Facially selective cu-catalyzed carbozincation of cyclopropenes using arylzinc reagents formed by sequential I/Mg/Zn exchange

Article abstract of DOI:10.1021/jo3019076

Described is a Cu-catalyzed directed carbozincation of cyclopropenes with organozinc reagents prepared by I/Mg/Zn exchange. This protocol broadens the scope with respect to functional group tolerance and enables use of aryl iodide precursors, rather than purified diorganozinc precursors. Critical to diastereoselectivity of the carbozincation step is the removal of magnesium halide salts after transmetalation with ZnCl₂.

Full text of DOI:10.1021/jo3019076

Note
pubs.acs.org/joc
Facially Selective Cu-Catalyzed Carbozincation of Cyclopropenes
Using Arylzinc Reagents Formed by Sequential I/Mg/Zn Exchange
Vinod Tarwade, Ramajeyam Selvaraj, and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware, 19716, United States
S
* Supporting Information
ABSTRACT: Described is a Cu-catalyzed directed carbozin-
cation of cyclopropenes with organozinc reagents prepared by
I/Mg/Zn exchange. This protocol broadens the scope with
respect to functional group tolerance and enables use of aryl
iodide precursors, rather than purified diorganozinc precursors.
Critical to diastereoselectivity of the carbozincation step is the removal of magnesium halide salts after transmetalation with
ZnCl2.
he directed carbometalation of cyclopropenes is a
powerful method for the construction of functionalized
Knochel and co-workers have elegantly demonstrated that
functionalized organomagnesium reagents can be made by I/
Mg exchange.13 The procedure involves combining reactive
Grignard reagents with aryl iodides that bear functional groups
including esters, halides, nitro, nitrile, alkoxy, and acetoxy
groups.13 Berman and Johnson showed that such functionalized
Grignard reagents can be treated with ZnCl2 to give rise to
functionalized diorganozinc reagents.14 Described herein is a
method for the Cu-catalyzed directed carbozincation of
cyclopropenes with functionalized organozinc reagents pre-
pared by I/Mg/Zn exchange.
T
cyclopropanes.1−3 In recent years, a number of facially selective
methods2,3 for carbomagnesation of cyclopropenes have been
described.4,5 While carbomagnesation reactions are effective
with a diverse range of nucleophiles, these protocols are not
currently compatible with cyclopropene carboxylic esters which
can be directly prepared by transition metal catalyzed reactions
of alkynes with α-diazoesters.4e Organozinc reagents tolerate a
much broader range of functional groups, including esters,
nitriles, and nitro groups.6 In pioneering work, Negishi7 and
Nakamura1 8 established that allylzinc reagents combine with
f,
Initial studies were carried out with 1-iodonaphthalene and i-
PrMgCl in diethyl ether at room temperature; I/Mg exchange
took place to form 1-naphthylmagnesium chloride. Without
isolation, this Grignard reagent was treated with ZnCl2 at room
temperature to provide (1-naphthyl)2Zn. After the trans-
metalation with zinc, it was found beneficial both in terms of
yield and diastereoselectivity to include toluene as a cosolvent.
Only complex mixtures were obtained when THF was the sole
solvent. A better result was obtained when cyclopropene
derivative 12f was treated with (1-naphthyl)2Zn in the presence
of CuCN in 1:2 diethyl ether/toluene; the desired product 3
was obtained in 66% yield but only 75:25 diastereoselectivity
(Scheme 1). It was considered that the poor diastereoselectivity
may be attributable to the presence of Mg-salts formed during
cyclopropenes. Nakamura has described the enantioselective
Fe-catalyzed addition of diorganozinc reagents to cyclo-
propenone ketals,9 and Richey has described addition reactions
of Et2Zn to spiro[2.5]oct-1-enes.10 More recently, Lautens has
described an enantioselective Pd-catalyzed carbozincation of
cyclopropenes.11
Recently, we described a facially selective method for
carbozincation of cyclopropenes.12 The stereoselectivity of
this reaction can be directed by ester or acyloxazolidinone
substituents. As only a limited number of diorganozinc reagents
are commercially available, we also investigated the in situ
formation of organozinc reagents from Grignard reagents.12 For
example, o-tolylMgBr was combined with ZnCl2, and the
resulting solution of (o-tolyl)2Zn was combined with methyl 3-
phenylcyclopropene carboxylate to give 2 after aqueous
quenching (eq 1). While this protocol broadened the scope
Scheme 1. Effect of Removing Mg-Salts on
Diastereoselectivity
of nucleophilic zinc reagents that could combine with
cyclopropenes, our protocol was still limited by the use of
preformed Grignard reagents, which excluded functional group
substitution on the nucleophile.
Received: September 4, 2012
Published: October 5, 2012
© 2012 American Chemical Society
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the dinaphthylzinc preparation. Magnesium salt byproducts
have been reported to affect the efficiency and selectivity of
reactions such as catalytic enantioselective additions of
organozinc reagents to imines.15 We speculated that the Mg-
salts reduce selectivity in the present reaction by coordinating
to the ester and impeding the ability of the ester to direct
carbozincation. Consistent with this hypothesis, it was found
that the diastereoselectivity increased to >95:5 when a slight
excess of 1,4-dioxane was added to the dinaphthyl zinc reagent
and the insoluble dioxane•MgX2 complex was removed by
centrifugation (Scheme 1).
naphthylzinc addition was combined with iodide and allyl
bromide to provide substituted cyclopropane derivatives 10 and
11 in 81% and 74% yield respectively (Scheme 2).
Scheme 2
The optimized conditions from Scheme 1 were applied to a
range of aryliodides in reactions with methyl 1-phenyl-
cycloprop-2-ene carboxylate. As shown in Table 1, phenyl,
Table 1. Sequential I/Mg/Zn Exchange and Cyclopropene
a
Carbozincation
The stereochemistry of compounds 3−11 were assigned by
analogy to rel-(1R, 2R)-methyl 1,2-diphenylcyclopropane
carboxylate, which is formed upon addition of Ph2Zn with
1.12 As expected, the methyl esters of 3−11 resonated at high
1
field (3.14 to 3.44 ppm) in the H NMR spectrum due to
shielding by the syn aryl group. For compound 6, two separable
diastereomers are formed. For the minor diastereomer of 6, in
which the aryl and methyl ester are anti, the methyl group
resonates at 3.66 ppm, considerably downfield relative to the
methyl ester for the major isomer of 6 (3.31 ppm).
In conclusion, functionalized diarylmagnesium halide re-
agents were prepared from the corresponding iodoarenes
following the Knochel protocol. These functionalized Grignard
reagents were converted to the corresponding diarylzinc
reagents by treatment with ZnCl2 and subsequently combined
with methyl 1-phenylcycloprop-1-ene carboxylate to provide
products of carbozincation. The removal of magnesium halide
salts by complexation with dioxane was critical for realizing high
diastereoselectivity in the carbozincation step. Carbozincation
adducts were quenched by water, iodine, or allyl bromide to
provide highly functionalized cyclopropanes.
EXPERIMENTAL SECTION
■
General Considerations. High grade ZnCl2 (anhydrous, beads,
−10 mesh, 99.999% or 99.99%) was used. LiCl was flame-dried under
vacuum and cooled under nitrogen. Ethyl 4-iodo-3-nitrobenzoate,16 i-
PrMgBr,17 and 12f were prepared using the reported literature
procedure.16 For 13C NMR, multiplicities were distinguished using
an APT pulse sequence, typical methylene and quaternary carbons
appear ‘up’ (u), and methine and methyl carbons appear ‘down’ (dn).
HRMS was performed using a triple-sector mass spectrometer. The
yields in Table 1 are reported as the average of two or more runs.
General Procedure for Addition of Diaryl Reagents to 1.
Diarylzinc reagents were prepared by I/Mg/Zn exchange, as described
for each individual preparation. After the point at which dioxane (or
dioxane/toluene) had been used to precipitate the Mg salts, the
mixture was centrifuged to separate the magnesium salts from the
reagent. The clear supernatant solution was carefully transferred via a
syringe to a 10 mL round-bottomed flask equipped with a stir bar and
CuCN (3.6 mg, 0.040 mmol). Care was taken not to take up the
precipitate into the syringe. The flask was cooled by an ice bath, and a
solution of 12f (35 mg, 0.20 mmol) in toluene (1 mL) was added
dropwise via syringe. After 5 min, the ice bath was removed, and the
resulting mixture was allowed to stir for 3−19 h while warming to rt.
The mixture was again cooled by an ice bath, and the reaction was
quenched by the addition of aq HCl (0.1 M). The mixture was
extracted with CH2Cl2 (25 mL × 3), and the combined organics were
a
b
All yields are the average of two runs. Diastereomers were
c
d
inseparable. Yield of the major diastereomer. PhMgBr was used
instead of i-PrMgCl. i-PrMgBr was used instead of i-PrMgCl.
e
naphthyl, and 2-thienyl iodides with a range of functionality
(nitrile, ester, nitro, alkoxy, CF3) participated in the I/Mg/Zn
exchange with subsequent carbozincation. Upon aqueous
quenching, good yields (55−81%) and high diastereoselectiv-
ities (84:16 to >95:5) were obtained in the preparations of
compounds 3−9. The carbometalation product of the di-1-
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dried (MgSO4), filtered, concentrated, and purified by chromatog-
raphy.
septum cap and a stir bar. It was evacuated through a needle and
refilled with N2 three times. 3-Iodobenzotrifluoride (0.116 mL, 0.804
mmol) was added via syringe followed by diethyl ether (0.5 mL), and
the mixture was cooled to −35 °C. To this solution was added
isopropylmagnesium chloride (0.408 mL of 1.97 M solution in THF,
0.804 mmol) via syringe. Care was taken to ensure that the Grignard
reagent did not touch the side of the tube during the addition. After 1
h at −35 °C, a solution of ZnCl2 (55 mg, 0.40 mmol) in diethyl ether
(0.5 mL) was added via syringe. Stirring was continued for 1 h at −35
°C. 1,4-Dioxane (89 mg, 0.090 mL, 1.0 mmol) was added dropwise via
syringe. Care was taken to ensure that the dioxane did not touch the
side of the tube during the addition. The mixture was then warmed to
rt and allowed to stir for 1 h. Toluene (1 mL) was added, and the
mixture was allowed to stir for 2 min. The general procedure for
addition of diarylzinc reagents to 1 was then followed, with 16 h of
stirring after addition of 1. In the GC analysis of the crude product,
two peaks were detected in a ratio of >99:1. Flash chromatography
with a gradient of hexanes to 5% diethyl ether in hexanes furnished 44
mg (0.14 mmol, 68%) of the title compound as an oil. The purity by
1H NMR was measured to be >95%. An identical experiment gave 46
mg (0.14 mmol, 71%) of the title compound.
rel-(1R, 2R)-Methyl 2-(Naphthalen-1-yl)-1-phenylcyclopro-
pane Carboxylate (3). A dry glass tube (16 mm × 150 mm
disposable culture tube, Borosilicate glass) was fitted with a septum
cap (Screw Thread, Black Phenolic, with open top, Kimble Glass Inc.,
Art. No. 73804-15425 and National Scientific, B7995-13) and a stir
bar. It was evacuated through a needle and refilled with N2 three times.
1-Iodonaphthalene (0.118 mL, 0.804 mmol) was added via syringe
followed by diethyl ether (0.5 mL). To this solution was added
isopropylmagnesium chloride (0.41 mL of 1.97 M solution in THF,
0.80 mmol) via syringe at rt. Care was taken to ensure that the
Grignard reagent did not touch the side of the tube during the
addition. After 1 h, a solution of ZnCl2 (55 mg, 0.40 mmol) in diethyl
ether (0.5 mL) was added via syringe and the mixture was allowed to
stir for 1 h. 1,4-Dioxane (89 mg, 0.090 mL, 1.0 mmol) was added
dropwise via syringe. Care was taken to ensure that the dioxane did
not touch the side of the tube during the addition. Stirring was
continued for 1 h. Toluene (1 mL) was added, and the mixture was
allowed to stir for 2 min. The general procedure for addition of
diarylzinc reagents to 1 was then followed, with 3 h of stirring after
addition of 1. Analysis of the crude product by 1H NMR showed >95%
diastereomeric purity. Flash chromatography with a gradient of
hexanes to 5% diethyl ether in hexanes furnished 48 mg (0.16
1H NMR (CDCl3, 400 MHz, δ): 7.61 (s, 1H), 7.56−7.50 (m, 4H),
7.46−7.37 (m, 3H), 7.35−7.30 (m, 1H), 3.33 (s, 3H), 2.89 (t, J = 8.0
Hz, 1H), 2.36 (dd, J = 7.6, 5.2 Hz, 1H), 1.69 (dd, J = 8.8, 4.8 Hz, 1H);
13C NMR (CDCl3, 100 MHz, δ): 170.9 (u), 139.9 (u), 138.0 (u),
1
mmol, 79%) of the title compound as an oil. The purity by H NMR
was measured to be >95%. An identical experiment gave 50 mg (0.17
mmol, 82%) of the title compound.
132.7 (dn), 130.7 (q, JCF = 32 Hz), 130.3 (dn), 128.7 (dn), 128.6
(dn), 127.8 (dn), 126.1−126.0 (q, dn), 124.4 (q, JCF = 273 Hz),
123.9−123.8 (q, dn), 52.2 (dn), 38.5 (u), 32.8 (dn), 18.7 (u); IR
(CDCl3, cm−1): 3031, 2954, 1722, 1495, 1437, 1330, 1272, 1213,
1168, 1130, 1076, 807; HRMS (CI) m/z [M+] calcd for C18H15F3O2
320.1024, found 320.1015.
1H NMR (CDCl3, 400 MHz, δ): 8.40 (app d, J = 8.8 Hz, 1H), 7.89
(app d, J = 8.8 Hz, 1H), 7.80 (app d, J = 7.6 Hz, 1H), 7.71−7.68 (m,
2H), 7.60−7.56 (m, 1H), 7.53−7.45 (m, 5H), 7.40−7.36 (m, 1H),
3.33 (app t, J = 8.2 Hz, 1H), 3.14 (s, 3H), 2.54 (dd, J = 7.6, 4.8 Hz,
1H), 1.82 (dd, J = 9.2, 5.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz, δ):
171.4 (u), 140.2 (u), 133.7 (u), 133.3 (u), 133.1 (u), 129.7 (dn), 128.8
(dn), 128.7 (dn), 127.8 (dn), 127.8 (dn), 127.5 (dn), 126.9 (dn),
126.1 (dn), 126.1 (dn), 125.7 (dn), 125.4 (dn), 124.3 (dn), 52.0 (dn),
37.6 (u), 31.0 (dn), 19.8 (u); IR (CH2Cl2, cm−1): 3030, 2953, 2872,
1723, 1599, 1498, 1436, 1317, 1237, 1199, 1175, 1113, 912; HRMS
(CI) m/z calcd for C21H18O2 302.1307, found 302.1313.
rel-(1R, 2R)-Methyl 2-(4-cyanophenyl)-1-phenylcyclopro-
pane Carboxylate (6). A dry glass tube was fitted with a septum
cap and a stir bar. It was evacuated through a needle and refilled with
N2 three times. 4-Iodobenzonitrile (184 mg, 0.804 mmol) was added
via syringe followed by THF (0.5 mL), and the mixture was cooled to
−35 °C. To this solution was added isopropylmagnesium chloride
(0.40 mL of 2.0 M solution in THF, 0.80 mmol) via syringe. Care was
taken to ensure that the Grignard reagent did not touch the side of the
tube during the addition. After 1.5 h at −35 °C, a solution of ZnCl2
(55 mg, 0.40 mmol) in THF (0.5 mL) was added via syringe. Stirring
was continued at −35 °C for 1 h. 1,4-Dioxane (89 mg, 0.090 mL, 1.0
mmol) was added dropwise via syringe. Care was taken to ensure that
the dioxane did not touch the side of the tube during the addition. The
mixture was then warmed to rt and allowed to stir for 2 h. Toluene (1
mL) was added, and the mixture was allowed to stir for 2 min. The
general procedure for addition of diarylzinc reagents to 1 was then
followed, with 16 h of stirring after addition of 1. In the GC analysis of
the crude product, two peaks were detected in a ratio of >91:9. Gravity
chromatography with a gradient of hexanes to 5% diethyl ether in
hexanes furnished 30 mg (0.11 mmol, 54%) of the major diastereomer
as a white solid, mp 120−123 °C, and 5 mg (0.02 mmol, 9%) of the
minor diastereomer as a viscous oil. The purity by 1H NMR was
measured to be >95%. An identical experiment gave 31 mg (0.11
mmol, 56%) of the major diastereomer.
rel-(1R, 2R)-Methyl 1-Phenyl-2-(thiophen-2-yl)cyclopropane
Carboxylate (4). A dry glass tube was fitted with a septum cap and a
stir bar. It was evacuated through a needle and refilled with N2 three
times. 1-Iodothiophene (0.082 mL, 0.80 mmol) was added via syringe
followed by THF (0.5 mL), and the mixture was cooled to −35 °C. To
this solution was added isopropylmagnesium chloride (0.40 mL of 2.0
M solution in THF, 0.80 mmol) via syringe. Care was taken to ensure
that the Grignard reagent did not touch the side of the tube during the
addition. After 1 h at −35 °C, a solution of ZnCl2 (55 mg, 0.40 mmol)
in THF (0.5 mL) was added via syringe. Stirring was continued for 45
min at −35 °C. 1,4-Dioxane (89 mg, 0.090 mL, 1.0 mmol) was added
dropwise via syringe. Care was taken to ensure that the dioxane did
not touch the side of the tube during the addition. The mixture was
then warmed to rt and allowed to stir for 2 h. Toluene (1 mL) was
added, and the mixture was allowed to stir for 2 min. The general
procedure for addition of diarylzinc reagents to 1 was then followed,
with 16 h of stirring after addition of 1. Flash chromatography with a
gradient of hexanes to 5% diethyl ether in hexanes furnished 36 mg
Spectral Properties of Major Diastereomer (6). 1H NMR
(CDCl3, 400 MHz, δ): 7.60−7.57 (m, 2H), 7.46−7.43 (m, 4H), 7.38−
7.27 (m, 3H), 3.31 (s, 3H), 2.84 (app t, J = 8.4 Hz, 1H), 2.33 (dd, J =
7.6, 5.2 Hz, 1H), 1.69 (dd, J = 9.2, 5.2 Hz, 1H); 13C NMR (CDCl3,
100 MHz, δ): 170.7 (u), 142.5 (u), 139.6 (u), 132.0 (dn), 130.2 (dn),
130.0 (dn), 128.6 (dn), 127.8 (dn), 119.1 (u), 110.8 (u), 52.4 (dn),
39.0 (u), 33.2 (dn), 18.9 (u); IR (CDCl3, cm−1): 3030, 2954, 2929,
2872, 2230, 1724, 1609, 1497, 1448, 1382, 1318, 1214, 1165, 1115,
1078, 1064, 1027, 910, 845; HRMS (CI) m/z [M+] calcd for
C18H15NO2 277.1103, found 277.1104.
1
(0.14 mmol, 69%) of the title compound as an oil. The purity by H
NMR was measured to be 94%. An identical experiment gave 36 mg
(0.14 mmol, 69%) of the title compound.
1H NMR (CDCl3, 400 MHz, δ): 7.50−7.48 (m, 2H), 7.40−7.30
(m, 3H), 7.20−7.18 (m, 1H), 6.97−6.96 (m, 2H), 3.43 (s, 3H), 2.89
(dd, J = 9.2, 7.2 Hz, 1H), 2.35 (dd, J = 7.2, 5.2 Hz, 1H), 1.73 (dd, J =
8.8, 4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz, δ): 170.7 (u), 140.5
(u), 139.7 (u), 130.3 (dn), 128.6 (dn), 127.7 (dn), 126.9 (dn), 126.4
(dn), 124.6 (dn), 52.4 (dn), 39.1 (u), 27.5 (dn), 20.4 (u); IR (CH2Cl2,
cm−1): 3030, 2955, 2873, 1723, 1496, 1437, 1383, 1311, 1237, 1202,
1173, 1111, 1079, 1041, 1026; HRMS (CI) m/z [M+] calcd for
C15H14O2S 258.0715, found 258.0717.
Spectral Properties of Minor Diastereomer (6a). 1H NMR
(CDCl3, 400 MHz, δ): 7.34−7.32 (m, 2H), 7.18−7.13 (m, 3H), 7.00−
6.98 (m, 2H), 6.84−6.82 (m, 2H), 3.67 (s, 3H), 3.14 (dd, J = 9.3, 7.4
Hz, 1H), 2.21 (dd, J = 9.2, 5.2 Hz, 1H), 1.91 (dd, J = 7.2, 5.2 Hz, 1H).
Impurity peaks at 1.55, 1.26, and 0.90−0.84 were also observed. 13C
rel-(1R,2R)-Methyl 1-Phenyl-2-(3-(trifluoromethyl)phenyl)-
cyclopropane Carboxylate (5). A dry glass tube was fitted with a
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Note
NMR (CDCl3, 100 MHz, δ): 173.9 (u), 142.7 (u), 134.0 (u), 131.9
(dn), 131.6 (dn), 128.8 (dn), 128.2 (dn), 127.7 (dn), 119.0 (u), 110.2
(u), 53.1 (dn), 38.5 (u), 32.8 (dn), 21.1 (u). An impurity peak was
observed at 29.9 ppm.
127.9 (dn), 125.2 (dn), 62.0 (u), 52.7 (dn), 38.4 (u), 30.2 (dn), 20.3
(u), 14.5 (dn); IR (CDCl3, cm−1): 2986, 2955, 1722, 1535, 1358,
1307, 1288, 1258, 914, 739, 651; HRMS (CI) m/z [M+] calcd for
C20H19NO6 369.1212, found 369.1205.
rel-(1R,2R)-Methyl 2-(2-nitrophenyl)-1-phenylcyclopropane
Carboxylate (7). A dry glass tube was fitted with a septum cap and
a stir bar. It was evacuated through a needle and refilled with N2 three
times. 1-Iodo-2-nitrobenzene (200 mg, 0.804 mmol) was added via
syringe followed by THF (0.5 mL), and the mixture was cooled to
−35 °C. To this solution was added phenylmagnesium bromide (0.81
mL of 1.0 M solution in THF, 0.80 mmol) via syringe. Care was taken
to ensure that the Grignard reagent did not touch the side of the tube
during the addition. After 25 min at −35 °C, a solution of ZnCl2 (55
mg, 0.40 mmol) in diethyl ether (0.5 mL) was added via syringe.
Stirring was continued at −35 °C for 30 min. 1,4-Dioxane (89 mg,
0.090 mL, 1.0 mmol) was added dropwise via syringe. Care was taken
to ensure that the dioxane did not touch the side of the tube during
the addition. The mixture was then warmed to rt and allowed to stir
for 1.5 h. The general procedure for addition of diarylzinc reagents to
1 was then followed, with 3 h of stirring after addition of 1. In the GC
analysis of the crude product, two peaks were detected in a ratio of
95:5. Gravity chromatography with a gradient of hexanes to 5% diethyl
ether in hexanes furnished 35 mg (0.12 mmol, 59%) of the title
compound as an oil. The purity by 1H NMR was measured to be 93%
(a mixture of two diastereomers in the ratio of 93:7). An identical
experiment gave 38 mg (0.13 mmol, 64%) of the title compound.
1H NMR (CDCl3, 400 MHz, δ): 7.86 (dd, J = 8.0, 1.2 Hz, 1H),
7.60−7.52 (m, 4H), 7.44−7.36 (m, 3H), 7.33−7.29 (m, 1H), 3.36 (s,
3H), 3.31 (app t, J = 8.0 Hz, 1H), 2.24 (dd, J = 7.6, 5.2 Hz, 1H), 1.73
(dd, J = 8.8, 5.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz, δ): 171.4 (u),
151.1 (u), 139.0 (u), 132.7 (dn), 132.5 (dn), 132.2 (u), 130.3 (dn),
128.6 (dn), 128.2 (dn), 127.7 (dn), 124.3 (dn), 52.6 (dn), 38.1 (u),
30.2 (dn), 20.0 (u); IR (CDCl3, cm−1): 3064, 3031, 2953, 2854, 1722,
1606, 1527, 1498, 1437, 1356, 1310, 1275, 1210, 1170, 1145, 783, 700;
HRMS (CI) m/z [M + H] calcd for C17H16NO4 298.1079, found
298.1089. Peaks attributed to the minor diastereomer were observed in
the 1H NMR spectrum: at 7.23−7.19 (m), 7.11−7.06 (m), 6.76−6.72
(m), 3.53 (t, J = 7.4 Hz), 2.18−2.11 (m), and in the 13C NMR
spectrum: 131.1 (dn), 129.1 (dn), 128.8 (dn), 128.0 (dn), 52.4 (dn),
30.3 (dn), 18.8 (u).
rel-(1R,2R)-Methyl 2-(4-Methoxyphenyl)-1-phenylcyclopro-
pane Carboxylate (9). A dry glass tube, fitted with a septum cap
and a stir bar, was charged with 4-iodoanisole (188 mg, 0.804 mmol).
It was evacuated through a needle and refilled with N2. This process
was repeated three times. Toluene (1 mL) was added via syringe. To
this solution was added isopropyl magnesium bromide (0.86 mL of
0.94 M solution in THF, 0.80 mmol) via syringe at rt. Care was taken
to ensure that the Grignard reagent did not touch the side of the tube
during the addition. The mixture was allowed to stir vigorously for 1 h.
After 1 h, a solution of ZnCl2 (55 mg, 0.40 mmol) in THF (0.5 mL)
was added via syringe and the mixture was allowed to stir for 1 h. 1,4-
Dioxane (177 mg, 0.172 mL, 2.01 mmol) was added dropwise via
syringe. Care was taken to ensure that the dioxane did not touch the
side of the tube during the addition. Stirring was continued for 2 h.
The general procedure for addition of diarylzinc reagents to 1 was then
followed, with 3 h of stirring after addition of 1. Analysis of the crude
product by GC showed a ratio of 88:12 for two diastereomers. Gravity
chromatography with a gradient of hexanes to 5% diethyl ether in
hexanes furnished 35 mg (0.12 mmol, 61%) of the title compound as
an oil. The dr by 1H NMR was measured to be 92:8. The purity by 1H
NMR was >95%. An identical experiment gave 34 mg (0.11 mmol,
60%) of the title compound.
1H NMR (CDCl3, 400 MHz, δ): 7.51 (d, J = 7.2 Hz, 2H), 7.38 (t, J
= 7.2 Hz, 2H), 7.29 (m, 3H), 6.87 (d, J = 8.4 Hz, 2H), 3.81 (s, 3H),
3.34 (s, 3H), 2.83 (app t, J = 8.4 Hz, 1H), 2.31 (dd, J = 7.6, 5.2 Hz,
1H), 1.60 (dd, J = 9.2, 5.2 Hz, 1H); Peaks in the 1H NMR attributable
to the minor diastereomer were observed at 7.15, 7.03, 6.70, 6.61, 3.70
(s), 3.67 (s), 3.07, 2.13, 1.85−1.78 ppm; 13C NMR (CDCl3, 100 MHz,
δ): 171.3 (u), 158.6 (u), 140.6 (u), 130.4 (dn), 130.2 (dn), 128.7 (u),
128.5 (dn), 127.5 (dn), 113.7 (dn), 55.4 (dn), 52.2 (dn), 38.2 (u),
32.8 (dn), 18.6 (u); Peaks in the 13C NMR attributable to the minor
diastereomer were observed at 132.2, 129.2, 128.5, 127.9, 127.1, 113.4,
55.3, 52.7, 20.7 ppm; IR (CH2Cl2, cm−1): 3005, 2954, 2839, 1720,
1612, 1515, 1497, 1438, 1306, 1247, 1214, 1197, 1179, 1164, 1119,
1063, 1036, 836; HRMS-CI (NH3) m/z: [M + Na] calcd for
C18H18O3Na 305.1154; found 305.1139.
rel-(1R,2R)-Ethyl 4-(2-(methoxycarbonyl)-2-phenylcyclo-
propyl)-3-nitrobenzoate (8). A dry glass tube was fitted with a
septum cap and a stir bar. It was evacuated through a needle and
refilled with N2 three times. The tube was then charged with ethyl 4-
iodo-3-nitrobenzoate16 (258 mg, 0.804 mmol) in THF (0.5 mL), and
the mixture was cooled to −40 °C. To this solution was added phenyl
magnesium chloride (0.40 mL of 2.0 M solution in THF, 0.80 mmol)
via syringe. Care was taken to ensure that the Grignard reagent did not
touch the side of the tube during the addition. After 25 min at −40 °C,
a solution of ZnCl2 (55 mg, 0.40 mmol) in THF (0.5 mL) was added
via syringe. Stirring was continued at −40 °C for 30 min. 1,4-Dioxane
(89 mg, 0.090 mL, 1.0 mmol) was added dropwise via syringe. Care
was taken to ensure that the dioxane did not touch the side of the tube
during the addition. The mixture was then warmed to rt and allowed
to stir for 2 h. Toluene (1 mL) was added, and the mixture was
allowed to stir for 2 min. The general procedure for addition of
diarylzinc reagents to 1 was then followed, with 19 h of stirring after
addition of 1. Analysis of the crude product by 1H NMR showed >95%
diastereomeric purity. Gravity chromatography with a gradient of
hexanes to 5% diethyl ether in hexanes furnished 45 mg (0.12 mmol,
61%) of the title compound as a light yellow solid, mp 118−120 °C.
The purity by 1H NMR was measured to be >95%. An identical
experiment gave 45 mg (0.12 mmol, 61%) of the title compound.
1H NMR (CDCl3, 400 MHz, δ): 8.50 (d, J = 2.0 Hz, 1H), 8.22 (dd,
J = 8.0, 1.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.54−7.51 (m, 2H),
7.40−7.35 (m, 2H), 7.33−7.29 (m, 1H), 4.42 (q, J = 6.8 Hz, 2H), 3.37
(s, 3H), 3.29 (app t, J = 8.0 Hz, 1H), 2.26 (dd, J = 7.6, 5.2 Hz, 1H),
1.78 (dd, J = 8.8, 5.2 Hz, 1H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz, δ): 171.2 (u), 164.5 (u), 151.1 (u), 138.6 (u),
136.8 (u), 133.1 (dn), 132.7 (dn), 130.8 (u), 130.2 (dn), 128.6 (dn),
rel-(1R,2S,3S)-Methyl 2-Iodo-3-(naphthalen-1-yl)-1-phenyl-
cyclopropane Carboxylate (10). The carbozincation procedure
was identical to that used to prepare 3, except that I2 was used instead
of aq. HCl to quench the cyclopropylzinc. Thus, after the
cyclopropylzinc reagent was stirred for 3 h at rt, solid I2 (254 mg,
1.00 mmol) was added in one portion and stirring was continued for
another 16 h. The mixture was again cooled by an ice bath, and the
reaction was quenched by the addition of aq HCl (0.1 M). A saturated
solution of sodium thiosulfate (10 mL) was added, and the mixture
was extracted with CH2Cl2 (25 mL × 3). The combined organics were
dried (MgSO4), filtered, and concentrated under reduced pressure.
Flash chromatography with a gradient of hexanes to 5% diethyl ether
in hexanes furnished 68 mg (0.16 mmol, 79%) of the title compound
as an oil. An identical experiment gave 70 mg (0.16 mmol, 81%) of the
title compound.
1H NMR (CDCl3, 400 MHz, δ): 8.19−8.16 (m, 1H), 7.91−7.89
(m, 1H), 7.85−7.83 (m, 1H), 7.72−7.69 (m, 1H), 7.63−7.60 (m, 2H),
7.53−7.40 (m, 6H), 3.86 (d, J = 8.8 Hz, 1H), 3.44 (s, 3H), 3.26 (d, J =
8.8 Hz, 1H). Peaks attributable to impurities were observed at 1.30,
1
1.00, and 0.91 ppm in H NMR; 13C NMR (CDCl3, 100 MHz, δ):
168.7 (u), 140.5 (u), 134.0 (u), 132.7 (u), 131.3 (u), 129.1 (2 carbons,
dn), 129.0 (dn), 128.3 (dn), 128.1 (dn), 127.5 (dn), 126.0 (dn), 125.8
(dn), 125.1 (dn), 124.3 (dn), 52.4 (dn), 38.5 (u), 32.8 (dn), 3.1 (dn);
Impurity peaks were observed at 34.9, 31.8, 25.5, 22.9, 20.9, 14.3 ppm.
IR (CH2Cl2, cm−1): 3053, 2986, 2954, 1734, 1447, 1436, 1306, 1264,
1197, 1176, 1156, 1046, 911, 804, 786, 721, 650; HRMS (CI) m/z [M
+ Na] calcd for C21H17IO2Na 451.0171, found 451.0171.
rel-(1R,2S,3S)-Methyl 2-Allyl-3-(naphthalen-1-yl)-1-phenyl-
cyclopropane Carboxylate (11). The carbozincation procedure
was identical to that used to prepare 3, except that allyl bromide was
9903
dx.doi.org/10.1021/jo3019076 | J. Org. Chem. 2012, 77, 9900−9904

The Journal of Organic Chemistry
Note
used instead of aq. HCl to quench the cyclopropylzinc. Thus, after the
cyclopropylzinc reagent was stirred for 3 h at rt, a solution of LiCl (3.4
mg, 0.08 mmol) in THF (1 mL) was added dropwise via syringe. After
5 min, allyl bromide (0.17 mL, 2.0 mmol) was added and the mixture
was allowed to stir for 16 h. The mixture was again cooled by an ice
bath, and the reaction was quenched by the addition of aq HCl (0.1
M). The mixture was extracted with CH2Cl2 (25 mL × 3). The
combined organics were dried (MgSO4), filtered, and concentrated
under reduced pressure. Flash chromatography with a gradient of
hexanes to 5% diethyl ether in hexanes furnished 50 mg (0.15 mmol,
(c) Banning, J. E.; Prosser, A. R.; Rubin, M. Org. Lett. 2010, 12, 1488−
1491. (d) Alnasleh, B. K.; Sherrill, W. M.; Rubina, M.; Banning, J.;
Rubin, M. J. Am. Chem. Soc. 2009, 131, 6906. (e) Alnasleh, B. K.;
Sherrill, W. M.; Rubin, M. Org. Lett. 2008, 10, 3231.
(4) Directed carbomagnesation reactions. (a) Liao, L.; Fox, J. M. J.
Am. Chem. Soc. 2002, 124, 14322. (b) Liu, X.; Fox, J. M. J. Am. Chem.
Soc. 2006, 128, 5600. (c) Yan, N.; Liu, X.; Fox, J. M. J. Org. Chem.
2008, 73, 563. (d) Simaan, S.; Marek, I. Org. Lett. 2007, 9, 2569. (e)
To date, our attempts to combine methyl cycloprop-2-ene carboxylate
with Grignard reagents under CuI-catalyzed conditions4a have only led
to complex mixtures.
(5) Directed substitution reactions with Grignard reagents:
(a) Masarwa, A.; Stanger, A.; Marek, I. Angew. Chem., Int. Ed. 2007,
46, 8039. (b) Simaan, S.; Masarwa, A.; Bertus, P.; Marek, I. Angew.
Chem., Int. Ed. 2006, 45, 3963. (c) Yang, Z.; Xie, X.; Fox, J. M. Angew.
Chem., Int. Ed. 2006, 45, 3960. (d) Xie, X.; Yang, Z.; Fox, J. M. J. Org.
Chem. 2010, 75, 3847.
(6) (a) Knochel, P.; Jones, P. Organozinc Reagents: A Practical
Approach; Oxford University Press: New York, 1999. (b) Knochel, P.;
Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F. In The Chemistry of
Organozinc Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley &
Sons: Chichester, U.K., 2006; p 287. (c) Knochel, P.; Millot, N.;
Rodrigues, A. L. Org. React. (N.Y.) 2001, 58. (d) Knochel, P.; Leuser,
H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F. In The Chemistry of
Organozinc Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley &
Sons: Chichester, U.K., 2006; p 287. (e) Lorthiois, E.; Meyer, C. In
The Chemistry of Organozinc Compounds; Rappoport, Z., Marek, I.,
Eds.; John Wiley & Sons: Chichester, U.K., 2006; p 863.
(7) Stoll, A. T.; Negishi, E.-i. Tetrahedron Lett. 1985, 26, 5671.
(8) (a) Kubota, K.; Isaka, M.; Nakamura, M.; Nakamura, E. J. Am.
Chem. Soc. 1993, 115, 5867. (b) Nakamura, M.; Arai, M.; Nakamura,
E. J. Am. Chem. Soc. 1995, 117, 1179. (c) Kubota, K.; Mori, S.;
Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 1998, 120, 13334.
(d) Nakamura, M.; Inoue, T.; Sato, A.; Nakamura, E. Org. Lett. 2000,
2, 2193.
1
73%) of the title compound as an oil. The purity of H NMR was
measured to be >95%. An identical experiment gave 52 mg (0.15
mmol, 76%) of the title compound.
1H NMR (CDCl3, 400 MHz, δ): 8.27−8.23 (m, 1H), 7.90−7.86
(m, 1H), 7.81−7.78 (m, 1H), 7.62−7.59 (m, 2H), 7.52−7.41 (m, 6H),
7.35 (m, 1H), 6.06−5.96 (m, 1H), 5.17−5.08 (m, 2H), 3.39 (d, J = 9.6
Hz, 1H), 3.37 (s, 3H), 2.74−2.59 (m, 2H), 2.19 (dt, J = 5.9, 9.5 Hz,
1H); 13C NMR (CDCl3, 100 MHz, δ): 171.4 (u), 142.8 (u), 137.9
(dn), 134.0 (u), 133.4 (u), 132.0 (u), 129.9 (dn), 129.0 (dn), 128.7
(dn), 127.9 (dn), 127.7 (dn), 127.3 (dn), 125.9 (dn), 125.7 (dn),
125.4 (dn), 124.5 (dn), 115.9 (u), 51.9 (dn), 37.7 (u), 34.5 (dn), 34.4
(dn), 29.8 (u); IR (CDCl3, cm−1): 3063, 3030, 3002, 2951, 1725,
1640, 1600, 1509, 1496, 1509, 1496, 1435, 1317, 1261, 1235, 1198,
1181, 1143, 1107, 922, 897, 804, 783, 753, 700, 650; HRMS (CI) m/z
[M + Na] calcd for C24H22O2Na 365.1518, found 365.1503.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of new compounds are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: jmfox@udel.edu.
■
(9) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000,
122, 978.
(10) Smith, M. A.; Richey, H. G., Jr. Organometallics 2007, 26, 609.
Notes
The authors declare no competing financial interest.
(11) Kramer, K.; Leong, P.; Lautens, M. Org. Lett. 2011, 13, 819.
̈
(12) Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009,
131, 5382.
ACKNOWLEDGMENTS
■
For financial support we thank NIGMS (NIH R01
GM068650). Spectra were obtained with instrumentation
supported by NSF CRIF:MU Grants: CHE 0840401 and
CHE-0541775.
(13) (a) Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124,
9390. (b) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
897.
(14) (a) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2005, 70, 364.
(b) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219.
̂ ́
(15) Cote, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771.
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