Direct amination of phenols under metal-free conditions

Article abstract of DOI:10.1055/s-0033-1338703

Herein, we disclose the metal-free synthesis of arylamines via the direct amination of phenols using aminating reagents. This reaction procedure uses easy accessible aminating reagents and provides a versatile synthetic route to a broad range of arylamines with various functionalities in good to excellent yield. By using a two-step route of amination and oxidative coupling reaction, we synthesized three naturally occurring carbazole alkaloids: murrayafoline A, mukonine, and clausenine from two commercially available phenols. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338703

1448▌
LETTER
lDettierrect Amination of Phenols under Metal-Free Conditions
Synthesis of Arylamines
Jianzhong Yu,a Yongtao Wang,a Peizhi Zhang,b Jun Wu*a
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87951895; E-mail: wujunwu@zju.edu.cn
b
School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310012, P. R. of China
Received: 16.03.2013; Accepted after revision: 11.04.2013
arenes or heteroarenes10 and construction of C(aryl)–N
Abstract: Herein, we disclose the metal-free synthesis of aryl-
bonds using arylboroxines11 or arylboronic acids.12
amines via the direct amination of phenols using aminating re-
agents. This reaction procedure uses easy accessible aminating
reagents and provides a versatile synthetic route to a broad range of
arylamines with various functionalities in good to excellent yield.
By using a two-step route of amination and oxidative coupling re-
action, we synthesized three naturally occurring carbazole alka-
loids: murrayafoline A, mukonine, and clausenine from two
commercially available phenols.
However, the substrate of those methods is limited. Since
the broad existence of phenols in nature and the synthetic
world, metal-free direct amination of environmentally be-
nign phenols is an ideal process for constructing C(aryl)–
N bonds. However, this process has not been widely ex-
plored due to its significant challenges. For example, Bu-
cherer
reaction13
and
an
alkylation–Smiles
Key words: amination, phenols, metal-free, arylamines, carbazoles
rearrangement–hydrolysis sequence14 have been used for
the preparation of primary arylamines from phenols, but
these methods require either harsh reaction conditions or
suffer from a limited substrate scope. Through our last
several years work in this field,15 here we report the metal-
free synthesis of arylamines, including diarylamines,
alkylarylamines, and primary arylamines via the direct
amination of phenols using aminating reagents.
Aromatic carbon–nitrogen bonds are ubiquitous in phar-
maceuticals, agrochemicals, natural products, and poly-
mers.1 Typically, C(aryl)–N bonds are formed by copper-
mediated Ullmann2- and Goldberg3-type reactions. These
methods suffer from several drawbacks including a lack
of tolerance towards functional groups, the need for the
stoichiometric amount of copper and harsh reaction con-
ditions as well. To address these limitations, transition-
metal-catalyzed C(aryl)–N cross-coupling reactions is de-
veloped in Buchwald–Hartwig’s research group to make
arylamines from aryl (pseudo) halides using palladium or
copper catalysts.4 Chan–Lam’s group has developed an
alternative way to arylamine from arylboronic acids or es-
ters.5 Recently, the transition-metal-catalyzed electrophil-
ic amination of various organometallic reagents with
aminating agents has received widespread attention and
represents an alternative approach for the direct formation
of C(aryl)–N bonds.6 Further on, the transition-metal-cat-
alyzed direct C–H amination of aromatic rings has re-
ceived considerable attention because of its
straightforward and economical advantages over present
procedures employing prefunctionalized substrates.7
Initially, we assessed the reactivity of various potential
aminating reagents toward phenols in a one-pot fashion
(Table 1). Attempted amination of 4-chlorophenol (1a)
with 2-bromo-2-methyl-N-phenylpropanamide (4) did not
yield the desired product 4-chlorodiphenylamine (3a, Ta-
ble 1, entry 1). Gratifyingly, 2-bromo-2-phenyl-N-phenyl-
acetamide (5) and 2-bromo-N-phenylacetamide (6) were
effective for the conversion of 4-chlorophenol (1a) into 4-
chlorodiphenylamine (3a, Table 1, entries 2 and 3). The
reaction with 2-bromo-N-phenylpropanamide (7a) afford-
ed the expected 4-chlorodiphenylamine (3a), resulting in
a higher yield (Table 1, entry 4). 2-Bromo-N-phenyl-
propanamide (7a) was selected as the preferred aminating
reagent.
We next investigated the effect of solvents and bases on
the transformation from 2a into 3a. Among the examined
solvents, N,N-dimethylformamide (DMF), N,N-dimethyl-
acetamide (DMAC), 1-methyl-2-pyrrolidone (NMP), and
dimethyl sulfoxide (DMSO) were suitable for the trans-
formation, but DMSO is a super solvent to produce the
best yield. Comparing bases including KOH, NaOH,
Na2CO3, K2CO3, and Cs2CO3, KOH performed much bet-
ter than others in the transformation and afforded product
3a in 76% yield (Table 2, entry 4). After the extensive
screening of various solvents and bases, we were pleased
to find that a combination of KOH/DMSO was the best
choice for the amination of 2a to furnish 3a.
However, the above-described methods require engage-
ment of transition metals, which make these methods ex-
pensive and environmentally less friendly. From the
economic and ecological point of view, it would be great
if metal-free aromatic amination is provided.8 Currently,
most of arylamine formation require aryl halides as the
starting materials,9 which are not environment friendly. In
recent years, a few of pioneers explore several good meth-
ods including metal-free oxidative C–H amination of
SYNLETT 2013, 24, 1448–1454
Advanced online publication: 17.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338703; Art ID: ST-2013-W0237-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Arylamines
1449
Table 1 Screening of Potential Aminating Reagents for the Conversion of 1a into 3aa
O
H
N
OH
R1
KOH (1.1 equiv)
130 °C, 2 h
aminating agent
O
Ph
N
H
KOH (1.0 equiv)
DMSO, 50 °C, 2 h
Cl
R2
Cl
Cl
1a
2
3a
Entry
Aminating reagent
Yield (%)b
O
Br
NHPh
1
0
4
O
Br
NHPh
2
3
4
30
65
76
Ph
5
O
Br
NHPh
6
O
Br
NHPh
7a
a Reaction conditions: (i) 4-chlorophenol (1a, 1.0 mmol), aminating reagent 4–7a (1.05 mmol), KOH (1.0 mmol), DMSO (3 mL), 50 °C, 2 h;
(ii) KOH (1.1 mmol), 130 °C, 2 h.
b Isolated yields.
With the optimized reaction conditions in hand, a wide
scope of substrates were tested, the detailed results are
summarized in Scheme 1 Pleasingly, this transformation
Table 2 Optimization of Reaction Conditionsa
afforded diarylamines 3 in good to excellent yields. This
O
H
N
reaction was compatible with a variety of substituents, re-
gardless of their electronic or steric properties. Single or
multiple halogen substituents at ortho, meta, and para po-
sitions were well-tolerated in the transformation, which
are typically sensitive in transition-metal-catalyzed ami-
nation reactions (Scheme 1, 3a–h,m,v).23 The reaction
even worked in the presence of base-sensitive functional
groups like nitrile, ester, and ketones (Scheme 1, 3i–l).
The amination of phenols 1 with an electron-withdrawing
group (CN, CO2Me, COMe, COEt, and NO2) resulted in
good to excellent yields (Scheme 1, 3i–l,u,v). The pres-
ence of electron-donating groups (Me, i-Pr, Ph, and MeO)
in phenols 1 did not prevent the amination, resulting in
moderate to excellent yields (Scheme 1, 3o–t). The steric
bulk of an ortho substituent also did not decrease reactiv-
ity (Scheme 1, 3t and 3s, 65% and 47% yield). Moreover,
a set of bicyclic phenols were aminated to afford the de-
sired product in good isolated yields (Scheme 1, 3w–z). In
addition, aminating reagent 7 was found working nicely in
the case of aromatic rings bearing the electron-donating
methyl group (Scheme 1, 3d and 3y) or the electron-with-
drawing chloro group (Scheme 1, 3m and 3v).
base
O
N
H
solvent
Cl
Cl
2a
3a
Entry Base
Solvent
Temp (°C)Time (h) Yield (%)b
1
2
3
4
5
6
7
8
KOH
KOH
KOH
KOH
DMF
130
130
130
130
130
130
130
130
2
2
70
68
59
76
68
8
DMAC
NMP
2
DMSO
DMSO
DMSO
DMSO
DMSO
2
NaOH
2
Na2CO3
K2CO3
Cs2CO3
16
16
10
43
56
a Reaction conditions: 2a (1.0 mmol), base (1.1 mmol), solvent (4.0
mL).
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1448–1454

1450
J. Yu et al.
LETTER
Under the same reaction conditions, a variety of aminat- cellent product yields (Table 3, entries 1–4). In addition,
ing reagents 8 were also investigated for the amination of benzyl aminating reagents 8c and 8d21 were also effective
phenols 1 (Table 3). Phenols 1 were smoothly aminated to for the amination of phenols 1 to afford the desired prod-
afford the designed alkylarylamines 9. The reactions with ucts 9e–h (Table 3, entries 5–8). It was found that both the
aliphatic aminating agents 8a and 8b proceeded without electron-rich and electron-deficient groups in aromatic
any difficulties to afford the alkylarylamines 9a–d in ex-
(i) DMSO, KOH (1.0 equiv)
50 °C, 2 h
H
N
H
OH
N
R1
Br
+
R1
R2
R2
O
(ii) KOH (1.1 equiv)
130 °C, 2 h
1
7
3
H
H
N
H
N
N
Cl
F
Br
X
X = H
X = Me 3d 93%
3c 86%
3a 76%
3b 65%
H
N
H
N
H
Br
N
I
Cl
3e 75%
3f 82%
3g 85%
H
N
Cl
H
H
N
N
MeO
NC
Cl
O
3h 58%
3i 84%
3j 50%
H
H
N
N
H
N
Cl
Et
O
O
3k 71%
3l 69%
3m 68%
H
H
N
H
N
N
i-Pr
X
Me
X = H
3n 83%
3o 91%
3p 85%
X = Me 3o 58%
X = Cl 3a 86%
H
N
H
H
N
N
MeO
Ph
MeO
3q 87%
3r 47%
3s 48%
H
N
H
N
H
N
O2N
X
OMe
X = H 3u 93%
X = Cl 3v 85%
3t 65%
3w 68%
H
N
N
H
N
O
O
X
X = H
X = Me
3x 71%
3y 64%
3z 72%
Scheme 1 Metal-free amination of phenols 1 with aminating reagents 7. Reagents and conditions: (i) phenol 1 (1.0 mmol), aminating reagent
7 (1.05 mmol), KOH (1.0 mmol), DMSO (3 mL), 50 °C, 2 h; (ii) KOH (1.1 mmol), 130 °C, 2 h; isolated yields are given.
Synlett 2013, 24, 1448–1454
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Arylamines
1451
rings were well tolerated and did not show distinct elec- (Table 4, entry 9) with good antiproliferative activity,
tronic effect.
which required up to six steps in the literature for its prep-
aration 11i.16
Encouraged by the results as described above, we turned
our attention to primary amination of phenols 1 using am- We subsequently conducted the amination reaction on a
inating reagent 1022 (Table 4). The reaction proceeded gram scale to demonstrate its practicality (Scheme 2). The
smoothly to afford primary arylamines 11 in good to ex- protocol used readily available 7-hydroxy-4-methylcou-
cellent yields when the temperature was raised to 140 °C. marin (12) as the starting material to afford the corre-
Gratifyingly, the reaction proceeded smoothly to give the sponding product 13 (coumarin 120), which is an
halo-substituted primary arylamines 11a–c (Table 4, en- important laser dye. This one-step synthetic method has
tries 1–3). The reaction worked equally well in the pres- much more advantages than the present method.17
ence of the unprotected ketone (Table 4, entry 4). Nitrile
This amination reaction can also be applied in the prepa-
was also unaffected (Table 4, entry 5). Moreover, the re-
ration of carbazoles,24 which are particular interesting in
action was effective even for a set of bicyclic phenols (Ta-
the field of bioactive compounds and organic materi-
ble 4, entries 6–8). Furthermore, a natural product
als.18,19 Most of the traditional synthetic routes to carba-
pterostilbene was readily converted into compound 11i
Table 3 Metal-Free Amination of Phenols 1 with Aminating Reagents 8a
(i) DMSO, KOH (1.0 equiv)
50 °C, 2 h
H
H
OH
N
N
R2
R1
R1
+
Br
R2
(ii) KOH (1.1 equiv)
130 °C, 2 h
O
1
8
9
Entry
8
Product
Yield (%)b
H
N
1
9a 98
Cl
H
N
H
N
Br
2
3
4
9b 98
9c 96
9d 83
O
H
N
H
H
N
N
Br
O
O
F
H
N
5
6
9e 92
9f 95
Cl
H
N
Br
N
H
7
8
9g 55
9h 88
O
O
N
H
H
N
H
N
O
O
Br
O
a Reaction conditions: (i) phenol 1 (1.0 mmol), aminating reagent 8 (1.05 mmol), KOH (1.0 mmol), DMSO (3 mL), 50 °C, 2 h; (ii) KOH (1.1
mmol), 130 °C, 2 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1448–1454

1452
J. Yu et al.
LETTER
(i) DMSO, KOH (1.0 equiv)
50 °C, 2 h
NH2
+
Br
(ii) KOH (1.1 equiv)
140 °C, 2 h
O
O
NH2
O
O
OH
O
70%
12 (2.0 g)
10
13
Scheme 2 Amination reaction of 7-hydroxy-4-methyl coumarin 12 on a gram scale using aminating reagent 10
zoles are lengthy, involving several steps from to access the naturally occurring carbazole alkaloids: mur-
commercially available materials, and typically suffer rayafoline A, clausenine, and mukonine. Using 4-methyl-
from low overall yields. For example, the synthesis of the guaiacol (17) as starting material, it was easy to convert
naturally occurring carbazole alkaloids: murrayafoline A into the corresponding diarylamines 18 and 19 via the am-
(14) and clausenine (15) requires three steps from com- ination reactions, followed by Pd(II)-catalyzed oxidative
mercially available 5-methyl-2-nitroanisole.20 The syn- coupling reactions20 to afford murrayafoline A and claus-
thesis of mukonine (16) needs five steps from 5-methyl-2- enine. A similar strategy for the synthesis of mukonine
nitroanisole.20 Scheme 3 showed a new two-step sequence was illustrated in Scheme 3.
Table 4 Metal-Free Amination of Phenols 1 with Aminating Reagents 10a
(i) DMSO, KOH (1.0 equiv)
50 °C, 2 h
OH
NH2
NH2
R1
R1
+
Br
(ii) KOH (1.1 equiv)
140 °C, 2 h
O
10
1
11
Entry
1
Phenol
Product
Yield (%)b
11a 74
Br
I
OH
Br
I
NH2
OH
NH2
2
3
11b 81
11c 71
Cl
Cl
Cl
Cl
O
NH2
OH
O
NH2
OH
4
5
6
11d 85
11e 80
11f 78
Ph
NC
Ph
OH
OH
NC
NH2
NH2
OH
NH2
N
N
7
8
11g 93
11h 71
O
O
NH2
O
O
OH
MeO
MeO
NH2
OH
9
11i 92
pterostilbene
MeO
MeO
a Reaction conditions: (i) phenol 1 (1.0 mmol), aminating reagent 10 (1.05 mmol), KOH (1.0 mmol), DMSO (3 mL), 50 °C, 2 h; (ii) KOH (1.1
mmol), 140 °C, 2 h.
b Isolated yield.
Synlett 2013, 24, 1448–1454
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Arylamines
1453
R1
R1
R2
(i) DMSO, KOH (1.0 equiv)
50 °C, 2 h
H
N
Br
+
OH
N
H
(ii) KOH (1.1 equiv)
130 °C, 12 h
O
R2
OMe
OMe
17 R1 = Me
20 R1 = COOMe
7a R2 = H
7b R2 = OMe
18 R1 = Me, R2 = H
63%
19 R1 = Me, R2 = OMe 68%
21 R1 = COOMe, R2 = H 55%
R1
R2
Pd(OAc)2 (5 mol%)
K2CO3 (10 mol%)
PivOH
110 °C, 16 h
N
H
MeO
14 murrayafoline A (R1 = Me, R2 = H) 50%
15 clausenine
16 mukonine
(R1 = Me, R2 = OMe) 79%
(R1 = COOMe, R2 = H) 90%
Scheme 3 Two-step process for the synthesis of naturally occurring carbazole alkaloids 14–16
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In summary, we have developed a direct amination strat-
egy from phenols and aminating reagents under metal-
free conditions. The transformation is simple to operate,
and affords structurally diverse arylamines such as diaryl-
amines, alkylarylamines, and primary arylamines in good
to excellent yields. In particular, a variety of halogenated
arylamines, which often cannot be prepared via the transi-
tion-metal-catalyzed amination, are also readily produced
using this method. In addition, the reaction can be readily
scaled up to gram scale. Moreover, this environmentally
benign amination can be applied in the synthesis of three
naturally occurring carbazole alkaloids: murrayafoline A,
mukonine, and clausenine.
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Acknowledgment
We thank the National Natural Science Foundation of China (No.
31071720) for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
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(22) The Procedure for the Synthesis of Amination Agent 10
A solution of 2-bromopropanoic acid (3.03 g, 20 mmol,) in
SOCl2 (15 mL) was heated at reflux for 3 h. After removal
of the excess SOCl2 under vacuum, the residue was added
slowly to a cold solution of aq NH4OH and stirred for 2 h.
The resulting white precipitate is collected by filtration to
give 10 as a white crystalline powder.
2-Bromopropanamide (10)25
White solid, yield 84%; mp 79–81 °C. 1H NMR (400 MHz,
CDCl3): δ = 6.36 (br s, 2 H), 4.39 (q, J = 7.2 Hz, 1 H), 1.87
(d, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 172.2,
43.9, 22.9 ppm.
(23) General Procedure for the Synthesis of Diarylamines
and Alkylarylamines
A mixture of phenols (1.0 mmol), KOH (56 mg, 1.0 mmol),
and aminating reagent 7 (1.05 mmol or 1.05 mmol aminating
reagent 8) in DMSO (3 mL) was stirred at 50 °C for 2 h.
After the reaction period, 62 mg (1.1 mmol) of KOH was
added, and the mixture was heated at 130 °C for 2–12 h. Sat.
brine was added to the solution and cooled slowly to r.t. The
aqueous phase was extracted with CH2Cl2 three times. The
combined organic layers were washed with three portions of
sat. brine and then dried over MgSO4 and filtered. Solvent
was removed under reduced pressure. The crude product was
purified through column chromatography on 300–400 mesh
silica gel with PE–EtOAc as eluent.
(19) (a) Thomas, K. R. J.; Lin, J. T.; Tao, Y. T.; Ko, C. W. J. Am.
Chem. Soc. 2001, 123, 9404. (b) Chen, C. T. Chem. Mater.
2004, 16, 4389.
(20) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou,
K. J. Org. Chem. 2008, 73, 5022.
(21) General Procedure for the Synthesis of Amination
Agents 7 and 8
A solution of 2-bromopropanoic acid (3.03 g, 20 mmol) in
SOCl2 (15 mL) was heated at reflux for 3 h. After removal
of the excess SOCl2 under vacuum, the resultant 2-
bromopropanoyl chloride was used without further
purification. 2-Bromopropanoyl chloride (20 mmol) was
slowly added dropwise to a mixture of RNH2 (20 mmol) and
Et3N (2.22 g, 22 mmol) in anhyd CH2Cl2 (30 mL) at 0 °C.
The reaction mixture was warmed to r.t. and stirred for an
additional 20 h. A solution of 1 M HCl (30 mL) was added,
and the mixture was stirred for 10 min. The organic phase
was separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 30 mL). The combined organic extracts were
washed with H2O (40 mL) and brine (40 mL) and then dried
over MgSO4, filtered, and concentrated in vacuo to give the
product. Recrystallization from 95% EtOH gave the pure
product.
2-Bromo-N-(furan-2-ylmethyl)propanamide (8d)
White solid, yield 79%; mp 121–122 °C. 1H NMR (400
MHz, CDCl3): δ = 7.34–7.35 (m, 1 H), 6.82 (br s, 1 H), 6.30–
6.32 (m, 1 H), 6.23–6.24 (m, 1 H), 4.39–4.44 (m, 3 H), 1.85
(d, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 169.2,
150.5, 142.4, 110.5, 107.7, 44.7, 37.2, 22.9 ppm. HRMS
(EI): m/z calcd for C8H10BrNO2 [M]+: 230.9895; found:
230.9904.
4-Bromo-N-(p-tolyl)aniline (3d)
White solid, yield 93%; mp 95–96 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.32 (d, J = 8.4 Hz, 2 H), 7.11 (d, J = 8.0 Hz, 2
H), 6.99 (d, J = 8.0 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 5.59
(br s, 1 H), 2.33 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ =
143.1, 139.5 131.9, 131.6 129.9, 119.3, 117.9, 111.7, 20.6
ppm. HRMS (EI): m/z calcd for C13H12BrN [M]+: 261.0153;
found: 261.0156.
(24) General Procedure for the Synthesis of Carbazoles20
A test tube with a magnetic stirring bar was charged with
diarylamines (0.5 mmol), Pd(OAc)2 (5 mol%), K2CO3 (10
mol%), and pivalic acid (450 mg). The uncapped test tube is
placed in an oil bath, and the mixture is stirred under air at at
110 °C for 16 h. The solution is then cooled to r.t., diluted
with CH2Cl2, washed with a sat. aq solution of Na2CO3,
dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude product is purified by silica gel column
chromatography to afford the corresponding coupling
product.
(25) Oakes, F. T.; Leonard, N. J. J. Org. Chem. 1985, 50, 4986.
Synlett 2013, 24, 1448–1454
© Georg Thieme Verlag Stuttgart · New York