Palladium-catalyzed mono- N -allylation of unprotected anthranilic acids with allylic alcohols in aqueous media

Article abstract of DOI:10.1021/jo201691e

Palladium-catalyzed N-allylation of anthranilic acids 1a-j with allyl alcohol 2a in the presence of Pd(OAc)₂, sodium diphenylphosphinobenzene-3-sulfonate (TPPMS) in THF-H₂O at room temperature gave only mono-N-allylated anthranilic a

Full text of DOI:10.1021/jo201691e

ARTICLE
pubs.acs.org/joc
Palladium-Catalyzed Mono-N-allylation of Unprotected Anthranilic
Acids with Allylic Alcohols in Aqueous Media
Hidemasa Hikawa* and Yuusaku Yokoyama*
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
S Supporting Information
b
ABSTRACT: Palladium-catalyzed N-allylation of anthranilic acids 1aꢀj with
allyl alcohol 2a in the presence of Pd(OAc)2, sodium diphenylphosphino-
benzene-3-sulfonate (TPPMS) in THFꢀH2O at room temperature gave only
mono-N-allylated anthranilic acids 3aꢀj in good yields (70ꢀ98%). The
reactions of 4-bromoanthranilic acid 1i with 2-methyl-3-buten-2-ol 2b
showed complete chemoselectivity in N-allylation (neutral conditions) and
C-vinylation (basic conditions). In our catalytic system, the keys to success are
use of an unprotected anthranilic acid as a starting material and the presence of water in the reaction medium. The carboxyl group of
anthranilic acid and water may play important roles for the smooth generation of the π-allyl palladium species by activation of the
hydroxyl group of the allylic alcohol.
’ INTRODUCTION
Scheme 1. Reaction of Anthranilic Acid 1a with Allylbromide
Protection of reactive functional groups such as amino,
hydroxyl, or carboxyl groups is essential in organic synthesis,
not only for suppressing side reactions but also for easy handling
by decreased polarity.1 However, protection sometimes causes
serious problems, e.g., increasing the number of synthetic steps
and difficulty in deprotecting unstable compounds. Therefore,
the development of unprotected syntheses should lead to a
breakthrough in organic synthesis. One of the most effective
ways for achieving such a concept is the development of selective
reactions toward various reactive functional groups.
During the total synthesis of clavicipitic acids, we found that
the reactivity of an unprotected amino acid could be controlled
by changing the pH in aqueous media. A palladium-catalyzed
allylation of free 4-bromotryptophan with 1,1-dimethylallyl
alcohol occurred at the amino group under weakly basic or neu-
tral conditions, whereas vinylation (Heck reaction) occurred
selectively at the C-4-position (bromine-substituted carbon
atom) under strongly basic conditions.2 It should be emphasized
that pH plays a critical role in the chemoselectivity of palladium-
catalyzed reactions.
Palladium-catalyzed allylations with allylic alcohols are espe-
cially interesting, because it is known that the reactivity of allylic
alcohols toward Pd(0) is poor compared with that of allylic
carbonates or acetates. Although palladium-catalyzed N-allylation
with allylic alcohols occurred in organic solvents by adding Lewis
acids,3 cationic PdII catalysts,4 Pt catalysts,5 or Pd-P(OPh)3 catalysts6
as additives, the same reaction proceeded smoothly in aqueous media
without such additives, in which water played an important role in the
activation of the allylic alcohol to form the π-allyl complex.7 This
finding was applied by us to the N-allylation of water-soluble free
amino acids to give the N-monoallylated products selectively in
good yields.7f Furthermore, halo-anilines, which are soluble
in organic solvents, showed pH-controlled chemoselectivity only
in the presence of water.7c On the basis of these works, we
became interested in further expanding the substrate scope of
this methodology to anthranilic acids, aromatic amino acids that
are also soluble in organic solvents. Anthranilic acids are not only
biologically important compounds as metabolites of tryptophan
but also key units in a wide range of relevant pharmacophores
with a broad spectrum of activities.8 Herein, we report a
palladium-catalyzed mono-N-allylation of anthranilic acids with
allylic alcohols in aqueous media.
To the best of our knowledge, the allylation of unprotected
anthranilic acids with allylic alcohols has not been described
before. Reductive amination,9 N-alkylation,10 and palladium-
catalyzed allylation11 of anthranilic acid ester have been reported.
In contrast, there are few examples of direct N-allylation of an-
thranilic acids. The reaction of anthranilic acid 1a with allylbro-
mide gives the corresponding allyl esters (Scheme 1).12
’ RESULTS AND DISCUSSION
When a mixture of anthranilic acid 1a and allyl alcohol 2a was
stirred in the presence of Pd(OAc)2 (5 mol %) and sodium
diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol %) in
Received: August 20, 2011
Published: September 15, 2011
r
2011 American Chemical Society
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Table 1. Effects of Catalysts and Solvent on N-Allylation
Table 2. N-Allylation of Various Anthranilic Acids 1a
of 1aa
yield
conditions [%]
entry
catalyst
solvent
1
2
3
4
5
6
7
8
9
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
none
H2O
H2O
H2O
rt, 48 h
0
70 °C, 16 h 73
70 °C, 16 h
0
92
92
87
66
0
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
THFꢀH2O (1:1) rt, 48 h
CHCl3ꢀH2O (1:1) rt, 48 h
tolueneꢀH2O (1:1) rt, 48 h
THFb
THF
rt, 48 h
rt, 48 h
Pd(OAc)2/PPh3
THFꢀH2O (1:1) rt, 48 h
THFꢀH2O (1:1) rt, 48 h
THFꢀH2O (1:1) rt, 48 h
47
72
73
0
c
10 Pd2(dba)3 /PPh3
11 Pd(PPh3)4
12 Pd(OAc)2/PPh3
THF
rt, 48 h
13 [PdCl(πꢀallyl)]2/TPPMS THFꢀH2O (1:1) rt, 48 h
72
81
28
c
14 Pd2(dba)3 /TPPMS
THFꢀH2O (1:1) rt, 48 h
THFꢀH2O (1:1) rt, 48 h
15 PdCl2/TPPMS
a Anthranilic acid 1a (1 mmol), Pd catalyst (5 mol %), ligand (10 mol %),
and allyl alcohol 2a (3 equiv). b H2O (1 equiv) was added. c 2.5 mol %.
H2O at room temperature for 48 h, no reaction occurred (entry 1
in Table 1). The reaction did proceed at 70 °C to give the desired
product 3a in 73% yield (entry 2). Only mono-N-allylated prod-
uct 3a was obtained in good yield despite the possibility of
forming the diallylated product or allyl ester. Since the reaction
did not proceed without the palladium catalyst (entry 3), a SN20-
type reaction mechanism was excluded in the formation of the
N-allylated product. In a THFꢀwater biphasic system, the reaction
proceeded even at room temperature to give the product 3a in
high yield (entry 4, 92%). With regard to the organic solvent in
the biphasic system, CHCl3 (entry 5, 92%) and toluene (entry 6,
87%) also gave good results. The presence of only 1 equiv of
water is enough to promote the reaction smoothly (entry 7,
66%), but no reaction occurred in only THF (entry 8). These
results clearly show that the reaction proceeded smoothly in
organic solvents only in the presence of water (at least 1 equiv).
Since the reaction also proceeded in water at high temperature
(entry 2), N-allylation might occur in both the organic and
aqueous phases. This consideration was supported by the use of a
water-insoluble ligand, PPh3, for the reaction, which proceeded
smoothly in the biphasic system (entries 9ꢀ11) but did not
proceed in the absence of water (entry 12). Water might be
required for the smooth generation of the π-allyl palladium
species by hydration of the hydroxyl group. With regard to the
palladium catalyst, the use of zero- or divalent palladium,
[PdCl(π-allyl)]2 or Pd2(dba)3, also gave the product in good
yields (entry 13, 72%; entry 14, 81%), although the use of PdCl2
resulted in a poor yield (entry 15).
a Anthranilic acid 1 (1 mmol), Pd(OAc)2 (5 mol %), TPPMS (10 mol %),
and allyl alcohol 2a (3 equiv) in THF (2 mL) and H2O (2 mL), rt, 72 h.
b 80 °C, 5 h.
are summarized in Table 2. All of the anthranilic acids examined
underwent mono-N-allylation smoothly to give the corresponding
mono-N-allyl anthranilic acids in overall yields ranging from 70%
to 98% (entries 1ꢀ9). It is noted that bromoanthranilic acids (1h
and 1i) gave only N-allylated products (3h and 3i) in good yield
despite the possible formation of a C-vinylated product by the
Heck reaction (entries 7 and 8). These results are consistent with
our previous report that the Pd-catalyzed allylations of bromoa-
nilines with 2-methyl-3-buten-1-ol gave N-allylated products
selectively under neutral conditions, whereas vinylation occurred
at the bromine-substituted carbon atom selectively under basic
conditions. Therefore, we next attempted the palladium-catalyzed
reaction of 4-bromoanthranilic acid 1i with 2-methyl-3-buten-
1-ol 2b under neutral and basic conditions (Scheme 2). Since
N-allylation of 1i with sterically hindered allylic alcohol 2b did
not proceed at room temperature in THFꢀwater, we investi-
gated the reaction at 100 °C in water. Under neutral conditions,
N-allylation occurred selectively to give N-allylated product 3l
Results for the N-allylation of a number of anthranilic acids
substituted by electron-withdrawing and electron-donating
groups 1bꢀj with allyl alcohol 2a using Pd(OAc)2 and TPPMS
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Table 3. N-Allylation with Various Allylic Alcohols 2a
a Anthranilic acid 1a (2 mmol), Pd catalyst (5 mol %), ligand (10 mol %), and allyl alcohol 2a (3 equiv). b E/Z mixture. c The regio- and stereoisomeric
ratios of 3 were determined by 1H NMR spectroscopy. d E/Z mixture of 2g (E/Z = 95/5) was used.
(76%) along with C-allylated product 4a (11%), which was formed
by aromatic amino-Claisen rearrangement of regioisomer 3k.
Cooper13 reported that N-(1,1-dimethylallyl)aniline was rear-
ranged to 2-(3,3-dimethylallyl)aniline using a catalytic amount of
p-toluenesulfonic acid in acetonitrileꢀwater (10:1) in 70% yield.
In contrast, under basic conditions (4 equiv of NaOH), the Heck
reaction occurred selectively to give C-vinylated product 5 in
98% yield. Since the carbon side chain could be introduced to the
bromine-substituted carbon atom, trisubstituted benzene deri-
vatives might be easily prepared regioselectively. As reported pre-
viously,7c chemoselectivity for N-allylation and C-vinylation can
be explained by the selective formation of a π-allyl palladium
complex under neutral conditions or of a σ-aryl palladium
complex under basic conditions. The formation of a σ-complex
might be inhibited under neutral conditions by suppression
of Pd(0) regeneration due to the absence of base, which
neutralizes HBr formed through decomposition of H-PdII-Br
during the reaction.
We next investigated the scope of different allylic alcohols 2 in
water at various temperatures, which was optimized on the basis
of TLC analysis (Table 3). The reaction of 2-methyl-3-buten-2-
ol 2b afforded the mono-N-allylated product 3m in 78% yield
along with rearrangement product, 2-amino-3-(3-methylbut-2-
enyl)benzoic acid 4b, from the corresponding isomer in 6% yield
(entry 1). Prenyl alcohol 2c also gave the same product 3m in
good yield (entry 2, 74%). The reaction of β-methallyl alcohol 2d
proceeded slowly (entry 3, 51%). Hydrophobic allylic alcohols
such as cinnamyl alcohol 2e, which are not soluble in water, gave
trans product 3o selectively in quantitative yield (entry 4),
whereas geraniol 2f gave an E/Z mixture of allylated product
3p (entry 5). Thus, this reaction should be applicable to the
N-allylation with various aliphatic allylic alcohols. When α-substituted
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Scheme 2. Chemoselective Palladium-Catalyzed Reaction:
Selectivity in the Reaction of 4-Bromoanthranilic Acid 1i with
2-Methyl-3-buten-1-ol 2b
Table 4. N-Allylation of Aminobenzoic Acid 8a
a Aminobenzoic acid 8 (1 mmol), Pd(OAc)2 (5 mol %), TPPMS
(10 mol %), and allyl alcohol 2a (3 equiv) in THF (2 mL) and H2O
(2 mL), rt, 72 h.
Scheme 3. N-Allylation of Anthranilic Acid Ethyl Ester 6
Scheme 5. Possible Mechanism for the Formation of N-Allyl
Anthranilic Acid 3a
Scheme 4. N-Allylation of Anthranilic Acid 1a in Aqueous
NaOH
acid (1 equiv) as an additive greatly improved the yield to 62%,
whereas NaOH suppressed the N-allylation of anthranilic acid 1a
(Scheme 4). These results suggested that the carboxyl group of
anthranilic acid may play a key role as an activator in our catalytic
system. In addition, the reaction of 3-aminobenzoic acid 8a gave
di-N-allylated 10a in 71% yield (Table 4, entry 1). In contrast,
4-amino-3-bromobenzoic acid 8b afforded only mono-N-ally-
lated 9b in 75% yield (entry 2). Thus, N-allylation of anthranilic
acids can give only mono-N-allylated product by the steric effect
of carboxyl group at the ortho position.
A possible mechanism for the formation of N-allyl anthranilic
acid 3a from anthranilic acid 1a and allyl alcohol 2a in water is
illustrated in Scheme 5. First, oxidative addition of alcohol 2a to a
Pd(0) species affords the π-allyl palladium complex 10. The
carboxyl group of anthranilic acid may play an important role for
the smooth generation of 10 by activation of the hydroxyl group.
Next, ligand exchange of the π-allyl system with the amino group
of 10 takes place at the π-allyl system to generate intermediate
11, followed by reductive elimination to give the mono-N-
allylated product 3a exclusively. Since the reaction did not occur
without water, water may activate the allyl alcohol via hydration
of the hydroxyl group for the smooth generation of the π-allyl
allylic alcohol 2g was used, the inseparable mixture of regio- and
stereoisomer 3q and 3r were obtained in 41% yield. The
substitution occurred mainly at less sterically hindered primary
carbon atom to give E/Z mixture. The obtained regio- and
stereoselectivities were almost the same as that using
γ-substituted allylic alcohol 2h, suggesting that the reaction
proceeds via the same π-allyl palladium intermediate (entries 6
and 7). The sterically demanding secondary alcohol 2i gave lower
yield (entry 8, 30%).
Manabe14 and Yang7b reported that carboxylic acids enhanced
the formation of the π-allyl complex in aqueous media. To
evaluate the effect of the carboxyl group of anthranilic acid in our
catalytic system, N-allylation of anthranilic acid ethyl ester 6 was
carried out. N-Allylation of 6 with allyl alcohol 2a using Pd-
(OAc)2 and TPPMS in THFꢀH2O (1:1) gave mono-N-allylated
7 in only 26% yield (Scheme 3). To our surprise, use of acetic
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palladium intermediate.7a Furthermore, concerning the role of
the carboxylic acid, water molecules play an important role in the
ionization of acids. Therefore, water assists proton transfer from
the carboxyl group to the hydroxyl group of allyl alcohol 2a and
also stabilizes the charged form 2a0 by solvation. Overall, the
carboxyl group of anthranilic acid and water may play important
roles for the smooth generation of the π-allyl palladium species
by activation of the hydroxyl group of allylic alcohols in our
catalytic system.
Our method also succeeds under neutral conditions in good
yield. In contrast, NaOH suppressed the N-allylation. Therefore,
pH plays a critical role in the palladium-catalyzed N-allylation,
and the outcome of the N-allylation can be controlled simply by
changing the basicity of the reaction media.
2-(Allylamino)benzoic Acid 3a15 (Table 1). Following the
general procedure (method A), 3a was obtained as a white solid. Mp
119ꢀ120 °C; IR (KBr) (cmꢀ1) 3378, 3300ꢀ2500, 1671; 1H NMR (400
MHz, DMSO-d6) δ 3.80ꢀ3.90 (m, 2H), 5.15 (dd, J = 10.4, 1.6 Hz, 1H),
5.23 (dd, J = 17.2, 1.6 Hz, 1H), 5.85ꢀ6.00 (m, 1H), 6.57 (dd, J = 7.2, 7.2
Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 7.30ꢀ7.40 (m, 1H), 7.80 (dd, J = 7.2,
1.6 Hz, 1H), 7.99 (brs, 1H), 12.6 (brs, 1H); 13C NMR (400 MHz,
DMSO-d6) δ 44.4, 110.0, 111.5, 114.3, 115.5, 131.6, 134.4, 135.3, 150.7,
170.0; MS-EI m/z (%) 177 (M+, 100).
2-(Allylamino)-5-methylbenzoic Acid 3b (Entry 1 in
Table 2). Following the general procedure (method A), 3b was
obtained as a white solid. Mp 103ꢀ105 °C; IR (KBr) (cmꢀ1) 3376,
3300ꢀ2500, 1666; 1H NMR (400 MHz, CDCl3) δ 2.24 (s, 3H),
3.80ꢀ3.90 (m, 2H), 5.18 (dd, J = 10.2, 1.4 Hz, 1H), 5.28 (dd, J =
17.1, 1.4 Hz, 1H), 5.89ꢀ6.00 (m, 1H), 6.60 (d, J = 8.8 Hz, 1H), 7.21 (dd,
J = 8.8, 2.2 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H); 13C NMR (400 MHz,
CDCl3) δ 20.1, 45.4, 108.6, 111.9, 116.1, 123.9, 132.2, 134.7, 136.7,
149.8, 173.5; MS-EI m/z (%) 191 (M+, 100).
’ CONCLUSION
In summary, we have developed a methodology for achieving a
palladium-catalyzed mono-N-allylation of unprotected anthrani-
lic acids 1 with allylic alcohols 2 in aqueous media. This meth-
odology offers a new synthetic strategy for the chemical
modification of anthranilic acids into N-allylated derivatives
using the TsujiꢀTrost reaction without additives for activation
of allylic alcohols in aqueous media. In our catalytic system, the
key is the use of an unprotected anthranilic acid, which accel-
erates the palladium-catalyzed N-allylation. In addition, water
also plays a key role as a solvent. Recently, organic reactions in
water have attracted attention not only for their environmental
and economical advantages but also for their unique reactivity.
Therefore, development of reactions in water is an important
goal of synthetic methodology. We are currently working on the
development of new reactions involving water-soluble com-
pounds in aqueous media.
2-(Allylamino)-4-methoxybenzoic Acid 3c (Entry 2 in Table 2).
Following the general procedure (method A), 3c was obtained as a white
1
solid. Mp 136ꢀ137 °C; IR (KBr) (cmꢀ1) 3363, 3300ꢀ2500, 1655; H
NMR (400 MHz, DMSO-d6) δ 3.76 (s, 3H), 3.80ꢀ3.90 (m, 2H), 5.16 (d,
J = 10.2 Hz, 1H), 5.24 (d, J = 17.3 Hz, 1H), 5.88ꢀ6.00 (m, 1H), 6.13 (d, J =
2.2 Hz, 1H), 6.17 (ddd, J = 8.8, 2.2, 1.0 Hz, 1H), 7.72 (dd, J = 8.8, 1.0 Hz,
1H), 8.07 (brs, 1H), 12.3 (brs, 1H); 13C NMR (400 MHz, DMSO-d6) δ
44.5, 55.0, 95.3, 101.8, 103.5, 115.6, 133.5, 135.3, 152.6, 164.2, 169.6; MS-EI
m/z (%) 207 (M+, 87), 189 (100); HRMS-EI m/z (M+) calcd for
C11H13NO 3 207.0895, found 207.0893.
5-Acetamido-2-(allylamino)benzoic Acid 3d (Entry 3 in
Table 2). Following the general procedure (method A), 3d was
obtained as an yellow solid. Mp 127ꢀ130 °C; IR (KBr) (cmꢀ1) 3378,
1
3279, 3300ꢀ2500, 1665; H NMR (400 MHz, DMSO-d6) δ 1.97 (s,
3H), 3.80ꢀ3.90 (m, 2H), 5.14 (dd, J = 10.2, 1.4 Hz, 1H), 5.22 (dd, J =
17.1, 1.4 Hz, 1H), 5.88ꢀ6.00 (m, 1H), 6.65 (d, J = 9.0 Hz, 1H), 7.54 (dd,
J = 9.0, 2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 9.65 (s, 1H); 13C NMR
(400 MHz, DMSO-d6) δ 23.6, 44.6, 109.6, 111.6, 115.5, 122.5, 126.9,
127.2, 135.5, 147.2, 167.5, 169.8; MS-EI m/z (%) 234 (M+, 100);
HRMS-EI m/z (M+) calcd for C12H14N2O3 234.1005, found
234.1007.
’ EXPERIMENTAL SECTION
General Procedure for N-Allylation (Method A). A mixture of
anthranilic acid 1 (1 mmol), palladium(II) acetate (12 mg, 0.05 mmol),
sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 36 mg, 0.1
mmol), and prop-2-en-1-ol 2a (204 μL, 3 mmol) in THF (2 mL) and
H2O (2 mL) was stirred at room temperature for 48 h. The reaction
mixture was poured into water and extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatography (silica
gel, hexanesꢀEtOAc) to give desired product 3aꢀd, 3f, 3hꢀj, and 7.
General Procedure for N-Allylation (Method B). A mixture of
anthranilic acid 1 (1 mmol), palladium(II) acetate (12 mg, 0.05 mmol),
sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 36 mg, 0.1
mmol), and prop-2-en-1-ol 2a (204 μL, 3 mmol) in THF (2 mL) and
H2O (2 mL) was heated at 80 °C for 5 h. After cooling, the reaction
mixture was poured into water and extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatography (silica
gel, hexanesꢀEtOAc) to give desired product 3e and 3g.
2-(Allylamino)-4-(trifluoromethyl)benzoic Acid 3e (Entry
4 in Table 2). Following the general procedure (method B), 3e was
obtained as a white solid. Mp 137ꢀ140 °C; IR (KBr) (cmꢀ1) 3383,
3300ꢀ2500, 1679; 1H NMR (400 MHz, DMSO-d6) δ 3.96 (d, J = 4.9
Hz, 2H), 5.17 (dd, J = 10.5, 1.5 Hz, 1H), 5.22 (dd, J = 17.1, 1.5 Hz, 1H),
5.88ꢀ6.00 (m, 1H), 6.85 (d, J = 8.3, 1.2 Hz, 1H), 6.92 (s, 1H), 7.97 (d,
J = 8.3 Hz, 1H), 8.18 (brs, 1H), 13.2 (brs, 1H); 13C NMR (400 MHz,
DMSO-d6) δ 44.3,108.0, 110.0, 113.2, 115.8, 122.5, 125.2, 132.9, 133.7,
134.0, 134.8, 150.5, 169.1; MS-EI m/z (%) 245 (M+, 91), 200 (100);
HRMS-EI m/z (M+) calcd for C11H10NO2F3 245.0664, found
245.0664.
2-(Allylamino)-5-chlorobenzoic Acid 3f15 (Entry5 in Table2).
Following the general procedure (method A), 3f was obtained as an off-
white solid. Mp 147ꢀ148 °C; IR (KBr) (cmꢀ1) 3375, 3300ꢀ2500, 1666;
1H NMR (400 MHz, DMSO-d6) δ 3.85ꢀ3.93 (m, 2H), 5.15 (dd, J = 10.2,
1.5 Hz, 1H), 5.21 (dd, J = 17.4, 1.5 Hz, 1H), 5.87ꢀ6.00 (m, 1H), 6.73 (d,
J = 9.0 Hz, 1H), 7.37 (dd, J = 9.0, 2.7 Hz, 1H), 7.73 (d, J = 2.7 Hz, 1H), 7.93
(brs, 1H), 13.0 (brs, 1H); 13C NMR (400 MHz, DMSO-d6) δ 44.4, 111.1,
113.7, 115.7, 117.6, 130.4, 133.9, 135.0, 149.4, 168.9; MS-EI m/z (%) 211
(M+, 100), 213 (M+ + 2, 31).
2-(Allylamino)-4-chlorobenzoic Acid 3g (Entry 6 in Table 2).
Following the general procedure (method B), 3g was obtained as a white
solid. Mp 148ꢀ149 °C; IR (KBr) (cmꢀ1) 3370, 3300ꢀ2500, 1670; 1H
NMR (400 MHz, DMSO-d6) δ 3.90 (d, J = 4.6 Hz, 2H), 5.16 (dd, J = 10.2,
1.7 Hz, 1H), 5.22 (dd, J = 17.3, 1.7 Hz, 1H), 5.87ꢀ6.00 (m, 1H), 6.59 (dd,
General Procedure for N-Allylation (Method C). A mixture of
anthranilic acid 1 (1 mmol), palladium(II) acetate (12 mg, 0.05 mmol),
sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 36 mg, 0.1 mmol),
and allylic alcohol 2 (1.3ꢀ5 mmol) in H2O (4 mL) was heated for
16ꢀ48 h. After cooling, the reaction mixture was poured into water and
extracted with EtOAc. The organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, hexanesꢀEtOAc) to give
desired product 3lꢀs and 4a,b.
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J = 8.6, 2.2 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 8.12
(s, 1H), 12.9 (brs, 1H); 13C NMR (400 MHz, DMSO-d6) δ 44.3, 109.0,
110.9, 114.3, 115.7, 133.4, 134.8, 139.2, 151.5, 169.3; MS-EI m/z (%) 211
(M+, 100), 213 (M+ + 2, 33); HRMS-EI m/z(M+) calcdfor C10H10NO2Cl
211.0400, found 211.0398.
48.7, 108.8, 111.0, 111.8, 114.8, 132.6, 135.4, 141.6, 151.9, 173.5; MS-EI m/z
(%) 191 (M+, 97), 132 (100).
2-(Cinnamylamino)benzoic Acid 3o16 (Entry 4 in Table 3).
Following the general procedure (method C), 3o was obtained as an off-
white solid. Mp 157ꢀ159 °C; IR (KBr) (cmꢀ1) 3377, 3300ꢀ2500,
1664; 1H NMR (400 MHz, CDCl3) δ 4.07 (dd, J = 5.4, 1.5 Hz, 2H), 6.31
(dt, J = 15.9, 5.4 Hz, 1H), 6.55ꢀ6.70 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H),
7.20ꢀ7.27 (m, 1H), 7.28ꢀ7.35 (m, 1H), 7.35ꢀ7.45 (m, 3H), 7.85 (brs,
1H), 8.00 (dd, J = 8.0, 1.7 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ
44.9, 108.9, 111.8, 115.0, 126.1, 126.4, 127.6, 128.6, 131.4, 132.7, 135.6,
136.8, 151.6, 173.7; MS-EI m/z (%) 253 (M+, 70), 117 (100).
2-(3,7-Dimethylocta-2,6-dienylamino)benzoic Acid 3p (Entry
5 in Table 3). Following the general procedure (method C), 3p was
obtained as a yellow oil. IR (neat) (cmꢀ1) 3378, 3300ꢀ2500, 1660; 1H
NMR (400 MHz, CDCl3) for (E)-3p δ 1.61 (s, 3H), 1.68 (s, 3H), 1.72
(s, 3H), 2.00ꢀ2.17 (m, 4H), 3.82 (d, J = 6.4 Hz, 2H), 5.05ꢀ5.20 (m,
1H), 5.30ꢀ5.40 (m, 1H), 6.60 (dd, J = 8.5, 8.2 Hz, 1H), 6.66 (d, J = 8.5
Hz, 1H), 7.37 (ddd, J = 8.5, 8.5, 1.6 Hz, 1H), 7.98 (d, J = 8.2, 1.6 Hz, 1H);
13C NMR (400 MHz, CDCl3) for (E)-3p δ 16.4, 17.7, 25.7, 26.5, 39.5,
41.0, 108.7, 111.6, 114.5, 121.1, 123.9, 132.7, 135.5, 139.1, 151.7, 173.9;
MS-EI m/z (%) 273 (M+, 84), 93 (100); HRMS-EI m/z (M+) calcd for
C17H23NO2 273.1729, found 273.1728.
2-(Allylamino)-5-bromobenzoic Acid 3h15 (Entry7inTable2).
Following the general procedure (method A), 3h was obtained as a pale
yellow solid. Mp 155ꢀ157 °C; IR (KBr) (cmꢀ1) 3372, 3300ꢀ2500, 1669;
1H NMR (400 MHz, CDCl3) δ 3.87ꢀ3.89 (m, 2H), 5.21 (dd, J = 10.3, 1.7
Hz, 1H), 5.28 (dd, J = 17.3, 1.7 Hz, 1H), 5.87ꢀ6.00 (m, 1H), 6.57 (d, J = 9.0
Hz, 1H), 7.43 (dd, J = 9.0, 2.4 Hz, 1H), 7.76 (brs, 1H), 8.08 (d, J = 2.4 Hz,
1H); 13C NMR (400 MHz, CDCl3) δ45.2, 106.1, 110.0, 113.7, 116.5, 133.8,
134.6, 138.2, 150.5, 172.5; MS-EI m/z (%) 255 (M+, 98), 257 (M+ + 2, 94),
210 (100).
2-(Allylamino)-4-bromobenzoic Acid 3i (Entry 8 in Table 2).
Following the general procedure (method A), 3i was obtained as a white
1
solid. Mp 161ꢀ163 °C; IR (KBr) (cmꢀ1) 3367, 3300ꢀ2500, 1671; H
NMR (400 MHz, CDCl3) δ 3.88 (d, J = 4.6 Hz, 2H), 5.23 (dd, J = 10.2, 1.4
Hz, 1H), 5.30 (dd, J = 17.4, 1.4 Hz, 1H), 5.87ꢀ6.00 (m, 1H), 6.75 (dd, J =
8.6, 2.0 Hz, 1H), 6.83 (d, J= 2.0 Hz, 1H), 7.81 (d, J= 8.6 Hz, 1H), 7.70ꢀ7.90
(brs, 1H); 13C NMR (400 MHz, CDCl3) δ 45.2, 107.6, 114.6, 116.7, 118.3,
131.0, 133.6, 133.8, 152.1, 173.1; MS-EIm/z(%) 255(M+,90), 257(M+ +2,
87), 210 (100). Anal. Calcd for C10H10BrNO2: C, 46.90; H, 3.94; N, 5.47.
Found: C, 46.99; H, 3.95; N, 5.11.
Mixture of 2-(but-2-enylamino)benzoic Acid 3q and 2-(But-3-
en-2-ylamino)benzoic Acid 3r (Entries 6 and 7 in Table 3).
Following the general procedure (method C), mixture of 3q and 3r was
obtained as a white solid. 1H NMR (400 MHz, CDCl3) for (E)- 3q δ 1.72
(dd, J = 6.3, 1.4 Hz, 3H), 3.81 (dt, J = 5.6, 1.2 Hz, 2H), 5.50ꢀ5.65 (m, 1H),
5.65ꢀ5.80 (m, 1H), 6.55ꢀ6.65 (m, 1H), 6.68 (d, J= 8.6 Hz, 1H), 7.30ꢀ7.45
(m, 1H), 7.98 (dd, J = 8.1, 1.7 Hz, 1H); 13C NMR (400 MHz, CDCl3) for
(E)- 3q δ 17.7, 44.7, 108.6, 111.7, 114.7, 127.1, 127.9, 132.6, 135.5, 151.7,
173.8; MS-EI m/z (%) 191 (M+, 100).
3-(Allylamino)-2-naphthoic Acid 3j (Entry 9 in Table 2).
Following the general procedure (method A), 3j was obtained as a
yellow solid. Mp 167ꢀ169 °C; IR (KBr) (cmꢀ1) 3398, 3300ꢀ2500,
1665; 1H NMR (400 MHz, DMSO-d6) δ 3.90ꢀ3.95 (m, 2H), 5.20 (dd,
J = 10.5, 1.7 Hz, 1H), 5.32 (dd, J = 17.3, 1.7 Hz, 1H), 5.95ꢀ6.10 (m,
1H), 6.89 (s, 1H), 7.15 (dd, J = 7.8, 6.8 Hz, 1H), 7.41 (dd, J = 7.8, 6.8 Hz,
1H), 7.60 (d, J = 7..8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 8.51 (s, 1H); 13
C
2-(Cyclohex-2-enylamino)benzoicAcid3s(Entry8inTable3).
Following the general procedure (method C), 3s wasobtainedasanoff-white
solid. Mp 95ꢀ97 °C; IR (KBr) (cmꢀ1) 3362, 3300ꢀ2500, 1666; 1H NMR
(400 MHz, CDCl3) δ1.50ꢀ1.90 (m, 3H), 1.90ꢀ2.20 (m, 3H), 4.11 (s, 1H),
4.05ꢀ4.15 (m, 1H), 5.76 (dd, J= 10.1, 2.6 Hz, 1H), 5.86ꢀ5.93 (m, 1H), 6.59
(dd, J = 8.0, 8.0 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 7.38 (ddd, J = 8.8, 8.0, 1.6
Hz, 1H), 7.98 (dd, J = 8.0, 1.6 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ
19.8, 25.1, 28.9, 47.1, 108.8, 111.8, 114.5, 127.8, 130.6, 132.9, 135.5, 150.9,
NMR (400 MHz, DMSO-d6) δ 44.9, 104.3, 114.5, 115.7, 121.8, 124.4,
125.2, 128.7, 129.1, 133.5, 135.1, 137.2, 146.3, 169.7; MS-EI m/z (%)
227 (M+, 100). Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16.
Found: C, 73.73; H, 5.77; N, 5.89.
4-Bromo-2-(3-methylbut-2-enylamino)benzoic Acid 3l
(Scheme 2). Following the general procedure (method C), 3l was
obtained as a white solid. Mp 145ꢀ147 °C; IR (KBr) (cmꢀ1) 3375,
3300ꢀ2500, 1665; 1H NMR (400 MHz, DMSO-d6) δ 1.71 (s, 3H),
1.73 (s, 3H), 3.76 (d, J = 6.6 Hz, 2H), 5.25 (t, J = 6.6 Hz, 1H), 6.71
(dd, J = 8.6, 1.7 Hz, 1H), 6.85 (d, J = 1.7 Hz, 1H), 7.68 (d, J=8.6 Hz,
1H), 7.80 (brs, 1H), 12.8 (brs, 1H); 13C NMR (400 MHz, DMSO-d6)
δ 17.8, 25.4, 109.2, 113.7, 116.9, 120.8, 128.5, 133.4, 135.3, 151.4,
169.4; MS-EI m/z (%) 283 (M+, 55), 285 (M+ + 2, 54), 252 (100);
HRMS-EI m/z (M+) calcd for C12H14BrNO2 283.0208, found
283.0212.
2-(3-Methylbut-2-enylamino)benzoic Acid 3m (Entry 1 in
Table 3). Following the general procedure (method C), 3m was
obtained as a yellow solid. Mp 114ꢀ116 °C; IR (KBr) (cmꢀ1) 3384,
3300ꢀ2500, 1650; 1H NMR (400 MHz, DMSO-d6) δ 1.70 (s, 3H), 1.72
(s, 3H), 3.76 (d, J = 6.6 Hz, 2H), 5.28 (t, J = 6.6 Hz, 1H), 6.55 (dd, J =
8.0, 6.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 7.36 (ddd, J = 8.8, 6.8, 1.7
Hz, 1H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H); 13C NMR (400 MHz, DMSO-
d6) δ 17.8, 25.4, 109.9, 111.3, 114.1, 121.5, 131.6, 134.4, 134.8, 150.7,
169.9; MS-EI m/z (%) 205 (M+, 73), 119 (100). Anal. Calcd
for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.23; H,
7.31; N, 6.62.
173.8; MS-ESI m/z218 (M+ + H). Anal. Calcd for C13H15NO2 0.1CH3OH:
3
C, 71.37; H, 7.04; N, 6.35. Found: C, 71.77; H, 7.23; N, 5.95.
2-Amino-4-bromo-3-(3-methylbut-2-enyl)benzoic Acid 4a
(Scheme 2). Following the general procedure (method C), 4a was
obtained as a white solid. Mp 181ꢀ183 °C; IR (KBr) (cmꢀ1) 3483,
1
3370, 3300ꢀ2500, 1658; H NMR (400 MHz, DMSO-d6) δ 1.66 (s,
3H), 1.77 (s, 3H), 3.43 (d, J = 6.4 Hz, 4H), 4.96 (t, J = 6.4 Hz, 1H), 6.79
(d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H); 13C NMR (400 MHz,
DMSO-d6) δ 18.1, 25.4, 29.6, 109.4, 118.7, 119.9, 125.2, 130.0, 130.4,
132.5, 150.2, 169.6; MS-EI m/z (%) 283 (M+, 45), 285 (M+ + 2, 40), 252
(100); HRMS-EI m/z (M+) calcd for C12H14BrNO2 283.0208, found
283.0211.
2-Amino-3-(3-methylbut-2-enyl)benzoic Acid 4b (Entry 1
in Table 3). Following the general procedure (method C), 4b was
obtained as a white solid. Mp 121ꢀ123 °C; IR (KBr) (cmꢀ1) 3436,
3340, 3300ꢀ2500, 1664; 1H NMR (400 MHz, CDCl3) δ 1.75 (s, 3H),
1.77 (s, 3H), 3.23 (d, J = 6.8 Hz, 2H), 5.22 (dt, J = 6.8, 1.4 Hz, 1H), 6.63
(dd, J = 8.0, 7.4 Hz, 6H), 7.23 (dd, J = 7.4, 1.5 Hz, 1H), 7.86 (dd, J = 8.0,
1.5 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 17.9, 25.7, 30.7, 109.3,
115.9, 120.9, 126.5, 130.2, 134.6, 134.9, 149.8, 173.5; MS-EI m/z (%)
205 (M+, 79), 252 (100). Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37;
N, 6.82. Found: C, 69.95; H, 7.34; N, 6.43.
2-(2-Methylallylamino)benzoic Acid 3n (Entry 3 in Table 3).
Following the general procedure (method C), 3n was obtained as an off-
white solid. Mp 91ꢀ93 °C; IR (KBr) (cmꢀ1) 3375, 3300ꢀ2500, 1659; 1H
NMR (400 MHz, CDCl3) δ 1.80 (s, 3H), 3.80 (s, 2H), 4.90 (s, 1H), 4.96 (s,
1H), 6.61 (dd, J = 8.0, 8.0 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8,
8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 20.3,
(E)-2-Amino-4-(3-hydroxy-3-methylbut-1-enyl)benzoic
Acid 5 (Scheme 2). A mixture of 4-bromoanthranilic acid 1i
(216 mg, 1 mmol), palladium(II) acetate (11 mg, 0.05 mmol), sodium
8438
dx.doi.org/10.1021/jo201691e |J. Org. Chem. 2011, 76, 8433–8439

The Journal of Organic Chemistry
ARTICLE
diphenylphosphinobenzene-3-sulfonate (TPPMS, 37 mg, 0.1 mmol),
and 2-methyl-3-buten-2-ol 2b (503 μL, 5 mmol) in 1 N aq NaOH
(4 mL) was heated 100 °C for 48 h. After cooling, the reaction mixture
was poured into 1 N aq HCl (4 mL) and extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by flash column chromatog-
raphy (silica gel, hexanesꢀEtOAc) to give desired product 5 (217 mg,
3377, 3300ꢀ2500, 1659; 1H NMR (400 MHz, DMSO-d6) δ 1.26 (s, 6H),
4.75 (s, 1H), 6.35 (d, J = 16.1 Hz, 1H), 6.40 (d, J = 16.1 Hz, 1H), 6.60 (dd,
J = 8.3, 1.5 Hz, 1H), 6.71 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H),; 13C
NMR (400 MHz, DMSO-d6) δ29.9, 69.3, 108.4, 112.5, 114.0, 124.6, 131.4,
141.3, 142.1, 151.7, 169.3; MS-EI m/z (%) 221 (M+, 39), 252 (100);
HRMS-EI m/z (M+) calcd for C12H15NO3 221.1052, found 221.1051.
Ethyl 2-(allylamino)benzoate 710b (Scheme 3). Following the
general procedure (method A), 7 was obtained as a yellow oil. IR (neat)
(cmꢀ1) 3364, 1681; 1H NMR (400 MHz, CDCl3) δ 1.37 (t, J = 7.1 Hz,
3H), 3.86 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 5.17 (dd, J = 10.4, 1.5 Hz,
1H), 5.30 (dd, J = 17.2, 1.5 Hz, 1H), 5.85ꢀ6.00 (m, 1H), 6.58 (dd, J =
7.9, 7.0 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 7.32 (ddd, J = 8.5, 7.0, 1.6 Hz,
1H), 7.90 (brs, 1H), 7.93 (dd, J = 7.9, 1.6 Hz, 1H); 13C NMR (400 MHz,
CDCl3) δ 14.4, 45.2, 60.2, 110.4, 111.5, 114.6, 116.0, 131.6, 134.4, 134.6,
151.0, 168.7; MS-EI m/z (%) 205 (M+, 100).
4-(Allylamino)-3-bromobenzoic Acid 9b (Entry 2 in Table 4).
Following the general procedure (method A), 9b was obtained as a white
solid. Mp 170ꢀ173 °C; IR (KBr) (cmꢀ1) 3412, 3300ꢀ2500, 1675, 1599;
1H NMR (400 MHz, CDCl3) δ 3.92 (s, 2H), 5.05 (brs, 1H), 5.24 (dt, J =
10.5, 1.2 Hz, 1H), 5.29 (dd, J = 17.4, 1.2 Hz, 1H), 5.85ꢀ6.05 (m, 1H), 6.60
(d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H); 13C NMR (400
MHz, CDCl3) δ 45.8, 108.5, 110.0, 117.1, 118.1, 131.3, 133.4, 134.7, 148.8,
170.9; MS-EI m/z (%) 255 (M+, 100), 257 (M+ + 2, 98). Anal. Calcd for
C10H10BrNO2: C, 46.90; H, 3.94; N, 5.47. Found: C, 47.13; H, 4.00;
N, 5.13.
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0.98 mmol) as an off-white solid. Mp 149ꢀ151 °C; IR (KBr) (cmꢀ1
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3-(Diallylamino)benzoic Acid 10a (Entry 1 in Table 4). Follow-
ing the general procedure (method A), 10a wasobtainedasanoff-whitesolid.
ꢀ
1
Mp 86ꢀ88 °C (Lit. 91 °C);17 IR (KBr) (cmꢀ1) 3300ꢀ2500, 1683; H
NMR (400 MHz, CDCl3) δ 3.97 (d, J = 4.6 Hz, 4H), 5.10ꢀ5.25 (m, 4H),
5.80ꢀ5.95 (m, 2H), 6.87ꢀ6.95 (m, 1H), 7.27 (dd, J = 7.8, 7.8 Hz, 1H), 7.42
(d, J = 7.1 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ 52.8, 113.6, 116.3,
117.4, 118.1, 129.1, 130.0, 133.4, 148.6, 172.9; MS-EI m/z(%) 217(M+, 100).
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’ ASSOCIATED CONTENT
Supporting Information. Copies of H and 13C NMR
1
S
b
spectra of the new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Brown, D. P.; Duong, H. Q. J. Heterocycl. Chem. 2008, 45,
435–443.
’ AUTHOR INFORMATION
(13) Cooper, M. A.; Lucas, M. A.; Taylor, J. M.; Ward, A. D.;
Williamson, N. M. Synthesis 2001, 621–625.
(14) Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5, 3241–3244.
(15) Zeng, L.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal.
2009, 351, 1671–1676.
Corresponding Author
*E-mail: hidemasa.hikawa@phar.toho-u.ac.jp; yokoyama@
phar.toho-u.ac.jp.
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Abstr. 1986, 104, 50678.
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2682–2684.
’ ACKNOWLEDGMENT
We are grateful to the “Open Research Center Project” for private
universities and a matching fund subsidy from the Ministry of
Education, Sports, Culture, Science, and Technology, Japan (MEXT).
’ REFERENCES
(1) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis; John Wiley & Sons, Inc.: Hoboken, NJ, 2007.
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dx.doi.org/10.1021/jo201691e |J. Org. Chem. 2011, 76, 8433–8439