 (6 Â CH3 SiiPr3), 26.0 (CH2 C-4
Et2O:hexane];
m
max(film)/cmÀ1 3426 (O–H), 2940, 2864, 1462, 1195, 1027, 881;
THF), 35.7 (CH2 C-3 THF), 74.3 (COH), 78.7 (CH C-2 THF), 82.2 (CH C-5 THF),
major diastereoisomer: dH (400 MHz; CDCl3) 0.94 (1H, dd, J 14.5 and 6.8,
SiCHaHb), 1.03–1.12 (21H, m, overlapping signals iPr3Si), 1.12 (1H, dd, J 14.5
and 7.4, SiCHaHb), 1.42–1.79 (3H, m, C-3 and C-4 THF), 2.03–2.15 (1H, m, C-4
THF), 3.06 (1H, d, J 1.6, OH), 4.08 (1H, q, J 7.4, C-5 THF), 4.19–4.29 (1H, m,
overlapping signals C-2 THF), 4.42 (1H, dd, J 7.9 and 1.6, HCOH), 7.24–7.39 (5H,
m, Ph); dC (100.6 MHz; CDCl3) 11.5 (3 Â CH SiiPr3), 17.7 (CH2 iPr3SiCH2), 19.0
(6 Â CH3 SiiPr3), 28.8 (CH2, C-4 THF), 36.1 (CH2, C-3 THF), 77.5 (COH), 77.6 (CH,
C-2 THF), 83.0 (CH, C-5 THF), 127.2 (2 Â o-CH, Ph), 128.0 (p-CH, Ph), 128.4
(2 Â m-CH, Ph), 140.4 (C, Ph); minor diastereoisomer: dH (400 MHz; CDCl3)
0.92 (1H, dd, J 14.4 and 7.9, SiCHaHb), 1.03–1.12 (22H, m, overlapping signals
iPr3SiCHaHb), 1.42–179 (2H, m, overlapping signals C-3 and C-4 THF), 1.89 (1H,
126.1 (2 Â o-CH, Ph), 127.4 (p-CH, Ph), 128.3 (2 Â m-CH, Ph), 140.5 (C, Ph);
i
LRMS (EI+, m/z): M+ not visible, 305 ([MÀ Pr]+, 9%), 287 (3), 263 (6), 241 (24),
157 (100), 131 (68), 103 (86), 75 (50); HRMS (ESP, m/z) 366.2822 [M+NH4]+,
C21H40O2NSi requires 366.2823. Diastereoselectivity calculated by analysis of
the 1H NMR integrals for the HCOH proton at 4.42 (major diastereoisomer) and
4.91 ppm (minor diastereoisomer). Crystal data.
Monoclinic; space group 2/c 1; a = 30.9404(12), b = 7.5968(3),
c = 21.0505(8) Å; volume 4106.4(3) Å3; T = 100 (2) K; Z 8; 24305 reflections
measured, 6227 unique [R(int) = 0.0183]. The final values: R1 = 0.0329,
wR2 = 0.0883 (observed) and R1 = 0.0379, wR2 = 0.0920 (all). CCDC 843974.
C21H36O2Si = 348.59;
C
1
R