Diastereoselective syntheses of highly substituted methylenecyclopropanes via copper- or iron-catalyzed reactions of 1,2-disubstituted 3-(hydroxymethyl)cyclopropenes with grignard reagents

Article abstract of DOI:10.1055/s-0033-1338876

Described are diastereoselective syntheses of highly substituted methylenecyclopropanes from 1,2-disubstituted 3-(hydroxymethyl)cyclopropenes with allylic ether leaving groups, compounds that were constructed via alkylation of cyclopropenecarboxylic acid

Full text of DOI:10.1055/s-0033-1338876

PAPER
▌1807
paper
Diastereoselective Syntheses of Highly Substituted Methylenecyclopropanes
via Copper- or Iron-Catalyzed Reactions of 1,2-Disubstituted 3-(Hydroxy-
methyl)cyclopropenes with Grignard Reagents
Reactions of 1,2-Disubstituted 3-(Hydroxymethyl)cyclopropenes
Xiaocong Xie, Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark DE 19716, USA
Fax +1(302)8316335; E-mail: jmfox@udel.edu
Received: 08.04.2013; Accepted after revision: 08.05.2013
Dedicated to Scott Denmark in recognition of his contributions to the chemistry of strained molecules
quaternary centers.9c Marek also showed that 2-methylcy-
Abstract: Described are diastereoselective syntheses of highly sub-
cloprop-1-enyl(phenyl)methyl acetate can undergo
stituted methylenecyclopropanes from 1,2-disubstituted 3-(hy-
sigmatropic rearrangement to give an alkylidenecyclopro-
droxymethyl)cyclopropenes with allylic ether leaving groups,
compounds that were constructed via alkylation of cyclopropene-
pane stereospecifically.9d Alternatively, Corey and co-
carboxylic acid dianions. Substitution reactions of 1,2-disubstituted workers have shown that 2-(bromomethyl)-1-tosylcyclo-
3-(hydroxymethyl)cyclopropenes with Grignard reagents proceed
with good yield and high diastereoselectivity. Under copper(I)-cat-
alyzed conditions, the substitution reactions proceed to give syn-ad-
with excellent diastereoselectivity.10 Rubin and co-work-
dition products, whereas Fe(acac)3 catalysis gives the products of
anti-addition.
prop-2-ene could be synthesized in 94% ee and treated
with nucleophiles to provide methylenecyclopropanes
ers have found that methylenecyclopropylphosphine ox-
ides could be synthesized with excellent diastereocontrol
Key words: cyclopropene, diastereoselective, dianion, methylene-
from aryl-1-(hydroxymethyl)cycloprop-2-enes.11 It has
cyclopropane, substitution
also been established that methylenecyclopropanes can be
generated by the base-catalyzed isomerization of 1-meth-
ylcyclopropene precursors.13
Methylenecyclopropanes are highly strained molecules
(39.5 kcal/mol)1 that serve as useful building blocks for
the assembly of complex molecular structures.2 Work in
recent years has established the ability of methylenecyclo-
propanes to participate in ring-opening,3 cycloaddition,4
ring-expansion,5 and carbon–carbon double-bond addi-
tion reactions.6 Furthermore, a number of the transforma-
tions of methylenecyclopropanes have shown to be
stereospecific.3f,4e,f,7
In earlier studies, our group had shown that Grignard re-
agents can convert 1-(alkoxymethyl)cyclopropenes into
methylenecyclopropanes, as illustrated in Scheme 1 (a).12
The regioselectivity of substitution reactions of Grignard
reagents with (alkoxymethyl)cyclopropenes contrasted
prior studies on carbomagnesation of 1-alkylcyclopro-
penes, where the normal course of reactivity is for the nu-
cleophile to add to the more substituted side of the double
bond.14 The reaction to form methylenecyclopropanes
proceeded with excellent regio- and diastereoselectivity.
Methyl-, alkyl- (1° or 2°), allyl-, and benzylmagnesium
halides were suitable nucleophiles, and MEM or SEM
ethers served as effective leaving groups.12 Herein, we de-
scribe studies that expand the scope of methylenecyclo-
propane formation via facially selective substitution
reactions of 1-(alkoxymethyl)cyclopropenes with
Grignard reagents.
As a consequence of this rich reactivity, there has been a
growing interest in the diastereoselective synthesis of
methylenecyclopropanes from cyclopropene precursors.
Inspiration for this approach to methylenecyclopropane
synthesis was provided by de Meijere, who reported that
palladium(0)-catalyzed nucleophilic SN2′ substitution
could form an alkylidenecyclopropane in low yield.8 Con-
temporaneously, Marek,9 Corey,10 Rubin,11 and our
group12 showed that common cyclopropene precursors
can be used to provide access to a range of highly substi-
tuted methylenecyclopropanes or alkylidenecyclopro-
panes. Marek showed that 1-(1-hydroxyalkyl)cycloprop-
1-enes can be resolved by Sharpless epoxidation, and then
treated with alkyl Grignard reagents to give alkylidenecy-
clopropanes or methylenecyclopropanes in good yield, di-
astereoselectivity and E/Z selectivity.9a,b Marek further
described copper-catalyzed carbomagnesation and hydro-
metalation reactions of chiral cyclopropenylcarbinol de-
rivatives, including formal SN2′ reactions to set chiral
a prior work
Ph
Ph
RMgX
OH
OH
OMEM
R
b challenges associated with substitution reactions with 1,2-disubstituted
cyclopropenes to create chiral quaternary centers
R1
R1
R3
R1
R4MgX
OH
OH
OR2
OH
OR2
vs
R3
R3
R4
R4
synthesis of 1,2-disubstituted
cyclopropenes with an appropriate allylic
ether leaving group
SYNTHESIS 2013, 45, 1807–1814
Advanced online publication: 06.06.2013
competing formation
of addition product
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338876; Art ID: SS-2013-C0278-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Substitution reactions of cyclopropenes with allylic ether
leaving groups

1808
X. Xie, J. M. Fox
PAPER
The diastereoselective synthesis of methylenecyclopro-
panes from cyclopropenes had been limited to examples
of ‘terminal’ cyclopropene precursors. We sought to de-
velop diastereoselective substitution reactions of ‘inter-
nal’ cyclopropenes15 with Grignard reagents. Challenges
for developing such reactions would include the synthesis
of 1,2-disubstituted cyclopropenes with appropriate allyl-
ic leaving groups, as well as the avoidance of competing
carbometalation products that would result from addition
of the Grignard reagent with the opposite regioselectivity
[Scheme 1 (b)]. Recently, Davies has reported an enantio-
selective method for the cyclopropenation of internal al-
kynes using gold catalysis.16 Complementary methods
that convert terminal cyclopropenes into internal cyclo-
propenes have been reported by Eckert-Maksić,17
Gevorgyan,18 and Lam.19 Our group has developed dian-
ion approaches to convert terminal cyclopropenes into in-
ternal cyclopropenes,13a,20 in which terminal cyclo-
propenes were treated with two equivalents of base to pro-
vide stable dianions that can subsequently combine with
electrophiles to give internal cyclopropenes. Building on
this dianion strategy, we envisioned the strategy for dia-
stereoselective methylenecyclopropane formation shown
in Scheme 2. Cyclopropenecarboxylic acids of structure A
are readily available in racemic or in enantiomerically en-
riched form through enantioselective cyclopropenation of
alkynes.21 Treatment of A with an organolithium would
produce the dianion B, which could be alkylated by
MOMCl to give ester C. Reduction to D would be fol-
lowed by diastereoselective substitution to give E.
Ph
CO2H
Ph
CO2R
OMe
1) MeLi;
MOMCl
Ph
DIBAL-H
OH
OMe
Bu
Bu
2) TMSCHN2
Bu
1
2a, R = MOM
2b, R = Me
3
46% yield from 1
CO2H
1) MeLi; MOMCl
OH
OMe
2) TMSCHN2
3) DIBAL-H
H13C6
H13C6
4
6
5
38% yield from 4
CO2H
1) MeLi; MOMCl
OH
OMe
2) TMSCHN2
3) DIBAL-H
H13C6
H13C6
7
50% yield from 6
Scheme 3 Synthesis of 1,2-disubstituted 3-(hydroxymethyl)cyclo-
propenes with allylic leaving groups
R1
R1
R2
R3MgX
OH
OH
OMe
Cu(I) (10 mol%)
R2
R3
hexanes–Et2O, r.t.
CuI-catalyzed
H
OH
OH
89%
12:1 dr
73%
>95:5 dr
H13C6
H13C6
8
9
R1
R2
CO2H
MeLi
R1
R2
CO2Li
Li
R1
R2
CO2MOM
OMe
H
H
OH
O
OH
MOMCl
71%
3:1 dr
86%
2:1 dr
H13C6
H13C6
A
B
C
10
11
O
[H]
R1
R1
R2
Ph
R3MgX
R2
OH
OMe
OH
OH
OH
68%
>95:5 dr
H13C6
H9C4
R3
61%
>95:5 dr
E
D
13
12
Scheme 2 Dianion alkylation/substitution as a route to methylenecy-
clopropanes
CuBr⋅SMe2-catalyzed
Ph
OH
OH
The use of dianion chemistry to prepare (methoxymeth-
yl)cyclopropenes is outlined in Scheme 3. Cyclopropene-
carboxylic acid 120 was sequentially treated with 2.2
equivalents of MeLi and 5 equivalents MOMCl. Without
chromatography, the crude reaction mixture was then
treated with TMSCHN2 to give the desired methyl ester 2
and the MOM-substituted ester (~1: 1). The crude mixture
of esters was then reduced by DIBAL-H to give alcohol 3
in 46% yield over three steps. Similar procedures were ap-
plied to 4 and 6 to give 5 and 7 in 38% and 50% yield over
three steps, respectively.
H13C6
H9C4
91%
>95:5 dr
75%
>95:5 dr
15
14
F
H
H
OH
OH
48%
14:1 dr
H13C6
H13C6
68%
10:1 dr
17
16
F
Substitution reactions of internal cyclopropenes 3, 5, and
7 with Grignard reagents were catalyzed by CuI in 61–
Scheme 4 Copper(I)-catalyzed addition of Grignard reagents to pro-
vide methylenecyclopropanes bearing quaternary centers
Synthesis 2013, 45, 1807–1814
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reactions of 1,2-Disubstituted 3-(Hydroxymethyl)cyclopropenes
1809
89% yield (Scheme 4). With MeMgBr, compounds 8 and to 5 gave the anti diastereomer 19 in 10:1 dr and 56%
9 were formed with 12:1 and >95:5 diastereoselectivity, yield. Also studied were the iron-catalyzed reactions be-
respectively, for the product of Grignard reagent addition tween 4-fluorophenylmagnesium bromide with 7 and
syn relative to the hydroxymethyl group. With 2-(1,3-di- methylmagnesium bromide with 3. Both 7 and 3 are di-
oxan-2-yl)ethylmagnesium bromide, compound 10 was substituted at C3 of the cyclopropene. For these sub-
formed from 5 in 71% yield with a dr of 3:1. Allylmagne- strates, where both faces are substituted at C3, the
sium bromide with 5 gave 11 in 86% yield with dr of 2:1. substitutions took place exclusively syn to the hydroxy-
Methylenecyclopropanes 12 and 13 could be prepared methyl group to give 15 and 20 (Scheme 6).
with excellent selectivity for the syn isomers from cyclo-
propenes 3 and 7, respectively. The higher selectivity with
OH
F
MgBr
3 and 7 is attributed to the influence of their C3 substitu-
ents, which accentuate the directing ability of the deprot-
onated hydroxymethyl group by blocking addition to the
opposite face of the cyclopropene.
H13C6
OH
OMe
(5 equiv)
Fe(acac)3
(10 mol%)
H13C6
7
67%
>95:5 dr
15
hexanes–Et2O, r.t.
F
Additions of aryl Grignard reagents were also investigat-
ed and CuBr·SMe2 was found to be the catalyst of choice
(Scheme 4). Several aryl Grignard reagents were studied
and found to give methylenecyclopropanes with good
yields. Cyclopropenes 3 and 7 gave methylenecyclopro-
panes 14 and 15, respectively, with high yields (75–91%)
and diastereoselectivity (>95:5 dr). The substitution reac-
tion of 1-hexyl-3-(hydroxymethyl)cyclopropene 5 with 4-
fluorophenylmagnesium bromide gave 16 in 68% yield
and 10:1 dr, and with 2-naphthylmagnesium bromide
gave 17 in 48% yield and 14:1 dr.
Ph
Ph
MeMgBr (5 equiv)
OH
OH
OMe
Fe(acac)3
(10 mol%)
52%
>95:5 dr
H9C4
H9C4
3
hexanes–Et2O, r.t.
20
Scheme 6 Iron-catalyzed carbomagnesation takes place on the syn-
face with cyclopropenes that are disubstituted at C3
In support of the stereochemical assignments, there are
significant shielding effects that are observed in the H
1
NMR spectra of aryl-substituted methylenecyclopro-
panes. For example, the diastereotopic protons on the
methylene of the hydroxymethyl for 18 resonate at δ =
3.94 and 3.77, whereas the analogous protons on isomeric
compound 16 resonate at δ = 3.43 and 3.12 (Figure 1). The
F
MgBr
OH
OH
OMe
(5 equiv)
Fe(acac)3
(10 mol%)
C6H13
H13C6
F
5
18
73%
8:1 dr
hexanes–Et2O, r.t.
3.94; 3.77 ppm
Me
3.43; 3.12 ppm
F
H
H
C6H13
MgBr
OH
H
H
HO
OH
OMe
(5 equiv)
HO
C6H13
Fe(acac)3
(10 mol%)
H13C6
C6H13
18
not shielded
5
19
16
shielded
56%
10:1 dr
hexanes–Et2O, r.t.
F
Scheme 5 Reversal of facial selectivity in Fe(acac)3-catalyzed addi-
tion of aryl Grignard reagents to 3-(hydroxymethyl)cyclopropenes
HO
Ph
HO
It was also observed that iron catalysts could be used to
catalyze the substitution reaction of Grignard reagents to
form methylenecyclopropanes. Previously, Nakamura
had shown that FeCl3 could be used to catalyze the addi-
tion reactions of Grignard reagents to cyclopropenone
acetals.22 In the present study, it was found that iron(III)-
catalyzed substitution reactions to form methylenecyclo-
propanes can proceed with the opposite sense of diaste-
reoselectivity relative to copper(I) catalyzed reactions
(Scheme 5). Fe(acac)3 was found to be the most selective
catalyst and aromatic Grignard reagents were the most se-
lective nucleophiles.
C3H7
12
C3H7
H
H
14
0.66 ppm
0.85 ppm
I
CH3
HO
HO
CH3
C3H7
C3H7
H
H
20
21
0.81 ppm
0.65 ppm
The Fe(acac)3 catalyzed reaction of 4-fluorophenylmag-
nesium bromide with 5 gave 18 in 73% yield with an
anti/syn ratio of 8:1. o-Tolylmagnesium bromide addition
Figure 1 Shielding effects in methylenecyclopropanes with aromat-
ic substituents support stereochemical assignments
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1807–1814

1810
X. Xie, J. M. Fox
PAPER
added via syringe and the mixture was allowed to stir at r.t. for 16
h. The reaction was quenched with sat. NH4Cl soln and extracted
with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine and dried (anhyd MgSO4), then filtered and con-
centrated in vacuo to afford the crude product as a colorless to yel-
low oil. In the case of aryl Grignard reagents, the combined organic
layers were additionally washed with 10% KOH (3 × 10 mL). The
crude product was purified by chromatography (silica gel, 10%
EtOAc–hexanes) to give the desired methylenecyclopropane.
upfield chemical shifts for 16 are consistent with the syn
relationship between the aryl substituent and the hydroxy-
methyl group. Likewise, the methylene protons on the hy-
droxymethyl group of compounds 14 (δ = 3.65, 3.19), 15
(δ = 3.18, 3.06), and 17 (δ = 3.40, 3.13) also resonate at
high field. For each of compounds 12, 14, and 20, one of
the diastereotopic protons on the butyl group is shielded
by the phenyl on the same face of the cyclopropane, re-
sulting in shift to high field (δ = 0.66–0.85). As noted pre-
viously, a similar effect is observed for compound 21,14b
where the analogous proton resonates at δ = 0.65 (Figure 1).
2-Butyl-1-(hydroxymethyl)-1-phenyl-3-(methoxymethyl)cyclo-
prop-2-ene (3)
General procedure A was followed with 2-butyl-1-phenylcyclo-
prop-2-enecarboxylic acid (1,20 251 mg, 1.16 mmol), 1.6 M MeLi
in Et2O (1.6 mL, 2.6 mmol), and MOMCl (467 mg, 5.80 mmol) in
In conclusion, diastereoselective syntheses of highly sub-
stituted methylenecyclopropanes from chiral, 1,2-disub- THF (7.0 mL); 2.0 M TMSCHN2 in hexanes (2.9 mL, 5.8 mmol) in
MeOH (10 mL); and finally 1.0 M DIBAL-H in THF (5.8 mL, 5.80
mmol) in THF (6.0 mL) to give 3 (130 mg, 0.528 mmol, 46%) as a
colorless oil.
stituted cyclopropenes have been developed. Dianion
chemistry was used to construct cyclopropene precursors
with allylic ether leaving groups. Substitution reactions 3-
(hydroxymethyl)cycloprop-1-enes with Grignard re-
agents can be catalyzed by copper(I) catalysts to give syn-
addition products, or with Fe(acac)3 to give anti-addition
products.
Small peaks attributed to inseparable impurities were found in the
1H NMR at δ = 4.72, 3.90, 3.37, 2.90, and in the 13C NMR at δ =
129.0, 63.7, 59.6.
IR (neat): 3440, 3058, 3024, 2957, 2930, 2872, 1600, 1494, 1465,
1448, 1377, 1192, 1153, 1098, 1006, 769, 700 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.33 (m, 4 H), 7.15–7.19 (m,
All reactions were carried out in round-bottom flasks that were
flame-dried and cooled under N2. All commercially available re-
agents were used as received. THF was distilled from Na/benzophe-
none. Hexanes and Et2O were dried with columns prepacked with
activated neutral alumina. Chromatography was carried out using
Silicycle silica gel (40–63D, 60Å). For 13C NMR, multiplicities
were distinguished using a ATP pulse sequence: typical methylene
and quaternary carbons appear ‘up’; methine and methyl carbons
‘down’.
1 H), 4.49 (d, J = 13.3 Hz, 1 H), 4.40 (d, J = 11.2 Hz, 1 H), 4.32 (dd,
J = 13.3, 1.2 Hz, 1 H), 3.69 (d, J = 11.2 Hz, 1 H), 3.44 (s, 3 H),
2.45–2.61 (m, 2 H), 1.89 (s, 1 H), 1.54–1.61 (m, 2 H), 1.36–1.45 (m,
2 H), 0.93 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.4 (C), 128.2 (CH), 126.2
(CH), 125.2 (CH), 118.7 (C), 110.5 (C), 68.3 (CH2), 64.6 (CH2),
58.8 (CH3), 34.5 (C), 29.6 (CH2), 24.0 (CH2), 22.5 (CH2), 13.8
(CH3).
HRMS-CI (NH3): m/z [M – OH] calcd for C16H21O: 229.1587;
found: 229.1595.
Methylenecyclopropane Synthesis; General Procedure A
A soln of 2.0 M cyclopropenecarboxylic acid in THF was added to
a round-bottomed flask. The mixture was cooled to –78 °C and
stirred for 5 min. MeLi (2.2 equiv) was added and the mixture was
stirred for a further 5 min. The acetone/dry ice bath was replaced
with an ice bath and the mixture was allowed to warm to 0 °C over
5 min. MOMCl (5 equiv) was added and the mixture was allowed
warm to r.t. while stirring for 1 h. The mixture was quenched with
H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried (anhyd MgSO4), then filtered and concen-
trated in vacuo to afford the crude product as a brown oil. The crude
product was dissolved in MeOH (~0.2 mmol/mL) and transferred to
a round-bottom flask and cooled to 0 °C with an ice bath.
TMSCHN2 was added dropwise until N2 evolution had ceased (~5
equiv). H2O (5 mL) was added to the mixture, which was then ex-
tracted with EtOAc (3 × 10 mL). The combined organic layers were
dried (anhyd MgSO4), filtered, and concentrated in vacuo to afford
the crude product as a yellow oil. The crude product was dissolved
in anhyd THF (~0.1 mmol/mL) and transferred to an oven-dried
round-bottom flask. The mixture was cooled to –78 °C and stirred
for 5 min. DIBAL-H (5 equiv) was added via syringe over the
course of 10 min and the mixture was stirred at –78 °C for 2 h.
EtOAc (10 mL) was added followed by 3 M HCl (10 mL), and the
mixture was allowed to warm to r.t. The mixture was extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried (an-
hyd MgSO4), then filtered and concentrated in vacuo. The residue
was purified by chromatography (silica gel, 50% EtOAc–hexanes)
to give the desired 3-(hydroxymethyl)cycloprop-1-ene.
2-Hexyl-1-(hydroxymethyl)-3-(methoxymethyl)cycloprop-2-
ene (5)
General procedure A with 2-hexylcycloprop-2-enecarboxylic acid
(4,20 251 mg, 1.49 mmol), 1.6 M MeLi in Et2O (2.1 mL, 3.4 mmol
), and MOMCl (601 mg, 7.47 mmol) in THF (9.0 mL); 2.0 M
TMSCHN2 in hexanes (3.7 mL, 7.5 mmol) in MeOH (15 mL); and
finally 1.0 M DIBAL-H in THF (7.5 mL, 7.5 mmol) in THF (7.5
mL) gave 5 (113 mg, 0.570 mmol, 38%) as a colorless oil.
Peaks attributable to inseparable impurities (~6%) were found in the
1H NMR at δ = 4.73, 3.49, 3.36, 1.07.
IR (neat): 3401, 2929, 2858, 1465, 1378, 1190, 1101, 1018 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.43 (d, J = 13.6 Hz, 1 H), 4.29 (d,
J = 13.6 Hz, 1 H), 3.77 (dd, J = 10.8, 3.8 Hz, 1 H), 3.45 (s, 3 H),
3.23 (dd, J = 10.8, 6.1 Hz, 1 H), 2.43–2.47 (m, 2 H), 1.80–1.82 (m,
2 H), 1.52–1.59 (m, 2 H), 1.28–1.39 (m, 6 H), 0.91 (t, J = 6.8 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 118.6 (C), 110.7 (C), 68.7 (CH2),
66.3 (CH2), 58.6 (CH3), 31.6 (CH2), 29.0 (CH2), 27.5 (CH2), 25.8
(CH2), 23.6 (CH), 22.6 (CH2), 14.1 (CH3).
HRMS-CI (NH3): m/z [M – OH] calcd for C12H21O: 181.1587;
found: 181.1593.
2-Hexyl-1-(hydroxymethyl)-1-methyl-3-(methoxymethyl)cyclo-
prop-3-ene (7)
General procedure A was followed with 2-hexyl-1-methylcyclo-
prop-2-enecarboxylic acid (6,20 563 mg, 3.09 mmol), 1.6 M MeLi
in Et2O (4.3 mL, 6.9 mmol), and MOMCl (1.244 g, 15.45 mmol) in
THF (16 mL); 2.0 M TMSCHN2 in hexanes (7.7 mL, 15 mmol) in
MeOH (5.0 mL); and finally 1.0 M DIBAL-H in THF (15.5 mL,
Grignard Reagent to 3-(Hydroxymethyl)cycloprop-1-enes Cat-
alyzed by Cu(I) or Fe(acac)3; General Procedure B
To a soln of the (hydroxymethyl)cyclopropene derivative in hex-
anes/Et2O (amounts specified below) was added the specified Cu(I)
or Fe(III) catalyst (10 mol%). The Grignard reagent (5 equiv) was
Synthesis 2013, 45, 1807–1814
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reactions of 1,2-Disubstituted 3-(Hydroxymethyl)cyclopropenes
1811
15.5 mmol) in THF (15 mL) to give 7 (324 mg, 1.53 mmol, 50%) as
a colorless oil.
143.5, 101.8, 61.0, 34.7, 31.7, 29.5, 29.2, 28.8, 27.3, 26.5, 25.4.
Small peaks attributed to inseparable impurities were found in the
1H NMR at δ = 3.69, 3.30, 0.91.
Small peaks attributed to an inseparable impurity (5%) were found
in the 1H NMR at δ = 4.71, 3.41, and in the 13C NMR at δ = 95.9,
60.4.
IR (neat): 3433, 3062, 2926, 2853, 2731, 2658, 1467, 1431, 1403,
1379, 1286, 1241, 1145, 1082, 1004, 944, 926, 887, 853, 728, 641,
583, 529 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.32 (d, J = 1.8 Hz, 1 H), 5.26 (app
s, 1 H), 4.51–4.56 (m, 1 H), 4.09–4.13 (m, 2 H), 3.73–3.82 (m, 3 H),
3.53–3.59 (m, 1 H), 2.03–2.07 (m, 1 H), 1.81–1.84 (m, 1 H), 1.26–
1.80 (m, 16 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 143.6 (C), 101.6 (CH), 101.5
(CH2), 66.5 (CH2), 61.0 (CH2), 35.3 (CH2), 32.3 (CH2), 31.4 (CH2),
29.1 (CH), 28.9 (CH2), 27.8 (C), 25.9 (CH2), 25.3 (CH2), 22.6
(CH2), 22.2 (CH2), 13.7 (CH3).
IR (neat): 3430, 2929, 2858, 1455, 1368, 1190, 1101, 1054, 1011,
914 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.38 (dt, J = 13.5, 0.9 Hz, 1 H),
4.28 (dt, J = 13.5, 1.8 Hz, 1 H), 3.67 (d, J = 10.6 Hz, 1 H), 3.42 (s,
3 H), 3.36 (d, J = 10.6 Hz, 1 H), 2.41–2.45 (m, 2 H), 1.70 (br s, 1
H), 1.50–1.57 (m, 2 H), 1.27–1.40 (m, 6 H), 1.16 (s, 3 H), 0.90 (t,
J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 124.4 (C), 115.9 (C), 70.1 (CH2),
65.7 (CH2), 58.5 (CH3), 31.6 (CH2), 29.1 (CH2), 27.6 (CH2), 27.6
(C), 25.0 (CH2), 22.6 (CH2), 20.5 (CH3), 14.1 (CH3).
HRMS-CI (NH3): m/z [M + H] calcd for C17H31O3: 283.2267;
found: 283.2263.
HRMS-CI (NH3): m/z [M – OH] calcd for C13H23O: 195.1743;
found: 195.1748.
3α-Allyl-3β-hexyl-2α-(hydroxymethyl)-1-methylenecyclopro-
pane (11)
3β-Hexyl-2α-(hydroxymethyl)-3α-methyl-1-methylenecyclo-
propane (8)
General procedure B with 5 (41 mg, 0.21 mmol), CuI (4 mg, 0.02
mmol), and 1.0 M allylmagnesium bromide in Et2O (1.1 mL, 1.1
mmol) in hexanes (3.0 mL) and Et2O (1.5 mL) gave 11 (35 mg, 0.17
mmol, 81%) as a pale yellow oil. A similar experiment with 5 (19
mg) gave 11 (18 mg, 90%).
General procedure B with 5 (41 mg, 0.21 mmol), CuI (4 mg, 0.02
mmol), and 3.0 M MeMgBr in Et2O (0.35 mL, 1.1 mmol) in hex-
anes (2 mL) and Et2O (1 mL) gave 8 (34 mg, 0.19 mmol, 90%) as a
pale yellow oil. A similar experiment with 5 (20 mg) gave 8 (16 mg,
87%).
Peaks attributable to the diastereomer of 11 (dr 2:1) were found in
1
the H NMR at δ = 5.74–5.85, 5.39, 5.33, 4.98–5.03, 3.74–3.79,
IR (neat): 3326, 2958, 2928, 2857, 1465, 1378, 1142, 1014, 886
cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.34 (dd, J = 2.4, 0.7 Hz, 1 H),
5.29 (app s, 1 H), 3.80 (dd, J = 11.6, 6.0 Hz, 1 H), 3.58 (dd, J = 11.6,
9.0 Hz, 1 H), 1.52–1.56 (m, 1 H), 1.28–1.45 (m, 11 H), 1.17 (s, 3 H),
0.90 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.3 (C), 101.2 (CH2), 61.5
(CH2), 39.1 (CH2), 31.4 (CH2), 28.9 (CH2), 28.4 (CH), 26.3 (CH2),
23.8 (C), 22.2 (CH2), 15.5 (CH3), 13.7 (CH3).
3.62–3.66, 2.23–2.29, 2.08–2.12, and in the 13C NMR at δ = 143.2,
135.7, 116.7, 102.5, 61.5, 40.1, 31.8, 29.7, 29.5, 28.6, 26.8. Peaks
attributable to an inseparable impurity were found in the 1H NMR
at δ = 5.00, 0.65, 0.50, and in the 13C NMR at δ = 32.8, 29.0.
IR (neat): 3328, 3076, 2958, 2928, 2857, 1640, 1466, 1439, 1140,
1015, 912, 888 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.86–5.96 (m, 1 H), 5.38 (m, 1 H),
5.31 (m, 1 H), 5.05–5.16 (m, 2 H), 3.81 (dd, J = 11.8, 5.8 Hz, 1 H),
3.58 (dd, J = 11.8, 9.2 Hz, 1 H), 2.29–2.35 (m, 1 H), 2.14–2.20 (m,
1 H), 1.53–1.65 (m, 2 H), 1.28–1.42 (m, 10 H), 0.90 (t, J = 7.0 Hz,
3 H).
HRMS-CI (NH3): m/z [M – OH] calcd for C12H21: 165.1638; found:
165.1642.
13C NMR (100 MHz, CDCl3): δ = 143.3 (C), 136.7 (CH), 116.4
(CH2), 102.3 (CH2), 61.6 (CH2), 35.9 (CH2), 34.2 (CH2), 31.8
(CH2), 29.3 (CH2), 29.2 (CH), 27.9 (C), 26.3 (CH2), 22.6 (CH2),
14.1 (CH3).
3β-Hexyl-2α-(hydroxymethyl)-2β,3α-dimethyl-1-methylenecy-
clopropane (9)
General procedure B with 7 (27 mg, 0.13 mmol), CuI (2 mg, 0.01
mmol), and 3.0 M MeMgBr in Et2O (0.22 mL, 0.66 mmol ) in hex-
anes (1.3 mL) and Et2O (0.6 mL) gave 9 (19 mg, 0.10 mmol, 76%)
as a pale yellow oil. A similar experiment with 7 (25 mg) gave 9 (16
mg, 70%). Small peaks attributed to an inseparable impurity were
found in the 1H NMR at δ = 1.19–1.22.
HRMS-CI (NH3): m/z [M – OH] calcd for C14H23: 191.1794; found:
191.1803.
3α-Allyl-3β-butyl-2α-(hydroxymethyl)-1-methylene-2β-phenyl-
cyclopropane (12)
IR (neat): 3352, 3060, 2985, 2927, 2858, 1446, 1377, 1015, 937,
886, 724, 603 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.23 (s, 1 H), 5.20 (s, 1 H), 3.65
(d, J = 11.7 Hz, 1 H), 3.59 (d, J = 11.7 Hz, 1 H), 1.56 (s, 1 H), 1.25–
1.47 (m, 13 H), 1.22 (s, 3 H), 0.90 (t, J = 7.2 Hz, 3 H).
General procedure B with 3 (34 mg, 0.14 mmol), CuI (2 mg, 0.01
mmol), and 1 M allylmagnesium bromide in Et2O (0.7 mL, 0.7
mmol) in hexanes (1.4 mL) and Et2O (0.7 mL) gave 12 (21 mg,
0.082 mmol, 59%) as a pale yellow oil. A similar experiment with
3 (34 mg) gave 12 (22 mg, 62%).
13C NMR (100 MHz, CDCl3): δ = 150.4 (C), 99.8 (CH2), 67.3
(CH2), 34.9 (CH2), 31.9 (CH2), 29.6 (CH2), 28.5 (C), 27.0 (CH2),
26.4 (C), 22.7 (CH2), 17.6 (CH3), 16.2 (CH3), 14.1 (CH3).
IR (neat): 3413, 3060, 3024, 2956, 2929, 2860, 1639, 1600, 1493,
1446, 1379, 1146, 1026, 912, 890, 763, 701, 620, 555, 527 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.36 (m, 5 H), 5.98–6.05 (m,
1 H), 5.69 (s, 1 H), 5.54 (s, 1 H), 5.15–5.22 (m, 2 H), 4.08 (d,
J = 11.6 Hz, 1 H), 3.81 (d, J = 11.6 Hz, 1 H), 2.62 (dd, J = 15.2, 7.0
Hz, 1 H), 2.31 (dd, J = 15.2, 6.6 Hz, 1 H), 1.03–1.44 (m, 6 H), 0.75
(t, J = 7.3 Hz, 3 H), 0.62–0.69 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 145.7 (C), 138.7 (C), 136.1 (CH),
129.4 (CH), 127.8 (CH), 126.3 (CH), 116.2 (CH2), 102.9 (CH2),
66.6 (CH2), 38.6 (C), 34.5 (CH2), 32.5 (C), 31.6 (CH2), 28.1 (CH2),
22.2 (CH2), 13.5 (CH3).
HRMS-CI (NH3): m/z [M – OH] calcd for C13H23: 179.1794; found:
179.1802.
3α-[2-(1,3-Dioxan-2-yl)ethyl]-3β-hexyl-2α-(hydroxymethyl)-1-
methylenecyclopropane (10)
General procedure B with 5 (30 mg, 0.15 mmol), CuI (4 mg, 0.02
mmol), and 0.5 M (1,3-dioxan-2-ylethyl)magnesium bromide in
THF (1.5 mL, 0.75 mmol) in hexanes (1.4 mL) gave 10 (32 mg, 0.11
mmol, 75%) as a pale yellow oil. A similar experiment with 5 (55
mg) gave 10 (52 mg, 66%).
HRMS-CI (NH3): m/z [M – OH] calcd for C18H23: 239.1794; found:
Peaks attributable to the diastereomer of 10 (dr 3:1) were detected
in the 1H NMR at δ = 5.34, 5.29, 3.60, and in the 13C NMR at δ =
239.1789.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1807–1814

1812
X. Xie, J. M. Fox
PAPER
3α-Allyl-3β-hexyl-2α-(hydroxymethyl)-2β-methyl-1-methyl-
enecyclopropane (13)
3α-(4-Fluorophenyl)-3β-hexyl-2α-(hydroxymethyl)-1-methyl-
enecyclopropane (16)
General procedure B with 7 (38 mg, 0.18 mmol), CuI (4 mg, 0.02
mmol), and 1.0 M MeMgBr in Et2O (0.90 mL, 0.90 mmol ) in hex-
anes (2 mL) and Et2O (1 mL) gave 13 (27 mg, 0.12 mmol, 68%) as
a pale yellow oil. A similar experiment with 7 (12 mg) gave 13 (9
mg, 67%).
General procedure B with 5 (21 mg, 0.11 mmol), CuBr·SMe2 (2 mg,
0.01 mmol), and 1.0 M 4-fluorophenylmagnesium bromide in THF
(0.55 mL, 0.55 mmol) in hexanes (1.0 mL) and Et2O (0.5 mL) gave
16 (18 mg, 0.069 mmol, 65%) as a pale yellow oil. A similar exper-
iment with 5 (27 mg) gave 16 (25 mg, 70%).
IR (neat): 3366, 3075, 2956, 2927, 2858, 1639, 1466, 1378, 1015,
912, 888 cm–1.
Small peaks attributed to the minor diastereomer of 16 were found
in the 1H NMR at δ = 7.44–7.51, 5.68, 5.51, 3.94, 3.76, 2.02, 1.85,
0.90 and in the 13C NMR at δ = 129.5, 115.1, 104.4, 61.5, 32.9, 31.9,
29.4, 27.4. Small peaks attributed to an inseparable impurity were
found in the 1H NMR at δ = 5.85, and in the 13C NMR at δ = 128.2,
126.2, 114.8, 32.2, 29.8.
1H NMR (400 MHz, CDCl3): δ = 5.88–5.98 (m, 1 H), 5.28 (s, 1 H),
5.25 (s, 1 H), 5.09–5.14 (m, 2 H), 3.66 (d, J = 11.8 Hz, 1 H), 3.62
(d, J = 11.8 Hz, 1 H), 2.41 (dd, J = 15.4, 5.7 Hz, 1 H), 2.23 (dd,
J = 15.4, 8.0 Hz, 1 H), 1.28–1.58 (m, 14 H), 0.91 (t, J = 6.6 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 148.9 (C), 137.2 (CH), 116.1
(CH2), 100.6 (CH2), 66.8 (CH2), 35.2 (CH2), 31.8 (CH2), 31.0
(CH2), 30.1 (C), 29.5 (CH2), 29.2 (C), 26.8 (CH2), 22.7 (CH2), 16.6
(CH3), 14.1 (CH3).
IR (neat): 3357, 2956, 2929, 2857, 1604, 1509, 1465, 1222, 1157,
1016, 894, 839 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.36 (m, 2 H), 6.98–7.05 (m,
2 H), 5.73 (d, J = 2.3 Hz, 1 H), 5.59 (d, J = 1.6 Hz, 1 H), 3.43 (dd,
J = 11.6, 5.8 Hz, 1 H), 3.12 (dd, J = 11.6, 8.9 Hz, 1 H), 2.20–2.27
(m, 1 H), 1.90–1.95 (m, 1 H), 1.60 (s, 1 H), 1.20–1.44 (m, 9 H), 0.85
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.6 (C) [d, 1J(CF) = 243 Hz],
140.7 (C), 134.9 (C) [d, 4J(CF) = 3 Hz], 130.6 (CH) [d, 3J(CF) = 8
Hz], 115.1 (CH) [d, 2J(CF) = 21 Hz], 105.3 (CH2), 61.9 (CH2), 40.1
(CH2), 33.0 (C), 31.7 (CH2), 31.0 (CH), 29.1 (CH2), 27.1 (CH2),
22.6 (CH2), 14.1 (CH3).
HRMS-CI (NH3): m/z [M – OH] calcd for C15H25: 205.1951; found:
205.1951.
3β-Butyl-2α-(hydroxymethyl)-1-methylene-2β,3α-diphenylcy-
clopropane (14)
General procedure B with 3 (27 mg, 0.11 mmol), CuBr·SMe2 (3 mg,
0.01 mmol) and 3.0 M PhMgBr in Et2O (0.18 mL, 0.55 mmol) in
hexanes (1.0 mL) gave 14 (27 mg, 0.092 mmol, 84%) as a pale yel-
low oil. A similar experiment with 3 (6 mg) gave 14 (7 mg, 98%).
HRMS-CI (NH3): m/z [M – OH] calcd for C17H22F: 245.1700;
found: 245.1701.
IR (neat): 3384, 3059, 3025, 2957, 2930, 2958, 1600, 1494, 1447,
1379, 1027, 896, 762, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.52 (m, 10 H), 5.95 (s, 1 H),
5.90 (s, 1 H), 3.65 (d, J = 11.7 Hz, 1 H), 3.19 (d, J = 11.7 Hz, 1 H),
1.81–1.88 (m, 1 H), 0.99–1.16 (m, 5 H), 0.80–0.90 (m, 1 H), 0.69 (t,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 143.4 (C), 139.4 (C), 138.2 (C),
129.3 (CH), 128.4 (CH), 127.9 (CH), 127.9 (CH), 126.5 (CH),
126.2 (CH), 105.3 (CH2), 67.4 (CH2), 39.9 (C), 38.1 (C), 35.9
(CH2), 28.8 (CH2), 22.0 (CH2), 13.4 (CH3).
3β-Hexyl-2α-(hydroxymethyl)-3α-(naphthalen-2-yl)-1-methyl-
enecyclopropane (17)
General procedure B with 5 (43 mg, 0.22 mmol), CuBr·SMe2 (9 mg,
0.04 mmol), and 0.25 M 2-naphthylmagnesium bromide in THF
(4.0 mL, 1.0 mmol) in hexanes (2 mL) gave 17 (33 mg, 0.11 mmol,
50%) as a pale yellow oil. A similar experiment with 5 (21 mg) gave
17 (14 mg, 45%).
Small peaks attributed to the diastereomer of 17 were found in the
1H NMR at δ = 5.76, 5.55, 3.96, 3.80, and in the 13C NMR at δ =
128.0, 127.6, 126.5, 126.2, 126.0, 125.5, 104.3, 61.5, 32.7, 32.4,
29.4, 27.5.
HRMS-CI (NH3): m/z [M – OH] calcd for C21H23: 275.1794; found:
275.1791.
IR (neat): 3341, 3063, 2955, 2929, 2856, 1594, 1507, 1463, 1395,
1378, 1341, 1131, 1073, 1020, 891, 803, 780, 736 cm–1.
3α-(4-Fluorophenyl)-3β-hexyl-2α-(hydroxymethyl)-2β-methyl-
1-methylenecyclopropane (15)
1H NMR (400 MHz, CDCl3): δ = 7.77–7.82 (m, 4 H), 7.42–7.55 (m,
3 H), 5.83 (d, J = 2.0 Hz, 1 H), 5.64 (d, J = 1.7 Hz, 1 H), 3.40 (dd,
J = 11.6, 5.8 Hz, 1 H), 3.13 (dd, J = 11.6, 9.0 Hz, 1 H), 2.36–2.43
(m, 1 H), 1.95–2.01 (m, 1 H), 1.15–1.45 (m, 10 H), 0.81 (t, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 140.9 (C), 136.7 (C), 133.3 (C),
132.3 (C), 128.1 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 126.8
(CH), 126.1 (CH), 125.7 (CH), 105.4 (CH2), 61.9 (CH2), 39.8
(CH2), 33.9 (C), 31.7 (CH2), 31.5 (CH), 29.1 (CH2), 27.3 (CH2),
22.6 (CH2), 14.0 (CH3).
General procedure B with 7 (34 mg, 0.16 mmol), CuBr·SMe2 (7 mg,
0.03 mmol), and 1.0 M 4-fluorophenylmagnesium bromide in THF
(0.8 mL, 0.80 mmol) in hexanes (1.6 mL) gave 15 (32 mg, 0.12
mmol, 72%) as a pale yellow oil. A similar experiment with 7 (16
mg) gave 15 (16 mg, 77%).
Alternatively, general procedure B with 7 (16 mg, 0.075 mmol),
Fe(acac)3 (3 mg, 0.01 mmol), and 1.0 M 4-fluorophenylmagnesium
bromide in THF (0.38 mL, 0.38 mmol) in hexanes (1 mL) and Et2O
(0.5 mL) gave 15 (14 mg, 0.051 mmol 67%) as a pale yellow oil.
IR (neat): 3369, 3064, 2924, 2857, 1604, 1507, 1465, 1379, 1222,
1157, 1107, 1094, 1016, 893, 841, 815, 733, 608, 534 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.22–7.27 (m, 2 H), 6.94–6.99 (m,
2 H), 5.61 (s, 1 H), 5.49 (s, 1 H), 3.18 (dd, J = 11.5, 6.0 Hz, 1 H),
3.06 (dd, J = 11.5, 5.0 Hz, 1 H), 1.99–2.05 (m, 1 H), 1.50–1.56 (m,
1 H), 1.43 (s, 3 H), 1.04–1.26 (m, 9 H), 0.83 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.5 (C) [d, 1J(CF) = 244 Hz],
146.6 (C), 136.5 (C) [d, 4J(CF) = 3 Hz], 130.4 (CH) [d, 3J(CF) = 8
Hz], 115.0 (CH) [d, 2J(CF) = 21 Hz], 103.4 (CH2), 67.2 (CH2), 35.5
(C), 35.0 (CH2), 31.7 (CH2), 31.2 (C), 29.2 (CH2), 27.3 (CH2), 22.6
(CH2), 15.6 (CH3), 14.0 (CH3).
HRMS-CI (NH3): m/z [M+] calcd for C21H26O: 294.1984; found:
294.1990.
3β-(4-Fluorophenyl)-3α-hexyl-2α-(hydroxymethyl)-1-methyl-
enecyclopropane (18)
General procedure B with 5 (18 mg, 0.091 mmol), Fe(acac)3 (6 mg,
0.02 mmol), and 1.0 M 4-fluorophenylmagnesium bromide in THF
(0.46 mL, 0.46 mmol) in hexanes (1 mL) and Et2O (0.5 mL) gave
18 (17 mg, 0.065 mmol, 71%) as a pale yellow oil. A similar exper-
iment with 5 (31 mg) gave 18 (31 mg, 75%).
Small peaks attributed to the diastereomer of 18 were found in the
1H NMR at δ = 5.73, 5.59, 3.42, 3.14, 2.23, 1.91, and in the 13C
NMR at δ = 140.8, 130.6, 115.0, 105.2, 61.8, 40.0, 31.0, 29.1, 27.1.
Small peaks attributed to an inseparable impurity were found in the
1H NMR at δ = 6.26, 4.33.
HRMS-CI (NH3): m/z [M – OH] calcd for C18H24F: 259.1857;
found: 259.1860.
Synthesis 2013, 45, 1807–1814
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reactions of 1,2-Disubstituted 3-(Hydroxymethyl)cyclopropenes
1813
IR (neat): 3331, 3068, 2929, 2857, 1604, 1509, 1466, 1378, 1296,
1222, 1157, 1138, 1113, 1093, 1015, 893, 838, 815, 727, 531 cm–1.
References
(1) Bach, R. D.; Dmitrenko, O. J. Am. Chem. Soc. 2004, 126,
4444.
1H NMR (400 MHz, CDCl3): δ = 7.27–7.32 (m, 2 H), 6.95–7.07 (m,
2 H), 5.68 (d, J = 2.6 Hz, 1 H), 5.51 (d, J = 2.0 Hz, 1 H), 3.94 (dd,
J = 11.6, 5.8 Hz, 1 H), 3.77 (dd, J = 11.6, 9.0 Hz, 1 H), 1.92–2.04
(m, 1 H), 1.83–1.88 (m, 1 H), 1.54–1.62 (m, 1 H), 1.44 (s, 1 H),
1.22–1.28 (m, 8 H), 0.86 (t, J = 6.7 Hz, 3 H).
(2) (a) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007,
107, 3117. (b) Brandi, A.; Goti, A. Chem. Rev. 1998, 98,
589. (c) Audran, G.; Pellissier, H. Adv. Synth. Catal. 2010,
352, 575. (d) Goti, A.; Cordero, F. M.; Brandi, A. Top. Curr.
Chem. 1996, 178, 1. (e) Nakamura, I.; Yamamoto, Y. Adv.
Synth. Catal. 2002, 344, 111. (f) Yu, L.; Guo, R. Org. Prep.
Proced. Int. 2011, 43, 209.
13C NMR (100 MHz, CDCl3): 161.4 (C) [d, 1J(CF) = 243 Hz], 141.5
(C), 139.6 (C) [ d, 4J(CF) = 3 Hz], 129.5 (CH) [d, 3J(CF) = 8 Hz],
2
115.0 (CH) [d, J(CF) = 21 Hz], 104.2 (CH2), 61.4 (CH2), 32.9
(CH2), 32.6 (C), 32.2 (CH), 31.7 (CH2), 29.4 (CH2), 27.3 (CH2),
22.6 (CH2), 14.0 (CH3).
(3) (a) Zhu, Z.-B.; Liu, L.-P.; Shao, L.-X.; Shi, M. Synlett 2007,
115. (b) Ohmura, T.; Taniguchi, H.; Kondo, Y.; Suginome,
M. J. Am. Chem. Soc. 2007, 129, 3518. (c) Shi, M.; Jiang,
M.; Liu, L.-P. Org. Biomol. Chem. 2007, 5, 438. (d) Shi, M.;
Liu, L.-P.; Tang, J. Org. Lett. 2006, 8, 4043. (e) Chen, Y.;
Shi, M. J. Org. Chem. 2004, 69, 426. (f) Taniguchi, H.;
Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2009, 131,
11298. (g) Hayashi, N.; Hirokawa, Y.; Shibata, I.; Yasuda,
M.; Baba, A. J. Am. Chem. Soc. 2008, 130, 2912.
(4) (a) Hu, B.; Zhu, J.-L.; Xing, S.-Y.; Fang, J.; Du, D.; Wang,
Z.-W. Chem. Eur. J. 2009, 15, 324. (b) Kurahashi, T.; de
Meijere, A. Angew. Chem. Int. Ed. 2005, 44, 7881. (c) de
Meijere, A.; Becker, H.; Stolle, A.; Kozhushkov, S. I.; Bes,
M. T.; Salaün, J.; Noltemeyer, M. Chem. Eur. J. 2005, 11,
2471. (d) Molchanov, A. P.; Diev, V. V.; Magull, J.;
Vidović, D.; Kozhushkov, S. I.; de Meijere, A.; Kostikov, R.
R. Eur. J. Org. Chem. 2005, 593. (e) Lautens, M.; Ren, Y.
J. Am. Chem. Soc. 1996, 118, 9597. (f) Corlay, H.; Fouquet,
E.; Magnier, E.; Motherwell, W. B. Chem. Commun. 1999,
183.
HRMS-CI (NH3): m/z [M – OH] calcd for C17H22F: 245.1706;
found: 245.1694.
3α-Hexyl-2α-(hydroxymethyl)-1-methylene-3β-(o-tolyl)cyclo-
propane (19)
General procedure B with 5 (18 mg, 0.091 mmol), Fe(acac)3 (6 mg,
0.02 mmol), and 1.6 M o-tolylmagnesium bromide in THF (0.29
mL, 0.46 mmol) in hexanes (1 mL) and Et2O (0.5 mL) gave 19 (12
mg, 0.047 mmol, 51%) as a pale yellow oil. A similar experiment
with 5 (15 mg) gave 19 (12 mg, 60%).
IR (neat): 3352, 3064, 3019, 2928, 2857, 1602, 1488, 1461, 1378,
1129, 1101, 1080, 1012, 890, 758, 731 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.23–7.25 (m, 1 H), 7.15–7.17 (m,
2 H), 7.09–7.12 (m, 1 H), 5.74 (d, J = 2.6 Hz, 1 H), 5.50 (d, J = 2.0
Hz, 1 H), 3.96 (dd, J = 11.6, 6.2 Hz, 1 H), 3.88 (dd, J = 11.6, 8.5 Hz,
1 H), 2.51 (s, 3 H), 1.82–1.95 (m, 2 H), 1.49–1.61 (m, 2 H), 1.21–
1.31 (m, 8 H), 0.85 (t, J = 6.7 Hz, 3 H).
13C NMR (90 MHz, CDCl3): δ = 142.5 (C), 140.9 (C), 137.3 (C),
130.6 (CH), 130.1 (CH), 126.8 (CH), 125.2 (CH), 103.8 (CH2), 61.6
(CH2), 32.9 (C), 32.1 (C), 31.7 (CH2), 30.5 (CH), 29.5 (CH2), 27.5
(CH2), 22.6 (CH2), 19.4 (CH3), 14.0 (CH3).
(5) (a) Taillier, C.; Lautens, M. Org. Lett. 2007, 9, 591. (b) Nair,
V.; Suja, T. D.; Mohanan, K. Synthesis 2006, 2531.
(c) Kamikawa, K.; Shimizu, Y.; Takemoto, S.; Matsuzaka,
H. Org. Lett. 2006, 8, 4011. (d) Scott, M. E.; Lautens, M.
Org. Lett. 2005, 7, 3045. (e) Masarwa, A.; Furstner, A.;
Marek, I. Chem. Commun. 2009, 5760.
HRMS-ESI: m/z [M + Na] calcd for C18H26ONa: 281.1881; found:
281.1877.
(6) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2009, 131,
5060.
3β-Butyl-2α-(hydroxymethyl)-3α-methyl-2-methylene-2β-phe-
nylcyclopropane (20)
(7) (a) Xie, X.-C.; Yang, Z.; Fox, J. M. J. Org. Chem. 2010, 75,
3847. (b) Lautens, M.; Ren, Y.; Delanghe, P. H. M. J. Am.
Chem. Soc. 1994, 116, 8821. (c) Boffey, R. J.; Whittingham,
W. G.; Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1 2001,
487.
General procedure B with 3 (19 mg, 0.077 mmol), Fe(acac)3 (5 mg,
0.02 mmol), and 3.0 M MeMgBr in Et2O (0.13 mL, 0.39 mmol ) in
hexanes (1 mL) and Et2O (0.5 mL) gave 20 (9 mg, 0.039 mmol,
51%) as a pale yellow oil. A similar experiment with 3 (34 mg) gave
20 (17 mg, 53%).
(8) Nüske, H.; Bräse, S.; de Meijere, A. Synlett 2000, 1467.
(9) (a) Simaan, S.; Masarva, A.; Bertus, P.; Marek, I. Angew.
Chem. Int. Ed. 2006, 45, 3963. (b) Simaan, S.; Masarwa, A.;
Zohar, E.; Stanger, A.; Bertus, P.; Marek, I. Chem. Eur. J.
2009, 15, 8449. (c) Simaan, S.; Marek, I. Chem. Commun.
2009, 292. (d) Masarwa, A.; Stanger, A.; Marek, I. Angew.
Chem. Int. Ed. 2007, 46, 8039.
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171.
(11) Rubina, M.; Woodward, E. W.; Rubin, M. Org. Lett. 2007,
9, 5501.
IR (neat): 3405, 3059, 3024, 2956, 2929, 2871, 1601, 1493, 1446,
1378, 1149, 1012, 889, 701 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.38 (m, 5 H), 5.66 (s, 1 H),
5.52 (s, 1 H), 4.08 (d, J = 11.5 Hz, 1 H), 3.82 (d, J = 11.5 Hz, 1 H),
1.55 (s, 1 H), 1.39 (s, 3 H), 1.04–1.38 (m, 5 H), 0.77–0.85 (m, 1 H),
0.74 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 147.4 (C), 139.5 (C), 129.7 (CH),
128.2 (CH), 126.7 (CH), 102.8 (CH2), 67.1 (CH2), 38.3 (C), 35.6
(CH2), 29.5 (C), 28.8 (CH2), 22.7 (CH2), 17.5 (CH3), 14.0 (CH3).
HRMS-CI (NH3): m/z [M – OH] calcd for C16H21: 213.1643; found:
213.1641.
(12) Yang, Z.; Xie, X.; Fox, J. M. Angew. Chem. Int. Ed. 2006,
45, 3960.
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(b) Vincens, M.; Dumont, C.; Vidal, M.; Domnin, I. N.
Tetrahedron 1983, 39, 4281. (c) D’yakonov, I. A.; Kostikov,
R. R. J. Gen. Chem. USSR (Engl. Transl.) 1964, 34, 1722.
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1987, 3, 462.
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(15) In analogy to the common nomenclature of alkynes,
cyclopropenes with a single alkene substituent are referred
Acknowledgment
For financial support we thank NIGMS (NIH R01 GM068650).
Data were obtained with instrumentation supported by NSF
CRIF:MU, CHE 0840401 and CHE 1048367; NIH S10 RR026962;
NIH COBRE 2P20RR017716.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
© Georg Thieme Verlag Stuttgart · New York
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