Preparation of alkyl carbamate of 1-protected indole-3-methylamine as a precursor of indole-3-methylamine

Article abstract of DOI:10.1080/00397910500287967

A series of alkyl carbamates 3 of 1-protected indole-3-methylamines, alkyl carbamates 6 of thiophenylmethylamines, and pyrrolylmethylamines were prepared from the corresponding acetamides 2 and 5 in good to excellent yields via diacetoxyiodobenzene-promot

Full text of DOI:10.1080/00397910500287967

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Preparation of Alkyl
Carbamate of 1‐Protected
Indole‐3‐methylamine
as a Precursor of
Indole‐3‐methylamine
Hao Song a , Wei Chen a , Yin Wang, a & Yong Qin a
a Department of Chemistry of Medicinal Natural
Products, West China School of Pharmacy , Sichuan
University , Chengdu, China
Published online: 22 Aug 2006.
To cite this article: Hao Song , Wei Chen , Yin Wang, & Yong Qin (2005) Preparation
of Alkyl Carbamate of 1‐Protected Indole‐3‐methylamine as a Precursor of
Indole‐3‐methylamine, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:21, 2735-2748
To link to this article: http://dx.doi.org/10.1080/00397910500287967
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Synthetic Communicationsw, 35: 2735–2748, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500287967
Preparation of Alkyl Carbamate
of 1-Protected Indole-3-methylamine
as a Precursor of Indole-3-methylamine
Hao Song, Wei Chen, Yin Wang, and Yong Qin
Department of Chemistry of Medicinal Natural Products, West China
School of Pharmacy, Sichuan University, Chengdu, China
Abstract: A series of alkyl carbamates 3 of 1-protected indole-3-methylamines,
alkyl carbamates 6 of thiophenylmethylamines, and pyrrolylmethylamines were pre-
pared from the corresponding acetamides 2 and 5 in good to excellent yields via
diacetoxyiodobenzene-promoted Hofmann rearrangement. For a successful Hofmann
rearrangement, an electron-withdrawing group on position 1 of indolylacetamide and
pyrrolylacetamide was required. The alkyl carbamate 3g was demonstrated to serve
well as a stable precursor of 1-protected indole-3-methylamine 1.
Keywords: Alkyl carbamate, Hofmann arrangement, indole-3-methylamine, precursor
INTRODUCTION
Indole-3-methylamine 1 is an important pharmaceutical intermediate[1] and a
starting material for the syntheses of phytoalexins.[2,3] Although its structure is
simple, indole-3-methylamine 1 is very unstable under basic conditions and
easily becomes deep red by forming polymerized compounds through a
3-methyleneindolenine intermediate when exposed to air. For most cases,
indole-3-methylamine 1 has to be used after in situ preparation. Indole-3-
methylamine 1 and its 1-protected derivatives were usually prepared by
reduction of indole-3-carboxaldehyde oximes or by displacement of gramine
methiodide.[3a,3d,4] These methods often encountered difficulties of low yield,
Received in Japan June 9, 2005
Address correspondence to Yong Qin, Department of Chemistry of Medicinal
Natural Products, West China School of Pharmacy, Sichuan University, Chengdu
610041, China. Tel./Fax: þ86 28 85503842.; E-mail: yanshuqin@yahoo.com
2735

2736
H. Song et al.
Scheme 1. 1 indole-3-methylamine.
non reproductability, and polymerization. Therefore, development of a simple
and practical method for the preparation of stable indole-3-methylamine
derivatives is highly desirable in light of the instability and usefulness of
indole-3-methylamine 1 (Scheme 1).
Classic Hofmann rearrangement usually requires a harsh basic aqueous
condition, which sometimes negates the possible usefulness of Hofmann
rearrangement in the preparation of base-sensitive amines. Polyvalent iodine
(III) chemistry is a field rapidly developed during the past decade, and it has
found numerous applications in organic chemistry.[5] In recent years, diacetoxy-
iodobenzene (DIB) has been reported as a mild reagent for Hofmann
rearrangement.[6,7] Because indole-3-methylamine 1isnotstableunderbasiccon-
ditions, we were curious to know whether an indole-3-methylamine isocyanate
intermediate formed during the Hofmann rearrangement could be captured
by a protic solvent under neutral conditions to afford an alkyl carbamate,
which should provide an alternative way to synthesize indole-3-methylamine
derivatives. Herein we report a convenient method for the preparation of
alkyl carbamates 3 of 1-protected indole-3-methylamine from 1-protected
indole-3-acetamide 2 via a DIB-promoted Hofmann rearrangement. Further-
more, the synthesized alkyl carbamates 3 could serve as stable precursors of
1-protected indole-3-methylamine 4 (Eq. (1)). The rearrangement studies of
thiophenylacetamide and pyrrolylacetamide are also presented in this article.
RESULTS AND DISCUSSION
Hofmann Rearrangement of 1-Protected Indole-3-acetamide
Our study first explored the possibility of preparing 1-unsubstituted alkyl
carbamate 3a directly from the commercially available indole-3-acetamide
2a through Hofmann rearrangement. Unfortunately, when amide 2a and

1-Protected Indole-3-methylamine
2737
DIB (1.2 equiv) were stirred with 10 equiv of methanol at room temperature in
different solvents such as methanol, methylene chloride, benzene, acetone,
THF, and acetonitrile, 2a was fully recovered (Table 1, entry 1).
It was reasonable to assume that a protecting group on indole nitrogen
could promote the formation of an isocyanate intermediate and stabilize the
resulting isocyanate intermediate during the Hoffmann rearrangement. As
shown in Table 1, after screening the reactivity of 1-protected indole-3-
acetamides 2b, 2c, and 2d with DIB in different solvents, we were able to
find that, with an electron-withdrawing group (Boc, Ts) on the indole
nitrogen, amides 2c and 2d reacted rapidly with DIB in methanol to afford
the corresponding methyl carbamate 3c in 97% yield (entry 3) and methyl
carbamate 3d in 99% yield (entry 4) respectively within 4 h. 1-Protected
indole-3-acetamides 2b and 2c were synthesized in 76% yield and 96%
yield respectively from commercially available indole-3-acetamide 2a by ben-
zylation and tosylation in a dry CH2Cl2/NaOH system catalyzed by 0.05 equiv
of tetrabutylammonium hydrogen sulphate.[8] Boc-protected indole-3-
acetamide 2d was prepared in 97% yield by reacting indole-3-acetamide 2a
with Boc2O in a CH2Cl2/Et3N/DMAP system. 1-Ts protected 2f and 2h
were prepared similar to 2c. Although methyl carbamate 3b was isolated in
Table 1. Hofmann rearrangement of amides 2 promoted by DIB
Entry
2
R1
R2
Solvent
Yield (%) of 3a
Time (h)
1b
2
2a
2b
2c
2d
2d
2d
2d
2d
2d
2d
2c
2d
H
Me
Me
Me
Me
Me
Me
Me
Et
MeOH
MeOH
MeOH
MeOH
CH2Cl2
PhH
0 (3a)
27 (3b)
97 (3c)
99 (3d)
70 (3d)
86 (3d)
88 (3d)
81 (3e)
79 (3f)
75 (3g)
80 (3h)
85 (3i)
24
4
Bn
Boc
Ts
3
4
4
4
5c
6
Ts
Ts
24
17
19
20
24
19
24
24
7
Ts
Ts
MeCN
EtOH
iPrOH
tBuOH
PhH
8
9
Ts
Ts
iPr
10
11d
12d
tBu
Bn
Bn
Boc
Ts
PhH
aIsolated yields.
bFully recovered amide 2.
cBy-products observed.
dSimilar result using acetonitrile.

2738
H. Song et al.
27% yield (entry 2), the reaction of 1-benzyl amide 2b with DIB gave a com-
plicated mixture. This might be partly due to the electron-donating character-
istics of the N-benzyl group. In the case of Ts-protected amide 2d, Hofmann
rearrangement also proceeded smoothly with 5–10 equiv of methanol in
methylene chloride, acetonitrile, and benzene, providing methyl carbamate
3d in good yields (Table 1, entries 5, 6, and 7).
The generality of forming different alkyl carbamates 3 via the DIB-
promoted Hofmann rearrangement was then tested in volatile alcohols. With
Ts-protected amide 2d, the rearrangement provided the corresponding alkyl
carbamates 3e–g in moderate to good yields (entries 8–10) by using a
variety of alcohols as solvent, but it required a longer reaction time compared
with the rearrangement using methanol as solvent. Because benzyl alcohol is
not volatile, the reactions of amides 2c and 2d with DIB were conducted in
benzene in the presence of 5 equiv of benzyl alcohol, affording benzyl carba-
mates 3h and 3i in good yields (entries 11, 12). It was interesting to note that
the reaction of acetamide 2c with DIB in tert-butanol afforded predominantly
the dimerized di-(1-Boc-indole-3-methylamino) urethane 3k in 70% yield and
10% of tert-butyl carbamate 3j (Eq. (2)). Methyl amine could fully compete
with ethanol to capture the isocyanate to give methyl urea 3l in 90% yield
when 2d was treated with 30% of MeNH2 in EtOH in the presence of
1.2 equiv of DIB for 10 h (Eq. (3)).
Hofmann Rearrangement of Substituted Indole-3-acetamide
We next carried out the DIB-promoted Hoffmann rearrangement of 2-methyl
or 5-methoxy substituted indole-3-acetamides 2e–2h. The results are shown
in Table 2. Like acetamide 2a, without an electron-withdrawing group on
the indole nitrogen, acetamides 2e and 2g did not react with DIB (Table 2,
entries 1 and 5), whereas the Hofmann rearrangement reactions of 2f and
2h with DIB in MeOH proceeded rapidly to give methyl carbamates 3n and
3r in greater than 93% yields (Table 2, entries 2 and 6). tert-Butyl carbamates
3o and 3s were obtained in 55% and 43% yields respectively when 2f and 2h
were treated with DIB in tert-butanol for 24 h (Table 2, entries 3 and 7). The

1-Protected Indole-3-methylamine
2739
Table 2. Hoffmann rearrangement of substituted indole-3-acetamide
Entry
2
R1
R2
R3
R
Solvent
Yield of 3a
Time (h)
1b
2
2e
2f
H
Me
Me
Me
Me
H
H
Me
Me
tBu
Bn
MeOH
MeOH
tBuOH
PhH
0 (3m)
93 (3n)
55 (3o)
37 (3p)
0 (3q)
24
3
Ts
Ts
Ts
H
H
3
2f
H
24
24
24
4
4
2f
H
5b
6
2g
2h
2h
2h
MeO
MeO
MeO
MeO
Me
Me
tBu
Bn
MeOH
MeOH
tBuOH
PhH
Ts
Ts
Ts
H
95 (3r)
43 (3s)
33 (3t)
7
H
24
24
8
H
aIsolated yields.
bFully recovered amide 2e or 2g.
reactions of amides 2f and 2h with DIB in the presence of 5 equiv of benzyl
alcohol in benzene provided the corresponding benzyl carbamates 3p and 3t
in less than 37% yields (Table 2, entries 4 and 8).
Hofmann Rearrangement of Thiopheneacetamide and
Pyrroleacetamide
The possible application of this method to generating the protected hetero-
cyclic methyleneamine functional group from related acetamides was also
tested. As shown in Table 3, the reactions of both thiophene-2-acetamide 5a
and thiophene-3-acetamide 5b with DIB (1.2 equiv) in MeOH proceeded
smoothly to give methyl carbamate 6a of thiophene-2-methylamine and
methyl carbamate 6b of thiophene-3-methylamine in moderate yields
(Table 3, entries 1 and 2). Pyrrole-2-acetamide 5c did not react with DIB in
MeOH (Table 3, entry 3). Unlike pyrrole-2-acetamide 5c, the N-Boc- and
N-Ts-substituted pyrrole-2-acetamides 5d and 5e reacted with DIB in
MeOH to give methyl carbamate 6d and methyl carbamate 6e in 80% and
75% yields respectively (Table 3, entries 4 and 5).
Deprotection of Alkyl Carbamate of Indole-3-methylamine
To demonstrate that the synthesized carbamate 3 could serve as a precursor of
indole-3-methylamine, we tried to remove the methylamine protecting group
in 3 (Eqs. (4), (5), and (6)). Unexpectedly, all the alkyl carbamate groups on

2740
H. Song et al.
Table 3. Hofmann rearrangement of amides 5 promoted by DIB
Entry
5
X
R
Solvent
Yield of 6a
Time (h)
1
5a
5b
5c
5d
5e
S
S
MeOH
MeOH
MeOH
MeOH
MeOH
51 (6a)
41 (6b)
0 (6c)
10
10
10
4
2
3b
4
N
N
N
H
Boc
Ts
80 (6d)
75 (6e)
5
6
aIsolated yields.
bFully recovered amide 5c.
methylamine were surprisingly stable under basic conditions, such as
hydrazine/MeOH, EtSLi/THF, aqueous NaOH/THF, K2CO3/THF, and
NaN(TMS)2/THF. The 1-deprotection always occurred dominantly instead
of removing the methylamine protecting group when carbamate 3 was
treated with these agents. For example, when 3c and 3d were hydrolyzed
with aqueous NaOH/THF for 1 h, methyl carbamate 7 was produced in
95% and 90% yields respectively (Eq. (4)). Surprisingly, the Cbz group on
3h was very stable. We failed to remove the Cbz protecting group from
compound 3h by hydrogenolysis under 200-psi pressure of hydrogen in
methanol (Eq. (5)). Fortunately, the Boc protecting group in 3g was easily
removed by treatment of 3g with 20% trifluoroacetic acid (TFA) in CH2Cl2
for 0.5 h to afford 1-Ts-indole-3-methylamine 4b in 94% yield (Eq. (6)).
1-Ts-indole-3-methylamine 4 was reported unstable in pure form (see Ref.
3(d)). In our experiment, 4 was stable enough at room temperature and can
survive chromatography. It has been stored at room temperature for three
months without decomposition.

1-Protected Indole-3-methylamine
2741
In conclusion, we have described a convenient method for directly
converting 1-protected indole-3-acetamides 2 into alkyl carbamates 3 via
DIB-promoted Hofmann rearrangement under neutral conditions. DIB also
can effectively promote the rearrangements of thiopheneacetamides 5a and
5b, and 1-protected pyrroleacetamides 5d and 5e, to afford the corresponding
alkyl carbamates 6. Most important, we have demonstrated that the syn-
thesized carbamate 3g can serve well as a stable precursor of 1-protected
indole-3-methylamine 1.
EXPERIMENTAL
All commercially available reagents were used without further purification.
All solvents were dried and distilled before use: THF was distilled from
sodium/benzophenone ketyl; dichloromethane was distilled from calcium
hydride; acetonitrile and acetone were distilled from P2O5; methanol and
ethanol were distilled from magnesium; tert-butanol was distilled from
calcium hydride; benzene was distilled from sodium. Chromatography was
conducted by using 200–300 mesh silica gel. IR spectra were recorded on a
FT IR spectrometer. NMR spectra were acquired on a 400-MHz NMR spec-
trometer. Chemical shifts are reported in ppm relative to TMS. HRMS
spectra were obtained by the electron spray ionization (ESI) method.
General Procedure for the DIB-Promoted Hofmann
Rearrangement of 1-Protected Acetamide 2
A mixture of 1 mmol of 1-protected indole-3-acetamide 2 and 1.2 equiv of
DIB were stirred in 10 mL of solvent as indicated in Table 1 in the presence
of an appropriate alcohol (5 equiv) at room temperature for 4–30 h. After
completion of the reaction (checked by TLC), the solvent was removed
under vacuum. The residue was purified by chromatography on silica gel to
give alkyl carbamate 3.
3b. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:5) afforded a white solid. Mp: 928C. IR: 1044, 1261, 1357, 1469, 1534,
1688, 3339 cm21 1H NMR (400 MHz, CDCl3) d 3.69 (s, 3H), 4.50
;
(d, J ¼ 6.8 Hz, 2H), 4.86 (s, 1H), 5.28 (s, 2H), 7.08–7.32 (m, 9H), 7.66
(d, J ¼ 6.4 Hz, 1H); 13C NMR (400 MHz, CDCl3) d 36.56, 49.92, 52.03,
109.82, 112.25, 119.05, 119.58, 122.16, 126.80, 126.88, 127.09, 127.65,
128.73, 136.74, 137.19, 156.88; EI-MS: m/z (%) 294 (26, Mþ), 279 (8),
235 (6), 221 (3), 220 (3), 203 (5); ESI-MS: m/z (%) 317 (100, M þ Naþ);
HRMS calcd. for C18H18N2NaO2: 317.1260; found 317.1247.
3c. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:5) afforded a white solid. Mp: 1218C. IR: 1086, 1152, 1225, 1372,
1
1455, 1372, 3336 cm21; H NMR (400 MHz, CDCl3) d 1.67 (s, 9H), 3.71

2742
H. Song et al.
(s, 3H), 4.50 (d, J ¼ 5.6 Hz, 2H), 4.89 (s, br, 1H), 7.26 (dt, J ¼ 1.2, 8.4 Hz,
1H), 7.34 (dt, J ¼ 1.2, 7.6 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J ¼ 7.6 Hz, 1H),
8.13 (d, br, J ¼ 7.2 Hz, 1H); 13C NMR (400 MHz, CDCl3) d 28.1, 36.3,
52.2, 83.8, 115.3, 117.7, 119.1, 122.7, 123.9, 124.7, 129.1, 135.7, 149.6,
156.9; ESI-MS: m/z (%) 327 (100, M þ Naþ): HRMS calcd. for
C16H20N2NaO4. 327.1317; found 327.1320.
3d. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:5) afforded a white solid. Mp: 1288C. IR: 965, 1174, 1271, 1365, 1448,
1
1529, 1701, 3337 cm21; H NMR (400 MHz, CDCl3) d 2.34 (s, 3H), 3.70
(s, 3H), 4.87 (d, J ¼ 8.0 Hz, 2H), 4.89 (s, br, 1H), 7.23 (d, J ¼ 8.4 Hz, 3H),
7.27 (t, J ¼ 7.6 Hz, 1H), 7.50 (s, 1H), 7.55 (d, J ¼ 8.0 Hz, 1H), 7.77
(d, J ¼ 8.4 Hz, 2H), 8.00 (d, J ¼ 8.4 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 21.5, 36.3, 52.3, 113.7, 119.6, 119.8, 123.3, 124.0, 125.0, 126.8, 127.2,
129.4, 129.9, 135.1, 135.3, 145.0, 156.9; ESI-MS: m/z (%) 381 (100,
M þ Kþ); HRMS calcd. for C18H18N2NKO4S: 381.0879; found 381.0868.
3e. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:6) afforded a white solid. Mp: 748C. IR: 974, 1020, 1119, 1250, 1368,
1
1448, 1522, 1700 cm21; H NMR (400 MHz, CDCl3) d 1.27 (t, J ¼ 7.6 Hz,
3H), 2.34 (s, 3H), 4.15 (q, J ¼ 2.0 Hz, 2H), 4.48 (d, J ¼ 5.6 Hz, 2H), 4.85
(s, br, 1H), 7.22 (d, J ¼ 4.8 Hz, 2H), 7.26 (d, J ¼ 8.0 Hz, 1H), 7.34
(t, J ¼ 4.8 Hz, 1H), 7.49 (s, 1H), 7.55 (d, J ¼ 8.0 Hz, 1H), 7.76
(d, J ¼ 8.4 Hz, 2H), 7.97 (d, J ¼ 8.4 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 14.5, 21.4, 36.0, 61.0, 113.6, 119.7, 119.7, 123.2, 123.9, 124.9,
126.7, 129.4, 129.8, 135.0, 135.2, 144.9, 156.2; EI-MS: m/z (%) 372
(14, Mþ), 343 (2), 217 (19), 189 (7), 145 (10), 118 (16); ESI-MS: m/z (%)
395 (5, M þ Naþ); HRMS calcd. for C19H20N2NaO4S: 395.1036; found
395.1048.
3f. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:5) afforded a white solid. Mp: 1358C. IR: 970, 1119, 1175, 1253, 1364,
1532, 1681, 1703, 3303 cm21
;
1H NMR (400 MHz, CDCl3) d 1.23
(d, J ¼ 6.3 Hz, 6H), 2.33 (s, 3H), 4.46 (d, J ¼ 5.6 Hz, 2H), 4.87 (s, br, 1H),
4.94 (m, J ¼ 6.4 Hz, 1H), 7.21 (d, J ¼ 8.4 Hz, 2H), 7.25 (t, J ¼ 8.0 Hz, 1H),
7.32 (t, J ¼ 8.0 Hz, 1H), 7.48 (s, 1H), 7.55 (d, J ¼ 7.6 Hz, 1H), 7.75
(d, J ¼ 8.4 Hz, 2H), 7.97 (d, J ¼ 8.4 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 21.52, 22.13, 29.68, 36.14, 68.47, 113.72, 119.68, 120.00, 121.85, 123.30,
123.97, 125.01, 126.82, 129.47, 129.90, 135.39, 144.98, 156.13; ESI-MS:
m/z (%) 409 (7, M þ Naþ); HRMS calcd. for C20H22N2NaO4S: 409.1192;
found 409.1203.
3g. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:7) afforded a white solid. Mp: 868C. IR: 937, 967, 1092, 1172, 1293,
1366, 1448, 1526, 1683, 2978, 3334 cm21; 1H NMR (400 MHz, CDCl3) d 1.46
(s, 9H), 2.34 (s, 3H), 4.42 (d, J ¼ 5.6 Hz, 2H), 4.72 (s, br, 1H), 7.23
(d, J ¼ 5.6 Hz, 2H), 7.24 (d, J ¼ 1.2 Hz, 1H), 7.33 (t, J ¼ 8.0 Hz, 1H), 7.48
(s, 1H), 7.55 (d, J ¼ 8.0 Hz, 1H), 7.76 (d, J ¼ 8.4 Hz, 2H), 7.97
(d, J ¼ 8.4 Hz, 1H); 13C NMR (400 MHz, CDCl3) d 21.4, 28.3, 35.7, 79.5,

1-Protected Indole-3-methylamine
2743
113.6, 119.7, 120.2, 123.2, 123.8, 124.8, 126.7, 129.4, 129.8, 130.2, 135.1,
135.3, 144.9, 155.7; ESI-MS: m/z (%) 423 (5, M þ Naþ); HRMS calcd. for
C21H24N2NaO4S: 423.1349; found 423.1338.
3h. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:10) afforded a white solid. Mp: 1208C. IR: 910, 1087, 1158, 1259,
1371, 1454, 1731, 3341 cm21
;
1H NMR (400 MHz, CDCl3) d 1.66
(s, 9H), 4.52 (d, J ¼ 5.6 Hz, 2H), 4.99 (s, br, 1H), 5.14 (s, 2H), 7.23
(d, J ¼ 7.6 Hz, 1H), 7.31 (d, J ¼ 1.2 Hz, 1H), 7.33 (s, 2H), 7.35
(d, J ¼ 4.0 Hz, 2H), 7.37 (s, 1H), 7.52 (s, 1H), 7.56 (d, J ¼ 7.6 Hz, 1H),
8.12 (d, J ¼ 8.0 Hz, 1H); 13C NMR (400 MHz, CDCl3) d 27.9, 36.1, 64.7,
66.6, 83.6, 115.1, 117.6, 118.9, 122.5, 123.7, 124.5, 126.7, 127.2, 128.2,
127.8, 127.9, 128.2, 128.3, 140.8, 149.4, 156.3; ESI-MS:m/z (%) 403
(4, M þ Naþ); HRMS calcd. for C22H24N2NaO4S: 403.1628; found 403.1628.
3i. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:10) afforded a white solid. Mp: 958C. IR: 969, 1097, 1173, 1267, 1372,
1
1530, 1694, 3325 cm21; H NMR (400 MHz, CDCl3) d 2.34 (s, 3H), 4.50
(d, J ¼ 5.6 Hz, 2H), 4.95 (s, br, 1H), 5.14 (s, 2H), 7.22 (d, J ¼ 8.0 Hz, 2H),
7.25 (m, 1H), 7.31 (m, 6H), 7.49 (s, 1H), 7.53 (d, J ¼ 8.0 Hz, 1H), 7.75
(d, J ¼ 8.4 Hz, 2H), 7.97 (d, J ¼ 8.4 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 21.49, 29.65, 36.28, 113.66, 119.66, 123.30, 124.01, 125.00, 126.77,
126.92, 127.56, 128.05, 128.14, 128.50, 129.34, 129.87, 135.11, 135.29,
144.98, 156.22; ESI-MS: m/z (%) 457 (5, M þ Naþ); HRMS calcd. for
C24H22N2NaO4S: 457.1192; found 457.1182.
3j. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:7) afforded a white solid. Mp: 808C. IR: 1099, 1152, 1283, 1371, 1458,
1
1717, 1750, 1802, 2990 cm21; H NMR (400 MHz, CDCl3) d 1.45 (s, 9H),
1.66 (s, 9H), 4.44 (d, J ¼ 5.6 Hz, 2H), 4.75 (s, br, 1H), 7.26 (dt, J ¼ 1.2,
7.6 Hz, 1H), 7.33 (dt, J ¼ 1.2, 7.6 Hz, 1H), 7.51 (s, 1H), 7.58
(d, J ¼ 8.0 Hz, 1H), 8.12 (d, J ¼ 7.6 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 27.8, 27.9, 29.6, 84.0, 115.0, 117.1, 119.4, 122.5, 124.3, 124.84, 129.3,
135.2, 149.0, 149.4, 154.6; EI-MS: m/z (%) 346 (3, Mþ), 230 (2); HRMS
calcd. for C19H26N2NaO4: 369.1893; found 369.1889.
3k. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:5) afforded a white solid. Mp: 2308C. IR: 973, 1120, 1173, 1367, 1448,
1559, 1596, 1636, 3410 cm21; 1H NMR (400 MHz, DMSO-d6) d 1.60 (s, 18H),
4.37 (d, J ¼ 5.6 Hz, 4H), 6.31 (t, J ¼ 5.6 Hz, 2H), 7.18 (t, J ¼ 7.2 Hz, 2H),
7.33 (t, J ¼ 7.2 Hz, 2H), 7.51 (s, 2H), 7.66 (d, J ¼ 8.0 Hz, 2H), 8.02
(d, J ¼ 8.4 Hz, 2H); 13C NMR (400 MHz, DMSO-d6) d 27.9, 34.5, 83.8,
114.9, 119.9, 120.3, 122.7, 123.4, 124.6, 129.4, 135.2, 148.3, 158.1; ESI-
MS: m/z 541 (100, M þ Naþ); HRMS calcd for C29H34N4NaO5: 541.2421;
found 541.2435.
3l. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 2:1) afforded a white solid. Mp: 1708C. IR: 970, 1171, 1369, 1619, 2924,
1
3328 cm21; H NMR (400 MHz, CDCl3) d 2.34 (s, 3H), 2.76 (s, 3H), 4.48
(d, J ¼ 5.2 Hz, 2H), 4.50 (s, br, 1H), 4.70 (s, br, 1H), 7.21 (d, J ¼ 8.0 Hz,

2744
H. Song et al.
2H), 7.25 (d, J ¼ 0.8 Hz, 1H), 7.32 (t, J ¼ 5.6 Hz, 1H), 7.48 (s, 1H), 7.56
(d, J ¼ 8.0 Hz, 1H), 7.75 (d, J ¼ 8.4 Hz, 2H), 7.95 (d, J ¼ 8.0 Hz, 1H); 13C
NMR (400 MHz, CDCl3) d 21.5, 27.3, 35.7, 113.6, 119.8, 120.5, 123.3,
123.8, 125.0, 126.8, 129.5, 129.9, 135.1, 135.3, 145.0, 158.5; EI-MS: m/z
(%) 357 (29, Mþ), 202 (30), 145 (100); HRMS calcd. for C18H19N3NaO3S:
380.1039; found 380.1032.
3n. Purification by chromatography on silica gel (acetone/petroleum
ether 2:3) afforded a light yellow solid. Mp: 104;8C. IR: 1000, 1176, 1238,
1
1365, 1455, 1522, 1702, 3333 cm21; H NMR (400 MHz, CDCl3) d 2.35
(s, 3H), 2.60 (s, 3H), 3.69 (s, 3H), 4.40 (d, J ¼ 5.2 Hz, 2H), 4.71 (s, br,
1H), 7.21 (d, J ¼ 8.4 Hz, 2H), 7.26 (d, J ¼ 5.2 Hz, 1H), 7.30 (td, J ¼ 1.2,
7.6 Hz, 1H), 7.48 (d, J ¼ 7.6 Hz, 1H), 7.66 (d, J ¼ 8.4 Hz, 2H), 8.20
(d, J ¼ 8.0 Hz, 1H); 13C NMR (400 MHz, CDCl3) d 12.5, 21.4, 34.9, 52.1,
114.5, 116.5, 118.3, 123.5, 124.3, 125.4, 126.3, 129.1, 129.8, 130.0, 134.8,
136.2, 144.8, 156.8. ESI-MS: m/z(%) 395 (100, M þ Naþ); HRMS calcd.
for C19H20N2NaO4S: 395.1036; found 395.1045.
3o. Purification by chromatography on silica gel (acetone/petroleum
ether 1:8) afforded a light yellow solid. Mp: 858C. IR: 911, 1007, 1176,
1
1238, 1455, 1508, 1701, 2930, 2976 cm21; H NMR (400 MHz, CDCl3) d
1.43 (s, 9H), 2.35 (s, 3H), 2.59 (s, 3H), 4.35 (d, J ¼ 5.2 Hz, 2H), 4.52
(s, br, 1H), 7.21 (d, J ¼ 8.0 Hz, 2H), 7.25 (dd, J ¼ 1.2, 7.6 Hz, 1H), 7.30
(td, J ¼ 1.2, 7.2 Hz, 1H), 7.49 (d, J ¼ 7.6 Hz, 1H), 7.66 (d, J ¼ 8.0 Hz, 2H),
8.20 (d, J ¼ 7.6 Hz, 1H); 13C NMR (400 MHz, CDCl3) d 12.5, 21.4, 28.3,
29.6, 34.4, 79.5, 114.4, 116.8, 116.4, 123.4, 124.2, 126.3, 126.3, 129.2,
129.8, 134.6, 136.2, 144.7, 155.6. ESI-MS: m/z 437 (100, M þ Naþ);
HRMS calcd. for C22H26N2NaO4S: 437.1505; found 437.1497.
3p. Purification by chromatography on silica gel (acetone/petroleum
1
ether 1:10) afforded a light yellow solid. Mp: 1308C. IR: cm21; H NMR
(400 MHz, CDCl3) d 2.34 (s, 3H), 2.59 (s, 3H), 4.41 (d, J ¼ 5.6 Hz, 2H),
4.80 (s, br, 1H), 5.10 (s, 2H), 7.19 (d, J ¼ 8.4 Hz, 2H), 7.23-7.35 (m, 7H),
7.47 (d, J ¼ 7.2 Hz, 1H), 7.65 (d, J ¼ 8.4 Hz, 2H), 8.19 (d, J ¼ 8.4 Hz, 1H);
13C NMR (400 MHz, CDCl3) d 12.6, 21.5, 34.9, 66.9, 114.5, 118.3, 123.5,
124.4, 126.3, 128.0, 128.1, 128.5, 129.9, 136.3, 144.8; EI-MS: m/z (%) 448
(4, Mþ), 357 (15), 203 (11); HRMS calcd. for C25H24N2NaO4S: 471.1349;
found 471.1327.
3r. Purification by chromatography on silica gel (acetone/petroleum
ether 2:3) afforded a light yellow solid. Mp: 958C. IR: 1033, 1119, 1265,
1
1370, 1476, 1518, 1721, 2926 cm21; H NMR (400 MHz, CDCl3) d 2.35
(s, 3H), 3.71 (s, 3H), 3.82 (s, 3H), 4.44 (d, J ¼ 5.6 Hz, 2H), 4.87 (s, br,
1H), 6.94 (dd, J ¼ 2.4, 8.8 Hz, 1H), 7.01 (s, 1H), 7.22 (d, J ¼ 8.0 Hz, 2H),
7.44 (s, 1H), 7.73 (d, J ¼ 7.6 Hz, 2H), 7.86 (d, J ¼ 8.8 Hz, 1H); 13C NMR
(400 MHz, CDCl3) d 21.5, 36.2, 52.3, 55.6, 101.9, 114.1, 114.5, 119.9,
124.7, 126.7, 129.8, 129.9, 130.3, 135.0, 144.9, 156.9; EI-MS: m/z (%) 388
(19, Mþ), 233 (71), 174 (6), 159 (11); HRMS calcd. for C19H20N2NaO5S:
411.0985; found 411.0976.

1-Protected Indole-3-methylamine
2745
3s. Purification by chromatography on silica gel (acetone/petroleum ether
1:4) afforded a light yellow solid. Mp: 908C. IR: 1033, 1173, 1265, 1369,
1
1507, 1710, 2852, 2925 3055 cm21; H NMR (400 MHz, CDCl3) d 1.46
(s, 9H), 2.38 (s, 3H), 3.82 (s, 3H), 4.38 (d, J ¼ 5.6 Hz, 2H), 4.70 (s, br,
1H), 6.93 (dd, J ¼ 2.4, 9.2 Hz, 1H), 7.02 (s, 1H), 7.21 (d, J ¼ 8.4 Hz, 2H),
7.42 (s, 1H), 7.73 (d, J ¼ 8.8 Hz, 2H), 7.85 (d, J ¼ 9.2 Hz, 1H); 13C NMR
(400 MHz, CDCl3) d 21.5, 28.7, 36.3, 52.3, 83.4, 101.8, 114.1, 114.5, 119.9,
124.7, 126.7, 129.8, 129.9, 130.3, 135.0, 144.9, 156.4, 156.9; EI-MS: m/z
(%) 430 (31, Mþ), 329 (6), 314 (15), 219 (100), 175 (43); HRMS calcd. for
C22H26N2NaO5S: 453.1562; found 453.1569.
3t. Purification by chromatography on silica gel (acetone/petroleum ether
1:4) afforded a light yellow solid. Mp: 1288C. IR: 979, 1034, 1173, 1227,
1
1370, 1476, 1516, 1717, 2917 cm21; H NMR (400 MHz, CDCl3) d 2.34
(s, 3H), 3.81 (s, 3H), 4.44 (d, J ¼ 6.0 Hz, 2H), 5.00 (s, br, 1H), 5.15
(s, 2H), 6.94 (dt, J ¼ 2.8, 9.6 Hz, 1H), 6.99 (s, 1H), 7.21 (m, 2H), 7.33
(m, 5H), 7.44 (s, 1H), 7.73 (m, 2H), 7.86 (d, J ¼ 8.8 Hz, 1H); 13C NMR
(400 MHz, CDCl3) d 21.5, 36.3, 55.6, 66.9, 101.9, 102.0, 114.2, 114.3,
114.6, 124.7, 124.8, 126.8, 128.0, 128.2, 128.5, 129.9, 134.4, 144.9, 156.45;
EI-MS: m/z (%) 464 (14, Mþ), 373 (27), 314 (4), 309 (10), 218 (19);
HRMS calcd. for C25H24N2NaO4S: 487.1306; found 487.1306.
General Procedure for the DIB-Promoted Hofmann
Rearrangement of Acetamides 5a, 5b, 5d, and 5e
A mixture of 1 mmol of acetamide 5 and 1.2 equiv of DIB were stirred in 10mL
of methanol at room temperature for 4–10h. The solvent was removed under
vacuum. The residue was purified by chromatography on silica gel to give
alkyl carbamate 6.
6a. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:10) afforded a white solid. Mp: 102 8C. IR: 1239.1, 1465.9, 1569.3,
1611.1, 2871.4, 3335.2cm21; 1H NMR (400MHz, CDCl3) d 3.70 (s, 3H), 4.54
(d, J ¼ 5.6 Hz, 2H), 5.11 (s, br, 1H), 6.96 (m, 2H), 7.2 (d, J ¼ 3.6 Hz, 1H); 13
C
NMR (400 MHz, DMSO-d6) d 38.4, 52.3, 121.3, 126.4, 127.8, 142.0, 158.1;
EI-MS: m/z (%) 112 (100, Mþ-COOCH3); anal. calcd. for C7H9N1O2S1: C,
49.10; H, 5.30; N, 8.18. Found: C, 49.14; H, 5.26; N, 8.22.
6b. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:10) afforded a white solid. Mp: 1058C. IR: 1263.9, 1423.8, 1617.4,
2924.5, 3353.2 cm21 1H NMR (400 MHz, CDCl3) d 3.70 (s, 3H), 4.53
.
(d, J ¼ 5.6 Hz, 2H), 5.10 (s, br, 1H), 6.92 (m, 2H), 7.2 (d, J ¼ 3.6 Hz, 1H);
13C NMR (400 MHz, DMSO-d6) d 38.32, 52.00, 124.9, 126.8, 127.9, 144.4,
157.6; EI-MS: m/z (%) 112 (100, Mþ-COOCH3); anal. calcd. for
C7H9N1O2S1: C, 49.10; H, 5.30; N, 8.18. Found: C, 49.07; H, 5.33; N, 8.15.
6d. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:10) afforded a white solid. Mp: 1258C. IR: 1131, 1339, 1508, 1734,

2746
H. Song et al.
1
2924, 3345 cm21; H NMR (400 MHz, CDCl3) d 1.60 (s, 9H), 3.65 (s, 3H),
4.46 (d, J ¼ 6.4 Hz, 2H), 5.63 (s, br, 1H), 6.08 (t, J ¼ 3.2 Hz, 1H), 6.21
(s, 1H), 7.25 (t, J ¼ 2.0 Hz, 1H); 13C NMR (400 MHz, CDCl3) d 28.0, 38.3,
52.0, 84.1, 110.3, 113.6, 121.5, 127.3, 131.9, 158.7; EI-MS: m/z (%) 254
(2, Mþ), 154 (18); HRMS calcd. for C12H18N2NaO4: 277.1159; found
277.1142.
6e. Purification by chromatography on silica gel (ethyl acetate/petroleum
ether 1:10) afforded a white solid. Mp: 105 8C. IR: 1052, 1155, 1264, 1367,
1
1515, 1716, 2924, 3445 cm21; H NMR (400 MHz, CDCl3) d 2.41 (s, 3H),
3.64 (s, 3H), 4.35 (d, J ¼ 6.4 Hz, 2H), 5.41 (s, br, 1H), 6.21 (t, J ¼ 3.2 Hz,
1H), 6.27 (s, 1H), 7.25 (t, J ¼ 1.6 Hz, 1H), 7.30 (d, J ¼ 8.0 Hz, 2H), 7.65
(d, J ¼ 8.0 Hz, 2H); 13C NMR (400 MHz, CDCl3) d 21.6, 37.3, 52.1, 111.9,
115.1, 123.3, 126.5, 130.1, 131.7, 136.0, 145.2; EI-MS: m/z (%) 308
(2, Mþ), 234 (9), 153 (100); HRMS calcd. for C14H16N2NaO4S: 331.0723;
found 331.0733.
1-Deprotection of Alkyl Carbamate 3c and 3d to Give 7
Carbamate 3c or 3d (0.5 mmol) was stirred with 2 mL of 1 M of NaOH in 2 mL
of THF for 1 h. The reaction mixture was extracted with EtOAc (2 ꢀ 5 mL).
The organic layers were dried and evaporated to give a residue. The residue
was purified by chromatography on silica gel (ethyl acetate/petroleum ether
1:3) to afford 7 as a white solid in 95% yield and 90% yield respectively.
1
Mp: 858C. IR: 1073, 1253, 1457, 1523, 1698, 2925, 3325 cm21; H NMR
(400 MHz, CDCl3) d 3.7 (s, 3H), 4.56 (d, J ¼ 5.2 Hz, 2H), 4.89 (s, br, 1H),
7.16 (m, 2H), 7.22 (d, J ¼ 7.2 Hz, 1H), 7.38 (d, J ¼ 8 Hz, 1H), 7.65
(d, J ¼ 7.6 Hz, 1H), 8.19 (s, 1H); 13C NMR (400 MHz, CDCl3) d 36.7,
52.1, 111.5, 112.6, 118.7, 119.6, 122.2, 123.2, 126.4, 136.5, 157.2; EI-MS:
m/z (%) 204 (100, Mþ), 189 (29), 145 (14), 130 (75), 118 (28); HRMS
calcd. for C11H12N2NaO2: 224.0799; found 224.0807.
Deprotection of Alkyl Carbamate 3g to Give 4b
A solution of carbamate 3g (0.398 g, 1 mmol) in 5 ml of CH2Cl2 was stirred at
room temperature for 0.5 h in the presence of 20% TFA. The reaction mixture
was quenched with saturated Na2CO3 and was extracted with CH2Cl2. The
combined organic layers were dried by Na2SO4. The solvent was removed
under vacuum. The residue was purified by chromatography on silica gel
(ethyl acetate/methanol 10:1) to afford 0.283 g of amine 4b (94% yield) as
1
a white solid. Mp: 858C. IR: 972, 1122, 1174, 1368, 1684, 2924 cm21; H
NMR (400 MHz, CDCl3) d 1.88 (s, 2H), 2.31 (s, 3H), 3.98 (s, 2H), 7.18
(d, J ¼ 8.4 Hz, 2H), 7.24 (m, 3H), 7.47 (s, 1H), 7.77 (d, J ¼ 8.2 Hz, 2H),
7.98 (d, J ¼ 8.0 Hz, 1H); 13C NMR (400 MHz, CDCl3) d 21.4, 37.3, 113.7,

1-Protected Indole-3-methylamine
2747
119.4, 122.7, 123.1, 124.4, 124.8, 126.7, 129.7, 129.8, 130.0, 135.5, 144.8; EI-
MS: m/z (%) 300 (68, Mþ), 284 (17), 145 (84), 129 (15); HRMS calcd. for
C16H16KN2O2S: 339.0564; found 339.0572.
ACKNOWLEDGMENT
Support from Ministry of Education (NCET, RFDP, and EYTP), the Excellent
Youth Foundation of Sichuan Province (No. 04ZQ026-011), Sichuan Univer-
sity (2005CF01), and the National Natural Science Foundation of China (No.
20372048) are gratefully acknowledged.
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2748
H. Song et al.
7. DIB was used to prepare methyl carbamates from primary alkyl- andaryl-
carboxamides under strong basic condition via Hofmann rearrangement; see
Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.; Tuladhar, S. M.
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8. Gribble, G.; Jiang, J.; Liu, Y. J. Org. Chem. 2002, 67, 1001.