Intramolecular cyclopropanation of epichlorohydrin-derived unsaturated chlorohydrins

Article abstract of DOI:10.1055/s-2005-869973

Concise stereoselective syntheses of bicyclo[3.1.0]hexan-2-ols and a bicyclo[4.1.0]heptan-2-ol are achieved via regioselective ring-opening of epichlorohydrin with allylic and homoallylic Grignard reagents, followed by lithium 2,2,6,6-tetramethylpiperidide-induced intramolecular cyclopropanation of the resulting unsaturated chlorohydrins. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869973

2
264
PRACTICAL SYNTHETIC PROCEDURES
Intramolecular Cyclopropanation of Epichlorohydrin-Derived Unsaturated
Chlorohydrins
a
a
b
I
D
ntramolecular Cyc
a
lopropanat
v
ion of
E
pich
i
lorohyd
d
rin-Derived Unsatu
Mr ated Chlorohydrins . Hodgson,* Ying Kit Chung, Jean-Marc Paris
a
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, UK
E-mail: david.hodgson@chem.ox.ac.uk
b
PSP
Rhodia Recherches, Centre de Recherches de Lyon, 85 Avenue des Frères Perret,
69192 Saint Fons, France
Received 7 March 2005; revised 6 April 2005
No52
Abstract: Concise stereoselective syntheses of bicyclo[3.1.0]hexan-2-ols and a bicyclo[4.1.0]heptan-2-ol are achieved via regioselective
ring-opening of epichlorohydrin with allylic and homoallylic Grignard reagents, followed by lithium 2,2,6,6-tetramethylpiperidide-induced
intramolecular cyclopropanation of the resulting unsaturated chlorohydrins.
Key words: intramolecular cyclopropanation, lithium 2,2,6,6-tetramethylpiperidide, unsaturated chlorohydrin, epichlorohydrin, Grignard
reagents
OH
OH
Cl
N
Li
O
O
RMgHal
CuI
Cl
Li
t-BuOMe
(n = 1)
n
n = 1 or 2
Scheme 1
OH
OH
Methods to access cyclopropanes that are fused to five-
1
and six-membered carbocycles are of interest, with such
bicyclic motifs being found widely in natural products.
We recently reported a way to make these bicyclic sys-
tems by intramolecular cyclopropanation of bishomoal-
lylic and trishomoallylic terminal epoxides using lithium
(
i) t-BuOK,
n-BuLi
Cl
N
Li
(ii) MgBr2
O
69%
(iii)
Cl
5
3%
1
2
>
99% ee
2,2,6,6-tetramethylpiperidide (LTMP), which proceeds
2
via a-lithiation of the epoxide (Schemes 1 and 2). The
Scheme 3
method is not viable to make cyclopropanes fused to larg-
er rings, or as an intermolecular process. It does, however, (–)-sabinol 2 (Scheme 3). This reaction likely proceeds
2
constitute a useful alternative to intramolecular cyclopro- via in situ epoxide formation.
panation via a-diazocarbonyl chemistry, to access bicyc-
Ring-opening of terminal epoxides at the terminal posi-
tion with Grignard reagents is an efficient process under
lo[3.1.0]hexanes and bicyclo[4.1.0]heptanes bearing
oxygenation at the 2-positions.
3
catalysis by copper salts (typically CuI). Chlorohydrins
can be easily accessed with this methodology using epi-
4
chlorohydrin as the epoxide substrate. As the individual
enantiomers of epichlorohydrin are commercially avail-
5
able (in multikilo quantities if needed), this is particularly
OH
O
N
O
Li
Li
t-BuOMe
0
°C to 20 °C
convenient for asymmetric synthesis. In the present paper
we describe the coupling of unsaturated (allylic and
homoallylic) Grignard reagents with epichlorohydrin, fol-
lowed by LTMP-induced intramolecular cyclopropa-
Scheme 2
In our previous work, we also disclosed a single example nation of the resulting unsaturated chlorohydrins, as a
of the use of an epichlorohydrin-derived unsaturated chlo- straightforward 2-step procedure to access bicy-
rohydrin 1 in an intramolecular cyclopropanation to make clo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols.
Ring-opening of (±)-epichlorohydrin with allylic and ho-
moallylic Grignard reagents 3a–e, is shown to afford un-
SYNTHESIS 2005, No. 13, pp 2264–2266
x
x.
x
x
.
2
0
0
5
saturated chlorohydrins 4a–e in good to excellent yields
Table 1).
Advanced online publication: 06.06.2005
DOI: 10.1055/s-2005-869973; Art ID: Z05205SS
Georg Thieme Verlag Stuttgart · New York
(
©

PRACTICAL SYNTHETIC PROCEDURES
Intramolecular Cyclopropanation of Chlorohydrins
2265
OH
OH
Cl
Table 1 Ring-Opening of (±)-Epichlorohydrin
OH
OH
OH
Cl
Cl
Cl
O
OH
Cl
Cl
CuI,
RMgHal
a–e
R
Cl
THF, −78 °C to 20 °C
3
4a–e
4
a
4b
4c
4d
4e
a
3
a
R
CuI (equiv) 4a–e
Yield (%)
75
t-BuOMe
N
Li
0.1
0 °C to 20 °C
OH
b
c
0.1
0.1
94
79
OH
OH
OH OH
b
5a
0%
5b
5c
5d
5e
66%
d
e
0.5
72
89
6
65%
65%
60%
–
Scheme 4
In summary, we have demonstrated that unsaturated chlo-
rohydrins are useful intramolecular cyclopropanation pre-
cursors, with the chlorohydrins being easily prepared
from epichlorohydrin and allylic/homoallylic Grignard
reagents.
a
Isolated yields
With respect to RMgHal.
b
Under CuI catalysis an unsymmetrical allylic Grignard re-
agent, such as prenylmagnesium chloride, is known to re-
act through the less substituted allylic terminus with an
6
epoxide. Indeed, the reaction to give chlorohydrin 4d has
Ring-Opening of Epichlorohydrin with Grignard Reagents;
General Procedure
Mg turnings (729 mg, 30 mmol) were activated by stirring rapidly
7
previously been carried out on about a 1-mol scale. Cou-
pling of epichlorohyrin with prenylmagnesium chloride in
9
the absence of a copper salt occurred through the more overnight under N . To a suspension of activated Mg in THF (15
2
substituted allylic position to give chlorohydrin 4e, as an- mL) at r.t. was added (CH Br) (5 drops), followed by the unsatur-
2 2
ated organohalide (12 mmol) at such a rate as to maintain the reac-
tion temperature at ca. 50 °C. On completion of the addition, the
reaction was stirred at r.t. for 2 h, the solids were then allowed to
settle and the supernatant Grignard solution was transferred by sy-
ringe over 2 min to a stirred solution of (±)-epichlorohydrin (0.63
mL, 8.0 mmol) and CuI (152 mg, 0.8 mmol, 0.1 equiv) in THF (8
ticipated from the reaction of this Grignard reagent with
6
other epoxides. Using such chlorohydrins as potential cy-
clopropanation precursors was found to offer an added
practical advantage when compared to using the corre-
sponding low molecular weight terminal epoxides. This is
because the latter have volatility issues during isolation, mL) at –78 °C. The resulting dark green solution was allowed to
but the corresponding chlorohydrins are much less vola- warm from –78 °C to –10 °C over 2 h, and was then stirred at r.t. for
a further 2 h. The mixture was then washed with sat. aq NH Cl (50
tile, making them easier to isolate.
4
mL), followed by extraction of the aqueous layer with Et O (2 × 40
2
The unsaturated chlorohydrins 4a–e were reacted with
LTMP following the conditions used earlier to make rated and chromatographed (SiO , Et O–petroleum ether, 1:4) to af-
mL). The combined organic fractions were dried (MgSO ), evapo-
4
2
2
2
(
[
–)-sabinol 2; that is, slow addition by cannula of LTMP ford the unsaturated chlorohydrin 4.
3.5 equiv, generated just prior to use from n-BuLi and
1
0
1-Chlorohex-5-en-2-ol (4a)
Using commercially available allylmagnesium chloride (2 M in
THF), 4a was synthesised as described in the general procedure.
commercially available 2,2,6,6-tetramethylpiperidine
(
8
TMP)] to the chlorohydrin at 0 °C. This procedure af-
forded the corresponding bicyclic alcohols 5a–e in good
yields (Scheme 4). At this stage, we considered if an ex-
perimentally more convenient one-flask procedure for the
synthesis of bicyclic alcohols from chlorohydrins, which
also used less TMP, was possible. We developed direct
addition of n-BuLi (3.5 equiv) to a mixture of chlorohy-
drin and TMP (2.5 equiv) at –78 °C followed by gradual
warming to ambient temperature, and this procedure has
been demonstrated with chlorohydrin 4c on a 10-mmol
scale to give bicyclic alcohol 5c in identical yield (65%)
Yield: 75%; colourless oil.
1
H NMR (CDCl , 400 MHz): d = 1.61–1.66 (m, 2 H, 2 × H-3),
3
2
1
.12–2.29 (m, 2 H, 2 × H-4), 2.31 (s, 1 H, OH), 3.49 (dd, J = 6.8,
1.2 Hz, 1 H, H-1), 3.63 (dd, J = 3.2, 10.8 Hz, 1 H, H-1¢), 3.80–3.86
(
5
m, 1 H, H-2), 4.98–5.09 (m, 2 H, 2 × H-6), 5.77–5.87 (m, 1 H, H-
).
1
3
C NMR (CDCl , 100 MHz): d = 29.6 (C-4), 33.2 (C-3), 50.3 (C-
3
1
), 70.7 (C-2), 115.3 (C-6), 137.6 (C-5).
11
1
-Chlorohept-6-en-2-ol (4b)
to that obtained earlier. Using less n-BuLi or TMP was Using 1-bromo-but-3-ene, 4b was synthesised as described in the
detrimental to the yield. This protocol likely proceeds by general procedure.
n-BuLi initially forming the lithium alkoxide of the chlo- Yield: 94%; colourless oil.
rohydrin, then further n-BuLi generating LTMP which re-
acts with the epoxide after it is formed during warming.
1
H NMR (CDCl , 400 MHz): d = 1.43–1.62 (m, 4 H, 2 × H-3,
3
2
× H-4), 2.07–2.12 (m, 2 H, 2 × H-5), 2.26 (d, J = 4.8 Hz, 1 H,
Synthesis 2005, No. 13, 2264–2266 © Thieme Stuttgart · New York

2
266
D. M. Hodgson et al.
PRACTICAL SYNTHETIC PROCEDURES
OH), 3.48 (dd, J = 7.2, 10.8 Hz, 1 H, H-1), 3.63 (dd, J = 3.6, 11.2
Hz, 1 H, H-1¢), 3.78–3.84 (m, 1 H, H-2), 4.96–5.05 (m, 2 H, 2 × H-
of SiO and chromatographed (SiO , Et O–petroleum ether, 3:7) to
2
afford bicyclic alcohol 5.
2
2
7
), 5.75–5.85 (m, 1 H, H-6).
2
Spectral data for 5a,b and 5d,e can be found in the literature.
1
3
C NMR (CDCl , 100 MHz): d = 24.7 (C-4), 33.5 (C-3), 33.6 (C-
3
5
), 50.5 (C-1), 71.3 (C-2), 114.9 (C-7), 138.2 (C-6).
Improved One-Flask Intramolecular Cyclopropanation (5c;
0-mmol Scale)
1
1
2
1-Chloro-5-methylhex-5-en-2-ol (4c)
Using 3-chloro-2-methyl-1-propene, 4c was synthesised as de-
n-BuLi (1.6 M in hexane, 21.9 mL, 35 mmol) was added over 2 min
to a stirred solution of 1-chloro-5-methylhex-5-en-2-ol 4c (1.49 g,
10 mmol) and 2,2,6,6-tetramethylpiperidine (4.3 mL, 25 mmol, 2.5
equiv) in t-BuOMe (75 mL) at –78 °C. The stirred mixture was
warmed to 0 °C over 2 h, then the cooling bath was removed and the
mixture left at r.t. for a further 16 h. The mixture was quenched with
MeOH (2 mL), washed with aq HCl (1 M, 100 mL) and the aqueous
scribed in the general procedure.
Yield: 79%; colourless oil.
1
H NMR (CDCl , 400 MHz): d = 1.67–1.72 (m, 2 H, 2 × H-3), 1.75
3
(
1
(
s, 3 H, Me), 2.08–2.25 (m, 3 H, 2 × H-4, OH), 3.51 (dd, J = 6.8,
0.8 Hz, 1 H, H-1), 3.65 (dd, J = 3.2, 10.8 Hz, 1 H, H-1¢), 3.79–3.86
m, 1 H, H-2), 4.73, 4.76 (s, 2 H, H-6, 6¢).
layer extracted with Et O (2 × 80 mL). The combined organic layers
2
were dried (MgSO ) and evaporated carefully under reduced pres-
4
1
3
sure to give a yellow oil, which was chromatographed (SiO , Et O–
2
C NMR (CDCl , 100 MHz): d = 22.3 (Me), 32.0 (C-3), 33.6 (C-
3
2
petroleum ether, 3:7) to afford exo-5-methylbicyclo[3.1.0]hexan-2-
4
), 50.3 (C-1), 71.0 (C-2), 110.5 (C-6), 144.9 (C-5).
1
ol 5c (729 mg, 65%) as a colourless oil.
3
7
1
-Chloro-6-methylhept-5-en-2-ol (4d)
1
H NMR (CDCl , 400 MHz): d = 0.22 (dd, J = 3.6, 4.8 Hz, 1 H, H-
3
6), 0.34 (dd, J = 5.2, 8.4 Hz, 1 H, H-6¢), 1.08 (dd, J = 3.2, 8.4 Hz, 1
H, H-1), 1.27 (s, 3 H, Me), 1.34–1.44 (m, 1 H, H-3), 1.54–1.85 (m,
Prenylmagnesium chloride was generated from prenyl chloride (20
mmol) in THF (20 mL) as described in the general procedure. The
resulting Grignard solution was added slowly to a stirred solution of
CuI (10 mmol) in THF (10 mL) at –78 °C, which was then warmed
to –30 °C over 30 min. (±)-Epichlorohydrin (0.63 mL, 8 mmol) was
added, the reaction mixture was warmed to –10 °C over 20 min and
then left at r.t. for 2 h. The work-up and purification procedures
were performed as described in the general procedure to give 4d.
4
H, OH, H-3¢, 2 × H-4), 4.17 (t, J = 4.0 Hz, 1 H, H-2).
1
3
C NMR (CDCl , 100 MHz): d = 14.2 (C-6), 21.3 (Me), 24.1 (C-
3
5
), 30.7 (C-4), 31.5 (C-1), 32.0 (C-3), 75.4 (C-2).
Acknowledgment
Yield: 72%; colourless oil.
We thank Rhodia for a studentship, the EPSRC for a research grant
(GR/S46789/01) and the EPSRC National Mass Spectrometry Ser-
vice Centre (Swansea) for mass spectra.
1
H NMR (CDCl , 400 MHz): d = 1.54–1.61 (m, 2 H, 2 × H-3), 1.63
3
(
s, 3 H, Me), 1.70 (s, 3 H, Me), 2.10–2.15 (m, 2 H, 2 × H-4), 2.28
br s, 1 H, OH), 3.48 (dd, J = 7.2, 11.2 Hz, 1 H, H-1), 3.63 (dd,
(
J = 3.2, 10.8 Hz, 1 H, H-1¢), 3.81 (br s, 1 H, H-2), 5.09–5.13 (m, 1
H, H-5).
References
1
3
C NMR (CDCl , 100 MHz): d = 17.6 (Me), 24.0 (C-4), 25.7 (Me),
3
(1) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977.
3
4.2 (C-3), 50.5 (C-1), 71.0 (C-2), 123.3 (C-5) 132.7 (C-6).
(
(
2) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am. Chem.
Soc. 2004, 126, 8664.
1
2
1
Using prenyl chloride, 4e was synthesised as described in the gen-
-Chloro-4,4-dimethylhex-5-en-2-ol (4e)
3) (a) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G.
Tetrahedron Lett. 1979, 1503. For reviews see:
(b) Gorzynski Smith, J. Synthesis 1984, 629. (c) Wakefield,
B. J. Organomagnesium Methods in Organic Synthesis;
Academic Press: London, 1995, 165.
eral procedure, without using CuI and (CH Br) .
2
2
Yield: 89%; colourless oil.
1
H NMR (CDCl , 400 MHz): d = 1.09 (s, 3 H, Me), 1.10 (s, 3 H,
3
Me), 1.52 (dd, J = 2.8, 14.4 Hz, 1 H, H-3), 1.61 (dd, J = 8.0, 14.4
Hz, 1 H, H-3¢), 2.22 (d, J = 4.0 Hz, 1 H, OH), 3.45 (dd, J = 6.8, 10.8
Hz, 1 H, H-1), 3.55 (dd, J = 3.6, 10.8 Hz, 1 H, H-1¢), 3.86–3.92 (m,
1 H, H-2), 5.00 (s, 1 H, H-6), 5.03 (app. d, 1 H, H-6¢), 5.89 (dd,
J = 10.8, 17.6 Hz, 1 H, H-5).
(4) For a recent example see: Schaus, S. E.; Branalt, J.;
Jacobsen, E. N. J. Org. Chem. 1998, 63, 4876.
(5) Larrow, J. F.; Hemberger, K. E.; Jasim, S.; Kabir, H.; Morel,
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(
(
6) Linstrumelle, G.; Lorne, R.; Dang, H. P. Tetrahedron Lett.
1978, 4069.
7) (a) Takayanagi, H.; Shirasaka, T.; Morita, Y. Synthesis 1991,
1
3
C NMR (CDCl , 100 MHz): d = 27.0 (Me), 27.5 (Me), 36.1 (C-4),
3
6.9 (C-3), 51.1 (C-1), 69.2 (C-2), 111.5 (C-6), 148.0 (C-5).
4
722. (b) See also: Takano, S.; Yanase, M.; Takahashi, M.;
Ogasawara, K. Chem. Lett. 1987, 2017.
8) For a Practical Synthetic Procedure to TMP, see:
Kampmann, D.; Stuhlmüller, G.; Simon, R.; Cottet, F.;
Leroux, F.; Schlosser, M. Synthesis 2005, 1028.
(9) Baker, K. V.; Brown, J. M.; Hughes, N.; Skarnulis, A. J.;
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(10) Fabris, H. J. J. Org. Chem. 1967, 32, 2031.
(11) Kobayashi, Y.; Watatani, K.; Kikori, Y.; Mizojiri, R.
Tetrahedron Lett. 1996, 37, 6125.
Intramolecular Cyclopropanation of Unsaturated Chlorohy-
drins with LTMP; General Procedure (1-mmol Scale)
(
n-BuLi (1.6 M in hexane, 2.2 mL, 3.5 mmol) was added over 20 s
to a stirred solution of 2,2,6,6-tetramethylpiperidine (0.6 mL, 3.5
mmol) in t-BuOMe (10 mL) at –78 °C. The resulting LTMP solu-
tion was removed from the dry-ice bath and stirred at r.t. for 15 min,
then cooled to 0 °C in an ice-bath. To a stirred solution of the unsat-
urated chlorohydrin 4 (1.0 mmol) in t-BuOMe (5 mL) at 0 °C was
added the LTMP solution slowly via cannula over 45 min. The re-
sulting mixture was stirred at r.t. for 16 h. The reaction mixture was
then quenched with MeOH (0.5 mL) and most of the solvent was re-
moved in vacuo. The residue was dry-loaded onto a small amount
(12) Imai, T.; Nishida, S. J. Org. Chem. 1990, 55, 4849.
(
13) Harada, T.; Yamaura, Y.; Oku, A. Bull. Chem. Soc. Jpn.
1987, 60, 1715.
Synthesis 2005, No. 13, 2264–2266 © Thieme Stuttgart · New York