Tandem cyclopropanation with dibromomethane under Grignard conditions

Article abstract of DOI:10.1021/jo8007397

(Chemical Equation Presented) Tertiary Grignard reagents and dibromomethane efficiently cyclopropanate allylic (and certain homoallylic) magnesium and lithium alcoholates at ambient temperature in ether solvents. Lithium (homo)allyl alcoholates are directly cyclopropanated with magnesium and CH ₂Br₂ under Barbier conditions at higher temperatures. The reaction rates depend on the substitution pattern of the (homo)allylic alcoholates and on the counterion with lithium giving best results. Good to excellent syn-selectivities are obtained from α-substituted substrates, which are in accord with a staggered Houk model. In tandem reactions, cyclopropyl carbinols are obtained from allyloxylithium or -magnesium intermediates, generated in situ by alkylation of conjugated aldehydes, ketones, and esters as well as from allyl carboxylates or vinyloxiranes. Using this methodology, numerous fragrance ingredients and their precursors were efficiently converted to the corresponding cyclopropyl carbinols.

Full text of DOI:10.1021/jo8007397

Tandem Cyclopropanation with Dibromomethane under Grignard
Conditions
Gerhard Brunner, Laura Eberhard, Ju¨rg Oetiker, and Fridtjof Schro¨der*
Research Chemistry Department, GiVaudan Schweiz AG, CH-8600 Du¨bendorf, Switzerland
fridtjof.schroeder@giVaudan.com
ReceiVed April 9, 2008
Tertiary Grignard reagents and dibromomethane efficiently cyclopropanate allylic (and certain homoallylic)
magnesium and lithium alcoholates at ambient temperature in ether solvents. Lithium (homo)allyl
alcoholates are directly cyclopropanated with magnesium and CH2Br2 under Barbier conditions at higher
temperatures. The reaction rates depend on the substitution pattern of the (homo)allylic alcoholates and
on the counterion with lithium giving best results. Good to excellent syn-selectivities are obtained from
R-substituted substrates, which are in accord with a staggered Houk model. In tandem reactions, cyclopropyl
carbinols are obtained from allyloxylithium or -magnesium intermediates, generated in situ by alkylation
of conjugated aldehydes, ketones, and esters as well as from allyl carboxylates or vinyloxiranes. Using
this methodology, numerous fragrance ingredients and their precursors were efficiently converted to the
corresponding cyclopropyl carbinols.1
Introduction
to facilitate carbenoid formation. The latter method5b has been
adapted for the industrial preparation of cyclopropanated
fragrance compounds,6 e.g. Javanol (2a). It is still desirable,
however, to replace the large quantities of zinc and the even
more eco-toxic copper of such processes by less harmful
reagents.
The Simmons-Smith cyclopropanation has evolved as a
widely used tool for the conversion of alkenes, e.g. allylic
alcohols, to the corresponding cyclopropanes, especially with
carbenoids of the general structure MCH2X (M ) Zn, Al, Sm,
and Cu).2 However, for processes on a larger scale,3 one has to
consider the use of stoichiometric amounts of environmentally
problematic, expensive, and/or pyrophoric metal reagents.
Stoichiometric quantities of iodinated carbenoid precursors such
as CH2I2 or ClCH2I are required to guarantee the necessary
reactivity for carbenoid formation,4 which in turn generates large
amounts of corrosive waste. CH2Br2 would be a much less
expensive and more easily purified and storable reagent. An
efficient cyclopropanation reaction with CH2Br2, however, has
so far only been reported by Friedrich,5 who activates zinc and
copper(I) chloride in the presence of CH2Br2 and the alkene
substrate either by ultrasound5a or by addition of acetyl halides5b
Results
Cyclopropanation of Allyl Alcohol 1a under Grignard
Conditions. An unusual cyclopropanation of allylic alcohols
promoted by a Grignard reagent has been reported by Bolm
and Pupowicz,7 who obtained moderate to good cyclopropana-
tion yields from γ- and R,γ-substituted allylic alcohols in the
presence of 4 equiv of iPrMgX(X ) Cl, Br, I) and 3 equiv of
CH2I2 in a mixture of CH2Cl2 and ether solvents after 2-3 days
at -70 °C. After slight changes, we could apply this method to
the cyclopropanation of one of our substrates (1a). To our
surprise, the cyclopropanated product 2a was readily obtained
in ether solvents alone and at ambient temperature (Scheme 1,
path A).
(1) Parts of this investigation were presented at the “Scale-Up of Chemical
Processes” Scientific Update Conference, Boston, MA, August 29-31, 2007.
(2) Review: Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1–415.
(3) DelMonte, A. J.; Dowdy, E. D.; Watson, D. J. Top. Organomet. Chem.
2004, 6, 97–122.
(4) The reactivity order of dihalomethanes is in accordance with that of the
radical halogen abstraction from these compounds. See for example: (a)
Menapace, L. H.; Kuivila, H. G. J. Am. Chem. Soc. 1964, 86, 3047–3051. (b)
Kosower, E. M.; Schwager, I. J. Am. Chem. Soc. 1964, 86, 5528–5535.
(5) (a) Friedrich, E. C.; Domek, J. M.; Pong, R. Y. J. Org. Chem. 1985, 50,
4640–4642. (b) Friedrich, E. C.; Lewis, E. J. J. Org. Chem. 1990, 55, 2491–
2494. (c) Friedrich, E. C.; Niyati-Shirkhodaee, F. J. Org. Chem. 1991, 56, 2202–
2205.
(6) Bajgrowicz, J. A.; Frater, G.; EP 801049, priority 29.3.1997 to Givaudan-
Roure (International) S.A. [Chem. Abstr. 127, 358652].
10.1021/jo8007397 CCC: $40.75
Published on Web 09/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7543–7554 7543

Brunner et al.
SCHEME 1. Cyclopropanation of 1a11 with CH2X2 and iPrMgCl (X ) Br, I) at Ambient Temperaturea
a Yields after distillation.
TABLE 1. Influence of the Organic Substituent R in RMgCl upon
Interestingly, Bolm and Pupowicz reported also a partial
(19%) cyclopropanation of cinnamyl alcohol (-70 °C, 60 h)7
using carbenoid precursor CH2Br2 instead of CH2I2. When we
employed the less reactive CH2Br2 for the cyclopropanation of
1a at ambient (!) temperature, a significantly improved yield
of 2a was again achieved (74%). However, 6 equiv of CH2Br2
and 8 equiv of iPrMgCl were necessary for an acceptable
conversion (Scheme 1, path B).
the Cyclopropanation of 1a11 with Diastereomer Ratios ∼1:1
Villie´ras has reported that iPrMgCl and dihalomethanes
undergo an exchange reaction at low temperatures, giving
carbenoids XCH2MgX (X ) Br, I) which are unstable above
-55 °C (eq 1).8 Pupowicz reported that the yields (0-47%)
obtained from Grignard alkylation and tandem iPrMgCl/CH2I2
cyclopropanation of E-cinnamaldehyde (5o) roughly correlated
to the order tBu (47%) g iPr . Et g Me (R in RMgX).7b
Because it was unclear from her experiments if this effect was
due to the different size of the RR-substituents in the corre-
sponding allyloxy magnesium intermediate or to the steric
demands of R in RMgX, we investigated the influence of
substituent R upon the cyclopropanation of allylic alcohol 1a,
keeping all other parameters constant (Table 1).
iPrMgX + CH2X2 f iPrX + XMgCH2X (X )
I . Br > Cl) (1)
We were pleased to see that 3 equiv of tertiary magnesium
chlorides completely converted allylic alcohol 1a to cyclopro-
pane 2a after 6 h at 25 °C (Table 1), and that these were thus
much better suited for this reaction than iPrMgCl. R-Unsubsti-
tuted alkyl magnesium chlorides (R ) Me, Et, nPr, or iBu in
RMgCl) did not effect cyclopropanation. Alkyl magnesium
bromides RMgBr used in place of the corresponding chlorides
were of no advantage. It is remarkable that even CH2Cl2 can
effect a partial cyclopropanation under Grignard conditions
(Scheme 2). The combination CH2I2/tBuMgCl reduced the load
of dihalide and Grignard reagent necessary for complete
conversion even further, although with slightly reduced isolated
yield. We continued our experiments with the most efficient
cyclopropanation system CH2Br2/tBuMgCl.
a Cosolvent Et2O. b Stirred after complete addition at 25 °C and
followed by GC. c tert-Pentylmagnesium chloride ) 1,1-dimethylpropyl-
magnesium chloride. d After 6 h. e Prepared from (1R)-(-)-menthyl
chloride according to ref 9. f 89% of 2a isolated after distillation. g Not
determined.
SCHEME 2. Cyclopropanation of 1a11 with the Carbenoid
a
Precursors CH2Cl2 and CH2I2
Allylic and Homoallylic Alcohols: Scope and Limits.
Cyclopropanation of differently substituted allylic alcohols 1
with 3 equiv of CH2Br2 and 3 equiv of tBuMgCl gave the
corresponding cyclopropanes 2 with good to very good yields
and purities. Clean and extensive conversions under these
conditions were obtained from substrates 1 that were at least
R,γ or ꢀ,γ-substituted (Table 2). More substituents such as
shown in 1d-h and 1j also gave good cyclopropanation rates.
a GC conversions and yield after distillation.
These substitution patterns are abundant in various terpenic
alcohols, which are important fragrance compounds, or their
precursors such as nor-radjanol 1b, R-santalol 1c, artemol 1e,
methylgeraniol 1f, Undecavertol 1g, pulegol 1j, and others
(Table 2). Less substituted allylic alcohols, which gave only
30-60% conversions under these conditions,10 could be nev-
ertheless completely cyclopropanated by using more CH2Br2
and tBuMgCl or by application of a further reaction cycle.
(7) (a) Bolm, C.; Pupowicz, D. Tetrahedron Lett. 1997, 38, 7349–7352. (b)
Pupowicz, D. Cyclopropanierungen mit Zink- und Magnesium-Carbenoiden,
Dissertation, Philipps-Universita¨t, Marburg, 1997.
(8) (a) Villie´ras, J. Comptes Rendus 1965, 261, 4137–4138. (b) Villie´ras, J.
Bull. Chem. Soc. Fr. 1967, 5, 1520–1532.
(9) Prepared from (-)-methyl chloride: (a) Krause, H. W.; Kinting, A. J.
Prakt. Chem. 1980, 322, 485–486.
7544 J. Org. Chem. Vol. 73, No. 19, 2008

Tandem Cyclopropanation with Dibromomethane
TABLE 2. CH2Br2/tBuMgCl Promoted Cyclopropanation of Allylic Alcohols 1
a Substrates 1 were prepared according to the literature,40 except for 1d (Scheme 7). b Determined by GC/MS of the crude product after workup. % )
syn + anti. c Yields after distillation. d Diastereomer ratio relative to substrate stereocenter(s) in brackets. Configuration determined by GC/MS retention
times (rT), NMR, and/or X-ray analysis (see below). e 2.5 equiv of CH2Br2 and tBuMgCl after deprotonation f Contains 1-4% of remote
cyclopropanation product 2a. g 4 equiv of CH2Br2 and tBuMgCl and CH2Br2 after deprotonation. h Completely converted after a second reaction cycle.
i Addition of 5 equiv of tBuMgCl to substrate in 5 equiv CH2Br2. j Addition of 4 equiv of tBuMgCl to substrate in 4 equiv CH2Br2.
The cyclopropanation of homoallylic alcohols 3 gave
mainly either no conversion or only disappointing conver-
sions. Nevertheless, some of these substrates, such as
terpinen-4-ol 3a and to a certain extent also Z-hept-4-en-2-
ol 3b, underwent cyclopropanation surprisingly well (Scheme
3). For more details vide infra Figure 2 and the corresponding
discussion of substrates and their substitution prerequi-
sites.
Sequential Cyclopropanation: Conjugated Aldehydes. The
direct conversion of conjugated aldehydes 5 to the corresponding
cyclopropyl carbinols 2 demonstrates powerfully the advantages
of a cyclopropanation under Grignard conditions. R,γ-, R,ꢀ,γ-,
(10) Allylic alcohols, which underwent incomplete conversions with 3 equiv
of CH2Br2 and 4 equiv of tBuMgCl (GC-conversion to the corresponding
cyclopropanes after 18 h in brackets): E-2-hexenol (35%), Z-2-hexenol (65%),
nonadienol (50%), geraniol (50%), nerol (10%), oct-1-en-3-ol (50%), linalool
(40%), nerolidol (50%).
J. Org. Chem. Vol. 73, No. 19, 2008 7545

Brunner et al.
TABLE 3. Sequential Grignard Addition and Cyclopropanation of Conjugated Aldehydes 5 via Intermediates 6
a E-Alkenes. Substrates 5 are commercial available, except 5k, which was prepared according to the literature.13 b Determined by GC/MS of the crude
product after workup. % ) syn + anti. c Yields after distillation. d Diastereomer ratio relative to substrate stereocenter(s) in brackets. Configuration
determined by GC/MS retention times (rT), NMR, and/or X-ray analysis (see below). e 4 equiv of CH2Br2 and tBuMgCl after Grignard addition.
or R,γ,γ-substituted allylic alcoholates 6 are reactive intermedi-
ates, which are further cyclopropanated. Thus, E-citral 5f or
E-2-methylpent-2-enal 5g (Table 3) gave, after pretreatment with
appropriate Grignard reagents and subsequent cyclopropanation
with excess tBuMgCl and CH2Br2, the corresponding cyclo-
propanes 2f and 2g in nearly the same yields and purities as
obtained already from the allylic alcohols 1f and 1g (Table 2).
Other conjugated aldehydes 5k-q underwent this tandem
alkylation/cyclopropanation with similar efficiency (Table 3).
By reverse addition of alkenyl magnesium halides to saturated
aldehydes the same intermediates 6 are cyclopropanated. Thus,
after pretreatment with E,Z-propenyl magnesiumbromide and
subsequent cyclopropanation, octanal gave 2l (as an E/Z-
FIGURE 1. Substituents necessary for high conversions of magnesium
alcoholates 6 to the corresponding cyclopropyl carbinols with 3-4 equiv
of CH2Br2 and tBuMgCl. Higher substitution grades (n ) 1-3) are
possible.
mixture) with a comparable yield to the one obtained from
croton aldehyde 5l and n-heptyl magnesiumbromide (Scheme
4).
Conjugated Ketones and Esters. tert-Allylic alcoholates are
unstable cyclopropanation substrates because of their sensitivity
7546 J. Org. Chem. Vol. 73, No. 19, 2008

Tandem Cyclopropanation with Dibromomethane
SCHEME 4. Addition of n-Heptyl Magnesium Bromide to
Croton Aldehyde 5l and “Inverse Addition” of Prop-1-enyl
Magnesium Bromide to Octanal, followed by
Cyclopropanation of the Common Intermediate 6 under
Grignard Conditions
FIGURE 2. Cyclopropanation of homoallylic alcohols under Grignard
conditions (as in Scheme 3). GC conversions in brackets. Substrates 3
are either commercially available (3a,d,e) or were prepared by known
procedures (3b13 and 3c,f,g35).
SCHEME 3. Cyclopropanation of Homoallylic Alcohols 3a
and 3b12 under Grignard Conditionsa
SCHEME 5. Tandem MeLi Alkylation/Cyclopropanation of
Conjugated Estersa
a 7g was prepared as described.19 Yields after distillation.
a Yields after distillation.
SCHEME 6. Sequential Ester Cleavage/Cyclopropanation of
Allyl Esters and Carbonates 9a
to elimination.14,15 Nevertheless, under Grignard conditions
conjugated ketones 7 underwent a relatively smooth tandem 1,2-
methylation/cyclopropanation (Table 4). MeLi addition/cyclo-
propanation gave yields and purities which were 15-30% better
than the ones obtained from the corresponding MeMgCl
addition/cyclopropanation sequence. Trans-isomers were gener-
ally not detected. Methylation/tandem cyclopropanation of 7c-e
proceed via an intermediate 6 with the highest substitution grade
(R,R,ꢀ,γ,γ) possible. A tandem 1,2-MeLi addition/Simmons-
Smith cyclopropanation of 7a has been reported to give cis-
Sabinene hydrate 8a with 64% isolated yield.15 However, even
with freshly prepared zinc-copper couple we had difficulties
reproducing this reaction.16
tert-Allylic alcoholates 6 are also accessible by exhaustive
(g2 equiv) MeLi addition to conjugated esters such as 7f and
a Preparation of 9c from 1d (Scheme 7): pyridine, cat. DMAP, (-)-
camphanoyl chloride, 77% (FC). The preparation of 9a and 9b is described
in the literature.20,21 Reagents and conditions: (a) 2-3 equiv of MeMgBr,
THF, then 4 equiv of CH2Br2/4 equiv of tBuMgCl, Et2O, 16 h. (b) 1.4
equiv of MeLi, Et2O, then 3 × 1.5 equiv of CH2Br2/tBuMgCl, yields after
flash chromatography.
(11) Preparation of substrates 1 according to the literature: (1a)Schro¨der, F.
WO 2006066436, priority 20.12.2005 to Givaudan S.A. Switz [Chem. Abstr.
145, 103855]. (1b) Bajgrowicz, J. A.; Frank, I.; Frater, G.; Hennig, M. HelV.
Chim. Acta 1998, 81, 1349–1358. (1c) (a) Tamura, M.; Suzukamo, G.
Tetrahedron Lett. 1981, 22, 577. (b) Tamura, M.; Suzukamo, G.; Hirose, K. EP
29603, Sumimoto Chemical Co., 1980 [Chem. Abstr. 95, 204220]. (1e) Levorse,
A. T. US 5234902, priority 28.2.1992 to International Flavors and Fragrances
Inc., USA [Chem. Abstr. 119, 210271]. (1f) Bajgrowicz, J. A.; Bringhen, A.;
Frater, G.; Mueller, U. EP 743297, priority 20.11.1996 to Givaudan-Roure,
Switzerland [Chem. Abstr. 126, 103856]. (1g) Kaiser, R.; Lamparsky, D. EP
45453, Givaudan L. et Cie S.A., 1980 [Chem. Abstr. 96, 199080]. (1h) Berg-
Schultz, K.; Bajgrowicz, J. A.; Baudin, J. WO 2005026092, priority to Givaudan
SA, Switz. 12.9.2003 [Chem. Abstr. 142, 336041]. (1i) Jacob, P., III; Brown,
H. C. J. Org. Chem. 1977, 42, 579–580. (1j) Martin, A. EP 770671, priority
30.10.1996 to Quest International B.V [Chem. Abstr. 126, 334220].
(12) Watson, S. C.; Malpass, D. B.; Yeargin, G. S. DE 2430287, Texas Alkyls
Inc., USA, 1975 [Chem. Abstr. 83, 27544].
7g. In situ cyclopropanation of the tertiary allylic alcoholate 6
gave the corresponding cyclopropyl carbinols 8f and 8g (Scheme
5).
Allylic Acetates and Carbonates. As the conversion of
allylic acetate 9a, allylic carbonate 9b, and allylic camphanate
9c to the cyclopropyl carbinols 2d and 2e is straightforward,
(13) Preparation of substrate 5k: (a) Hall, J. B.; Wiegers, W. J. US 4010207,
International Flavors & Fragrances Inc., 1977 [Chem. Abstr. 87, 5396].
(14) Fanta, W. I.; Erman, W. F. J. Org. Chem. 1968, 33, 1656–1658.
(15) Cheng, D.; Kreethadumrongdat, T.; Cohen, T. Org. Lett. 2001, 3, 2121–
2123.
(16) Attempted reproduction on a 10 mmol scale and with freshly prepared
zinc-copper couple under the conditions described in footnote 9 of ref 15 gave
no conversion according to GC/MS.
(18) Preparation of substrates 7 according to the literature: (7a) Jurkauskas,
V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett. 2003, 5, 2417–2420. (7c) Berube,
G.; Fallix, A. G. Can. J. Chem. 1991, 69, 77–78. (7d) Trost, B. M.; Keeley,
D. E. J. Am. Chem. Soc. 1976, 98, 248–250. (7e) Berthelot, P.; Vaccher, C.;
Devergnies, M.; Flouquet, N.; Debaert, M. J. Heterocycl. Chem. 1988, 25, 1525–
1529.
(19) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624–2626.
(20) Agarwal, V. K.; Thappa, R. K.; Agarwal, S. G.; Mehra, M. S.; Dhar,
K. L.; Atal, C. K. Indian Perfumer 1983, 27, 112–118.
(17) 2-Hexylcyclopent-2-enone ) Isojasmone B 11. Commercially available
from Oxford Chemicals.
J. Org. Chem. Vol. 73, No. 19, 2008 7547

Brunner et al.
TABLE 4. Sequential MeLi Addition/Cyclopropanation of Conjugated Ketones 7
a Substrates 7 are commercially available (7b)17 or were prepared by known procedures.18 b Determined by GC/MS of the crude product after workup.
c Yields after flash chromatography or distillation.
SCHEME 7. Preparation of 1d via 6d and
Cyclopropanation under the Conditions of Table 2
SCHEME 8. SN2′ Allylic Substitution of Vinyl Oxiranes 11a
and 11c,24 and Cyclopropanation of the Corresponding
Z-Allyloxy Lithium Intermediatesa
we shall give only three examples of these relatively simple
sequential transformations (Scheme 6).
a Yields after distillation.
Vinyl Oxiranes. An interesting extension of the tandem
alkylation/cyclopropanation method is the SN2′ allylic substitu-
tion of vinyl oxiranes. We first turned our attention to the
cyclopropanation of allyloxy magnesium halide 6d, prepared
under CuBr-catalysis as described by Jung (Scheme 7).22 This
intermediate, however, did not undergo cyclopropanation after
addition of excess CH2Br2 and tBuMgCl, whereas 1d, once
isolated, gave readily 2d (Table 2).
allylic substitution, giving mainly (Z)-configurated 4-alkyl-2-
methylbut-2-en-1-ols.23 Indeed, the allyloxy lithium interme-
diates of this reaction were cleanly cyclopropanated under
Grignard conditions giving the corresponding cyclopropyl
carbinols 12 with the expected cis, syn-configuration (Scheme
8).
Consequently, alkyl lithium reagents were employed, which
Discussion and Further Results
are known to open isoprene oxide 11a without additives by 1,3-
Mechanism. As described already by Villie´ras, carbenoid
XCH2MgX should be formed from RMgX in the presence of
excess CH2X2 (eq 1). So far it has not been explained why
iPrMgCl is especially useful for this purpose,7,8 as we still cannot
say why Grignard reagents with a higher degree of R-branching,
such as tBuMgCl, give better cyclopropanation rates than their
(21) Barras, J.-P.; Bourdin, B.; Schro¨der, F. Chimia 2006, 60, 574–579.
(22) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379–7388.
(23) (a) Tamura, M.; Suzukamo, G. Tetrahedron Lett. 1981, 22, 577–580.
(b) Tamura, M.; Suzukamo, G.; Hirose, K. EP 0029603, Sumitomo Chemical
Company Ltd., 1981 [Chem. Abstr. 95, 204220]. (c) Netland, P. Org. Proc. Prep.
Int. 1980, 12, 261–262, and references cited therein.
7548 J. Org. Chem. Vol. 73, No. 19, 2008

Tandem Cyclopropanation with Dibromomethane
TABLE 5. Cyclopropanation of ꢀ- or γ-Cyclopropyl-Substituted Allylic Alcoholates 6
a Substrates 1r-t prepared by known procedures.30 b Determined by GC/MS of the crude product after workup. c Yields after flash chromatography or
distillation. d Yield (98%, crude, corrected by purity) not optimized.
SCHEME 9. Formation of Transition State 13a
prefractions shows that the missing isobutane is incorporated
into oligomeric structures.27
The final intramolecular cyclopropanation of carbenoid 13,
however, should be concerted.28 Depending on the E- or
Z-configuration of the substrate double bond, the corresponding
trans- or cis-cyclopropanes are obtained stereospecifically. The
observed syn-selectivity is further evidence. To check the
nonradical nature of the intramolecular cyclopropanation more
thoroughly, some ꢀ- or γ-cyclopropyl-substituted allylic alco-
holates (from 1r-t) were cyclopropanated under Grignard
conditions. The expected biscyclopropyl carbinols 2r-t (Table
5) were obtained readily, and no ring-opening of the cyclopropyl
groups,29 as a consequence of radical intermediates generated
from the alkene to be cyclopropanated, was observed.
a M ) Li, Na, MgX. X ) Cl, Br. Rn ) alkyl- or aryl-substituents at the
R-, ꢀ-, and γ-positions of the allylic alcoholate with n ) 2-5. The most
simple equations for the generation of 13 from CH2Br and tBuMgCl are
depicted; other exchange reactions and magnesium species (higher ag-
gregates) are possible.25
Ether 14 (Scheme 11), which cannot form transition state 13,
did not undergo cyclopropanation with CH2Br2 and tBuMgCl.
Cyclopropanation under Barbier Conditions. The mech-
anism in Scheme 9 posed the question as to what extent
cyclopropanation occurs if carbenoid XMgCH2X is not formed
from tBuMgCl, but directly from Mg and CH2Br2 in the
presence of the alkene substrate. For this purpose, 1b was
deprotonated with g1 equiv of BuLi or LiH prior to the addition
of magnesium turnings.31 Subsequent dropwise addition of
CH2Br2 at reflux (70 °C) kept the reaction controllable. After
complete conversion and workup, this gave 65% of 2ab (20:
75). Other substrates were cyclopropanated with similar ef-
ficiency under these conditions (Table 6). It should be noticed
that cyclopropanation occurs here at a temperature more than
less branched analogues (Table 1). Hoffmann has considered
the influence of the substituents R upon possible transition states
and reaction profiles of the halogen/metal exchange reaction
R1X + R2M T R1M + R2X,25 without correlation to reaction
rates. The formation of higher aggregates and different possible
carbenoids such as XMgCH2X, XCH2MgCH2X, or tBuMgCH2X
make such a correlation in our case even more complex (Scheme
9).
Without substrate, tBuMgCl and CH2Br2 react exothermically
and vigorously with each other and a gaseous isobutane,
isobutylene, neopentane (4:3:1) mixture is collected from this
test reaction as well as in the presence of 1a. The formation of
these byproducts shows that radical mechanisms are at least
partially involved (Scheme 9).26 Deprotonation of 1a with 1
equiv of tBuMgCl produced the expected 1 equiv of isobutane,
less than 1 equiv of isobutane was collected during addition of
CH2Br2 and the next 3 equiv of tBuMgCl as well as after
aqueous quench of the mixture. GC/MS of the distillation
(26) See also: (a) Ashby, E. C.; Deshpande, A. K.; Doctorovich, F. J. Org.
Chem. 1994, 59, 6223–6232. (b) Walton, J. C. In Houben-Weyl, Methoden der
Organischen Chemie; de Meijere, A. Ed.; Georg Thieme Verlag: New York,
1997; Vol. E17c, pp 2438-2525.
(27) Among other byproducts identified by GC/MS: 2,2,4,4-tetramethylpen-
tane (CAS 1070-87-7), 2,2,6,6-tetramethyl-4-methyleneheptane (CAS 141-70-
8), 2-tert-butyltetrahydrofuran (CAS 38624-45-2), 2,2-dimethyldecane (CAS
17302-37-3), 2,2,8-trimethyldecane (CAS 62238-01-1), 2,2-dimethylundecane
(CAS 17312-64-0), tert-butyl bromide (CAS 507-19-7), 1-bromo-2,2-dimeth-
ylpropane (CAS 630-17-1), 2-bromotetrahydrofuran (CAS 59253-21-3), 3-bromo-
2,2,4,4-tetramethylpentane (CAS 107713-49-5).
(24) Sakaguchi, T.; Nagashima, K.; Yoshida, T. JP 49047345, Takasago
Perfumery Co., Ltd., 1974 [Chem. Abstr. 81, 104862].
(25) (a) Mu¨ller, M.; Bro¨nstrup, M.; Knopff, O.; Schulze, V.; Hoffmann, R. W.
Organometallics 2003, 22, 2931–2937. (b) Hoffmann, R. W.; Bro¨nstrup, M.;
Mu¨ller, M. Org. Lett. 2003, 5, 313–316. (c) Hoffmann, R. W. Chem. Soc. ReV.
2003, 32, 225–230.
(28) Hoveyda, A. M.; Evans, D. A.; Fu, G. C. Chem. ReV 1993, 93, 1307–
1370, and references cited therein.
(29) Mariano, P. S.; Bay, E. J. Org. Chem. 1980, 45, 1763–1769.
J. Org. Chem. Vol. 73, No. 19, 2008 7549

Brunner et al.
TABLE 6. Cyclopropanation under Barbier Conditionsa
a Deprotonation with BuLi (0 °C, 30 min) or LiH (THF, 70 °C, 3 h) followed by addition of Mg and CH2Br2 at 70 °C. Stirred at this temperature
until no further conversion was detected by GC. b Substrates are either commercially available (1u) or were prepared by literature procedures (1b, 1g11
and 3b12). c Yields after distillation corrected by purity. d Determined by GC/MS of the crude product after workup. % ) syn + anti. Percentage of
nonconverted substrate in brackets. e For the precise structures of 2a, 2b, 2u, and 2u′ see Table 2, Table 7, and Scheme 10.
SCHEME 10. Remote Cyclopropanation of nor-Radjanol
Remote cyclopropanation seems to be effected directly by
BrMgCH2Br under Barbier conditions and not by a ROMgCH2X
type carbenoid such as 13 (Scheme 10) because the trans-
configurated cyclopentane 2a was obtained,32 as well as the
trans-configurated products 16 and 17 from 14 and 15,
respectively (Scheme 11).
1b11 and Geraniol 1u under Barbier Conditionsa
Not surprisingly the more sensitive tertiary allylic alcoholates
6 gave mainly decomposition (elimination) and only traces of
cyclopropylcarbinols 8 under the relatively harsh Barbier
conditions.33
a Yields after distillation corrected by purity.
Substrates, Substitution Pattern, and Counterion. All
substrates are either commercially available or can be prepared
by known procedures (see the legends of schemes and tables).
The substitution pattern has a profound effect upon the reaction
rates, especially when magnesium alcoholates 6 (M ) MgX)
are cyclopropanated in situ. At least two substituents, one in
the γ- (E or Z) and another one in the R- or ꢀ-position (Figure
1), are necessary to achieve high conversions through subsequent
addition of 3-4 equiv of CH2Br2 and tBuMgCl.34
SCHEME 11. Partial Cyclopropanation of 1411 and 1511
under Barbier Condition Giving 1611 and 17, respectivelya
Allyl alcoholates 6 lacking this substitution pattern gave only
partial conversions under these conditions. These could be
brought to completion by subjecting the crude substrate/product
a Reference compound 17 was prepared from 1a11 by ethylation with
NaH, EtI (see SI): (a) Conditions as in Scheme 10. (b) Same conditions
but without prior deprotonation. GC-conversions.
(30) (1r) Ullrich, F. W.; Rotscheidt, K.; Breitmaier, E. Chem. Ber 1986,
119, 1737–1744. (1s) Traas, P. C.; Boelens, H. Rec. TraV. Chim. Pays -Bas
1973, 92, 985–995. (1t) Arbuzov, B. A.; Isaeva, Z. G.; Timoshina, T. N.;
Efremov, Y. Y. R. J. Org. Chem. 1993, 29, 1647–1650.
(31) Alternative deprotonation reagents such as NaH or MeMgCl were less
efficient. Alternative dihalides such as ClCH2Br, ClCH2I, and CH2I converted
1b similarly to 2b but without remote cyclopropanation to 2a. Evidence for
exchangereactionsbetweenlithiumalkoxidesandGrignardreagents: Micha-Screttas,
M.; Constantinos, G.; Steele, B. R.; Heropoulos, G. A. Tetrahedron Lett. 2002,
43, 4871–4873.
(32) The trans-configuration of the 5-ring carbacycles 2a and 21 cannot arise
from hypothetical 8- or 10-membered carbenoid transition states.
(33) MeLi addition to 7b followed by addition of Mg and CH2Br2 at reflux
gave only traces of 8b.
(34) For the mention of similar effects see ref 7b. A probable correlation
between substitution pattern, conformation, and reactivity of the (homo)allylic
alcohols is presently under investigation and will be communicated in due course.
100 °C above the decomposition temperature (-55 °C) of
carbenoid BrCH2MgBr reported by Villie´ras.8
Cyclopropanation of substrate 1b under Grignard conditions
(Table 2) had not only given allylic cyclopropanation product
2b, but also traces (1-4%) of the remote cyclopropanation
product 2a. Under Barbier conditions, a much higher content
(20%) of remote cyclopropanation product 2a was obtained.
The 2ab mixture could be completely converted to 2a after
application of another two reaction cycles (Scheme 11). The
same bis-cyclopropanation strategy was applied to geraniol 1u,
which gave 2u′ via intermediate 2u after three reaction cycles
(Scheme 10).
7550 J. Org. Chem. Vol. 73, No. 19, 2008

Tandem Cyclopropanation with Dibromomethane
TABLE 7. Cyclopropanation of Lithium Allylic Alcoholates in Comparison to the Cyclopropanation of the Corresponding Magnesium-Ate
Complexes
a Substrates 1 are commercially available, for the preparation of 3b see ref 13. b Equivalents of CH2Br2 and tBuMgCl in brackets. c Yield after
distillation. d Decomposition after addition of g5 equiv. e 50% conversion after addition of 4 equiv of CH2Br2 and tBuMgCl.
SCHEME 12. Transformation of 2p and 2q to 19a
FIGURE 3. X ) Cl, Br. R ) alkyl, aryl, alkenyl. n ) 1-5 at CR, Cꢀ,
Cγ. Covalently bonded allyloxy magnesium carbenoid (transition state
13) versus XMgCH2X carbenoid coordinated to allyloxy-MgX (transi-
tion state 18).
a Reagents and conditions: (a) MeOH, CH2Cl2, -78 °C, O3, then 2 equiv
of NaBH4. (b) NaH, THF, -20 °C, 1.5 h, then TBDPSCl, -20 °C, 2.5 h.
Encouraged by the better performance of lithiated (6, M )
Li) rather than magnesiated tertiary allylic alcoholates as well
as by the much better conversions obtained from lithiated
(homo)allylic alcoholates under Barbier conditions (compared
to the corresponding magnesiated ones), some less reactive
(homo)allylic alcohols34 were deprotonated with 1.3 equiv of
BuLi and cyclopropanated in situ with CH2Br2 and tBuMgCl
(Table 7). Again, this gave much better and often complete
conversions. A possible explanation for this rate enhancement
is the more covalent character of the Mg-O bond of the MgX-
mixture (after workup) to another cyclopropanation cycle. More
substituents such as those in tri- or tetrasubstituted alkenes were
tolerated.
The cyclopropanation of homoallylic alcohols 3 was more
sensitive to number and position of substituents (Figure 2). 3c
underwent no cyclopropanation, in strong contrast to the
excellent conversion of 3a. Whereas Z-hept-4-en-2-ol 3b gave
an acceptable conversion to 4b, homoallylic alcohols 3d-f were
less reactive or unreactive.34
J. Org. Chem. Vol. 73, No. 19, 2008 7551

Brunner et al.
FIGURE 4. Staggered Houk models of 13, according to refs 7b and 39. X ) Cl, Br. Repulsive interaction by 1,2-allyl strain, 1,3-allyl strain, and
between RR and the carbenoid. Rγ ) alkyl or H with at least one Rγ ) alkyl. Higher substitution grades as well as higher magnesium aggregates
are possible.
rT(anti) < rT(syn) on polar GC columns.38 This analytical
SCHEME 13. Formation of the Syn/Anti Mixture 2t from
1ta
method has been used by others for the determination of the
relative configuration of these compounds.39 We routinely found
the same elution order on a less polar GC column.40 The relative
configuration of all cyclopropyl carbinols was also routinely
analyzed by NMR (NOESY, COSY, HMBC, and HMQC). This
was especially necessary in the case of exocyclic syn/anti
mixtures, e.g. 2e and 12c, which were inseparable by our GC
method, and in the case of diastereopure cyclopropyl carbinols.
If the NOESY experiment in water-free DMSO (to detect the
OH-proton)41 gave ambiguous results, ethylation or benzylation
of the hydroxy function furnished more encumbered derivatives,
whose relative configuration was tentatively assigned by this
method. If that was not possible (e.g., on 2e or 4b), the
corresponding camphanates were analyzed by X-ray analysis
a Reagents: (a) MeLi, then 3 × CH2Br2/tBuMgCl, 57%.
after crystallization (see SI). The syn-configuration of γ-alk-
alcoholates (6, M ) MgX, Scheme 9) versus the lithium
enylcyclopropyl carbinols 2p and 2q (where all these methods
alcoholate ion pair (6, M ) Li, Scheme 9). The latter undergoes
failed) was determined after conversion to the known syn-
an exchange reaction of alcoholate 6 with carbenoide XMgCH2X
TBDPS ether 19 (Scheme 12) and NMR comparison.42
to allyloxy magnesium carbenoide 13 (Scheme 9) more
A staggered Houk model such as 13a (Figure 4)44 explains
readily.36 Improved reaction rates have also been reported from
the formation of syn-isomers from cyclopropanation reactions
the in situ cyclopropanation of lithiated tertiary allylic alcohols
with Mg-, Sm-, and Zn-allyloxy carbenoids.7b,28,39 In this model
under Simmons-Smith conditions.15
(13a) RR occupies the most favorable position antiperiplanar to
Allylic ethers such as 15 and 17 (Scheme 11) cannot undergo
the incoming carbenoid to minimize steric interaction between
cyclopropanation anymore, neither under Grignard nor under
RR and Rγ. It was proposed that hyperconjugation between the
Barbier conditions, because carbenoide 13 cannot be formed.
σ
C(R)-C(RR) and the π-π* orbitals enhances the nucleophilicity
This is a significant difference compared to certain Simmons-
Smith-like systems, which do cyclopropanate allylic ethers.37
In this context we prefer transition state 13 (generated by a
Li-Mg ate exchange reaction) over 18 (Figure 3) because if
18 would be effective, allylethers such as 15 and 17 also should
be cyclopropanated to a certain extent, which is not the case.
Syn-Configuration of the Cyclopropylcarbinol Products.
Cyclopropanation of R,γ-substituted allyl alcoholates 6 gave
cyclopropyl carbinols, which were mainly (>80%) or exclu-
sively (>99%) syn configurated. The (nearly) identical mass
spectra of the syn- and anti-diastereomers allow the detection
of the minor isomer (anti) by GC/MS. Because of the higher
sterical congestion of the anti-diastereomers, mixtures of syn-
and anti-cyclopropyl carbinols show the typical elution order
of the olefin.28
The cyclopropanation under relatively simple Grignard condi-
tions gives higher syn-selectivities at ambient or higher tem-
peratures than by other methods at lower (-10 °C)38,39a or much
lower temperatures (-78 °C).39b,c Anti-byproducts (<20%) were
detected in the case of the smallest substituent (RR ) Me), where
interaction between RR and the incoming carbenoid is mini-
mized, thus allowing transition state 13b. Already with the first
higher substituent RR ) Et, this effect was negligible (see 2h).
Similarly, it can be explained why tertiary allyl alcohols are
tricky cyclopropanation substrates. Here (13c), interaction
between RR and the carbenoid cannot be avoided,39b,c and a
shift to the less encumbered 13a is structurally forbidden.
(35) (3c) Inhoffen, H. H.; Weissermel, K.; Quinkert, G. Chem. Ber. 1955,
88, 1313–21. (3e) Yoshida, T.; Mookherjee, B. D.; Kamath, V.; Hall, J. B.;
Taylor, W. I.; Schmitt, F. L. US 4173585, IFF, 1979 [Chem. Abstr. 92, 75959].
(3f) Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J. Am. Chem. Soc.
1982, 104, 555-563.
(36) Excess nBuLi cannot be responsible for the better conversion because
the attempted cyclopropanation of the lithium alcoholates 6 with CH2Br2/BuLi
or CH2Br2/tBuLi failed. Exchange reactions of lithium or magnesium alcoholates
with Grignard reagents are well-known, see for example: Nu¨tzel, K. In Houben-
Weyl, Methoden der Organischen Chemie; Mu¨ller, E. Ed.; Georg Thieme Verlag:
Stuttgart, Germany, 1973; Vol.XIII/2a, pp 193-194.
(37) (a) Morikawa, T.; Sasaki, H.; Hanai, R.; Shibuya, A.; Taguchi, T. J.
Org. Chem. 1994, 59, 97–103. (b) Barret, A. G. M.; Kasdorf, K.; Williams, D.
J. Chem. Commun. 1994, 1781–1782. (c) Charette, A. B.; Lebel, H. J. Org.
Chem. 1995, 60, 2966–2967. (d) Charette, A. B.; Lacasse, M.-C. Org. Lett. 2002,
4, 3351–3353.
(38) (a) Roquet, F.; Sevin, A.; Chodkiewicz, W. C. R. Acad. Sc. Paris (C)
1970, 848–851. (b) Ratier, M.; Castaing, M.; Godet, J.-Y.; Pereyre, M. J. Chem.
Res.; Miniprint 1978, 2309-2318.
(39) (a) Ratier, M.; Castaing, M.; Godet, J.-Y.; Pereyre, M. J. Chem. Res.
(S) 1978, 179. (b) Molander, G. A.; Etter, J. B. J. Org. Chem. 1987, 52, 3942–
3944. (c) Molander, G. A.; Harring, L. S. J. Org. Chem. 1989, 54, 3525–3532.
(40) GC analysis on a 5% phenyl-95% dimethylpolysiloxane column.
(41) Pretsch, E.; Bu¨hlmann, P.; Affolter, C. Structure determination of
Organic Compounds; Springer Verlag: Berlin, Germany, 2000; p 202.
(42) Yamamoto, T.; Matsuda, A.; Shuto, S. Tetrahedron 2004, 60, 6689–
6703. Yamamoto, T.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 3511-
3521.
(43) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc.
1982, 104, 7162–7166.
(44) Commercial Citral was purified by distillation over a Sulzer column to
afford a geranial/neral 88:12 mixture.
7552 J. Org. Chem. Vol. 73, No. 19, 2008

Tandem Cyclopropanation with Dibromomethane
120 °C/0.07 Torr giving 4.7 g (89%) of Javanol 2a (dr ) 1:1),
whose analytical data are consistent with those described for this
compound in the literature.6
Whereas good to excellent syn-selectivities can be expected
from this method, the cyclopropanation of 1t (see also Table
5) represents an exception. Because the syn/anti diastereomers
of 2t are formed in nearly equal amounts from a 1:1 diastere-
omer mixture of 1t, the anti-diastereomer of 2t must be formed
from diastereomer B of 1t exclusively (Scheme 13). Repulsive
interaction of the gem-dimethyl group with the incoming
carbenoid hinders the cyclopropanation from the ꢀ-face and
explains why the syn-diastereomer is formed much faster than
the anti-diastereomer.
(syn,trans)-1-((E)-2-Methyl-2-(4-methylpent-3-enyl)cyclopropyl)-
ethanol (2f). Prepared from (a) 1f (3.6 g, 24 mmol)11 and 3 M
methylmagnesium chloride in THF (8 mL, 24 mmol), or (b) (E)-
Citral (4 g, 24 mmol)44 and 3 M methylmagnesium chloride in
THF (8 mL, 24 mmol), or (c) 9a (5 g, 24 mmol)20 and 3 M
methylmagnesium chloride in THF (19 mL, 60 mmol), or (d) 9b
(6 g, 24 mmol)21 and 3 M methylmagnesium chloride in THF (25
mL, 60 mmol). Subsequent cyclopropanation of the alcoholate thus
prepared (a-d) by portionwise addition of dibromomethane (3 ×
4.2 g, 72 mmol) and 2 M tert-butylmagnesium chloride in diethyl
ether (3 × 12 mL, 72 mmol) according to method B. Workup after
16 h at 25 °C and bulb-to-bulb distillation gives 3.7 g (86%) of
product. Odour: citrus, weak. Analytical data are identical with those
reported for this compound.39c The syn-configuration was also
confirmed by COSY, HSQC, and NOESY in CDCl3.
(syn)-1-(2-Methylcyclopropyl)-octan-1-ol (2l). Heptyl magne-
siumbromide was prepared from heptyl bromide (26 g, 0.14 mol)
and magnesium (3.43 g, 0.14 mol) in tetrahydrofuran (68 mL) at
70 °C. This Grignard reagent was used in the preparation of 2l
from heptyl magnesiumbromide and E-crotonaldehyde (8.4 g, 0.12
mol) in tetrahydrofuran, dibromomethane (62.5 g, 0.36 mol), and
2 M tert-butylmagnesium chloride in diethyl ether (3 × 60 mL,
0.36 mol) at 10-20 °C according to method B. Workup and
distillation at 60 °C/0.04 Torr gave 24.4 g (86%) of the trans-
isomer as a colorless oil. Odour: green, earthy, substantive.
Alternatively, this compound was prepared by Grignard reaction
of octanal (18 g, 0.14 mol) with E/Z-1-propenyl magnesiumbromide
(prepared from magnesium (3.8 g, 0.14 mol), 1-bromopropene (17
g, 0.14 mol) in tetrahydrofuran (60 mL) at 60 °C), followed by
tandem cyclopropanation and workup as described above giving
23.5 g (83%) of 2l (cis/trans ) 1:1).
Conclusion
Tertiary Grignard reagents such as tert-butylmagnesium
chloride and dibromomethane efficiently cyclopropanate allylic
(and certain homoallylic) magnesium and lithium alcoholates
at ambient temperature in ether solvents. The reaction rates
depend on the substitution pattern of the (homo)allyl alcoholates
and on the counterion. Lithium allyl alcoholates gave best
cyclopropanation rates, e.g. under Barbier conditions or in the
cyclopropanation of relatively unsubstituted allyl or sensitive
R-tertiary allyl alcoholates, which are less reactive. Under these
relatively simple conditions good to excellent syn-selectivities
are obtained, which are higher than the ones obtained from other
cyclopropanation methods, which are carried out at lower
temperatures. In conclusion we provide a new cyclopropanation
method, which proceeds simply and rapidly with relatively
inexpensive reagents, and which has relatively positive envi-
ronmental and safety aspects. This method can be integrated
into the sequential conversion of conjugated aldehydes and
ketones, allylic acetates and carbonates, as well as vinyl
oxiranes, to give cyclopropyl carbinols with syn-stereochemistry
and good yields. We are confident that this method will find its
use in preparative organic chemistry.
1H NMR (CDCl3) (trans-isomer): δ 0.25 (m, 1 H), 0.4 (m, 1 H),
0.6 (m, 1 H), 0.9 (t, 3 H), 1.05 (d, 3 H), 1.2-1.45 (10 H), 1.5-1.55
(3 H), 2.88 (m, 1 H) ppm. 13C NMR (CDCl3) (trans-isomer): δ
10.7 (t), 11.15 (d), 14.1 (q), 18.3 (q), 22.6 (t), 25.7 (t), 26.9 (d),
29.3 (t), 29.7 (t), 31.8 (t), 37.4 (t), 76.4 (d). The synconfiguration
was confirmed by NMR analysis of the benzyl ether (see SI). MS
(EI): m/z (%) 166 ([M - 18]+, 2), 85 (100), 67 (32), 57 (50), 55
(30), 43 (42), 41 (45). IR (film): 3355 (br), 2953 (m), 2924 (s),
2855 (m), 1455 (m), 1379 (w), 1269 (w), 1075 (w), 1046 (w), 1029
(m), 895 (w), 866 (w), 788 (w), 722 (w). Anal. Calcd for C12H24O:
C, 78.20; H, 13.12. Found: C, 78.13; H, 13.02.
(cis,syn)-1-(2-Ethylcyclopropyl)propan-2-ol (4b). 4b was prepared
as described in method B but in two reaction cycles from (Z)-hept-
4-en-2-ol (4 g, 35 mmol) and dibromomethane (2 × 18.2 g, 0.2
mol) in diethyl ether by dropwise addition of 2 M tert-butylmag-
nesium chloride in diethyl ether (2 × 52 mL, 0.2 mol) at 10-20
°C. After complete conversion the mixture is quenched with 2 M
HCl and extracted with tert-butyl methyl ether. Washing with
concentrated NaHCO3 and concentrated NaCl, drying over MgSO4,
filtration, and evaporation of the solvent gives 5.7 g of a crude oil,
which is distilled at 100 °C/10 mbar giving 2.5 g (55%) of a
colorless oil (97% purity, syn/anti ) 83:17).
Alternatively it can be prepared (method A1) from (Z)-hept-4-
en-2-ol (3 g, 26 mmol),12 n-butyllithium (16.5 mL, 26 mmol),
magnesium powder (3.8 g, 0.16 mol), and dibromomethane (27 g,
0.16 mol). Workup and distillation as above gives 2.1 g (57% corr)
of a colorless oil (syn/anti ) 73:27).
It also can be prepared by dropwise addition of 1.6 M
n-butyllithium in hexane (15.4 mL, 24 mmol) to (Z)-hept-4-en-2-
ol (2 g, 18 mmol)12 in 10 mL of tetrahydrofuran under cooling,
followed by portionwise addition of dibromomethane (5 × 1.25
mL, 90 mmol) and 2 M tert-butylmagnesium chloride in diethyl
ether (5 × 8.8 mL, 90 mmol) at 10-20 °C as described in method
B. Workup and distillation as above gives 2.2 g (98%) of a colorless
oil.
Experimental Section
(1-Methyl-2-(((1S,3R,5R)-1,2,2-trimethylbicyclo[3.1.0]hexan-3-
yl)methyl)-cyclopropyl)methanol (Javanol) (2a). Method A. nor-
Radjanol 1b (200 g, 1 mol)11 and lithium hydride (10 g, 1.24 mol)
[see Method A1 below] in tetrahydrofuran are heated under strong
stirring and argon for 6 h at 65 °C until hydrogen evolution ceases.
Magnesium turnings (100 g, 4.1 mol) and 1900 mL of tetrahydro-
furane are added at 25 °C. After addition of dibromoethane (8.5 g,
50 mmol) the mixture is heated to 65 °C, and dibromomethane
(280 mL, 4 mol) is added over 7 h. After another hour at 65 °C the
suspension is quenched with 2 M HCl under cooling. tert-Butyl
methyl ether extraction, washing of the organic phase with H2O
until pH 7, drying over MgSO4, and concentration gives a crude
(65% corr.) mono- and biscyclopropane mixture (2a/2b ) 20:75)
which, after two further reaction cycles, gives 95 g (43%) of pure
Javanol 2a after distillation (100 °C/0.05 Torr), whose analytical
data (NMR, MS, IR, odor) are consistent with the ones described
for this compound in the literature.6
Method A1. Alternative deprotonation with 1.6 M n-butyllithium
in hexane (775 mL, 1.24 mol) followed by cyclopropanation under
the conditions in method A gave similar yields.
Method B. Allyl alcohol 1a (5 g, 24 mmol)11 is added under
cooling and stirring to 3 M methylmagnesium chloride in tetrahy-
drofuran (8 mL, 24 mmol) under nitrogen. This is followed by three
additions of both dibromomethane (4.2 g) and tert-butylmagnesium
chloride 2 M in diethyl ether (12 mL) in that order at 10-20 °C
(making a total of 72 mmol each). Quenching with concentrated
NH4Cl, tert-butyl methyl ether extraction, washing of the organic
phase with H2O until pH 7, drying over MgSO4, and concentration
gives 16.6 g of an oily residue, which is bulb-to-bulb distilled at
J. Org. Chem. Vol. 73, No. 19, 2008 7553

Brunner et al.
1H NMR (CDCl3): δ -0.2 (m, 1 H), 0.6 - 0.8 (2 m, 2 H), 1.0
(t, 3H), 1.2 (d, 3 H), 1.2-1.4 (3 H), 1.6 (1 H), 2.3 (br, OH), 3.9
(m, 1 H) ppm. 13C NMR (syn-isomer): δ 10.5 (t), 12.4 (d), 14.2
(q), 16.6 (d), 22.0 (t), 23.0 (q), 37.8 (t), 68.8 d). 13C NMR (anti-
isomer): δ 10.5 (t), 12.3 (d), 14.2 (q), 17.3 (d), 22.1 (t), 23.1 (q),
37.9 (t), 68.6 d). The syn-configuration was confirmed by conversion
to the camphanoyl ester and X-ray analysis (see SI). MS (EI): m/z
(%)110 ([M - 18]+, 3), 95 (12), 84 (11), 81 (20), 68 (23), 55 (50),
45 (100). RT ) 5.82 (syn), 5.86 (anti) min. IR (film): 3340 (br),
2961 (s), 2929 (m), 2872 (m), 1456 (m), 1374 (m), 1308 (w), 1120
(m), 1084 (m), 1063 (m), 1022 (m), 994 (w), 940 (m), 927 (m),
855 (w), 815 (w), 739 (w). HRMS calcd for C7H13O [M - 15]
113.09664, found 113.09541.
(cis)-5-Isopropyl-2-methylbicyclo[3.1.0]hexan-2-ol (8a). 8a was
prepared from 7a,18 and 1.6 M methyllithium in diethyl ether (2.8
mL, 4.5 mmol) at -78 °C, followed by addition of dibromomethane
(2.8 g, 16 mmol) and dropwise addition of 2 M tert-butylmagnesium
chloride in diethyl ether (8 mL, 16 mmol) at 0-10 °C. Inverse
quench on concentrated NH4Cl after 6 h, tert-butyl methyl ether
extraction, and flash chromatography over silica gel (hexane/tert-
butyl methyl ether 3:1) gave 0.23 g (45%) of a colorless oil. MS
(EI): m/z (%) 196 (M+, 5), 139 ([M - 15]+, 14), 136 ([M - 18]+,
29), 121 (38), 107 (12), 93 (100), 71 (60), 55 (34), 43 (85). The
other analytical data were identical with the ones reported for this
compound.15
over MgSO4, filtration, and evaporation of the solvents give a
residue that is purified by bulb-to-bulb distillation at 98 °C/0.05
1
mbar giving 2.6 g (65%) of a colorless oil (dr ) 93:7). H NMR
(CDCl3): δ 0.3 (m, 1 H), 0.5 (m, 1 H), 0.8 (m, 1 H), 0.8-1.1 and
1.2-2.4 (22 H), 3.25 (1 H) ppm. 13C NMR (CDCl3): δ 14.1 (q),
20.7 (t), 22.7 (t), 23.3 (t), 23.5 (t), 24.3 (d), 26.5 (t), 26.8 (t), 28.9
(t), 29.4 (s), 29.7 (t), 30.4 (t), 31.2 (t), 31.7 (t), 73.7 (d). The ∆3-
cis-configuration is assigned by COSY, HMBC, HSQC, and
NOESY in DMSO-d6. MS (EI): m/z (%) 224 (M+, 1), 206 ([M -
18]+, 10), 178 (4), 163 (5), 149 (12), 135 (22), 126 (24), 109 (22),
107 (24), 98 (58), 97 (33), 96 (80), 95 (46), 93 (54), 69 (41), 68
(42), 67 (84), 55 (100), 41 (80). IR (film): 3362 (br, OH), 2919
(s), 2852 (m), 1456 (m), 1364 (w), 1106 (w), 1029 (m), 989 (m),
811 (w), 741 (w), 726 (w). HRMS calcd for C15H28O 224.21402,
found 224.21737. HRMS calcd for C15H26 206.20345, found
206.20372.
Acknowledgment. We thank Prof. C. Bolm (Marburg) for
sending us the dissertation of Dr. D. Pupowicz.7b For valuable
input we thank Prof. Sir Jack Baldwin (Oxford), Prof. A.
Hoveyda (Boston), Prof. A. Vasella (ETH Zu¨rich), Prof. G.
Fráter, Dr. P. Gygax, Dr. P. Kraft (all Givaudan Du¨bendorf),
and Dr. A. Goeke (Givaudan Shanghai). For skillful experiments
we thank P. Aebersold, B. Bonfils, S. Elmer, B. Rothmund, and
F. Ru¨thi. For GC/MS- and HRMS measurements we thank Dr.
J. Schmid, Dr. F. Kuhn, and H. Gfeller. For X-ray analysis we
thank A. M. Alker (Hoffmann La Roche AG, Basel). For
proofreading we thank T. McStea.
(1SR,3RS,4RS)-1-Pentylspiro[2.7]decan-4-ol (12c). 11c (3 g, 18
mmol)24 is added dropwise to 1.6 M n-butyllithium in hexane (11
mL, 18 mmol) in diethyl ether (20 mL) at -78 °C. After 1 h at
-78 °C the solution is slowly warmed to room temperature.
Dibromomethane (12.5 g, 72 mmol) is added followed by dropwise
addition of tert-butylmagnesium chloride (36 mL, 72 mmol) at
10-20 °C. After 24 h at 25 °C the mixture is poured upon 2 M
HCl. Extraction with tert-butyl methyl ether, washing of the organic
phase with concentrated NaHCO3 and concentrated NaCl, drying
Supporting Information Available: Experimental proce-
dures and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO8007397
7554 J. Org. Chem. Vol. 73, No. 19, 2008