Solid-phase synthesis of aryl, heteroaryl, and sterically hindered alkyl amines using the Curtius rearrangement

Article abstract of DOI:10.1016/j.tet.2008.11.012

An efficient method for the solid-phase synthesis of aryl amines, heteroaryl amines, and sterically hindered alkyl amines has been developed. The key step in this process was the formation of resin-bound carbamates (B) by the Curtius rearrangement of aryl

Full text of DOI:10.1016/j.tet.2008.11.012

Tetrahedron 65 (2009) 638–643
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solid-phase synthesis of aryl, heteroaryl, and sterically hindered alkyl amines
using the Curtius rearrangement
*
Satoshi Sunami , Mitsuru Ohkubo
Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2008
Received in revised form 5 November 2008
Accepted 6 November 2008
Available online 12 November 2008
An efficient method for the solid-phase synthesis of aryl amines, heteroaryl amines, and sterically hin-
dered alkyl amines has been developed. The key step in this process was the formation of resin-bound
carbamates (B) by the Curtius rearrangement of aryl carboxylic acids with Wang resin providing the
trapping hydroxyl group. N-Alkylation reactions of B gave secondary amines in good yield. Some biaryl
amines, which are found widely in biologically active substances, were also prepared by the Suzuki
reaction of resin-bound carbamates of 2-iodoaniline (16) or 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)aniline (21). The developed methods can be applied to the preparation of libraries containing aryl,
heteroaryl, and sterically hindered alkyl amine structures as the pharmacophores.
Keywords:
Solid-phase synthesis
Curtius rearrangement
Resin-bound carbamate
Aryl and heteroaryl amines
Sterically hindered alkyl amines
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Wang resin to obtain the corresponding resin-bound anilines with
a carbamate bond.5 However, the number of easily available phe-
Solid-phase synthetic technologies have gained increasing im-
portance, especially in the pharmaceutical industry. Since bio
logically active compounds often possess a variety of amine struc-
tures in their essential pharmacophores, the construction of such
amine libraries is useful for the discovery of lead compounds for new
drugs. Carbamate groups are most commonly used for N-protection
of amines.1,2 However, the direct introduction of N-carbamates es-
pecially to aryl or heteroaryl amines and sterically hindered alkyl
amines is notan easy task. It requireslong reaction times and/orhigh
temperatures, andoftentimes results in moderateyields, duelargely
to the poor nucleophilicity of the aryl amines and steric hindrance of
such alkyl amines. For this reason, carbamates of such amines have
usually been prepared from the corresponding carboxylic acids via
the Curtius rearrangement in solution-phase, followed by trapping
the isocyanate intermediate with alcohols.3
nylisocyanate derivatives is limited. To overcome these problems,
we developed the efficient synthesis of aryl and heteroaryl amines
(C) via solid-phase Curtius rearrangement (Scheme 1).6 The key
step in this process was the formation of resin-bound aryl or het-
eroaryl carbamates (B) by the Curtius rearrangement of aryl car-
boxylic acids (A) with Wang resin (1) providing the trapping
hydroxyl group. We believe that by this method, combinatorial li-
braries with more structural diversity can be prepared because
many carboxylic acids, which are the starting materials for the
Curtius rearrangement, can be easily obtained.
Recently, we have found that the solid-phase Curtius rear-
rangement could be applied to the synthesis of sterically hindered
alkyl amines. To the best of our knowledge, this is the first example
for the immobilization of sterically hindered alkyl amines such as
primary tert-alkyl amines to solid-supports. Here, we report the
In solid-phase chemistry, the reaction of aryl amines with
p-nitrophenylcarbonate resin gives carbamates in poor yield. For
example, the coupling of 4,6-dimethyl-2-aminopyridine to
p-nitrophenylcarbonate resin using potassium bis(trimethylsilyl)-
amide as a base according to the previously published solution-
phase method4 resulted in a 40% yield despite the use of a threefold
excess of the amine and a long reaction time (20 h). Buchstaller
described the reaction of some phenylisocyanate derivatives and
HN
O
R
O
a
b
O
C
R-CO2H
R
NH2
N
R
B
C
A
O
OH
1: Wang resin
* Corresponding author. Tel.: þ81 29 877 2000; fax: þ81 29 877 2029.
E-mail address: satoshi_sunami@merck.com (S. Sunami).
Scheme 1. (a) Compound 1, diphenylphosphoryl azide, triethylamine, toluene; (b) 50%
trifluoroacetic acid (TFA)/CH2Cl2.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.012

S. Sunami, M. Ohkubo / Tetrahedron 65 (2009) 638–643
639
efficient synthesis of aryl, heteroaryl, and sterically hindered alkyl
100.0
80.0
60.0
40.0
20.0
0.0
amines via the solid-phase Curtius rearrangement, as well as some
applications of the resin-bound carbamates (B), including the
synthesis of secondary amines (E) by an N-alkylation reaction of B
(Scheme 2) and biaryl amines (19, 24) by the Suzuki coupling re-
action of resin-bound 2-iodoaniline (16) or 3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)aniline (21; Scheme 3).
4000.0 3000.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0
1/cm
R'N R
O
HN
O
R
b
Figure 1. IR spectrum of the commercial Wang resin (Novabiochem, 100–200 mesh,
0.72 mmol/g).
a
O
O
R-NHR'
D
E
B
Scheme 2. (a) (1) NaH or LiHMDS, DMF (2) R0-X; (b) 50% TFA/CH2Cl2.
100.0
80.0
60.0
40.0
20.0
2. Results and discussion
2.1. The Curtius rearrangement of aryl and heteroaryl
carboxylic acids
0.0
1735.8
4000.0 3000.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0
1/cm
At first, the Curtius rearrangement of a range of aryl and het-
eroaryl carboxylic acids was carried out in the presence of com-
mercial polystyrene Wang resin as the trapping hydroxyl group
source (Scheme 1: Wang resin (1)/3-fold excess of carboxylic acid
(A)/5-fold excess of diphenylphosphoryl azide/10-fold excess of
triethylamine/toluene/100 ꢀC/16 h). The formation of resin-bound
carbamate B was monitored by IR spectroscopy, and a strong ab-
Figure 2. IR Spectrum of the resin-bound carbamate (B) of p-methylaniline.
2.2. The Curtius rearrangement of alkyl carboxylic acids
sorbance appeared at about 1730 cmꢁ1
progressed (Figs. 1 and 2).
(nC]O) as the reaction
We also applied this solid-phase method to a range of sterically
hindered alkyl carboxylic acids. The results are shown in Table 2.
Several 1-substituted cycloalkylcarboxylic acids of three-, four-,
and five-membered rings were tested (entries 1–4). This
procedure worked well on 1-methyl-cyclopropylcarboxylic acid
(4a) and 1-phenyl-cyclopropylcarboxylic acid (4b), as well as
1-trifluoromethylcyclobutylcarboxylic acid (4c) and 1-phenyl-
cyclopentylcarboxylic acid (4d). Severely sterically hindered car-
boxylic acids such as 2,2-dimethylpent-4-enoic acid (4e) and
dicyclohexylacetic acid (4f) also gave the corresponding amines
(5e, 5f) with satisfactory results (entries 5 and 6). Even carboxylic
acids at sterically hindered junction positions of bridged bicyclic
carbocycle systems (4g, 4h) were converted to the corresponding
amines (5g, 5h) with excellent results (entries 7 and 8). Methyl 1-
aminocyclopropanecarboxylate (5i) was obtained in >95% yield
Figure 2 shows the IR spectrum of the polystyrene resin of type
B, which was generated by the Curtius rearrangement of p-toluic
acid (2a) with 1. Compared to the IR spectrum of the starting Wang
resin (Fig. 1), the appearance of the strong C]O absorbance of the
carbamate bond at 1735.8 cmꢁ1 was clear.
After the product was cleaved from the resin by treatment with
50% TFA in CH2Cl2, the desired aryl and heteroaryl amines 3a–3j
were afforded in good yield with good purity. The results are shown
in Table 1. This procedure worked well for benzoic acids with both
a strong electron-withdrawing substituent (2b: entry 2) and an
electron-donating substituent (2c: entry 3) as well as p-toluic acid
(2a: entry 1). The sterically hindered 2-iodobenzoic acid (2d) also
provided the corresponding 2-iodoaniline (3d) in >95% yield with
acceptable purity (entry 4). The reaction of pyridine carboxylic acids
(2e–2g) proceeded smoothly with all regioisomers (entries 5–7).
Other heteroaryl carboxylic acids, such as pyrazinyl (2h) and 2-
thienyl carboxylic acids (2i, 2j), also gave good results (entries 8–10).
with
good
purity
from
easily
available
1,1-cyclo-
propanedicarboxylic acid mono methyl ester7 (4i: entry 9). Olefin
(entry 5), ketone (entry 7), and methyl ester (entry 9) functional
groups were all tolerated under these reaction conditions.
B(OH)2
17
I
HN
c
CO2H
b
HN
O
a
O
H2N
O
O
I
19
18
16
2d
I
O
B
HN
O
HN
O
d
c
CO2H
22
a
O
O
O
B
O
O
H2N
24
23
21
20
Scheme 3. (a) Compound 1, diphenylphosphoryl azide, triethylamine, toluene, 100 ꢀC; (b) 17, Pd(PPh3)4, 2 M Na2CO3, 1,2-dimethoxyethane (DME), 100 ꢀC; (c) 50% TFA/CH2Cl2; (d)
22, Pd(PPh3)4, 2 M Na2CO3, DME, 100 ꢀC.

640
S. Sunami, M. Ohkubo / Tetrahedron 65 (2009) 638–643
Table 2
The Curtius rearrangement has been used with a variety of
The solid-phase Curtius rearrangement of sterically hindered alkyl carboxylic acids
carboxylic acids under solution-phase conditions and we have now
shown that the solid-phase Curtius rearrangement will be as
widely applicable.
Entry Starting carboxylic acid
Product amines
Yielda (%) Purityb (%)
1
4a
4b
4c
4d
4e
4f
5a >95
92
90
90
91
88
85
CO2H
NH2
2.3. Application of the resin-bound carbamates
2
5b >95
5c >95
5d 76
CO2H
NH2
Once an efficient method for immobilization of various amines
to resins was found, we then focused on some applications of the
resin-bound carbamates. The N-alkylation of the resin-bound car-
bamates (B) was tested as the first example (Scheme 2).
3
F3C
NH2
F3C
CO2H
The results are shown in Table 3. Both resin-bound carba-
mates of 4-methylaniline (7: entries 1 and 2) and 6-methyl-2-
aminopyridine (8: entries 3 and 4), which were synthesized
from 2a and 6, respectively, were treated with a 5-fold excess of
NaH in DMF for 1.5 h at room temperature, followed by a 10-
fold excess of alkylating reagents at 80 ꢀC. Within 16 h, ethyl
iodide as well as the more reactive allyl bromide reacted com-
pletely with those resins. After being cleaved from the resin, the
desired secondary amines (10–13) were obtained in good yield
and purity.
4
CO2H
NH2
5
5e 57
NH2
NH2
CO2H
CO2H
6
5f 60
On the other hand, N-alkylation of the resin-bound carbamates
of 1-phenylcyclopropylamine (9) required higher temperature and
stronger base. Compound 9 was treated with a 10-fold excess of
lithium hexamethyldisilazide in DMF for 1.5 h at room temperature,
followed by a 10-fold excess of alkylating reagents at 120 ꢀC. Within
16 h, ethyl iodide as well as the more reactive benzyl bromide
reacted completely with those resins. After being cleaved from the
7
4g
5g >95
92
HO2C
O
H2N
O
8
4h
4i
5h >95
5i >95
93
90
HO2C
H2N
9
Table 1
MeO2C
MeO2C
CO2H
NH2
The solid-phase Curtius rearrangement of aryl and heteroaryl carboxylic acids
a
Yield was based on the TFA salt relative to a theoretical loading of the resin
Entry Starting carboxylic acid
Product amines
Yield (%) Purityb (%)
(1.08 mmol/g).
Purity was deterimined by HPLC and 1H NMR.
b
1
2a
2b
3a >95a
83
94
CO2H
NH2
2
3b >95
O2N
CO2H
CO2H
O2N
NH2
NH2
resin, the desired secondary amines (14, 15) were obtained with
good results (entries 5 and 6).
Next, we tried the Suzuki coupling reaction of resin-bound
carbamates of 2-iodoaniline (16) and 3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)aniline (21) (Scheme 3).
The results are shown in Table 4. The Suzuki coupling reaction of
16 with phenylboronic acid (17) under typical conditions
[0.05 equiv of Pd(PPh3)4, 2 M Na2CO3, DME, 100 ꢀC, 16 h] followed
by treatment with TFA provided the desired biphenyl-2-amine (19)
in 85% yield with 91% purity (entry 1).
3
4
5
2c
2d
2e
3c >95a
84
82
91
Me2N
Me2N
NH2
CO2H
3d >95
I
I
3e >95a
CO2H
NH2
N
N
Introduction of an aniline with a boronate moiety to the solid
support was successfully conducted by the solid-phase Curtius
rearrangement of the commercially available 3-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)benzoic acid (20) to give 21. To
the best of our knowledge, this is the first example of the Cur-
tius rearrangement on a carboxylic acid containing a boronate
moiety. The Suzuki coupling reaction of 21 with 2,6-dimethy-
liodobenzene (22) under the same conditions as entry 1 fol-
lowed by cleavage from the resin with TFA gave the desired
3-(2,6-dimethylphenyl)aniline (24) in 98% yield with 90% purity
(entry 2).
Although aryl halides are the usual immobilized coupling
partners for the solid-phase Suzuki coupling reaction, immobili-
zation of an arylboronate moiety is also profitable. Combined use of
resin-bound haloanilines and anilines with boronate moieties will
make it possible to prepare a variety of biaryl amines, which are
found widely in biological active compounds.
3f >95a
3g >95a
82
83
CO2H
CO2H
NH2
NH2
6
7
2f
N
N
2g
N
N
N
N
8
2h
3h 90a
86
N
S
CO2H
CO2H
N
S
NH2
NH2
9c
2i
2j
3i >95
3j >95
85
90
10c
O2N
O2N
CO2H
NH2
S
S
a
b
c
Yield was based on the TFA salt.
Purity was determined by HPLC and 1H NMR.
This reaction was carried out at 80 ꢀC.

S. Sunami, M. Ohkubo / Tetrahedron 65 (2009) 638–643
641
Table 3
N-Alkylation of the resin-bound carbamates 7–9
Entry
1
Starting carboxylic acid
Resin-bound carbamate
Product amines
Yielda (%)
85
Purityb (%)
91
O
N
H
10
O
O
N
H
HOOC
2a
2
92
94
7
N
H
11
O
3
4
98
97
93
84
N
H
N
12
N
H
N
HOOC
N
6
N
H
N
8
13
5
67
75
93
94
N
H
O
14
O
N
H
HOOC
6
N
4b
H
9
15
a
Yield was based on the TFA salt relative to a theoretical loading of the resin (1.2 mmol/g for 7, 8 and 0.82 mmol/g for 9).
b
Purity was determined by HPLC and 1H NMR.
cleavage was recorded on the HP 100 series system (pump; Binary
Pump G1312A, autosampler; ALS G1329A, diode array detector; DAD
G1315A) using a CAPCELLPAK ODS-UG120A (5 mm) column (gradient
as follows: 5–95% acetonitrile (0.1% TFA)/water (0.1% TFA), 0.2 ml/min
for 20 min), and Waters LC-MS 2690 Separations Module system
(diodearraydetector;996 PhotodiodeArrayDetector, MS; micromass
Table 4
The Suzuki coupling reaction of resin-bound carbamates 16 and 21
Entry Starting carboxylic acid
Product amines
Yielda (%) Purityb (%)
COOH
H2N
I
1
2
2d
20
19 85
91
ZMD (ESI)) using a YMC Pack ODS AQ (5 mm) column (gradient as
follows: 0–60% acetonitrile (0.1% TFA)/water (0.1% TFA), 0.2 ml/min
for 20 min). Mass spectra (MS) were measured on a Waters ZQ2000
(ESI) withBinaryHPLC Pump Waters1525, and micromass Quattoro II
with HP 1100 series HPLC system. HRMS were measured on a GC
(Agilent 6890 series)dMS (JEOL JMS-700 V) system (EI), or LC (Wa-
ters CapLC)dMS (micromass Q-Tof-2) system (ESI).
COOH
H2N
24 98
90
O
B
O
a
4.2. General procedure of the solid-phase Curtius
rearrangement for the synthesis of aryl and heteroaryl
amines (3a–3j)
Yield was based on the TFA salt relative to a theoretical loading of the resin
(1.2 mmol/g).
b
Purity was determined by HPLC and 1H NMR.
3. Conclusion
A mixture of Wang resin 1 (1.0 g, 1.2 mmol; loading 1.2 mmol/g),
carboxylic acid 2a–2j (3.6 mmol), diphenylphosphoryl azide
(1.3 ml, 6 mmol), and triethylamine (1.67 ml, 12 mmol) in toluene
(10 ml) was heated at 100 ꢀC or 80 ꢀC for 16 h. The resin was
washed successively with DMF (4ꢂ15 ml), DMF/H2O (1:1)
(4ꢂ15 ml), MeOH (4ꢂ15 ml), and CH2Cl2 (4ꢂ15 ml). The product
resin was shaken with 50% TFA/CH2Cl2 (5 ml) for 30 min, filtered,
washed with CH2Cl2 (2 mlꢂ2), and evaporated to dryness to leave
desired amines 3a–3j.
A useful method has been developed to provide resin-bound
amine carbamates via the solid-phase Curtius rearrangement
starting from carboxylic acids. This method is applicable to a variety
of carboxylic acids with various substituents. Following N-alkyl-
ation, the Suzuki coupling reaction of the resultant resin-bound
carbamates gives various monoalkylated aryl amines and biaryl
amines in good yields.
4. Experimental section
4.1. General
4.2.1. 4-Methylaniline (3a)8
Yield 237.5 mg (96%) of 3a as a TFA salt from 489 mg of 2a; 1H
NMR (300 MHz, CD3OD)
d
2.37 (3H, s), 7.23 (2H, d, J¼8.5 Hz), 7.31
(2H, d, J¼8.5 Hz); MS (ESI) m/z¼108 [MþH]þ.
Wang resin was purchased from Novabiochem. 1H NMR spectra
were recorded on Varian VXR-300 and Varian MERCURY 400 spec-
trometers with tetramethylsilane(TMS) as an internal standard. IR
absorption spectra were recorded with a SHIMADZU FTIR-8900
spectrometer on KBr bed. Analytical HPLC of the products after
4.2.2. 4-Nitroaniline (3b)9
Yield 151.5 mg (98%) of 2 from 601 mg of 2b; 1H NMR (300 MHz,
CD3OD)
d
6.62 (2H, d, J¼8.7 Hz), 7.98 (2H, d, J¼8.7 Hz); MS (ESI)
m/z¼139 [MþH]þ.

642
S. Sunami, M. Ohkubo / Tetrahedron 65 (2009) 638–643
4.2.3. 4-Dimethylaminoaniline (3c)8
4.3.3. 1-(Trifluoromethyl)cyclobutanamine (5c)
Yield 395.4 mg (97%) of 3 as two TFA salts from 594 mg of 2c; 1H
Yield 26.2 mg (96%) of 5c as a TFA salt from 91 mg of 4c; 1H NMR
NMR (300 MHz, CD3OD)
d
3.07 (6H, s), 7.06 (2H, d, J¼8.5 Hz), 7.12
(400 MHz, CD3OD) d 2.01–2.20 (2H, m), 2.40–2.50 (2H, m), 2.55–
(2H, d, J¼8.5 Hz); MS (ESI) m/z¼137 [MþH]þ.
2.63 (2H, m); ESI-HRMS calcd for C5H9F3N [MþH]þ: 140.0687,
found 140.0684.
4.2.4. 4-Iodoaniline (3d)9
Yield 268.2 mg(98%) of 3d from892 mgof 2d; 1H NMR (400 MHz,
4.3.4. 1-Phenyllcyclopentanamine (5d)
DMSO-d6)
d
6.38 (1H, d, J¼7.8 Hz), 6.80 (1H, t, J¼7.8 Hz), 7.07 (1H, t,
Yield 22.6 mg (76%) of 5d as a TFA salt from 102 mg of 4d; 1H
J¼7.8 Hz), 7.54 (1H, d, J¼7.8 Hz); MS (ESI) m/z¼220 [MþH]þ.
NMR (400 MHz, CD3OD) d 1.84–1.93 (4H, m), 2.23–2.33 (4H, m),
7.33–7.50 (5H, m); MS (ESI) m/z¼162 [MþH]þ; the 1H NMR data is
4.2.5. 2-Aminopyridine (3e)8
in accordance with that of an authentic sample.13
Yield 370.9 mg (96%) of 3e as two TFA salts from 442 mg of 2e;
1H NMR (300 MHz, CD3OD)
d
6.85 (1H, ddd, J¼1.1, 6.8, 7.4 Hz), 6.98
4.3.5. 2-Methylpent-4-en-2-amine (5e)
(1H, dd, J¼1.1, 8.8 Hz), 7.79 (1H, dt, J¼1.5, 6.8 Hz), 7.89 (1H, ddd,
Yield 8.8 mg (57%) of 5e as a TFA salt from 69 mg of 4e; 1H NMR
J¼1.5, 7.4, 8.8 Hz); MS (ESI) m/z¼95 [MþH]þ.
(400 MHz, CD3OD)
d
1.32 (6H, s), 2.35 (2H, d, J¼7.7 Hz), 5.19–5.27
(2H, m), 5.79–5.89 (1H, m); ESI-HRMS calcd for C6H14N [MþH]þ:
4.2.6. 3-Aminopyridine (3f)8
100.1126, found 100.1126.
Yield 374.8 mg (97%) of 3f as two TFA salts from 442 mg of 2f; 1H
NMR (300 MHz, CD3OD)
d
7.65–7.66 (2H, m), 7.89 (1H, dd, J¼1.1,
4.3.6. 1,1-Dicyclohexylmethanamine (5f)
3.3 Hz), 7.95 (1H, d, J¼1.1 Hz); MS (ESI) m/z¼95 [MþH]þ.
Yield 20 mg (60%) of 5f as a TFA salt from 121 mg of 4f; 1H NMR
(400 MHz, DMSO-d6)
d 0.84–1.28, 1.52–1.77 (22H, m), 2.58–2.67
4.2.7. 4-Aminopyridine (3g)8
(1H, m); MS (ESI) m/z¼196 [MþH]þ; the 1H NMR data is in accor-
Yield 370.8 mg (96%) of 3g as two TFA salts from 44 mg of 2g; 1H
dance with that of an authentic sample.14
NMR (300 MHz, CD3OD)
d
6.81 (2H, d, J¼7.3 Hz), 7.99 (2H, d,
J¼7.3 Hz); MS (ESI) m/z¼95 [MþH]þ.
4.3.7. (1S)-1-Amino-7,7-dimethylbicyclo[2.2.1]heptan-2-one (5g)
Yield 28.3 mg (98%) of 5g as a TFA salt from 101 mg of 4g; 1H
NMR (400 MHz, DMSO-d6) d 0.90 (3H, s), 1.07 (3H, s), 1.44–1.69 (2H,
m), 1.99–2.18 (4H, m), 2.49–2.52 (1H, m); MS (ESI) m/z¼154
[MþH]þ; the 1H NMR data is in accordance with that of an au-
thentic sample.15
4.2.8. Aminopyrazine (3h)8
Yield 225.7 mg (90%) of 3h as a TFA salt from 446 mg of 2h; 1H
NMR (300 MHz, CD3OD)
d
7.83–7.88 (2H, m), 8.23 (1H, d, J¼2.5 Hz);
MS (ESI) m/z¼96 [MþH]þ.
4.2.9. 2-Aminothiophene (3i)9
4.3.8. 4-Pentylbicyclo[2.2.2]octan-1-amine (5h)
Yield 114.0 mg (96%) of 3i from 457 mg of 2i; 1H NMR (400 MHz,
Yield 32.4 mg (97%) of 5h as a TFA salt from 121 mg of 4h; 1H
CDCl3)
d
6.20 (1H, dd, J¼3.4, 1.2 Hz), 6.51 (1H, dd, J¼5.4, 1.2 Hz), 6.68
NMR (400 MHz, DMSO-d6)
d
0.82 (3H, t, J¼7.1 Hz), 1.00–1.69 (2H,
(1H, dd, J¼5.4, 3.4 Hz); MS (ESI) m/z¼100 [MþH]þ.
m), 1.99–1.29 (8H, m), 1.35–1.46 (6H, m), 1.57–1.66 (6H, m), H; ESI-
HRMS calcd for C13H25N [MþH]þ: 196.2065, found 196.2066.
4.2.10. 5-Nitro-2-aminothiophene (3j)
Yield 169.3 mg (98%) of 3j from 619 mg of 2j; 1H NMR
4.3.9. Methyl 1-aminocyclopropanecarboxylate (5i)8
(300 MHz, CD3OD)
d
7.71 (1H, d, J¼6.5 Hz), 7.98 (1H, d, J¼6.5 Hz);
Yield 23.7 mg (96%) of 5i as a TFA salt from 78 mg of 4i; 1H NMR
MS (ESI) m/z¼145 [MþH]þ; the 1H NMR data is in accordance with
(400 MHz, DMSO-d6) d 1.39–1.44 (2H, m), 1.90–1.95 (2H, m), 3.82
that of an authentic sample.10
(3H, s); MS (ESI) m/z¼116 [MþH]þ.
4.3. General procedure of the solid-phase Curtius
rearrangement for the synthesis of sterically hindered
alkyl amines (5a–5i)
4.4. General procedure of N-alkylation of resin-bound
carbamates for the synthesis of secondary aryl amines (10–13)
A mixture of 1 (100 mg, 0.108 mmol; loading 1.08 mol/g), car-
boxylic acids 4a–4i (0.54 mmol), diphenylphosphoryl azide
(0.116 ml, 0.54 mmol), and triethylamine (0.15 ml, 1.08 mmol) in
toluene (3 ml) was heated at 110 ꢀC for 16 h. The resin was washed
successively with DMF (4ꢂ2 ml), MeOH (4ꢂ2 ml), and CH2Cl2
(4ꢂ2 ml). The product resin was shaken with 50% TFA/CH2Cl2 (2 ml)
for 30 min, filtered, washed with CH2Cl2 (1 mlꢂ2), and evaporated
to dryness to leave desired amines 5a–5i.
A mixture of 1 (1.0 g, 1.2 mmol; loading 1.2 mmol/g), carboxylic
acid 2a or
6 (3.6 mmol), diphenylphosphoryl azide (1.3 ml,
6 mmol), and triethylamine (1.67 ml, 12 mmol) in toluene (10 ml)
was heated at 100 ꢀC for 16 h. The resin was washed successively
with DMF (4ꢂ15 ml), DMF/H2O (1:1) (4ꢂ15 ml), MeOH (4ꢂ15 ml),
and CH2Cl2 (4ꢂ15 ml). The resin was dried under high vacuum for
10 h. The resin (30 mg, 0.036 mmol) and NaH (60% in oil, 7.2 mg,
0.18 mmol) were shaken in DMF (0.5 ml) for 1.5 h. Then, alkylating
agent (0.36 mmol) was added and heated at 80 ꢀC for 16 h. The
resin was washed successively with DMF (3ꢂ3 ml), MeOH
(3ꢂ3 ml), and CH2Cl2 (3ꢂ3 ml). The product resin was shaken with
50% TFA/CH2Cl2 for 5 min, filtered, washed, and evaporated to
dryness to leave desired secondary aryl amines 10–13.
4.3.1. 1-Methylcyclopropanamine (5a)
Yield 19.4 mg (97%) of 5a as a TFA salt from 54 mg of 4a; 1H NMR
(400 MHz, DMSO-d6)
d 0.58–0.63 (2H, m), 0.83–0.86 (2H, m), 1.33
(3H, s); MS (ESI) m/z¼72 [MþH]þ; the 1H NMR data is in accordance
with that of an authentic sample.11
4.4.1. 3-(4-Methylphenylamino)-1-propene (10)
4.3.2. 1-Phenyllcyclopropanamine (5b)
Yield 8.0 mg (85%) of 10 as a TFA salt from 489 mg of 2a and
Yield 25.9 mg (97%) of 5b as a TFA salt from 87 mg of 4b; 1H
44 mg of allyl bromide; 1H NMR (300 MHz, CD3OD)
d 2.39 (3H, s),
NMR (400 MHz, DMSO-d6)
d
1.17–1.21 (2H, m), 1.33–1.38 (2H, m),
3.98 (2H, d, J¼7.4 Hz), 5.43–5.52 (2H, m), 5.88–6.02 (1H, m), 7.30
7.32–7.45 (5H, m); MS (ESI) m/z¼134 [MþH]þ; the 1H NMR data is
(2H, d, J¼8.5 Hz), 7.37 (2H, d, J¼8.5 Hz); EI-HRMS calcd for C9H13
N
ꢃ
in accordance with that of an authentic sample.12
(Mþ ): 147.1048, found 147.1055.

S. Sunami, M. Ohkubo / Tetrahedron 65 (2009) 638–643
643
4.4.2. 2-(4-Methylphenylamino)ethane (11)
2 M Na2CO3 (0.2 ml, 0.4 mmol) were shaken in DME (2 ml) at
100 ꢀC for 16 h. The resin was washed successively with DMF/H2O
(1:1, 3ꢂ3 ml), MeOH (3ꢂ3 ml), and CH2Cl2 (3ꢂ3 ml). The product
resin was shaken with 50% TFA/CH2Cl2 for 30 min, filtered, washed,
and evaporated to dryness to give TFA salt of 19 as a colorless oil
Yield 8.3 mg (92%) of 11 as a TFA salt from 56 mg of iodoethane;
1H NMR (300 MHz, CD3OD)
d
1.28 (3H, t, J¼7.8 Hz), 2.36 (3H, s), 3.31
(2H, q, J¼7.8 Hz), 7.18 (2H, d, J¼8.6 Hz), 7.29 (2H, d, J¼8.6 Hz); EI-
ꢃ
HRMS calcd for C10H13N (Mþ ): 135.1048, found 135.1039.
(28.9 mg, 85%). 1H NMR (400 MHz, DMSO-d6)
MS (ESI) m/z¼170 [MþH]þ.
d 7.12–7.64 (9H, m);
4.4.3. 3-(6-Methyl-2-pyridylamino)-1-propene (12)
Yield 13.3 mg (98%) of 12 as two TFA salts from 493 mg of 6 and
44 mg of allyl bromide; 1H NMR (300 MHz, CD3OD)
d
2.52 (3H, s),
4.6.2. 20,60-Dimethylbiphenyl-2-amine (24)
4.03–4.08 (2H, m), 5.25–5.36 (2H, m), 5.87–6.01 (1H, m), 6.72 (1H,
A mixture of 1 (100 mg, 0.12 mmol; loading 1.2 mmol/g), 3-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid 20
d, J¼8.1 Hz), 6.88 (1H, d, J¼9.4 Hz), 7.82 (1H, d, J¼9.4 Hz), 7.84 (1H,
ꢃ
d, J¼8.1 Hz); EI-HRMS calcd for C9H12N2 (Mþ ): 148.1000, found
(89 mg, 0.36 mmol), diphenylphosphoryl azide (0.13 ml,
0.66 mmol), and triethylamine (0.17 ml, 1.2 mmol) in toluene
(5 ml) was heated at 100 ꢀC for 16 h. The resin was washed suc-
cessively with DMF (4ꢂ15 ml), DMF/H2O (1:1) (4ꢂ15 ml), MeOH
(4ꢂ15 ml), and CH2Cl2 (4ꢂ15 ml). The resin, 22 (139.2 mg,
0.6 mmol), Pd(PPh3)4 (7 mg, 5 mol %) and 2 M Na2CO3 (0.2 ml,
0.4 mmol) were shaken in DME (2 ml) at 100 ꢀC for 16 h. The
resin was washed successively with DMF/H2O (1:1, 3ꢂ3 ml),
MeOH (3ꢂ3 ml), and CH2Cl2 (3ꢂ3 ml). The product resin was
shaken with 50% TFA/CH2Cl2 for 30 min, filtered, washed, and
evaporated to dryness to give TFA salt of 24 as a colorless oil
148.0994.
4.4.4. 2-(6-Methyl-2-pyridylamino)ethane (13)
Yield 12.7 mg (97%) of 13 as two TFA salts from 56 mg of iodo-
ethane; 1H NMR (300 MHz, CD3OD)
d
1.32 (3H, t, J¼7.5 Hz), 2.50
(3H, s), 3.43 (2H, q, J¼7.5 Hz), 6.67 (1H, d, J¼6.9 Hz), 6.84 (1H, d,
J¼9.6 Hz), 7.76 (1H, d, J¼6.9 Hz), 7.78 (1H, d, J¼9.6 Hz); EI-HRMS
ꢃ
calcd for C8H12N2 (Mþ ): 136.1000, found 136.1003.
4.5. General procedure of N-alkylation of resin-bound
carbamates for the synthesis of secondary alkyl amines
(14, 15)
(36.6 mg, 98%); 1H NMR (400 MHz, DMSO-d6)
d 1.94 (6H, s), 7.02
(1H, t, J¼1.5 Hz), 7.07–7.19 (4H, m), 7.24–7.30 (1H, m), 7.52 (1H, t,
J¼7.8 Hz); ESI-HRMS calcd for C14H16N (MþH)þ: 198.1283, found
198.1286.
A mixture of 1 (1.0 g, 0.82 mmol; loading 0.82 mmol/g), 1-phe-
nylcyclopropanecarboxylic acid 4b (4.1 mmol), diphenylphos-
phoryl azide (0.88 ml, 4.1 mmol), and triethylamine (1.14 ml,
8.2 mmol) in toluene (10 ml) was heated at 120 ꢀC for 16 h. The
resin was washed successively with DMF (4ꢂ15 ml), DMF/H2O (1:1)
(4ꢂ15 ml), MeOH (4ꢂ15 ml), and CH2Cl2 (4ꢂ15 ml). The resin was
dried under high vacuum for 10 h. The resin (100 mg, 0.082 mmol)
and LiHMDS (1 M solution in THF: 0.82 ml, 0.82 mmol) were
shaken in DMF (1.0 ml) for 1.0 h. Then, alkylating agent (0.82 mmol)
was added and heated at 120 ꢀC for 16 h. The resin was washed
successively with DMF (3ꢂ3 ml), MeOH (3ꢂ3 ml), and CH2Cl2
(3ꢂ3 ml). The product resin was shaken with 50% TFA/CH2Cl2 for
5 min, filtered, washed, and evaporated to dryness to leave desired
secondary alkyl amines (14, 15).
Acknowledgements
The authors thank Mr. H. Ohsawa for HRMS measurements.
References and notes
1. For solution phase synthesis: (a) Katoh, T.; Nagata, Y.; Yoshino, T.; Nakatani, S.;
Terashima, S. Tetrahedron 1997, 53, 10253–10270; (b) Mouna, A. M.; Nguyen, C.;
Rage, I.; Xie, J.; Nee, G.; Mazaleyrat, J. P.; Wakselman, M. Synth. Commun. 1994,
24, 2429–2435; (c) Krakowiak, K. E.; Bradshaw, J. S. J. Heterocycl. Chem. 1995, 32,
1639–1640; (d) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc., Perkin
Trans. I 1992, 553–559; (e) Wensbo, D.; Annby, U.; Gronowitz, S. Tetrahedron
1995, 51, 10323–10342; (f) Roux, F.; Maugras, I.; Poncet, J.; Neil, G.; Jouin, P.
Tetrahedron 1994, 50, 5354–5360.
2. For solid phase synthesis: (a) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W.
Tetrahedron Lett. 1996, 37, 937–940; (b) Ho, C. Y.; Kukla, M. J. Tetrahedron Lett.
1997, 38, 2799–2802; (c) Gouilleux, L.; Fehrentz, J.; Winternitz, F.; Martinez, J.
Tetrahedron Lett. 1996, 37, 7031–7034; (d) Kaljuste, K.; Unden, A. Tetrahedron
Lett. 1996, 37, 3031–3034; (e) Zaragoza, F. Tetrahedron Lett. 1995, 36, 8677–
8680; (f) Kaljuste, K.; Unden, A. Tetrahedron Lett. 1995, 36, 9211–9214.
3. Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151–2157.
4. Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35, 9003–9006.
5. Buchstaller, H.-P. Tetrahedron 1998, 54, 3465–3470.
4.5.1. N-Ethyl-1-phenylcyclopropanamine (14)
Yield 15.2 mg (67%) of 14 as a TFA salt from 128 mg of iodo-
ethane; 1H NMR (400 MHz, CD3OD)
1.26 (2H, m), 1.37–1.41 (2H, m), 2.94 (2H, q, J¼7.4 Hz), 7.42–7.55
(5H, m); ESI-HRMS calcd for C11H15N [MþH]þ: 162.1283, found
162.1283.
d
1.18 (3H, t, J¼7.4 Hz), 1.22–
4.5.2. N-Benzyl-1-phenylcyclopropanamine (15)
6. Sunami, S.; Sagara, T.; Ohkubo, M.; Morishima, H. Tetrahedron Lett. 1999, 40,
1721–1724.
Yield 20.7 mg (75%) of 15 as a TFA salt from 140 mg of benzyl
7. Westermann, J.; Schneider, M.; Platzek, J.; Petrov, O. Org. Process Res. Dev. 2007,
11, 200–205.
bromide; 1H NMR (400 MHz, CD3OD)
d 1.25–1.45 (4H, m), 4.85 (2H,
s), 7.28–7.63 (10H, m); ESI-HRMS calcd for C16H17N [MþH]þ:
8. The 1H NMR data are in accordance with those of the TFA salts of commercial
reagents.
224.1439, found 224.1444.
9. The 1H NMR data are in accordance with those of commercial reagents.
10. Galvez, C.; Garcia, F. J. Heterocycl. Chem. 1981, 18, 851–853.
11. Vaidyanathan, G.; Wilson, J. W. J. Org. Chem. 1989, 54, 1815–1820.
12. Bertus, P.; Szymoniak, J. J. Orgc. Chem. 2003, 68, 7133–7136.
13. Balderman, D.; Kalir, A. Synthesis 1978, 12, 24–26.
4.6. Synthesis of biaryl amines
4.6.1. Biphenyl-2-amine (19)8
The resin-bound carbamate of 2-iodoaniline 16 (100 mg,
0.12 mmol), 17 (72.6 mg, 0.6 mmol), Pd(PPh3)4 (7 mg, 5 mol %), and
14. Bowles, P.; Clayden, J.; Helliwell, N.; McCarthy, C.; Tomkinson, M.; Westlund, N.
J. Chem. Soc., Perkin Trans. I 1997, 2607–2616.
15. Beak, P.; Harris, B. R. J. Am. Chem. Soc. 1974, 96, 6363–6372.