Reaction of magnesium cyclopropylidene with N-lithio arylamines: a method for generation of α-amino-substituted cyclopropylmagnesiums and a study for their reactivity with electrophiles

Article abstract of DOI:10.1016/j.tet.2006.01.080

Magnesium cyclopropylidene was generated from 1-chlorocyclopropyl phenyl sulfoxide with i-PrMgCl in THF at -78 °C in high yield by a sulfoxide-magnesium exchange reaction. The generated magnesium cyclopropylidene was found to be reactive with N-lithio ary

Full text of DOI:10.1016/j.tet.2006.01.080

Tetrahedron 62 (2006) 4253–4261
Reaction of magnesium cyclopropylidene with N-lithio
arylamines: a method for generation of a-amino-substituted
cyclopropylmagnesiums and a study for their reactivity
with electrophiles
a
b
b
Tsuyoshi Satoh,a, Mariko Miura, Ken Sakai and Yoshimi Yokoyama
*
aDepartment of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
bDepartment of Chemistry, Faculty of Science, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 812-8581, Japan
Received 30 November 2005; accepted 16 January 2006
Available online 10 March 2006
Abstract—Magnesium cyclopropylidene was generated from 1-chlorocyclopropyl phenyl sulfoxide with i-PrMgCl in THF at K78 8C
in high yield by a sulfoxide–magnesium exchange reaction. The generated magnesium cyclopropylidene was found to be reactive with
N-lithio arylamines to give a-amino-substituted cyclopropylmagnesiums. The reaction of the a-amino-substituted cyclopropylmag-
nesiums with several electrophiles was examined and a new method for a synthesis of cyclopropane amino acid derivatives was
realized.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we are interested in the chemistry of the
magnesium carbenoids derived from a-haloalkyl sulfox-
ides4 or a-haloalkenyl sulfoxides5 by the sulfoxide–
magnesium exchange reaction.6 In the studies, we have
found that the magnesium cyclopropylidenes 2, which were
derived from 1-chlorocyclopropyl phenyl sulfoxides 1 with
a Grignard reagent by the sulfoxide–magnesium exchange
reaction, are much more stable and controllable compared to
the corresponding lithium cyclopropylidenes and could be
used in organic synthesis.7
Carbenes and carbenoids have long been recognized as
highly reactive carbon species and are frequently used as
useful intermediates in organic synthesis.1 In the
synthetic viewpoint, however, many carbenes are rela-
tively short-lived and are too reactive to control.
Recently, carbene–metal complexes (metal carbenes or
metallocarbenes) were found to be controllable and
highly effective carbenoids and are used widely in
organic synthesis.1b
In continuation of our interest in the use of the magnesium
cyclopropylidenes in organic synthesis we investigated the
reaction of the magnesium cyclopropylidenes 2 with several
nucleophiles and found that the reaction with N-lithio
arylamines gave a-amino-substituted cyclopropylmag-
nesiums 3. We also investigated the reaction of the
cyclopropylmagnesiums 3 with several electrophiles and
developed this chemistry to a new method for a synthesis of
cyclopropane amino acid derivatives 4 (EZCOOCH3)
(Scheme 1).
Cyclopropylidenes (carbenacyclopropanes) are the carbenes
or carbenoids of cyclopropanes and are also known as
interesting reactive intermediates. Cyclopropylidenes are
usually known as the fleeting intermediates of the reaction
of 1,1-dihalocyclopropanes with alkylmetals giving
allenes.2 These reactions are called the Doering–Moore–
Skattebol reaction or the Doering–LaFlamme allene
synthesis.3
Cyclopropane amino acids (1-aminocyclopropane-1-
carboxylic acid) and their derivatives have recently received
considerable attention.8 The reaction described below is
worth noting as a unique way for the synthesis of
cyclopropane amino acid derivatives.
Keywords: Sulfoxide; Sulfoxide–magnesium exchange; Magnesium cyclo-
propylidene; a-Amino-substituted cyclopropylmagnesium; Cyclopropane
amino acid.
*
Corresponding author. Tel.: C81 3 5228 8272; fax: C81 3 3235 2214;
e-mail: tsatoh@ch.kagu.tus.ac.jp
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.080

4254
T. Satoh et al. / Tetrahedron 62 (2006) 4253–4261
Scheme 1.
2. Results and discussion
of this reaction is a-amino-substituted cyclopropylmag-
nesium 7.
2.1. Generation of magnesium cyclopropylidene 6 from
1-chlorocyclopropyl phenyl sulfoxide 5 by the sulfoxide–
magnesium exchange reaction and their reaction with
N-lithio arylamines
The temperature of the reaction mixture was further allowed
to warm to room temperature (entries 3–5); however, the
yields were the same within experimental error. The results
in entries 2–5 implied that the reaction of 6 with N-lithio
N-methyl p-anisidine was almost completed at about
K40 8C and the resulting a-amino-substituted cyclopropyl-
magnesium 7 is stable at room temperature. When this
reaction was conducted with 2 equiv of N-lithio N-methyl
p-anisidine, the same yield of 8 was obtained (entry 6). It is
noted that the reaction with 1.5 equiv of the amine gave a
diminished yield (61%) of 8.
First, 1-chlorocyclopropyl phenyl sulfoxide 5 was syn-
thesized from commercially available cyclopropyl phenyl
sulfide7b and it was treated with 2.5 equiv of i-PrMgCl in
THF at K78 8C. The sulfoxide–magnesium exchange
reaction took place instantaneously to afford 1-chloro-
cyclopropyl magnesium chloride 6 in high yield.7 To this
reaction mixture, 3.5 equiv of N-lithio N-methyl p-anisidine
(prepared from N-methyl p-anisidine with n-BuLi in THF)
was added through a cannula and the reaction mixture was
slowly allowed to warm to K50 8C (Scheme 2, entry 1).
Encouraged by these results, we investigated the reaction of
magnesium cyclopropylidene 6 with other N-lithioamines
and the results are summarized in Table 1. N-Methylaniline,
4-chloro-N-methylaniline, and N-benzyl-p-anisidine gave
60–67% yield of the desired N-cycloproyl aryl amines
(9a–9c) and quenching with CD3OD gave the deuterated
compounds with high deuterium content (entries 1–3).
Diphenylamine gave the desired cyclopropyl amine 9d;
however, the yield was not satisfactory (entry 4).
Interestingly, dibenzylamine did not afford any
Fortunately, the desired N-cyclopropyl N-methyl p-anisi-
dine 8 was obtained in 42% yield. When the temperature of
the reaction was allowed to warm to K40 8C, the yield of 8
was improved to 82% (entry 2). Interestingly, quenching of
this reaction with CD3OD gave the deuterated compound 8
(D) and the deuterium incorporation was measured to be
98% by 1H NMR. This result indicated that the intermediate
Scheme 2. Generation of magnesium cyclopropylidene 6 and reation with N-lithio N-methyl p-anisidine followed by CH3OH or CD3OD.

T. Satoh et al. / Tetrahedron 62 (2006) 4253–4261
4255
Table 1. Reaction of magnesium cyclopropylidene 6 with N-lithio amines followed by CH3OH or CD3OD
Entry
R1
R2
Equiv of amine
9
Yield (%)
67
D-content (%)
93
1
2
3
CH3
3.5
3.5
3.5
9a
9b
9c
CH3
60
60
90
98
CH2Ph
4
5
3.5
3.5
9d
9e
42
0
92
99
CH2Ph
CH2Ph
6a
2.0
9f
87
b
7a
2.0
2.0
2.0
2.0
2.0
9g
9h
9i
55
43
75
21
12
—
b
—
8a
b
—
9a
b
—
10a
11a
9j
b
—
9k
a Temperature of the reaction mixture was allowed to warm to room temperature.
b The reaction was quenched with methanol.
cyclopropylamine at all (entry 5). Only isopropyl phenyl
sulfoxide and dibenzylamine were observed from the
reaction mixture. This result indicated that the magnesium
cyclopropylidene 6 only reacts with N-lithio arylamines.
This result consistents with that of the reaction of N-lithio
amines with the magnesium carbenoids generated from
1-chloroalkyl phenyl sulfoxides reported before.4c
compound 9i; however, indole and indazole gave very poor
yields (entries 10 and 11). These results implied that the
yields of the reaction of 6 with N-lithio nitrogen-containing
heterocyclic compounds are fairly variable with the used
heterocyclic compounds.
2.2. Investigation of the reactivity of the a-amino-
substituted cyclopropylmagnesiums 7 with electrophiles
and a new synthesis of cyclopropane amino acid
derivatives
Further, we investigated the reaction of 6 with N-lithio
nitrogen-containing heterocyclic compounds. In these
cases, we used 2 equiv of the nucleophiles. Phenoxazine
gave excellent yield of 9f with perfect deuterium
incorporation (entry 6). Phenothiazine and carbazole gave
moderate yields of the desired compounds 9g and 9h
(entries 7 and 8). Indoline gave good yield of the desired
As described above, the reaction of the magnesium
cyclopropylidene 6 with N-lithio arylamines gave
a-amino-substituted cyclopropylmagnesiums, which were
deuterated with high deuterium incorporation. If these

4256
T. Satoh et al. / Tetrahedron 62 (2006) 4253–4261
Table 2. Generation of a-amino-substituted cyclopropylmagnesium 7 and reaction with several electrophiles
Entry
Electrophile
PhCHO
Equiv
Conditions
10
Yield (%)
1
2
5.5
5.5
K40 to K20 8C, 1 h
K40 to K20 8C, 1 h
10a
10b
40
53
3
5.5
K40 to K20 8C, 1 h
10c
0a
4
5
CH3CH2CHO
ClCOOC2H5
ClCOOC2H5
ClCOOCH3
NCCOOC2H5
CO2
5.5
3.0
5.5
5.5
5.5
5.5
K40 to K20 8C, 1 h
K40 8C, 10 min
K40 8C, 10 min
K40 8C, 10 min
K40 8C, 10 min
K40 8C, 10 min
0a
10d
10d
10e
10
20
11
0a
6b
7b
8b
9b
Complex
a No reaction was observed.
b 3.5 equiv of N-lithio N-methyl p-anisidine was used in this reaction.
cyclopropylmagnesiums have enough nucleophilicity to
several electrophiles, addition of the electrophiles to the
reaction mixture was expected to give N-cyclopropylamines
having a substituent at the a-position 10 (Table 2). We tried
to trap the a-amino-substituted cyclopropylmagnesium 7
with several electrophiles and the results are summarized in
Table 2.
that the nucleophilicity of 7 is quite low. Next, with
great anticipation, we investigated the reaction of 7
with ethyl chloroformate; however, only maximum 20%
yield of the desired cyclopropane amino acid derivative
10d was obtained. Methyl chloroformate, ethyl
cyanoformate, and carbon dioxide were not effective
(entries 7–9).
Benzaldehyde and p-anisaldehyde gave the desired
adduct 10a and 10b in moderate yield; however,
p-chlorobenzaldehyde and propionaldehyde gave none
of the desired adduct (entries 1–4). These results implied
Finally, we investigated the reaction of 7 with carbon
disulfide (Scheme 3).9 a-Chlorocyclopropyl phenyl sulf-
oxide 5 was treated with 2.5 equiv of i-PrMgCl followed
by N-lithio N-methyl p-anisidine (2.0 equiv) and the
Scheme 3. Generation of a-amino-substituted cyclopropylmagnesium chloride 7 and reaction with CS2 followed by iodomethane.

T. Satoh et al. / Tetrahedron 62 (2006) 4253–4261
4257
Scheme 4. Methanolysis of the dithioester 11 with Hg(OCOCF3)2 in methanol.
temperature of the reaction mixture was allowed to warm
to K40 8C. To this reaction mixture was added 5.5 equiv
of carbon disulfide and the reaction mixture was stirred at
K40 8C for 10 min. Iodomethane (10 equiv) was added
finally to this reaction mixture (Scheme 3, entry 1). From
this reaction the desired dithioester 11 was obtained;
however, cyclopropylamine 8 was found to be the main
product.
Hg(OCOCF3)2 at room temperature (entry 1). The reaction
completed with 3 equiv of Hg(OCOCF3)2; however, the
reaction gave some byproducts and the yield was not
satisfactory (entry 2). The reaction was conducted with
3 equiv of Hg(OCOCF3)2 at 0 and K20 8C, and the best
yield (92%) of the cyclopropane amino acid derivatives 10e
was obtained at K20 8C (entry 4).
As the generality of this reaction, we further investigated the
reaction of 5 with N-benzyl-p-anisidine (Scheme 5).
Treatment of 5 with i-PrMgCl followed by N-lithio
N-benzyl-p-anisidine gave the a-amino-substituted cyclo-
propylmagnesium. Carbon disulfide followed by iodo-
methane was added to the reaction mixture as above to
afford the desired dithioester 12 in 59% overall yield from 5.
As the solubility of 12 was found to be low in methanol,
methanolysis of the dithoester 12 was carried out in a
mixture of CH3OH–THF with excess Hg(OCOCF3)2 to give
the methylester 13 in 60% yield. Finally, the benzyl group
was hydrogenolized with hydrogen in the presence of Pd–C
to give cyclopropane amino acid derivative 14 in 81% yield.
The reaction time for the treatment with carbon disulfide
was prolonged to 1 h (entry 2) or the reaction temperature
was allowed to warm to K20 8C and stirred 1 h (entry 3) to
give the desired dithioester 11 in up to 72% yield. The best
yield was obtained when the reaction with carbon disulfide
was warmed to room temperature and stirred for 2 h
(entry 4).
Methanolysis of the dithioester 11 was successfully carried
out with mercury(II) trifluoroacetate in methanol10 at the
concentration of 0.2 mol/L and the results are summarized
in Scheme 4. The reaction did not complete with 2 equiv of
Scheme 5. A synthesis of cyclopropane amino acid derivative 14 from 5 with N-benzyl-p-anisidine.

4258
T. Satoh et al. / Tetrahedron 62 (2006) 4253–4261
Figure 1. An ORTEP view for the structure of 10e showing the atom labeling diagram (left), together with a view perpendicular to the cyclopropane ring
showing the location of the (4-methoxyphenyl)methylamino group with regard to the cyclopropane ring (right).
2.3. X-ray crystallographic analysis of the cyclopropane
amino acid derivative 10e
insertion. Silica gel 60 (MERCK) containing 0.5%
fluorescence reagent 254 and a quartz column were used
for column chromatography and the products having UV
absorption were detected by UV irradiation. In experiments
requiring a dry solvent, THF was distilled from benzo-
phenone ketyl.
During the course of this work, we encountered an unusual
phenomenon in the 1H NMR spectrum measured in a CDCl3
solution of the cyclopropane amino acid derivative 10e. If
the rotational motion of the (4-methoxyphenyl)methyl-
amino moiety about the N–C(cyclopropane) bond axis is
undertaken very rapidly within a timescale much shorter
3.1.1. 1-Chlorocyclopropyl phenyl sulfoxide (5). To a
solution of cyclopropyl phenyl sulfide (3 g; 19.9 mmol) in
CH2Cl2 (80 mL) was added m-chloroperbenzoic acid (about
70% purity; 5.4 g; 21.9 mmol) with stirring at 0 8C. The
reaction mixture was stirred at 0 8C for 30 min. To the
reaction mixture was added aq Na2SO3 to reduce excess
m-chloroperbenzoic acid and the solution was diluted with
CH2Cl2 and the organic layer was washed with 5% NaOH
followed by satd aq NH4Cl. The organic layer was dried
over MgSO4 and the solvent was evaporated to give an oil,
which was purified by silica gel column chromatography to
afford 3.3 g (99%) of cyclopropyl phenyl sulfoxide as a
cololess oil; IR (neat) 3007, 1652, 1478, 1444, 1087, 1044,
1
than the timescale of H NMR, the structure of 10e should
be regarded as symmetrical leading to the observation of
two sets of magnetically non-equivalent protons on the
cyclopropane ring. In spite of the fact that three methyl
groups of 10e showed quite sharp signals, four protons on
the cyclopropane ring are observed at d 1.20 with a broad
signal (two protons) and at d 1.47 and 1.81 as two very broad
signals (each one proton), indicating that the two carbon
atoms on its 2- and 3-positions are not equivalent
magnetically. In order to better understand the structure of
10e and to elucidate the unusual observation described
above, the crystal structure of 10e has been determined by
X-ray diffraction. The ORTEP diagram of 10e is shown
in Figure 1.11
1022 (SO), 880, 750, 692 cmK1
.
A solution of the cyclopropyl phenyl sulfoxide (2.14 g;
13 mmol) in CCl4 (26 mL) was stirred with N-chloro-
succinimide at room temperature for 13 h. The precipitate
was filtered off and the solvent was evaporated to give an
oil, which was purified by silica gel column chromato-
graphy to afford 2.5 g (96%) of 5 as a colorless crystals; mp
49–50 8C (AcOEt–hexane); IR (KBr) 3084, 1477, 1443,
Obviously, the crystal structure is not symmetrical with
regard to the cyclopropane ring. The result also indicates
that the methoxycarbonyl moiety is so bulky that the fast
rotation of the (4-methoxyphenyl)methylamino moiety
around the N–C (cyclopropane) bond is prohibited. The
molecular modeling studies using either the crystal structure
or a computed structure (density functional method) also
showed that such a rotation mode is not favored due to the
steric contacts between these bulky moieties. It is also
noteworthy that compound 8 whose structure is given by the
substitution of the methoxycarbonyl unit in 10e by a proton
shows two sets of symmetrical signals in its 1H NMR. As a
whole, the unexpected 1H NMR signals of 10e can be
understood from the structure in Figure 1.
1089 (SO), 1059 (SO), 754, 691 cmK1 1H NMR d
;
1.21–1.27 (1H, m), 1.36–1.42 (1H, m), 1.65–1.72 (2H, m),
7.52–7.59 (3H, m), 7.70–7.73 (2H, m). MS m/z (%) 200
(MC, 8), 125 (100), 97 (19), 77 (20), 51 (13). Calcd for
C9H9ClOS: M, 200.0061. Found: m/z 200.0054. Anal. Calcd
for C9H9ClOS; C, 53.86; H, 4.52; Cl, 17.67; S, 15.98.
Found: C, 53.94; H, 4.17; Cl, 17.58; S, 15.97.
3.1.2. N-Cyclopropyl-N-(4-methoxyphenyl)methylamine
(8). To a solution of i-PrMgCl (0.75 mmol) in THF (1.5 mL)
at K78 8C was added a solution of 5 (60 mg; 0.3 mmol) in
1.5 mL of THF dropwise with stirring. After 10 min, a
solution of N-lithio N-methyl p-anisidine (prepared from
N-methyl p-anisidine (1.05 mmol) and n-BuLi (1.16 mmol)
in 1.5 mL of THF at 0 8C) was added to a solution of the
magnesium cyclopropylidene 6 through a cannula and the
reaction mixture was slowly allowed to warm to K40 8C
over 1 h. The reaction was quenched with MeOH and the
3. Experimental
3.1. General
1H NMR spectra were measured in a CDCl3 solution with
JEOL JNM-LA 300 and 500 spectrometer. Electron-impact
mass spectra (MS) were obtained at 70 eV by direct

T. Satoh et al. / Tetrahedron 62 (2006) 4253–4261
4259
whole was extracted with CHCl3 and the organic layer was
washed with satd aq NH4Cl and dried over MgSO4. After
removal of the solvent, the product was purified by silica gel
column chromatography to give 8 (43.6 mg; 82%) as a light
yellow oil; IR (neat) 3004, 2933, 1513, 1455, 1361, 1245,
(MC, 65), 222 (100), 207 (10), 182 (41), 127, (10). Calcd
for C15H13NO: M, 223.0996. Found: m/z 223.0998.
3.1.8. 10-Cyclopropyl-10H-phenothiazine (9g). Colorless
crystals; mp 118–121 8C (AcOEt–hexane); IR (KBr) 3055,
1
1040, 818 cmK1; H NMR d 0.58 (2H, m), 0.77 (2H, m),
1
1572, 1459, 1313, 1243, 1023, 755 cmK1; H NMR d 0.72
2.27 (1H, m), 2.92 (3H, s), 3.77 (3H, s), 6.84 (2H, d, JZ
9.2 Hz), 6.97 (2H, d, JZ9.2 Hz). MS m/z (%) 177 (MC,
100), 176 (60), 162 (80), 146 (18), 134 (16), 121 (57). Calcd
for C11H15NO: M, 177.1154. Found: m/z 177.1135.
(2H, m), 1.15 (2H, m), 2.79 (1H, m), 6.93 (2H, t, JZ
5.5 Hz), 7.11 (2H, dd, JZ1.2, 7.6 Hz), 7.14–7.25 (4H, m).
MS m/z (%) 239 (MC, 86), 238 (100), 223 (17), 210 (12),
198 (35), 154 (9). Calcd for C15H13NS: M, 239.0768.
Found: m/z 239.0770. Anal. Calcd for C15H13NS: C, 75.28;
H, 5.47; N, 5.85; S, 13.40. Found: C, 74.93; H, 5.83; N,
5.58; S, 12.98.
3.1.3. N-Cyclopropyl-N-methylphenylamine (9a). Light
yellow oil; IR (neat) 2933, 1601, 1503, 1363, 751, 692 cmK1
;
1H NMR d 0.61 (2H, m), 0.81 (2H, m), 2.37 (1H, m), 2.97 (3H,
s), 6.76 (1H, t, JZ7.3 Hz), 6.99 (2H, d, JZ8.0 Hz), 7.21–7.26
(2H, m). MS m/z (%) 147 (MC, 100), 146 (89), 132 (46), 120
(20), 104 (23), 91 (40), 77 (42). Calcd for C10H13N: M,
147.1048. Found: m/z 147.1057.
3.1.9. 9-Cyclopropyl-9H-carbazole (9h). Colorless crys-
tals; mp 118–120 8C (AcOEt–hexane); IR (KBr) 3063,
1596, 1480, 1457, 1375, 1317, 1233, 1158, 1034, 753, 748,
1
723 cmK1; H NMR d 1.11 (2H, m), 1.26 (2H, m), 3.30
(1H, m), 7.23 (2H, ddd, JZ0.9, 7.4, 7.5 Hz), 7.46 (2H, ddd,
JZ1.3, 7.4, 8.6 Hz), 7.65 (2H, d, JZ8.3 Hz), 8.06 (2H, d,
JZ7.6 Hz). MS m/z (%) 207 (MC, 63), 206 (100), 204 (18),
180 (15), 166 (12), 140 (10). Calcd for C15H13N: M,
207.1046. Found: m/z 207.1041.
3.1.4. N-(4-Chlorophenyl)-N-cyclopropylmethylamine
(9b). Colorless amorphous; IR (neat) 2935, 1599, 1497,
1360, 1115, 813, 668 cmK1; 1H NMR d 0.60 (2H, m), 0.81
(2H, m), 2.36 (1H, m), 2.95 (3H, s), 6.89 (2H, d, JZ8.9 Hz),
7.17 (2H, d, JZ8.9 Hz). MS m/z (%) 181 (MC, 100), 180
(86), 166 (67), 146 (50), 144 (50), 140 (68), 125 (47), 111
(59), 91 (39). Calcd for C10H12ClN: M, 181.0659. Found:
m/z 181.0659.
3.1.10. 1-Cyclopropyl-2,3-dihydro-1H-indole (9i). Color-
less oil; IR (neat) 2926, 2822, 1607, 1488, 1453, 1368, 1277,
1
1021, 869, 748 cmK1; H NMR d 0.64 (2H, m), 0.67 (2H,
m), 2.11 (1H, m), 2.90 (2H, t, JZ8.3 Hz), 3.36 (2H, t, JZ
8.3 Hz), 6.70 (1H, dt, JZ0.9, 7.3 Hz), 6.83 (1H, dd, JZ0.9,
7.3 Hz), 7.08 (2H, m). MS m/z (%) 159 (MC, 87), 158 (100),
144 (66), 130 (48), 117 (27), 91 (24), 77 (18). Calcd for
C11H13N: M, 159.1047. Found: m/z 159.1043.
3.1.5. N-Benzyl-N-cyclopropyl(4-methoxyphenyl)amine
(9c). Colorless amorphous; IR (neat) 2943, 1513, 1454,
1366, 1243, 1043, 818, 729 cmK1; 1H NMR d 0.65 (2H, m),
0.78 (2H, m), 2.52 (1H, m), 3.74 (3H, s), 4.55 (2H, s), 6.79
(2H, d, JZ9.2 Hz), 6.87 (2H, d, JZ9.2 Hz), 7.15–7.30 (5H,
m). MS m/z (%) 253 (MC, 84), 252 (44), 162 (99), 147 (26),
134 (54), 132 (70), 91 (100). Calcd for C17H19NO: M,
253.1465. Found: m/z 253.1463.
3.1.11. 1-Cyclopropyl-1H-indole (9j). Colorless oil; IR
(neat) 3013, 2925, 1509, 1476, 1464, 1370, 1314, 1235, 765,
1
741 cmK1; H NMR d 0.99–1.09 (4H, m), 3.34 (1H, m),
6.42 (1H, dd, JZ0.6, 3.0 Hz), 7.08–7.13 (2H, m), 7.19–7.25
(1H, m), 7.55–7.61 (2H, m). MS m/z (%) 157 (MC, 75), 156
(100), 130 (21), 128 (10). Calcd for C11H11N: M, 157.0891.
Found: m/z 157.0886.
3.1.6. N-Cyclopropyldiphenylamine (9d). Colorless oil;
IR (neat) 3022, 1590, 1491, 1358, 1298, 1267, 1025, 748,
693 cmK1; 1H NMR d 0.64 (2H, m), 0.85 (2H, m), 2.75 (1H,
m), 6.99 (2H, m), 7.07 (4H, m), 7.28 (4H, m). MS m/z (%)
209 (MC, 100), 208 (82), 193 (19), 167 (28), 117, (88), 104
(63), 91 (38), 77 (91). Calcd for C15H15N: M, 209.1203.
Found: m/z 209.1203.
3.1.12. 1-Cyclopropyl-1H-indazole (9k). Colorless oil; IR
1
(neat) 2925, 1615, 1466, 1425, 1218, 768, 743 cmK1; H
NMR d 1.17 (2H, m), 1.24 (2H, m), 3.59 (1H, m), 7.16 (1H,
t, JZ7.4 Hz), 7.39 (1H, t, JZ7.4 Hz), 7.61 (1H, d, JZ
8.2 Hz), 7.71 (1H, d, JZ7.4 Hz), 7.94 (1H, s). MS m/z (%)
158 (MC, 82), 157 (58), 131 (100), 130 (60), 104 (37), 103
(24), 77 (21), 76 (28). Calcd for C10H10N2: M, 158.0844.
Found: m/z 158.0847.
3.1.7. 10-Cyclopropyl-10H-phenoxazine (9f). To a solu-
tion of i-PrMgCl (0.5 mmol) in THF (1.0 mL) at K78 8C
was added a solution of 5 (40 mg; 0.2 mmol) in 1.0 mL of
THF dropwise with stirring. After 10 min, a solution of
N-lithio phenoxazine (prepared from phenoxazine
(0.4 mmol) and n-BuLi (0.44 mmol) in 0.6 mL of THF at
0 8C) was added to the solution of the magnesium
cyclopropylidene 6 through a cannula and the reaction
mixture was slowly allowed to warm to room temperature
over 2 h. The reaction was quenched with MeOH and the
whole was extracted with CHCl3 and the extract was washed
with aq NH4Cl and dried over MgSO4. After removal of the
solvent, the product was purified by silica gel column
chromatography to give 9f (38.9 mg; 87%) as colorless
crystals; mp 111–112 8C (AcOEt–hexane); IR (KBr) 2956,
3.1.13. {1-[(4-Methoxyphenyl)methylamino]cyclopropyl}-
phenylmethanol (10a). To a solution of i-PrMgCl
(0.75 mmol) in THF (1.5 mL) at K78 8C was added a
solution of 5 (60 mg; 0.3 mmol) in 1.5 mL of THF dropwise
with stirring. After 10 min, a solution of N-lithio N-methyl-
p-anisidine (prepared from N-methyl-p-anisidine
(0.6 mmol) and n-BuLi (0.66 mmol) in 0.9 mL of THF at
0 8C) was added to a solution of the magnesium
cyclopropylidene 6 through a cannula and the reaction
mixture was slowly allowed to warm to K40 8C for 1 h.
Benzaldehyde (1.65 mmol) was added to the reaction
mixture dropwise with stirring and the solution was slowly
allowed to warm to K20 8C over 1 h. The reaction was
1
1590, 1483, 1338, 1268, 745 cmK1; H NMR d 0.72 (2H,
m), 1.10 (2H, m), 2.38 (1H, m), 6.75 (4H, m), 6.86–6.91
(2H, m), 6.98 (2H, d, JZ8.0 Hz). MS m/z (%) 223

4260
T. Satoh et al. / Tetrahedron 62 (2006) 4253–4261
quenched with MeOH and the whole was extracted with
CHCl3 and the extract was washed with aq NH4Cl and dried
over MgSO4. After removal of the solvent, the product was
purified by silica gel column chromatography to give 10a
(34.5 mg; 40%) as a colorless oil; IR (neat) 3446 (OH),
a solution of N-lithio N-methyl-p-anisidine (prepared from
N-methyl-p-anisidine (0.6 mmol) and n-BuLi (0.66 mmol)
in 0.9 mL of THF at 0 8C) was added to solution of the
magnesium cyclopropylidene 6 through a cannula and the
reaction mixture was slowly allowed to warm to K40 8C
over 1 h. Carbon disulfide (1.65 mmol) was added to the
reaction mixture dropwise with stirring and the solution was
slowly allowed to warm to room temperature over 2 h.
Iodomethane (3.0 mmol) was added to the reaction mixture
dropwise with stirring and the reaction mixture was stirred
for 15 min. The reaction was quenched with MeOH and the
whole was extracted with CHCl3 and the extract was washed
with aq NH4Cl and dried over MgSO4. After removal of the
solvent, the product was purified by silica gel column
chromatography to give 11 (72.8 mg; 91%) as a colorless
light yellow amorphous; IR (KBr) 2910, 1516, 1343, 1278,
1
2904, 1512, 1453, 1242, 1039, 818, 745, 702 cmK1; H
NMR d 0.80 (2H, s), 0.94 (1H, br s), 1.11 (1H, br s), 2.62
(3H, br s), 3.77 (3H, s), 5.01 (1H, s), 6.78–6.84 (4H, m),
7.26–7.35 (5H, m). MS m/z (%) 283 (MC, 21), 177 (21), 176
(100), 146 (13), 145 (17), 144 (15), 121 (75). Calcd for
C18H21NO2: M, 283.1571. Found: m/z 283.1577.
3.1.14. N-(4-Methoxyphenyl)-N-[1-{(4-methoxyphenyl)-
hydroxymethyl}cyclopropyl]methylamine (10b). Color-
less oil; IR (neat) 3469 (OH), 2934, 1514, 1464, 1243, 1036,
1
818 cmK1; H NMR d 0.77–0.80 (2H, m), 0.93 (1H, br s),
1
1246, 1175, 1030, 814 cmK1; H NMR d 1.32 (1H, br s),
1.07–1.12 (1H, m), 2.62 (3H, br s), 3.76 (3H, s), 3.80 (3H,
s), 4.97 (1H, s), 6.77–6.85 (6H, m), 7.22 (2H, d, JZ8.6 Hz).
MS m/z (%) 313 (MC, 14), 176 (100), 145 (22), 144 (17),
135 (12), 121 (71), 77 (11). Calcd for C19H23NO3: M,
313.1676. Found: m/z 313.1669.
1.55 (1H, br s), 2.03 (1H, br s), 2.44 (1H, br s), 2.51 (3H, s),
3.08 (3H, s), 3.76 (3H, s), 6.66 (2H, d, JZ9.2 Hz), 6.84
(2H, d, JZ9.2 Hz). MS m/z (%) 267 (MC, 100), 252 (47),
219 (27), 174 (19), 122 (22), 121 (27). Calcd for
C13H17NOS2: M, 267.0751. Found: m/z 267.0757.
3.1.15. Ethyl 1-[(4-methoxyphenyl)methylamino]cyclo-
propanecarboxylate (10d). To a solution of i-PrMgCl
(0.75 mmol) in THF (1.5 mL) at K78 8C was added a
solution of 5 (60 mg; 0.3 mmol) in 1.5 mL of THF dropwise
with stirring. After 10 min, a solution of N-lithio N-methyl-p-
anisidine (prepared from N-methyl-p-anisidine (1.05 mmol)
and n-BuLi (1.16 mmol) in 1.5 mL of THF at 0 8C) was added
to a solution of the magnesium cyclopropylidene 6 through a
cannula and the reaction mixture was slowly allowed to warm
to K40 8C for 1 h. Ethyl chloroformate (1.65 mmol) was
added to the reaction mixture dropwise with stirring and the
reaction mixture was stirred for 10 min. The reaction was
quenched with MeOH and the whole was extracted with
CHCl3 and the extract was washed with aq NH4Cl and dried
over MgSO4. After removal of the solvent, the product was
purified by silica gel column chromatography to give 10d
(14.8 mg; 20%) as a colorless oil; IR (neat) 2936, 1723 (CO),
1513, 1294, 1245, 1186, 1143, 1039, 818 cmK1; 1H NMR d
1.14 (3H, t, JZ7.0 Hz), 1.19 (2H, br s), 1.45 (1H, br s), 1.78
(1H, br s), 3.03 (3H, s), 3.75 (3H, s), 4.09 (2H, q, JZ7.0 Hz),
6.74 (2H, d, JZ9.2 Hz), 6.81 (2H, d, JZ9.2 Hz). MS m/z (%)
249 (MC, 43), 220 (59), 176 (68), 175 (27), 144 (18), 135
(21), 121 (100). Calcd for C14H19NO3: M, 249.1363. Found:
m/z 249.1368.
3.1.18. Methyl 1-[(4-methoxypenyl)methylamino]cyclo-
propanecarboxylate (10e). To a solution of 11 (80 mg;
0.3 mmol) in MeOH (1.5 mL) at K20 8C was added
mercury (II) trifluoroacetate (0.9 mmol) with stirring and
the reaction mixture was stirred for 30 min. The reaction
mixture was diluted with CHCl3 and the solution was
washed with 10% NaOH and dried over MgSO4. After
removal of the solvent, the product was purified by silica gel
column chromatography to give 10e (65 mg; 92%) as
colorless crystals. Melting point and all the spectral data
were identical with the product described above.
3.1.19. 1-[N-Benzyl-N-(4-methoxyphenyl)amino]cyclo-
propanecarbodithioic acid methyl ester (12). Light
yellow amorphous; IR (neat) 3000, 2930, 1511, 1440,
1353, 1278, 1236, 1186, 1147, 1036, 955, 817, 757 cmK1
;
1H NMR d 1.59 (2H, m), 1.84 (1H, m), 2.55 (3H, s), 2.66
(1H, m), 3.72 (3H, s), 4.75 (1H, d, JZ18.0 Hz), 4.95 (1H, d,
JZ18.0 Hz), 6.60 (2H, d, JZ9.2 Hz), 6.77 (2H, d, JZ
9.2 Hz), 7.11 (2H, d, JZ8.0 Hz), 7.21–7.34 (3H, m). MS
m/z (%) 343 (MC, 52), 252 (100), 218 (27), 205 (19), 204
(34), 160 (55), 91 (89). Calcd for C19H21NOS2: M,
343.1064. Found: m/z 343.1071.
3.1.16. Methyl 1-[(4-methoxypenyl)methylamino]cyclo-
propanecarboxylate (10e). Colorless crystals; mp 59–
61 8C (AcOEt–hexane); IR (KBr) 2958, 1722 (CO), 1512,
3.1.20. Methyl 1-[N-Benzyl-(4-methoxyphenyl)amino]-
cyclopropanecarboxylate (13). To a solution of 12
(34 mg; 0.1 mmol) in MeOH (0.82 mL) and THF
(0.61 mL) at K20 8C was added mercurry (II) trifluoroace-
tate (0.66 mmol) and the reaction mixture was stirred for
30 min. The reaction mixture was diluted with CHCl3 and
the solution was washed with 10% NaOH and dried over
MgSO4. After removal of the solvent, the product was
purified by silica gel column chromatography to give 13
(18.6 mg; 60%) as a colorless amorphous; IR (neat) 2950,
2832, 1726 (CO), 1509, 1451, 1291, 1244, 1163, 1044,
1
1433, 1301, 1248, 1195, 1035, 817 cmK1; H NMR d 1.20
(2H, br s), 1.47 (1H, br s), 1.81 (1H, br s), 3.03 (3H, s), 3.63
(3H, s), 3.75 (3H, s), 6.74 (2H, d, JZ8.9 Hz), 6.82 (2H, d,
JZ8.9 Hz). MS m/z (%) 235 (MC, 49), 220 (42), 176 (72),
175 (49), 121 (100). Calcd for C13H17NO3: M, 235.1208.
Found: m/z 235.1213. Anal. Calcd for C13H17NO3: C, 66.36;
H, 7.28; N, 5.93. Found: C, 66.29; H, 7.33; N, 5.88.
1
3.1.17. 1-[N-Methyl-(4-methoxylphenyl)amino]cyclo-
propanecarbodithioic acid methyl ester (11). To a
solution of i-PrMgCl (0.75 mmol) in THF (1.5 mL) at
K78 8C was added a solution of 5 (60 mg; 0.3 mmol) in
1.5 mL of THF dropwise with stirring. After 10 min,
819 cmK1; H NMR d 1.25–1.43 (3H, m), 1.91 (1H, br s),
3.69 (3H, s), 3.72 (3H, s), 4.66 (2H, d, JZ14.4 Hz), 6.63
(2H, d, JZ9.5 Hz), 6.75 (2H, d, JZ9.5 Hz), 7.16 (2H, d,
JZ7.6 Hz), 7.22 (1H, t, JZ7.6 Hz), 7.30 (2H, t, JZ7.6 Hz).
MS m/z (%) 311 (MC, 30), 252 (27), 220 (43), 190 (55), 160

T. Satoh et al. / Tetrahedron 62 (2006) 4253–4261
4261
Ward, H. R. J. Org. Chem. 1960, 25, 2073. (e) Skattebol, L.
Tetrahedron Lett. 1961, 167. (f) Moore, W. R.; Ward, H. R. J.
Org. Chem. 1962, 27, 4179.
(24), 92 (22), 91 (100). Calcd for C19H21NO3: M, 311.1519.
Found: m/z 311.1517.
3.1.21. Methyl 1-(4-methoxyphenylamino)cyclopropane-
carboxylate (14). To a solution of 13 (21 mg; 0.07 mmol) in
MeOH (0.7 mL) and AcOEt (0.7 mL) at room temperature
was added 10%-Pd/C (21 mg). The reaction mixture was
stirred for 5 h under hydrogen atmosphere. The catalyst was
filtered off and the solvent was removed. The product was
purified by silica gel column chromatography to give 14
(13 mg; 81%) as a colorless oil; IR (neat) 3380 (NH), 2953,
4. (a) Satoh, T.; Takano, K. Tetrahedron 1996, 52, 2349. (b)
Satoh, T.; Kondo, A.; Musashi, J. Tetrahedron 2004, 60, 5453.
(c) Satoh, T.; Osawa, A.; Kondo, A. Tetrahedron Lett. 2004,
45, 6703. (d) Satoh, T.; Musashi, J.; Kondo, A. Tetrahedron
Lett. 2005, 46, 599. (e) Miyashita, K.; Satoh, T. Tetrahedron
2005, 61, 5067.
5. (a) Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda, K.;
Koyama, M. Tetrahedron 1998, 54, 5557. (b) Satoh, T.;
Sakamoto, T.; Watanabe, M. Tetrahedron Lett. 2002, 43, 2043.
(c) Satoh, T.; Ogino, Y.; Nakamura, M. Tetrahedron Lett.
2004, 45, 5785. (d) Watanabe, M.; Nakamura, M.; Satoh, T.
Tetrahedron 2005, 61, 4409. (e) Satoh, T.; Sakurada, J.;
Ogino, Y. Tetrahedron Lett. 2005, 46, 4855.
1
1725 (CO), 1512, 1236, 1038, 822, 754 cmK1; H NMR d
1.16 (2H, m), 1.56 (2H, m), 3.65 (3H, s), 3.74 (3H, s), 4.32
(1H, br s), 6.65 (2H, d, JZ8.9 Hz), 6.77 (2H, d, JZ8.9 Hz).
MS m/z (%) 221 (MC, 53), 190 (56), 162 (100), 161 (55),
160 (52), 146 (49), 130 (42), 121 (29). Calcd for
C12H15NO3: M, 221.1051. Found: m/z 221.1059.
6. (a) Satoh, T. J. Synth. Org. Chem. Jpn. 1996, 54, 481. (b)
Satoh, T. J. Synth. Org. Chem. Jpn. 2003, 61, 98. (c) Satoh, T.
The Chemical Record 2004, 3, 329.
Acknowledgements
7. (a) Satoh, T.; Kurihara, T.; Fujita, K. Tetrahedron 2001, 57,
5369. (b) Satoh, T.; Saito, S. Tetrahedron Lett. 2004, 45, 347.
8. (a) Kirihara, M.; Kawasaki, M.; Takuwa, T.; Kakuwa, T.;
Kakuda, H.; Wakikawa, T.; Takeuchi, Y.; Kirk, K. L.
Tetrahedron: Asymmetry 2003, 14, 1753. (b) Adams, L. A.;
Aggarwal, V. K.; Bonnert, R. V.; Bressel, B.; Cox, R. J.;
Shepherd, J.; de Vincente, J.; Walter, M.; Whittingham, W. G.;
Winn, C. L. J. Org. Chem. 2003, 68, 9433. (c) Allwein, S. P.;
Secord, E. A.; Martins, A.; Mitten, J. V.; Nelson, T. D.; Kress,
M. H.; Dolling, U. H. Synlett 2004, 2489. (d) Wurz, R. P.;
Charette, A. B. J. Org. Chem. 2004, 69, 1262 and the
references cited therein.
The authors thank Professor Isamu Shiina of this university
for helpful discussions.
References and notes
1. Some monographs and reviews concerning carbenes and
carbenoids: (a) Kirmse, W. Carbene Chemistry; Academic:
New York, 1971. (b) Dorwald, F. Z. Metal Carbenes in
Organic Synthesis; Wiley-VCH: Weinheim, 1999. (c) Carbene
Chemistry; Bertrand, G., Ed.; Marcel Dekker: New York,
2002. (d) Kobrich, G. Angew. Chem., Int. Ed. Engl. 1972, 11,
473. (e) Stang, P. J. Chem. Rev. 1978, 78, 383. (f) Burke, S. D.;
Grieco, P. A. Org. React. 1979, 26, 361. (g) Schaefer, H. F., III
Acc. Chem. Res. 1979, 12, 288. (h) Wynberg, H.; Meijer, E. W.
Org. React. 1982, 28, 1. (i) Oku, A.; Harada, T. J. Synth. Org.
Chem. Jpn. 1986, 44, 736. (j) Oku, A. J. Synth. Org. Chem.
Jpn. 1990, 48, 710. (k) Padwa, A.; Krumpe, K. E. Tetrahedron
1992, 48, 5385. (l) Padwa, A.; Weingarten, M. D. Chem.
Rev. 1996, 96, 223. (m) Braun, M. Angew. Chem., Int. Ed.
1998, 37, 430.
9. (a) Cazes, B.; Julia, S. Tetrahedron Lett. 1978, 4065. (b)
Metzner, P.; Thuillier, A. Sulfur Reagents in Organic
Synthesis; Academic: London, 1994.
10. Berrada, S.; Desert, S.; Metzner, P. Tetrahedron 1988, 44, 3575.
11. C13H17NO3, MZ235.28, Orthorhombic, space group Pbca
˚
(#61), aZ12.8035(12), bZ7.7201(8), cZ24.955(2) A, VZ
3
2466.7(4) A , ZZ8, F(000)Z1008, DcalcZ1.267 g cmK3
,
˚
m(Mo Ka)Z0.9 cmK1
,
TZ296 K, radiationZ0.71073 A,
˚
R1Z0.2567 for IO2.0s(I), wR2Z0.3582 for all data (2824
reflections), GOFZ1.508 (157 parameters), crystal dimen-
sions 0.3!0.08!0.08 mm3. A quality single crystal of the
compound (colorless prism) was mounted on a glass fiber.
Diffraction data were measured on a Bruker APEX CCD-
Detector X-ray diffractometer with monochromated Mo Ka
radiation. The data reduction, structure solution and refine-
ment, and all the necessary computational data processes were
performed using SMART, SAINT, SHELXTL, KENX, and
TEXSAN programs. Data deposited at the Cambridge
Crystallographic Data Centre; deposition number CCDC
285997.
2. (a) Brandsma, L.; Verkruijsse, H. D. Synthesis of Acetylenes,
Allenes and Cumulenes; Elsevier Scientific: Amsterdam, 1981.
(b) Schuster, H. F.; Coppola, G. M. Allenes in Organic
Synthesis; Wiley: New York, 1984.
3. Some monographs and papers: (a) Hassner, A.; Stumer, C.
Organic Syntheses Based on Name Reactions and Unnamed
Reactions; Elsevier: Oxford, 1994. (b) Li, J. J. Name
Reactions; Springer: Berlin, 2002. (c) Doering, W. von E.;
LaFlamme, P. M. Tetrahedron 1958, 2, 75. (d) Moore, W. R.;