Reaction of 2-silylmethylcyclopropyl ketones with in situ oxirane-derived aldehydes and formation of 2-hydroxymethyl tetrahydrofurans

Article abstract of DOI:10.1016/j.tetlet.2009.05.107

The enolates formed from Lewis acid treatment of (2-trimethylsilylmethyl)cyclopropyl alkyl and aryl ketones reacted with aldehydes formed in situ from alkoxy-, aryl- and vinyl-substituted oxiranes to generate aldol products in good yields. Selected aldol

Full text of DOI:10.1016/j.tetlet.2009.05.107

Tetrahedron Letters 50 (2009) 4647–4650
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Tetrahedron Letters
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Reaction of 2-silylmethylcyclopropyl ketones with in situ oxirane-derived
aldehydes and formation of 2-hydroxymethyl tetrahydrofurans
*
Veejendra K. Yadav , Archana Gupta
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The enolates formed from Lewis acid treatment of (2-trimethylsilylmethyl)cyclopropyl alkyl and aryl
ketones reacted with aldehydes formed in situ from alkoxy-, aryl- and vinyl-substituted oxiranes to gen-
erate aldol products in good yields. Selected aldol products were conveniently transformed into highly
substituted tetrahydrofurans under oxidative conditions.
Received 19 April 2009
Revised 26 May 2009
Accepted 28 May 2009
Available online 2 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
(2-Trimethylsilylmethyl)cyclopropyl ketone
Oxirane
Aldol
Oxidative ring closure
2-Hydroxymethyl tetrahydrofuran
The ring strain present in a three-membered ring makes it a
useful synthon in organic synthesis. Vicinal placement of a donor
and an acceptor group on the ring provides dual activation that
renders the cleavage of the in-between rC–C bond feasible under
mild Lewis acid conditions. A silylmethyl group acts as a donor
group for the b-effect of silicon.1 We have previously reported
reactions of enolates generated from the ring cleavage of 2-trim-
ethylsilylmethylcyclopropyl alkyl/aryl ketones with aldehydes, ke-
tones and imines to deliver aldol and iminoaldol products that
were subsequently transformed into tetrahydofurans and pyrrol-
idines, respectively, under oxidative conditions.2
screening of Lewis acids for the reaction of an isomeric mixture
of 1a with the oxirane 2a (Ar = C6H5, R = CH2OBn). TiCl4 (1.2 equiv,
CH2Cl2, ꢀ78 °C), Et2AlCl (1.2 equiv, CH2Cl2, ꢀ30 °C), LiClO4 in
CH3NO2 (3 equiv, 0.25 M, 25 °C), ZnCl2 (1.5 equiv, CH2Cl2, 25 °C),
InCl3 (1.2 equiv, CH2Cl2, 25 °C), SnCl4 (1.2 equiv, CH2Cl2, ꢀ78 °C),
Yb(OTf)3 (5 mol %, CH2Cl2, 25 °C) and Zn(OTf)2 (5 mol %, CH2Cl2,
0?25 °C) were unsatisfactory. These reactions were either compli-
cated, leading to the formation of several products, or did not occur
at all. In some instances, the cyclopropane had simply transformed
into 3-butenyl phenyl ketone, 4, and the oxirane had rearranged to
a-benzyloxymethyl-a-phenylacetaldehyde, 5, quantitatively.
As an extension of this protocol, we envisioned reactions of 2-
trimethylsilylmethylcyclopropyl ketones with aldehydes formed
in situ from oxiranes to generate aldols in a single step. Applica-
tion of oxiranes as in situ precursors to aldehydes appeared
appealing because (a) generation of oxiranes from alkenes is sim-
ple and (b) alkenes bearing diverse substituents are readily avail-
able by following literature methods.3 We report herein the
construction of tetrahydrofuran skeleton through the addition of
a cyclopropane-derived enolate to an in situ oxirane-derived alde-
hyde followed by ring closure under oxidative conditions. The
resultant 2-hydroxymethyltetrahydrofuran constitutes a common
structural feature present in acetogenins that have desirable bio-
logical properties such as antineoplastic and immunosuppressive
activities.4
The use of BF3ꢁOEt2 (1.5 equiv, CH2Cl2, ꢀ30 °C, 1 h) generated
the desired product 3a as a 1:1.2 diastereomeric mixture in 40%
overall yield based on the cyclopropyl ketone used. All the cyclo-
propyl ketone had reacted; the balance material was transformed
into 3-butenyl phenyl ketone. All the oxirane had also reacted.
However, the above carbonyl product 5 was not isolated. It is likely
that 5 had polymerized under the acidic condition of the reaction.
Intense very polar spots were indeed visible on TLC.
An experiment with additional suspended K2CO3 (2 equiv) fur-
nished the product repeatedly in slightly improved yield (45–
48%).6,7 Though the diastereomeric ratio had improved to 3:1 with
Sc(OTf)3 (5 mol %, CH2Cl2, 25 °C, 45 min), the overall yield based on
the cyclopropane reactant had reduced considerably to 21% due
probably to the predominant transformation of the enolate into
3-butenyl phenyl ketone. Though the reversal in diastereoselectiv-
ity is interesting, we do not have an explanation for this observa-
tion at present. We considered examining other reactions with
the BF3ꢁOEt2–K2CO3 combination to assess the generality of the
protocol.
The rearrangement of oxiranes to aldehydes in the presence of
Lewis acids is known.5 We commenced our studies with the
* Corresponding author. Tel.: +91 512 2597439; fax: +91 512 2597436.
E-mail address: vijendra@iitk.ac.in (V.K. Yadav).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.107

4648
V. K. Yadav, A. Gupta / Tetrahedron Letters 50 (2009) 4647–4650
The results are collected in Table 1. A comparison of the results
Table 1 (continued)
in entries a–e suggests that an electron-withdrawing group on the
oxirane ring has little effect on the overall success of the reaction.
Electron-withdrawing substituents on the aryl ring also do not
have a noticeable effect on the overall success of the reaction (en-
tries k–n); the only exception was the p-nitro substituent (entry o)
that retarded the reaction completely.
Separate reactions of cis-1a and trans-1a with 2a were carried
out to estimate the relative reactivities. Both the reactions were
completed in one hour and each furnished the same 1:1.2 diaste-
Entry Oxirane
Reacting
aldehyde
Yield of
30s drb
3a (%)
O
O
O
COPh
COPh
COPh
COPh
Ph
k
61
60
58
56
8:4:1
p-ClC H
6
4
H
C H Cl-p
6
4
O
O
O
Ph
l
8:1:1
o-ClC H
6
4
H
C H Cl-o
6
4
O
O
O
Table 1
4:1:5:1c
1:2.6:2.6d
Ph
m
n
o
Reactions of 1a with different oxiranes 2a–o in the presence of BF3ꢁOEt2–K2CO3 at
p-FC H
6
4
5
H
C H F-p
6
4
ꢀ30 °C.
O
OH
O
O
Lewis acid
CH2Cl2/1h
O
R
O
O
+
+
SiMe
Ph
O
Ph
3
Ph
Ar
2a-o
R
Ph
Ar
3a-o
o-FC H
6
H
C H F-o
6 4
1a
4
Entry Oxirane
Reacting
aldehyde
Yield of
30s drb
3a (%)
O
COPh
No reaction
p-O NC H
6 5
O
2
O
OBn
Ph
a
OBn
45
47
36
41
38
NR
73
71
56
61
1:1.2
a
H
Ph
Isolated overall yield.
Diastereomers were separated by radial chromatography over E-Merck silica
gel PF254 using mixtures of hexanes and EtOAc as the eluent. The ratios shown are in
the order of the polarity characteristics, the least polar diastereomer appears first
and the most polar diastereomer appears last.
b
O
O
b
1:1
4:1
CH Ph
2
c
The stereostructure of the acetate of the major diastereomer was determined by
H
Ph
single-crystal X-ray structure analysis. However, this diastereomer was not sub-
jected to oxidative cyclization.
The diastereomeric ratio was estimated from 1H integrals of the isomeric
d
O
O
O
CO Et
2
mixture because they were inseparable.
OEt
c
Ph
Ph
Ph
Ph
H
reomeric mixture of the corresponding aldol products. This sug-
gests competitive enolate generation from both the
diastereomers preceding the reaction with the in situ-formed alde-
hyde. The relative stereostructure of the major diastereomer of 3l
as shown at entry 6 in Table 2 was ascertained by single-crystal
X-ray structure analysis.
We next replaced the aryl substituent with a vinyl group and
studied the oxiranes 2p and 2q (Scheme 1). The reactions pro-
ceeded well and diastereomeric mixtures of the desired products
3p (dr = 1:10:8:2.6)8 and 3q (the dr could not be ascertained be-
cause neither the diastereomeric 1H signals could be discerned
nor the diastereomers could be separated) were obtained in 45%
and 60% overall yields, respectively. From the reaction of 2p, the
double bond-isomer 6p was also isolated in 10% yield. Such a prod-
uct was not formed from the reaction of 2q. Instead, a small
amount of 7q was formed in 8% yield by SN20 cleavage of the oxi-
rane. A vinyl group, therefore, acts as an attractive alternative to
an aryl group on the oxirane ring that raises the synthetic utility
of the present protocol.
O
O
O
O
COCH
COPh
3
d
1:1:1:1
2:7:1
Ph
H
O
O
Ph
e
Ph
H
O
O
O
H
CH
3
COCH
O
3
f
Ph
CH Ph
2
O
COPh
O
Ph
g
2:11:1
2.3:1c
1:4
p-MeC H
C H CH -p
6
4
6
4
3
H
O
O
O
COPh
Ph
h
i
The reaction of
a diastereomeric mixture of 1b (cis/
o-MeC H
6
4
H
C H CH -o
6
4
3
trans = 1:1.3) with styrene oxide 2b for 1 h furnished an insepara-
ble 1.2:1 diastereomeric mixture9 of the desired product 8b in 70%
yield based on the reacted cyclopropane substrate (Scheme 2). The
unreacted cyclopropane substrate (recovered in 36% yield) was dis-
covered to be trans-1b, indicating that the trans-isomer had re-
acted slower than the cis-isomer. The species equivalent to 4,
that is, 3-butenyl t-butyl ketone was not formed.
The result of the reaction of an inseparable diastereomeric mix-
ture of 1c (cis/trans = 1:1.7) with 2b was similar to that of 1b; cis-
1c reacted faster than trans-1c and generated an inseparable 1:5
O
O
O
COPh
COPh
Ph
p-MeOC H
6
4
H
C H OMe-p
6
4
CHO
O
Ph
O
O
O
O
j
4
diastereomers
O

V. K. Yadav, A. Gupta / Tetrahedron Letters 50 (2009) 4647–4650
4649
Table 2
diastereomeric mixture of 9b in 84% yield based on the reacted
cyclopropane substrate (Scheme 2).10 Trans-1c was recovered
along with a trace amount of 3-butenyl butyl ketone. The high dia-
stereomeric ratio observed for the reaction of 1c with 2b in com-
parison to those observed from the reactions of 1a and 1b is
interesting. Also, when we compared the reaction of the cis/trans
mixture of 1a with 2b against the reactions of the cis/trans mix-
tures of 1b and 1c, trans-1a appeared to be more reactive than
trans-1b and trans-1c.
Conversion of diastereomerically homogeneous selected aldol products into tetrahy-
drofuran derivatives on oxidation with m-CPBA.
OH
PhOC
Ar
O
m-CPBA
R
Ph
CH Cl , 0 ºC-rt
2
2
O
Ar
OH
R
Entry Substrate
Productsa
Yield
(%)b/
ratio
The success with the aryl- and vinyl-substituted oxiranes
encouraged us to attempt reactions using a heteroatom-substi-
tuted oxirane. When 1a was reacted with 2r11, the product 3r
(Scheme 3) was obtained as the sole product in 45% overall yield
after chromatographic purification. Some of the cyclopropyl ketone
had transformed into 4 and, also, a significant amount of the oxi-
rane had rearranged to 3-hydroxychromone.12 Likewise, 1b re-
acted with 2r to generate 8r in 65% overall yield. Further, as
noted previously as well, 3-butenyl t-butyl ketone was not formed.
The relative stereochemistries of 3r and 8r were assessed from the
J values (9.8 Hz) of the pyran ring hydrogens. These examples consti-
tute, to our best information, the first examples of oxirane ring cleav-
age by a cyclopropane-derived enolate under Lewis acid conditions.
Some of the diastereomerically pure aldol products were trans-
formed into substituted tetrahydrofuran species on oxidative ring
closure using m-CPBA.2,13 The relative stereochemistry, deter-
mined from NOE measurements, was correlated to that of the
O
O
OH
O
Ph
Ph
BnO
Ph
1
68/1:1
71/5:1
Ph
3a
O
O
BnO
Ph
BnO
OH
OH
Ph
O
11
10
O
OH
O
Ph
Ph
Ph
Ph
Ph
O
2
Ph
O
O
OH
OH
3b
12
13
O
O
OH
Ph
EtO C
EtO
Ph
3
64
2
Ph
O
OH
OH
OH
Ph
3c
14
O
O
O
O
OH
O
O
Ph
Ph
O
O
Ph
Ph
Ph
4
5
65/1:1c
O
OH
O
Ph
Ph
Ph
Ph
O
O
O
BF3.OEt2/K2CO3
tBu
OH
But
SiMe3
3e
Ph
+
Ph
15
16
CH2Cl2, -30 ºC, 1h
70%a
Ph
Ph
Ph
2b
O
1b
O
8b
O
OH
Ph
O
OH
O
Ph
BF3.OEt2/K2CO3
CH2Cl2, -30 ºC, 1h
84%a
n-Bu
+
n-Bu
SiMe3
O
52
Ph
1c
2b
9b
17
a yield is based on the reacted cyclopropane substrate.
OMe
3i
OMe
O
Scheme 2. Reactions of 1b and 1c with styrene oxide.
O
O
OH
O
Ph
O
Ph
O
Ph
Cl
Ph
6
61/
O
COPh
Ph
Cl
Ph
Cl
O
O
O
2.6:1c
OH
OH
O
BF3.OEt2/K2CO3
+
+
O
O
Ph
SiMe3
SiMe3
18
19
3l
CH2Cl2, -30 ºC, 1 h
OH
3r
O
O
1a
1b
2r
2r
a
O
The NOE studies were performed on the diastereomers 10, 11, 14, 15, 17 and 18.
The relative stereochemistry of the other diastereomer, wherever formed, was
derived on account of the expected facial differences in oxirane formation.
COBu-t
O
O
BF3.OEt2/K2CO3
But
b
All the yields are isolated yields of purified products.
The stereostructures of 16 and 3l were ascertained by single-crystal X-ray
CH2Cl2, -30 ºC, 1 h
c
OH
8r
O
O
analysis.
Scheme 3. Reactions of 1a and 1b with the oxirane 2r.
O
O
OH O
O
O
OH O
O
Ph
BF3.OEt2
Ph
O
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
SiMe3
SiMe3
+
+
+
CH2Cl2, -30 ºC, 1 h
O
1a
1a
2p
6p (10%)
Ph
3p (45%)
OH
O
O
O
Ph
CH2Cl2, -30 ºC, 1 h
BF3.OEt2
Ph
Ph
Ph
+
OH
O
2q
7q (8%)
3q (60%)
Ph
Scheme 1. Reactions of 1a with vinyl-substituted oxiranes.

4650
V. K. Yadav, A. Gupta / Tetrahedron Letters 50 (2009) 4647–4650
3. Carruthers, W. In Some Modern Methods of Organic Synthesis, 3rd edition;
Cambridge University Press, 1986. Chapter 2.
acyclic reactant diastereomer. The results of the ring-closure reac-
tions are collected in Table 2. Although we cannot offer a rationale
at present, the formation of single diastereomers at entries 3 and 5
is noteworthy. The presence of the other diastereomer was not de-
tected by TLC and 1H and 13C NMR spectroscopy. The relative ste-
reochemistry of 16 was ascertained from a single-crystal X-ray
structure analysis as well.
In conclusion, 2-trimethylsilylmethylcylopropyl alkyl/aryl ke-
tones reacted with alkoxy-, aryl- and vinyl-substituted oxiranes
in the presence of BF3ꢁOEt2–K2CO3 to generate aldol products that
served as convenient precursors for the construction of 2,3,5-tri-
substituted tetrahydrofuran products under oxidation with
m-CPBA in dichloromethane. This protocol is expected to find
application in the design of strategies for the synthesis of highly
substituted tetrahydrofuran molecules. A further extension of this
methodology to the reaction of 2-trimethylsilylmethylcyclopropyl
ketones with aziridines under Lewis acidic conditions with the
ultimate aim of generating substituted piperidines has been
planned and the same is presently under investigation.
4. Alali, F. Q.; Liu, X.-X.; McLaughlin, J. T. J. Nat. Prod. 1999, 62, 504; Cave, A.;
Figadere, B.; Laureno, A.; Cortes, D.. In Progress in the Chemisty of Natural
Products; Hery, W., Kirby, G. W., Moore, R. E., Steglich, W., Tamm, C., Eds.;
Springer: New York, 1997; Vol. 70, p 81; Zeng, L.; Ye, Q.; Oberlines, N. H.; Shi,
G.; Gu, Z.-M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 275.
5. Mathew, P.; Mathew, D.; Asokan, C. V. Synth. Commun. 2007, 37, 661–665; Vital,
P.; Tanner, T. Org. Bio. Chem. 2006, 4, 4292–4298; Banerjee, M.; Roy, U. K.;
Sinha, P.; Roy, S. J. Organomet. Chem. 2005, 690, 1422–1428; House, H. O. J. Am.
Chem. Soc. 1954, 76, 1235–1237; Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63,
8212–8216; Attah-Poku, S. K.; Chau, F.; Yadav, V. K.; Fallis, A. G. J. Org. Chem.
1985, 50, 3418.
6. General experimental procedure: Anhydrous K2CO3 (138 mg, 1 mmol) was
suspended in a solution of the cyclopropane reactant (116 mg, 0.5 mmol) and
an oxirane (0.5 mmol) in anhydrous CH2Cl2 (3 mL) under an argon atmosphere
and the resultant mixture was stirred magnetically for 5 min. This was cooled
to ꢀ30 °C and BF3ꢁEt2O (95
lL, 0.75 mmol) was added. The reaction mixture
was stirred for the indicated length of time, then quenched with saturated aq
NaHCO3 (2 mL) and diluted with CH2Cl2 (5 mL). The layers were separated and
the aqueous layer was extracted with CH2Cl2 (2 ꢂ 5 mL). The combined organic
solution was dried and filtered. Removal of the solvent furnished the crude
product which was purified by radial chromatography over Merck silica gel
PF254 using mixtures of EtOAc in hexanes.
7. Removal of trace moisture from the reaction mixture by K2CO3 and, thus, the
arrest of hydrolysis of BF3ꢁEt2O are likely to be the reasons for the observed
marginal improvement in the yields of the products.
Acknowledgements
8. The diastereomeric ratio was calculated from the relative 1H integrals of the Me
doublets, downfield to upfield.
9. The diastereomeric ratio was calculated from the relative 1H integrals of the t-
Bu signals, from downfield to upfield.
A.G. thanks the University Grants Commission, Government of
India, for the award of a Research Fellowship and V.K.Y. thanks
the Council of Scientific & Industrial Research and the Department
of Science & Technology, Government of India, for financial
assistance.
10. The diastereomeric ratio was calculated from the relative 13C integrals of the
carbonyl carbon, downfield to upfield.
11. Al-Awadi, S. A.; Abdallah, M. R.; Dib, H. H.; Ibrahim, M. R.; Al-Awadi, N. A.; El-
Dusouqui, O. M. E. Tetrahedron 2005, 61, 5769–5777; Cui, D.-M.; Kawamura,
M.; Shimada, S.; Hayashi, T.; Tanaka, M. Tetrahedron Lett. 2003, 44, 4007–4010;
Shanker, C. G.; Mallaiah, B. V.; Srimannarayana, G. Synthesis 1982, 310;
Constantino, M. G.; Junior, V. L.; Jose da Silva, G. V. J. Heterocycl. Chem. 2003, 40,
369–371.
Supplementary data
12. (a) Constantino, M. G.; Lacerda, V., Jr.; Jose da Silva, G. V. J. Heterocycl. Chem.
2003, 40, 369–371; (b) Rao, C. P.; Srimannarayana, G. Synth. Commun. 1987, 17,
1507–1512; (c) Moriarty, R. M.; Prakash, O.; Musallam, H. A. J. Heterocycl. Chem.
1985, 22, 583–584.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.107.
13. Typical experimental procedure for the ring closure to tetrahydrofuran: The
aldol 3a (42 mg, 0.1 mmol) in benzene (1 mL) was added slowly at 0?5 °C to a
stirred solution of m-CPBA (77%, 45 mg, 0.2 mmol) in benzene (1 mL). The
resulting mixture was stirred at ambient temperature for 24 h and then
quenched with saturated aq Na2SO3 (5 mL). EtOAc (10 mL) was added and the
layers were separated. The organic solution was washed with saturated aq
NaHCO3 (2 ꢂ 5 mL) and brine (1 ꢂ 5 mL), dried and concentrated to obtain the
crude product. This was purified by silica gel column chromatography using 5–
10% EtOAc in hexanes as the eluent to obtain a diastereomeric mixture of the
expected tetrahydrofuran derivatives 10 and 11, 29 mg, 68% yield. Separation
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