The synthesis of 1,1′-disubstituted bis-cyclopropanes by the reaction of substituted propargylic alcohols with CH2I2-R3Al

Article abstract of DOI:10.1016/j.tetlet.2009.04.114

A new efficient method for the synthesis of 1,1′-disubstituted bis-cyclopropanes is described, which involves treatment of 2-alkyn-1-ols with trialkylaluminium and diiodomethane.

Full text of DOI:10.1016/j.tetlet.2009.04.114

Tetrahedron Letters 50 (2009) 4233–4235
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Tetrahedron Letters
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The synthesis of 1,10-disubstituted bis-cyclopropanes by the reaction
of substituted propargylic alcohols with CH2I2–R3Al
a
a
b,
Ilfir R. Ramazanov a, , Alsu V. Yumagulova , Usein M. Dzhemilev , Oleg M. Nefedov
*
a Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Russian Federation
b N.D. Zelinskii Institute of Organic Chemistry of Russian Academy of Sciences, 47 Lenin Prosp., Moscow 117913, Russian Federation
a r t i c l e i n f o
a b s t r a c t
A new efficient method for the synthesis of 1,10-disubstituted bis-cyclopropanes is described, which
involves treatment of 2-alkyn-1-ols with trialkylaluminium and diiodomethane.
Ó 2009 Published by Elsevier Ltd.
Article history:
Received 24 February 2009
Revised 23 April 2009
Accepted 28 April 2009
Available online 3 May 2009
We have previously reported the reaction of alkyl- and phenyl-
substituted alkynes with CH2I2–Et3Al which gave cyclopropylic
compounds.1 To extend the scope of this transformation, we exam-
ined the reaction of heteroatom-substituted acetylenic compounds
with CH2I2 in the presence of trialkylaluminiums.
expected bis-cyclopropanes 1k–n. 2-Butyn-1,4-diol and its
dimethyl ether were not active in this reaction. However, the
methyl ether of 2-nonyn-1-ol gave bis-cyclopropane 1a in 82%
yield. Hence, the chemistry of substituted propargylic alcohols,
their esters and ethers is the same in this reaction.
Here we report a convenient and versatile one-pot method for the
synthesis of bis-cyclopropanes from readily available substituted
propargylic alcohols, CH2I2 and trialkylaluminiums (Scheme 1).
The identification of polycyclopropanated natural compounds2
and their biological activity3 has promoted studies on the develop-
ment of stereoselective methods to prepare polycyclopropanes.4
The Simmons-Smith reaction is widely used for the preparation
of 2,20-disubstituted bis-cyclopropanes.5
CH2I2 (5 eq)
R'3Al (6 eq)
R
R'
OH
R1
R1
R
rt, CH2Cl2
R2
R2
1a-h
68-89%
R = alkyl, Ph; R1=H, alkyl; R2=H;
R' = Et, i-Bu
The reaction of 2-nonyn-1-ol with CH2I2 and Et3Al in CH2Cl2
gave 1-ethyl-10-hexyl-bis-cyclopropane 1a in 77% yield after 3 h
at room temperature (Table 1, entry 1).6 The reaction proceeds in
hexane but does not occur in ethereal solvents (tetrahydrofuran
and diethyl ether).
The complete structure elucidation of bis-cyclopropane 1a was
carried out by a variety of NMR correlation methods (COSY, HSQC
and HMBC).7
The alkyl- and phenyl-substituted propargylic alcohols
RC„CCH2OH (where R = n-Bu, n-Am, Ph) reacted in the same
way to give the products 1b–d. 2-Alkyl-substituted 2-alkyn-1-ols
(3-octyn-2-ol, 5-decyn-4-ol) gave mixtures of regioisomeric bis-
cyclopropanes in 1:1 ratios in 81% (1e) and 68% (1f) overall yields.
On the other hand, a 2,2-dimethyl-substituted 2-alkyn-1-ol (2-
methyl-3-octyn-2-ol) did not react with CH2I2–Et3Al. The terminal
propargylic alcohols (propargylic alcohol, 3-methyl-1-pentyn-3-ol,
1-ethynylcyclohexanol and 1-hexyn-3-ol) and their esters (2-pro-
pyn-1-yl acetate and 2-propyn-1-yl propionate) did not afford
Scheme 1. The synthesis of bis-cyclopropanes from propargylic alcohols.
Table 1
The synthesis of bis-cyclopropanes from propargylic alcoholsa
Entry
R
R0
R1
R2
Bis-cyclopropane
GC yield (%)
1
2
3
4
5
6
7
8
9
10
10
11
12
13
14
15
n-C6H13
n-Bu
n-C5H11
Ph
n-Bu
n-Bu
n-Bu
Ph
n-Bu
n-Bu
n-Bu
H
Et
Et
Et
Et
Et
Et
i-Bu
i-Bu
Me
Et
Et
Et
Et
Et
Et
Et
H
H
H
H
Me
n-Pr
H
H
H
Me
Me
H
n-Pr
Me
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
77
87
89
72
81
68
85
74
—
—
—
—
—
H
Me
Me
H
H
Et
1j
1j
1k
1l
1m
1n
1o
H
H
H
—
—
—
–(CH2)5–
* Corresponding author. Tel./fax: +7 347 284 2750.
E-mail addresses: iramazan@inbox.ru, ink@anrb.ru (I.R. Ramazanov).
Fax: +7 095 135 5328.
CH2OH
H
H
a
Reaction conditions: alkyne:CH2I2:R3Al = 1:5:6, CH2Cl2, 20–25 °C.
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.04.114

4234
I. R. Ramazanov et al. / Tetrahedron Letters 50 (2009) 4233–4235
CH2I2 + R'3Al
R'2AlCH2I + R'I
R2
R1
R2
R1
R'2AlO
R'2AlO
R
R2
R'2AlO
R
R'3Al
OH
R
R'2AlCH2I
R1
AlR'2
R'
R
2
- R'2AlI
R1
I
AlR'2
R
I
AlR'2
B
- R'2AlI
A
R=alkyl, Ph
R'=Et, i-Bu
R'2Al
R'
R'2AlCH2I
R1,R2=H,H; Me,H;
R2
R'2AlO R2
R
R'
R2
R1
R'2AlCH2I
- R'2AlI
R1
R
R1
R
-R'2AlOAlR'2
AlR'2
R'
R'
1
D
C
Scheme 2. A possible mechanism for the transformation.
D
D
H
Hexn
OH
rt, CH2Cl2
D
D
D
Hexn
+ CD2I2 + Et3Al
H
Et
D
63% isolated yield
Scheme 3. The reaction of 2-nonyn-1-ol with CD2I2 and Et3Al.
The use of i-Bu3Al instead of Et3Al resulted in the formation of
iso-butyl-substituted bis-cyclopropanes 1g, h in high yields (74–
85%). However, the reaction of 2-heptyn-1-ol with CH2I2–Me3Al
did not give the expected methyl-substituted bis-cyclopropane
1i. The reaction of 2-nonyn-1-ol with CH2I2 in the presence of
i-Bu2AlH, i-Bu2AlCl or Et2AlCl did not proceed.
We assume that mechanistically the generation of dial-
kyl(iodomethyl)aluminium8 occurs initially followed by carboa-
lumination of the propargylic alcohol with the formation of
iodo-containing alkenylaluminium A9 (Scheme 2). Rearrange-
ment under the action of R03Al affords unsaturated organoalu-
minium compound B. Cyclopropanation of the double bond10
and elimination of (R02Al)2O give substituted vinylcyclopropane
D. Finally, cyclopropanation of the latter leads to the formation
of substituted bis-cyclopropane 1.
We carried out the reaction of 2-nonyn-1-ol with CD2I2 and
Et3Al to confirm the proposed mechanism (Scheme 3) and obtained
the corresponding deuterated bis-cyclopropane. The positions of
the deuterium atoms in the product were determined by compar-
ison of its 1H and 13C NMR spectra with those of 1a and were as
expected.
As follows from the mechanism, the low reactivity of terminal
propargylic alcohols and 2-methyl-3-octyn-2-ol in this reaction
could result from hindered carboalumination of the triple bond
by dialkyl(iodomethyl)aluminium. We assume that the low reac-
tivity of terminal propargylic alcohols was caused predominantly
by electronic factors,11 whereas in the case of the 2,2-disubstituted
2-alkyn-1-ol, it may be explained by steric hindrance. As noted
above, Me3Al did not react with propargylic alcohols probably as
a result of its low reactivity12 with CH2I2 and its greater tendency
to form aggregates (compared to Et3Al and i-Bu3Al).13 The same is
true for Bu2AlH, i-Bu2AlCl and Et2AlCl.
Federation (Grant NSc 2349.2008.3), which are gratefully
acknowledged.
References and notes
1. (a) Dzhemilev, U. M.; Ramazanov, I. R.; Ibragimov, A. G.; Dyachenko, L. I.;
Lukjyanova, M. P.; Nefedov, O. M. J. Organomet. Chem. 2001, 636, 91; (b)
Ramazanov, I. R.; Lukyanova, M. P.; Sharipova, A. Z.; Ibragimov, A. G.;
Dzhemilev, U. M.; Nefedov, O. M. Russ. Chem. Bull. 2001, 50, 1406.
2. (a) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.; Shigematsu, N.;
Okuhara, M.; Kohsaka, M.; Horikoshi, K. J. Antibiot. 1990, 43, 748; (b) Kuo, M. S.;
Zielinski, R. J.; Cialdella, J. I.; Marschke, C. K.; Dupuis, M. J.; Li, G. P.;
Kloosterman, D. A.; Spilmann, C. H.; Marshall, V. P. J. Am. Chem. Soc. 1995,
117, 10629.
3. (a) Barrett, A. G. M.; Kasdorf, K.; Williams, D. J. J. Chem. Soc., Chem. Commun.
1994, 1781; (b) Barrett, A. G. M.; Doubleday, W. W.; Tustin, G. J.; White, A. J. P.;
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Angew. Chem. 1969, 81, 1046.
6. Synthesis of 1-ethyl-10-hexyl-bis-cyclopropane (1a): To a solution of 2-nonyn-1-
ol (0.42 g, 3 mmol) and diiodomethane (4.02 g, 15 mmol) in CH2Cl2 (15 mL),
triethylaluminium (2.7 mL, 18 mmol) was added at 0 °C under an argon
atmosphere. The mixture was stirred at room temperature for 3 h. The reaction
was terminated by dilution with CH2Cl2 (20 mL) followed by treatment with a
7
wt% aq solution of HCl. The aqueous layer was extracted with CH2Cl2
(3ꢀ10 mL). The combined organic layers were then washed with saturated
NaHCO3 solution and dried over anhydrous CaCl2. The solvent was removed
under reduced pressure and the residue distilled to yield 0.40 g of an oily
product (69% isolated yield, 77% GC yield). Bp 67–70 °C (1 Torr).
7. The 1H NMR spectrum of 1a in CDCl3 shows an AA0BB0 multiplet for the
cyclopropyl hydrogen atoms at 0.05–0.15 ppm which is typical for
unsymmetrical 1,1-disubstituted cyclopropanes. The spectral parameters of
the AA0BB0 multiplet are not discussed due to overlapping of the signals of the
two cyclopropane fragments. The APT spectrum of 1a shows resonances due to
the CH2 groups of two three-membered cycles at 9.10 and 9.20 ppm. There are
four cross peaks in the HMBC spectrum between the hydrogen atoms of the
cyclopropyl moieties and the carbon atoms C(6), C(7), C(8) and C(9). The
spectrum shows cross peak between the hydrogen atoms of C(10)H3 and
carbon C(8). 1H NMR (d, ppm): 0.05–0.15 (m, 8H, C(11–14)H2), 0.90 (t,
Acknowledgments
3
3JCH = 7.0 Hz, 3H, C(1)H3), 0.96 (t, JCH = 7.4 Hz, 3H, C(10)H3), 1.2–1.5 (m, 12H,
This work was supported by the Russian Foundation for Basic
Research and the Government of Bashkortostan Republic (Grant
No. 08-03-97007), Ministry of Science and Education of Russian
C(2–6,9)H2). 13C NMR (d, ppm): 9.10 and 9.20 (4C, C(11–14)), 11.13 (C(10)),
14.05 (C(1)), 20.06 (C(7)), 20.69 (C(8)), 22.70 (C(2)), 26.79 (C(5)), 29.81 (C(9)),
29.91 (C(4)), 31.96 (C(3)), 37.24 (C(6)). EIMS m/z (relative intensity, %): 194 (1)

I. R. Ramazanov et al. / Tetrahedron Letters 50 (2009) 4233–4235
4235
[M]+, 166 (65) [M-C2H4]+, 137 (20), 123 (17), 109 (51), 96 (53), 95 (70), 81
(100). Anal. Calcd for C14H26: C, 86.52; H, 13.48. Found: C, 86.89; H, 13.11.
9. Hoberg, H. Liebigs Ann. 1962, 656, 1.
10. Maruoka, K.; Fukutani, Y.; Yamamoto, H. J. Org. Chem. 1985, 50, 4412.
11. In the case of 1-ethynylcyclohexanol, deuterolysis of the reaction mixture did
not result in 1-(deuteroethynyl)cyclohexanol which indicates that metallation
processes can be excluded from consideration.
12. Treatment of CH2I2 with Et3Al or i-Bu3Al (1:1 molar ratio) in CH2Cl2 at room
temperature resulted in the disappearance of CH2I2 in 5 min due to aluminium
carbenoid formation. In the case of Me3Al, the conversion of CH2I2 was 73%
after 2 h.
1
2
5
6
9
10
7
8
3
4
11
14
12
13
13. Smith, M. B. J. Organomet. Chem. 1972, 46, 31.
8. Miller, D. B. Tetrahedron Lett. 1964, 989.