Diastereoselective one-pot knoevenagel condensation/corey-chaykovsky cyclopropanation

Article abstract of DOI:10.1021/jo302443k

Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure

Full text of DOI:10.1021/jo302443k

Note
pubs.acs.org/joc
Diastereoselective One-Pot Knoevenagel Condensation/Corey−
Chaykovsky Cyclopropanation
Jeremy J. Clemens,* Juliana L. Asgian, Brett B. Busch, Timothy Coon, Justin Ernst, Leonard Kaljevic,
Paul J. Krenitsky, Timothy D. Neubert, Edwin J. Schweiger,† Andreas Termin, and Dean Stamos
Department of Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: Efforts to substitute the cyclopropane ring in a series of
aryl cyclopropylnitriles led to the discovery of an operationally simple
one-pot method for Knoevenagel condensation and subsequent Corey−
Chaykovsky cyclopropanation giving diastereomerically pure products as
a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the
reaction are reported. A concise synthesis of ( )-bicifadine in two steps is provided to demonstrate the utility of the method.
risubstituted aryl cyclopropylnitriles have found utility in
benzyloxyacetaldehyde 2a the method was found to proceed
Torganic synthesis as precursors to a wide variety of natural favorably by utilizing catalytic cesium carbonate as the base in
products,1,2 biologically active compounds,3,4 and important
N-methylpyrrolidinone (NMP) to give a mixture of aldol
adduct 3 and desired olefin 4 in a 4:1 ratio and 79% combined
materials.5,6 Current methodology to rapidly assemble these
yield (Scheme 1). The products are separated, and compound 3
is dehydrated by treatment with methanesulfonyl chloride and
pyridine to give additional 4 in 73% yield. The resulting
acrylonitrile was then subjected to a Corey−Chaykovsky
cyclopropanation using potassium tert-butoxide in DMSO
giving compound 5 in 66% yield and 41% overall yield for
the three-step process.
compounds primarily relies on addition/cyclization reactions
between aryl acetonitriles and epihalohydrins7,8 or 1,4-additions
of aryl acetonitriles in anionic9−12 or ylide13−15 forms to
Michael acceptors followed by a cyclization step. Additional
approaches to access trisubstituted aryl cyclopropylnitriles
include carbenoid chemistry16−18 or the treatment of
acrylonitriles with sulfur/sulfoxonium ylides19,20 or photo-
chemical conditions.21 A rapid method for the introduction of a
wider variety of groups on the cyclopropyl ring directly from
aryl acetonitriles in one step is, however, lacking. Dimethylsul-
foxonium methylide, or “the Corey ylide,” has proven to be an
excellent tool in the synthesis of a wide variety of functional
groups including epoxides, aziridines, and cyclopropanes since
its inception nearly five decades ago. In one embodiment of
use, the ylide is known to readily cyclopropanate α,β-
unsaturated nitriles to give the corresponding cyclopropylni-
triles in excellent yields.22,23
Here, we wish to report a one-pot procedure in which the
basic conditions utilized to generate the Corey ylide in situ
combine to catalyze a Knoevenagel condensation between aryl
acetonitriles and aldehydes with the intermediate α,β-
unsaturated nitriles undergoing cyclopropanation to give tri-
and tetrasubstituted aryl cyclopropylnitriles diastereoselectively
as a racemic mixture of two enantiomers. The reported reaction
represents the transformation of a methylene group into an all-
carbon quaternary center in one pot. Method development,
scope, and an example of the utility of this facile transformation
are reported.
The observation that both the condensation and cyclo-
propanation reactions take place under basic conditions in polar
solvent led to the hypothesis that the reactions could be
performed in tandem in one pot. To this end, compounds 1a
and 2a (1 equiv each) were combined in DMSO followed by
the addition of trimethylsulfoxonium iodide and potassium tert-
butoxide (1.1 equiv each). The mixture was stirred for 30 min
at room temperature giving product 5 in 40% yield as a single
diastereomer after workup and purification (racemic mixture of
enantiomers; relative stereochemistry proven by NOE after
reduction of the nitrile; see Supporting Information).
Manipulating the stoichiometry of the reaction resulted in an
optimized 62% yield using 2 equiv of activated methylene
compound, trimethylsulfoxonium iodide, and potassium tert-
butoxide accompanied with 1 equiv of aldehyde (Table 1).
In a scan of reaction conditions, lithium, sodium, and
potassium bis(trimethylsilyl)amide as well as potassium tert-
butoxide were found to be suitable bases. The utilization of
cesium carbonate, 1,8-diazabicylclo[5.4.0]undec-7-ene, or
sodium tert-butoxide suppressed the yield of the reaction.
Both DMSO and THF were found to be suitable solvents.
Manipulating the order of addition, temperature, concentration,
and duration and attempting to preform the Corey ylide did
not improve the yield. In summary, optimal yields were
Arising from our desire to diastereoselectively substitute the
cyclopropyl ring of a geminal aryl/nitrile cyclopropane with
functionality syn with respect to the nitrile, we envisioned a
two-step process involving Knoevenagel condensation of aryl
acetonitriles with aldehydes followed by cyclopropanation of
the resulting olefin. In the case of phenylacetonitrile 1a and
Received: November 13, 2012
© XXXX American Chemical Society
A
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Note
Scheme 1. Three-Step Synthesis of Compound 5
the Knoevenagel adduct intermediate of aryl nitrile to aldehyde
was observed in the crude mixture (Scheme 3).
Table 1. Optimization of Reaction Stoichiometry
In order to demonstrate the utility of the method, the
synthesis of bicifadine was targeted in an attempt to produce
this biologically interesting serotonin/norepinephrine reuptake
inhibitor in racemic form rapidly.24,25 To this end, 4-
methylphenylacetonitrile 13 and benzyloxyacetaldehyde 2a
were subjected to the cyclopropanation method giving
compound 14 in 55% yield (Scheme 4). Compound 14 was
next heated to 175 °C by microwave irradiation in the presence
of lithium aluminum hydride in an effort to effectively reduce
the nitrile. On inspection of the reaction, however, the
displacement of the benzyloxy anion by the newly produced
amine had occurred giving ( )-bicifadine as the HCl salt after
purification in 66% yield.
In summary we have reported a novel, one-pot Knoevenagel
condensation/Corey−Chaykovsky cyclopropanation sequence
between activated methylenes and aldehydes to produce
differentially substituted and diastereomerically pure cyclo-
propanes. An optimized method is provided along with results
for variably substituted aryl acetonitriles and benzaldehydes in
the reaction. Additionally the method was applied to a concise
synthesis of ( )-bicifadine in two steps and 36% overall yield.
equivalents
O(CH3)3S+I−
a
1a
2a
KOtBu
yield (%)
1
1
1
1
1
2
1
1
1
1
2
1
1.1
1.5
1.1
2
1.1
1.5
2
40
40
42
40
26
62
1.1
2
2
2
2
a
Reactions run at 0.25 mmol scale, 1 M in DMSO, quenched by
addition of saturated aqueous ammonium chloride.
obtained by adding 2 equiv of potassium tert-butoxide to a
stirring solution of activated methylene compound (2 equiv),
aldehyde (1 equiv), and trimethylsulfoxonium iodide (2 equiv)
in DMSO at room temperature followed by stirring for 20 min
and quenching with saturated aqueous ammonium chloride.
With reaction conditions determined, the reactivity of a set of
seven aryl acetonitriles with benzyloxyacetaldehyde as well as
nine benzaldehydes with phenylacetonitrile was assessed, the
results of which are included in Table 2. Yields in the
transformation fell generally in the ∼50−75% range.
In all cases, analysis of crude reaction mixtures by LCMS
showed the formation of diastereomerically pure products
(racemic mixture of enantiomers). The cyclopropyl substitution
arising from the aldehyde bears a syn relationship to the nitrile
group in the case of phenylacetonitrile and benzyloxyacetalde-
hyde (proven by NOE after reduction of the nitrile of 5; see
Scheme 2 and Supporting Information). This observation can
be rationalized by increased steric repulsion imparted by the
aryl ring (relative to the nitrile) on the aldehyde derived side
chain during 1,3-elimination of dimethylsulfoxide in the
cyclopropanation of the intermediate acrylonitrile. This effect
has previously been reported in the construction of similar
cyclopropanes from cyanohydrins.1,8
EXPERIMENTAL SECTION
■
General. Reactions were performed in sealed glass vials under an
air atmosphere. Commercially available reagents and solvents were
used without further purification. 1D-NMR spectra were recorded
using a 400 or 500 MHz spectrometer with TMS as the internal
standard. 2D-NMR was recorded on a 500 MHz spectrometer.
Chemical shifts (δ) are given in parts per million (ppm) and coupling
constants (J) are reported in Hertz (Hz). Column chromatography
was performed on normal phase silica gel (230−400 mesh, 35−70
μm). Reversed-phase preparatory HPLC was performed on a 5 μm
C18 column. HRMS analysis was performed on an ESI-TOF mass
spectrometer or Orbitrap mass spectrometer. A 2 mg/mL solution of
sodium iodide in isopropanol was infused through a reference channel
and used as a lock mass for correction calculations. Mass accuracy
errors were obtained using the formula: [[(observed mass) − (exact
mass)]/exact mass − 1] * 1000000 = error (ppm).
General Procedure for the One-Pot Knoevenagel Con-
densation/Corey−Chaykovsky Cyclopropanation. General Pro-
cedure A. To a stirring solution of activated methylene compound (2
mmol) and aldehyde (1 mmol) in 1 mL of DMSO was added
trimethylsulfoxonium iodide (2 mmol) followed by potassium tert-
butoxide (2 mmol), and the suspension was stirred at room
temperature for 20 min. Saturated aqueous ammonium chloride (5
mL) was added, and the mixture was extracted with diethyl ether (3 ×
5 mL). The organic phases were combined, dried (magnesium sulfate),
filtered, concentrated, and purified as indicated below. Compounds
purified by reversed-phase HPLC used a gradient from 1 to 99%
mobile phase B (mobile phase A = 0.1% HCl in water, mobile phase B
= 0.1% HCl in CH3CN). Compounds purified by silica gel
Construction of the pyrrolidine ring of ( )-bicifadine as
described below also demonstrates the syn relationship between
the nitrile group and aldehyde derived functionality. Minimal
byproducts were observed in the crude reaction mixtures, with
the mass balance of the low yielding reactions comprised of
unreacted starting materials or degradation to unidentifiable
products. Occasionally a small amount of byproduct 12 (0−
20% by UV detection in LCMS at 254 nm) presumably arising
from nucleophilic 1,4-addition of deprotonated aryl nitrile to
B
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Note
Table 2. Synthesis of 8a−p by the One-Pot Knoevenagel Condensation/Corey−Chaykovsky Cyclopropanation Reaction
a
Isolated yields. Reactions run at 1 mmol scale, 1 M in DMSO, quenched by addition of saturated aqueous ammonium chloride.
10.7 Hz, 1H), 2.03−1.84 (m, 1H), 1.67−1.53 (m, 2H). 13C NMR (101
Scheme 2. Reduction of 5 and Determination of Relative
Stereochemistry of Cyclopropane Ring
MHz, CDCl3) δ 138.0, 136.0, 129.1, 128.7, 128.1, 128.02, 127.96,
126.2, 120.7, 73.6, 70.6, 29.5, 21.8, 19.7. HRMS calculated for [M +
H]+ (C18H17NOH+) 264.1388, found 264.1396.
2-(Benzyloxymethyl)-1-(pyridin-2-yl)cyclopropanecarbo-
nitrile (8a). Prepared in 69% yield (182.4 mg) from 2-(pyridin-2-
yl)acetonitrile and benzyloxyacetaldehyde using General Procedure A.
Purification by silica gel column chromatography gave 8a as a colorless
oil. 1H NMR (400 MHz, CDCl3) δ 8.46−8.39 (m, 1H), 7.73−7.68 (m,
1H), 7.68−7.61 (m, 1H), 7.41−7.29 (m, 4H), 7.29−7.23 (m, 1H),
chromatography used a gradient from 100% hexanes to 100% ethyl
acetate unless otherwise noted.
7.16−7.10 (m, 1H), 4.62 (d, J = 11.8 Hz, 1H), 4.58 (d, J = 11.8 Hz,
1H), 3.91 (dd, J = 5.3, 10.8 Hz, 1H), 3.65 (dd, J = 8.3, 10.8 Hz, 1H),
2-(Benzyloxymethyl)-1-phenylcyclopropanecarbonitrile (5).
2.43−2.31 (m, 1H), 2.02 (dd, J = 4.6, 8.9 Hz, 1H), 1.58 (dd, J = 4.6,
Prepared in 62% yield (163.3 mg) from phenylacetonitrile and
7.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 154.1, 149.5, 137.8,
benzyloxyacetaldehyde using General Procedure A. Purification by
1
136.6, 128.4, 127.83, 127.75, 122.0, 120.9, 120.0, 73.3, 70.1, 30.8, 23.3,
21.0. HRMS calculated for [M + H]+ (C17H16N2OH+) 265.1341,
found 265.1340.
reversed-phase preparatory HPLC gave 5 as a tan oil. H NMR (400
MHz, CDCl3) δ 7.44−7.16 (m, 10H), 4.64 (d, J = 11.8 Hz, 1H), 4.59
(d, J = 11.8 Hz, 1H), 3.86 (dd, J = 5.7, 10.7 Hz, 1H), 3.70 (dd, J = 7.9,
C
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120.0, 119.0, 73.8, 70.1, 31.5, 23.4, 19.3. HRMS calculated for [M +
H]+ (C17H16N2OH+) 265.1341, found 265.1353.
Scheme 3. Proposed Mechanism for the Formation of
Product 11 and Minor Byproduct 12
2-(Benzyloxymethyl)-1-(thiophen-2-yl)cyclopropanecarbo-
nitrile (8d). Prepared in 45% yield (121.2 mg) from 2-(thiophen-2-
yl)acetonitrile and benzyloxyacetaldehyde using General Procedure A.
Purification by silica gel column chromatography using a gradient from
100% hexanes to 30% ethyl acetate/hexanes gave 8d as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.44−7.33 (m, 4H), 7.33−7.26 (m,
1H), 7.18 (dd, J = 1.2, 5.2 Hz, 1H), 7.06 (dd, J = 1.2, 3.6 Hz, 1H), 6.93
(dd, J = 3.6, 5.2 Hz, 1H), 4.64 (d, J = 11.8 Hz, 1H), 4.59 (d, J = 11.8
Hz, 1H), 3.83 (dd, J = 5.6, 10.8 Hz, 1H), 3.66 (dd, J = 7.9, 10.8 Hz,
1H), 2.04−1.92 (m, 1H), 1.62 (two overlapping doublet of doublets, J
= 5.6, 8.0, 6.1, 7.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 140.2,
137.9, 128.7, 128.0 (2C), 127.4, 126.2, 125.0, 119.9, 73.6, 70.1, 30.8,
23.3, 15.8. HRMS calculated for [M + H]+ (C16H15NOSH+) 270.0952,
found 270.0944.
2-(Benzyloxymethyl)-1-(4-chlorophenyl)cyclopropane-
carbonitrile (8e). Prepared in 51% yield (152.0 mg) from 4-
chlorophenylacetonitrile and benzyloxyacetaldehyde using General
Procedure A. Purification by reversed-phase preparatory HPLC gave
1
8e as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.42−7.26 (m,
7H), 7.26−7.19 (m, 2H), 4.63 (d, J = 11.8 Hz, 1H), 4.59 (d, J = 11.8
Hz, 1H), 3.87 (dd, J = 5.5, 10.7 Hz, 1H), 3.65 (dd, J = 8.0, 10.7 Hz,
1H), 1.93−1.82 (m, 1H), 1.58 (two overlapping doublet of doublets, J
= 5.8, 8.2, 6.0, 7.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 137.9,
134.7, 133.9, 129.3, 128.7, 128.0 (2C), 127.7, 120.3, 73.7, 70.4, 29.7,
21.7, 19.2. HRMS calculated for [M + H]+ (C18H16ClNOH+)
298.0998, found 298.0989.
2-(Benzyloxymethyl)-1-(4-bromophenyl)cyclopropane-
carbonitrile (8f). Prepared in 61% yield (208.7 mg) from 4-
bromophenylacetonitrile and benzyloxyacetaldehyde using General
Procedure A. Purification by reversed-phase preparatory HPLC gave 8f
as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.50−7.43 (m, 2H),
7.40−7.32 (m, 4H), 7.32−7.26 (m, 1H), 7.20−7.13 (m, 2H), 4.64 (d, J
= 11.8 Hz, 1H), 4.59 (d, J = 11.8 Hz, 1H), 3.86 (dd, J = 5.5, 10.7 Hz,
1H), 3.65 (dd, J = 8.0, 10.7 Hz, 1H), 1.95−1.82 (m, 1H), 1.58 (two
overlapping doublet of doublets, J = 5.8, 7.7, 6.5, 7.8 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 137.9, 135.2, 132.3, 128.7, 128.09, 128.08,
128.0, 122.0, 120.2, 73.7, 70.4, 29.7, 21.8, 19.3. HRMS calculated for
[M + H]+ (C18H16BrNOH+) 342.0493, found 342.0509.
Scheme 4. Two-Step Synthesis of ( )-Bicifadine Utilizing
the One-Pot Knoevenagel Condensation/Corey−
Chaykovsky Cyclopropanation Reaction
2-(Benzyloxymethyl)-1-(4-iodophenyl)cyclopropanecarbo-
nitrile (8g). Prepared in 48% yield (187.2 mg) from 4-
iodophenylacetonitrile and benzyloxyacetaldehyde using General
Procedure A. Purification by reversed-phase preparatory HPLC gave
1
8g as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.71−7.63 (m,
2H), 7.41−7.32 (m, 4H), 7.32−7.27 (m, 1H), 7.07−7.00 (m, 2H),
4.64 (d, J = 11.8 Hz, 1H), 4.59 (d, J = 11.8 Hz, 1H), 3.86 (dd, J = 5.5,
10.7 Hz, 1H), 3.66 (dd, J = 8.0, 10.7 Hz, 1H), 1.95−1.83 (m, 1H),
1.60 (two overlapping doublet of doublets, J = 5.8, 6.7, 5.8, 6.3 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 138.2, 137.9, 136.0, 128.7,
128.12, 128.09, 128.07, 120.2, 93.3, 73.7, 70.4, 29.8, 21.9, 19.4. HRMS
calculated for [M + H]+ (C18H16INOH+) 390.0355, found 390.0364.
1,2-Diphenylcyclopropanecarbonitrile (8h). Prepared in 60%
yield (131.6 mg) from phenylacetonitrile and benzaldehyde using
General Procedure A. Purification by reversed-phase preparatory
2-(Benzyloxymethyl)-1-(pyridin-3-yl)cyclopropanecarbo-
nitrile (8b). Prepared in 74% yield (195.5 mg) from 2-(pyridin-3-
yl)acetonitrile and benzyloxyacetaldehyde using General Procedure A.
Purification by reversed-phase preparatory HPLC gave 8b as a yellow
oil. 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J = 1.7 Hz, 1H), 8.80 (d, J
= 5.3 Hz, 1H), 8.52 (d, J = 8.1 Hz, 1H), 7.94 (dd, J = 5.6, 8.1 Hz, 1H),
7.40−7.31 (m, 4H), 7.31−7.25 (m, 1H), 4.63 (d, J = 11.8 Hz, 1H),
4.59 (d, J = 11.8 Hz, 1H), 4.04 (dd, J = 4.3, 10.9 Hz, 1H), 3.58 (dd, J =
8.6, 10.9 Hz, 1H), 2.29−2.18 (m, 1H), 2.08 (dd, J = 6.4, 9.1 Hz, 1H),
1.91 (dd, J = 6.6, 7.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 143.7,
140.0, 138.5, 138.1, 137.6, 128.7, 128.23, 128.16, 127.1, 117.9, 73.9,
69.6, 32.6, 23.3, 18.2. HRMS calculated for [M + H]+ (C17H16N2OH+)
265.1341, found 265.1328
2-(Benzyloxymethyl)-1-(pyridin-4-yl)cyclopropanecarbo-
nitrile (8c). Prepared in 57% yield (150.6 mg) from 2-(pyridin-4-
yl)acetonitrile and benzyloxyacetaldehyde using General Procedure A.
Purification by reversed-phase preparatory HPLC gave 8c as an orange
oil after addition of aqueous sodium bicarbonate and extraction with
ethyl acetate. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 5.5 Hz, 2H),
7.40−7.32 (m, 4H), 7.32−7.27 (m, 1H), 7.20−7.15 (m, 2H), 4.63 (d, J
= 11.8 Hz, 1H), 4.58 (d, J = 11.8 Hz, 1H), 3.90 (dd, J = 5.3, 10.7 Hz,
1H), 3.68 (dd, J = 7.9, 10.7 Hz, 1H), 2.07−1.96 (m, 1H), 1.73 (two
overlapping doublet of doublets, J = 5.9, 11.2, 6.0, 12.7 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 150.3, 145.7, 137.7, 128.7, 128.2, 128.1,
1
HPLC gave 8h as a colorless oil. H NMR (400 MHz, CDCl3) δ
7.46−7.36 (m, 6H), 7.36−7.28 (m, 4H), 2.79 (dd, J = 8.4 Hz, 1H),
2.20 (dd, J = 6.2, 7.8 Hz, 1H), 2.01 (dd, J = 7.6, 16.5 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 136.4, 135.1, 129.2, 128.9, 128.3, 128.1,
128.0, 125.9, 120.1, 35.6, 24.0, 22.0. HRMS calculated for [M + H]+
(C16H13NH+) 220.1121, found m/z 220.1122.
2-(Naphthalen-2-yl)-1-phenylcyclopropanecarbonitrile (8i).
Prepared in 64% yield (172.9 mg) from phenylacetonitrile and 2-
naphthaldehyde using General Procedure A. Purification by silica gel
column chromatography gave 8i as a slightly off-white solid. 1H NMR
(400 MHz, CDCl3) δ 7.90−7.81 (m, 3H), 7.80−7.75 (m, 1H), 7.53−
7.29 (m, 8H), 2.96 (t, J = 8.4 Hz, 1H), 2.35 (dd, J = 6.2, 7.8 Hz, 1H),
2.09 (dd, J = 6.2, 8.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 136.4,
133.5, 133.2, 132.7, 129.3, 128.7, 128.1, 128.03, 127.95, 127.2, 126.6,
D
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126.4, 126.3, 125.9, 120.1, 35.9, 24.2, 22.2. HRMS calculated for [M +
H]+ (C20H15NH+) 270.1282, found 270.1295.
2-(3,5-Dimethoxyphenyl)-1-phenylcyclopropanecarbonitrile
(8p). Prepared in 53% yield (148.5 mg) from phenylacetonitrile and
3,5-dimethoxybenzaldehyde using General Procedure A. Purification
by reversed-phase preparatory HPLC gave 8p as a yellow oil. 1H NMR
(400 MHz, CDCl3) δ 7.43−7.35 (m, 4H), 7.35−7.29 (m, 1H), 6.47
(d, J = 2.2 Hz, 2H), 6.42 (t, J = 2.2 Hz, 1H), 3.80 (s, 6H), 2.73 (t, J =
8.4 Hz, 1H), 2.16 (dd, J = 6.2, 7.8 Hz, 1H), 1.97 (dd, J = 6.2, 8.9 Hz,
1H). 13C NMR (101 MHz, CDCl3) δ 161.1, 137.4, 136.4, 129.2, 128.0,
125.9, 120.0, 106.5, 100.1, 55.6, 35.8, 23.9, 22.2. HRMS calculated for
[M + H]+ (C18H17NO2H+) 280.1337, found 280.1346.
(2-(Benzyloxymethyl)-1-phenylcyclopropyl)methanamine
(9). To a stirring solution of 3 (35.7 mg, 0.1356 mmol) in 0.5 mL of
THF under a nitrogen atmosphere lithium aluminum hydride (2.5 M
in THF, 54.2 μL, 0.1356 mmol) was added dropwise. The solution was
warmed to room temperature, stirred 16 h, filtered, and washed with
MeOH and the filtrate was concentrated and purified by reversed-
phase preparatory HPLC using a gradient from 1 to 99% mobile phase
B (mobile phase A = 0.1% HCl in water, mobile phase B = 0.1% HCl
in CH3CN) giving 5.0 mg of 9 as a colorless oil in 14% yield (5.0 mg).
1H NMR (400 MHz, DMSO) δ 7.84 (bs, 2H), 7.38 (d, J = 4.4 Hz,
2-(4-(Dimethylamino)phenyl)-1-phenylcyclopropanecarbo-
nitrile (8j). Prepared in 73% yield (192.1 mg) from phenylacetonitrile
and 4-(dimethylamino)benzaldehyde using General Procedure A with
the exception that saturated aqueous sodium bicarbonate was used to
quench and ethyl acetate was used in extraction. Purification by silica
1
gel column chromatography gave 8j as a yellow solid. H NMR (400
MHz, CDCl3) δ 7.42−7.34 (m, 4H), 7.34−7.27 (m, 1H), 7.23−7.16
(m, 2H), 6.79−6.69 (m, 2H), 2.96 (s, 6H), 2.72 (t, J = 8.4 Hz, 1H),
2.15 (dd, J = 6.1, 7.9 Hz, 1H), 1.95 (dd, J = 6.1, 9.0 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 142.7, 136.8, 129.1, 129.0, 127.7, 125.7,
122.5, 120.6, 112.7, 40.7, 35.8, 23.9, 22.2. HRMS calculated for [M +
H]+ (C18H18N2H+) 263.1548, found 263.1559.
2-(3-(Dimethylamino)phenyl)-1-phenylcyclopropanecarbo-
nitrile (8k). Prepared in 58% yield (152.7 mg) from phenylacetonitrile
and 3-(dimethylamino)benzaldehyde using General Procedure A.
Purification by reversed-phase preparatory HPLC gave 8k as a yellow
oil after addition of saturated aqueous sodium bicarbonate and
1
extraction with ethyl acetate. H NMR (400 MHz, CDCl3) δ 7.40−
7.35 (m, 4H), 7.34−7.27 (m, 1H), 7.27−7.20 (m, 1H), 6.70−6.64 (m,
3H), 2.95 (s, 6H), 2.74 (t, J = 8.4 Hz, 1H), 2.17 (dd, J = 6.1, 7.9 Hz,
1H), 1.95 (dd, J = 6.1, 9.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
150.9, 136.7, 135.8, 129.4, 129.1, 127.8, 125.8, 120.2, 116.1, 112.4,
112.3, 40.7, 36.3, 23.8, 22.3. HRMS calculated for [M + H]+
(C18H18N2H+) 263.1548, found 263.1537.
4H), 7.36 (d, J = 4.3 Hz, 4H), 7.32 (dd, J = 4.3, 8.3 Hz, 1H), 7.28 (dd,
J = 4.3, 8.7 Hz, 1H), 4.58 (d, J = 12.0 Hz, 1H), 4.53 (d, J = 12.0 Hz,
1H), 3.82 (dd, J = 5.9, 10.9 Hz, 1H), 3.55 (dd, J = 9.1, 10.8 Hz, 1H),
3.37 (dd, J = 7.0, 14.0 Hz, 1H), 3.02 (d, J = 13.7 Hz, 1H), 1.51−1.39
(m, 1H), 1.25 (dd, J = 5.1, 8.8 Hz, 1H), 1.13−1.02 (m, 1H). 13C NMR
(126 MHz, DMSO) δ 144.5, 138.6, 129.0, 128.3, 128.1, 127.5, 127.4,
126.1, 71.8, 69.8, 46.2, 23.7, 16.1.
2-(4-Methoxyphenyl)-1-phenylcyclopropanecarbonitrile
(8l). Prepared in 93% yield (232.6 mg) from phenylacetonitrile and 4-
methoxybenzaldehyde using General Procedure A. Purification by
2-(Benzyloxymethyl)-1-p-tolylcyclopropanecarbonitrile
(14). Prepared in 55% yield (153.0 mg) from 4-methylphenylacetoni-
trile (6.658 mmol) and benzyloxyacetaldehyde (3.329 mmol) using
General Procedure A. Purification by silica gel column chromatog-
1
silica gel column chromatography gave 8l as a colorless oil. H NMR
(400 MHz, CDCl3) δ 7.42−7.34 (m, 4H), 7.34−7.28 (m, 1H), 7.28−
7.22 (m, 2H), 6.96−6.88 (m, 2H), 3.81 (s, 3H), 2.75 (t, J = 8.4 Hz,
1H), 2.15 (dd, J = 6.1, 7.8 Hz, 1H), 1.98 (dd, J = 6.1, 9.0 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 159.5, 136.5, 129.5, 129.2, 127.8, 127.2,
125.7, 120.3, 114.3, 55.5, 35.3, 23.9, 22.2. HRMS calculated for [M +
H]+ (C17H15NOH+) 250.1232, found 250.1223.
1
raphy gave 14 as a pale orange oil. H NMR (400 MHz, CDCl3) δ
7.41−7.31 (m, 4H), 7.31−7.25 (m, 1H), 7.21−7.16 (m, 2H), 7.16−
7.09 (m, 2H), 4.63 (d, J = 11.8 Hz, 1H), 4.58 (d, J = 11.8 Hz, 1H),
3.84 (dd, J = 5.7, 10.7 Hz, 1H), 3.68 (dd, J = 7.9, 10.7 Hz, 1H), 2.32
(s, 3H), 1.92−1.81 (m, 1H), 1.57 (dd, J = 5.6, 8.7 Hz, 1H), 1.51 (dd, J
= 5.6, 7.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 138.0, 137.8,
133.0, 129.7, 128.6, 128.0, 127.9, 126.2, 120.8, 73.5, 70.6, 29.2, 21.5,
21.1, 19.3. HRMS calculated for [M + H]+ (C19H19NOH+) 278.1545,
found 278.1555.
2-(3-Methoxyphenyl)-1-phenylcyclopropanecarbonitrile
(8m). Prepared in 61% yield (152.6 mg) from phenylacetonitrile and
3-methoxybenzaldehyde using General Procedure A. The crude
product was purified by reversed-phase preparatory HPLC giving
1
8m as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.43−7.36 (m,
1-p-Tolyl-3-azabicyclo[3.1.0]hexane·HCl (( )-Bicifadine·HCl).
To a stirring solution of 14 (300 mg, 1.082 mmol) in THF (10.85
mL) under a nitrogen atmosphere at 0 °C lithium aluminum hydride
(2.5 M in THF, 2.705 mL, 5.410 mmol) was added dropwise. The
solution was warmed to room temperature, capped, and heated under
microwave irradiation to 175 °C for 2.5 h. The reaction was quenched
with water followed by 5 N NaOH (3 mL) and diluted with saturated
aqueous potassium sodium tartrate (100 mL). This solution was
extracted with dichloromethane (3 × 75 mL), and the organic
fractions were combined, dried (MgSO4), filtered, and concentrated to
a clear oil which was purified by reversed-phase preparatory HPLC
using a gradient from 1 to 99% mobile phase B (mobile phase A =
0.05% HCl in water, mobile phase B = 0.05% HCl in CH3CN) giving
( )-bicifadine•HCl as a white solid in 66% yield (149 mg). 1H NMR
(400 MHz, DMSO) δ 9.53 (bs, 2H), 7.17−7.11 (m, 4H), 3.65 (d, J =
11.2 Hz, 1H), 3.47 (dd, J = 3.8, 11.2 Hz, 1H), 3.40 (d, 1H), 3.35 (d,
1H), 2.27 (s, 3H), 2.10−2.01 (m, 1H), 1.31 (t, J = 6.5 Hz, 1H), 1.03
(t, J = 7.2 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 136.2, 135.7,
129.0, 126.5, 49.5, 46.9, 30.1, 23.0, 20.6, 15.3. HRMS calculated for [M
+ H]+ (C12H15NH+) 174.1282, found 174.1283.
4H), 7.36−7.28 (m, 2H), 6.95−6.90 (m, 1H), 6.89−6.84 (m, 2H),
3.82 (s, 3H), 2.77 (t, J = 8.4 Hz, 1H), 2.19 (dd, J = 6.2, 7.8 Hz, 1H),
2.00 (dd, J = 6.1, 8.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 160.0,
136.7, 136.4, 129.9, 129.2, 128.0, 125.9, 120.5, 120.1, 114.2, 113.5,
55.5, 35.7, 24.0, 22.1. HRMS calculated for [M + H]+ (C17H15NOH+)
250.1232, found 250.1227.
2-(2-Methoxyphenyl)-1-phenylcyclopropanecarbonitrile
(8n). Prepared in 61% yield (152.6 mg) from phenylacetonitrile and 2-
methoxybenzaldehyde using General Procedure A. Purification by
1
reversed-phase preparatory HPLC gave 8n as a white solid. H NMR
(400 MHz, CDCl3) δ 7.53−7.47 (m, 2H), 7.43−7.36 (m, 2H), 7.36−
7.29 (m, 2H), 7.21−7.15 (m, 1H), 7.02−6.93 (m, 2H), 3.90 (s, 3H),
2.82 (t, J = 8.3 Hz, 1H), 2.10 (dd, J = 5.8, 7.9 Hz, 1H), 1.91 (dd, J =
5.8, 8.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 159.3, 137.0, 129.4,
129.0, 128.5, 127.9, 127.0, 124.3, 120.8, 120.7, 110.6, 55.7, 30.2, 22.8,
20.9. HRMS calculated for [M + H]+ (C17H15NOH+) 250.1232, found
250.1228.
2-(3,4-Dimethoxyphenyl)-1-phenylcyclopropanecarbonitrile
(8o). Prepared in 63% yield (176.5 mg) from phenylacetonitrile and
3,4-dimethoxybenzaldehyde using General Procedure A. Purification
by reversed-phase preparatory HPLC gave 8o as a yellow oil. 1H NMR
(400 MHz, CDCl3) δ 7.44−7.35 (m, 4H), 7.35−7.29 (m, 1H), 6.89−
6.87 (m, 2H), 6.86−6.82 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 2.76 (t, J
= 8.2 Hz, 1H), 2.17 (dd, J = 6.2, 7.8 Hz, 1H), 1.99 (dd, J = 6.1, 9.0 Hz,
1H). 13C NMR (101 MHz, CDCl3) δ 149.2, 149.0, 136.5, 129.2, 127.9,
127.6, 125.6, 120.3, 120.3, 111.7, 111.4, 56.1, 56.1, 35.7, 24.0, 22.4.
HRMS calculated for [M + H]+ (C18H17NO2H+) 280.1337, found
280.1328.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra, compiled HRMS data, and LCMS traces. This
material is available free of charge via the Internet at http://
pubs.acs.org.
E
dx.doi.org/10.1021/jo302443k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
AUTHOR INFORMATION
Corresponding Author
*E-mail: jeremy_clemens@sd.vrtx.com.
■
Present Address
†DART NeuroScience LLC, 10420 Wateridge Ct., San Diego,
CA 92121.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Khisal Alvi and Xiaoli Wang for analytical
support. We thank Professors Michael E. Jung and Brian M.
Stoltz for useful discussions as well as Dr. John Saunders for
research support. Dedicated to Professor Michael E. Jung on
the occasion of his 65th birthday.
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