Palladium-catalyzed benzylation of unprotected anthranilic acids with benzyl alcohols in water

Article abstract of DOI:10.1021/ol2028042

Palladium-catalyzed benzylation of unprotected anthranilic acids with benzyl alcohols in the presence of Pd(OAc)₂ (5 mol %) and sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol %) in water at 120-C for 16 h gave only dibenzylated anthranilic acids in good yields. Water may play important roles for the smooth generation of the (?³-benzyl)palladium species by activation of the hydroxyl group of the benzyl alcohol. 2011 American Chemical Society.

Full text of DOI:10.1021/ol2028042

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6512–6515
Palladium-Catalyzed Benzylation of
Unprotected Anthranilic Acids with Benzyl
Alcohols in Water
Hidemasa Hikawa* and Yuusaku Yokoyama*
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi,
Chiba 274-8510, Japan
hidemasa.hikawa@phar.toho-u.ac.jp; yokoyama@phar.toho-u.ac.jp
Received October 18, 2011
ABSTRACT
Palladium-catalyzed benzylation of unprotected anthranilic acids with benzyl alcohols in the presence of Pd(OAc)2 (5 mol %) and sodium
diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol %) in water at 120 °C for 16 h gave only dibenzylated anthranilic acids in good yields.
Water may play important roles for the smooth generation of the (η3-benzyl)palladium species by activation of the hydroxyl group of the benzyl
alcohol.
Palladium-catalyzed benzylation via a (η3-benzyl)palladium
intermediate is one of the most powerful and useful
methodologies for the formation of carbonÀcarbon and
carbonÀnitrogen bonds. Because of the poor reactivity of
benzylic alcohols toward Pd0, the reaction typically em-
ploys activated benzylic alcohols such as benzylic halides,1
esters,2 carbonates,3 and phosphates.4 Therefore, the de-
velopment of a direct catalytic substitution of benzylic
alcohols, which produces the desired products along with
water asthe sole coproduct, is highly desired. To the best of
our knowledge, the palladium-catalyzed N-benzylation
with benzyl alcohols has not been described before.5 On
the other hand, palladium-catalyzed N-allylation with
allylic alcohols proceeds smoothly in water, which plays
an important role in the activation of the allylic alcohol
to form the π-allyl complex.6 We applied this finding to
the N-allylation of water-soluble free amino acids7 and
anthranilic acids8 to give the mono-N-allylated products
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r
10.1021/ol2028042
Published on Web 11/16/2011
2011 American Chemical Society

Thus, N-benzylation of anthranilic acid 1a may proceed to
give the mono-N-benzylated product 4a first, which is then
C-benzylated at the benzylic position to give dibenzylated
3a. To the best of our knowledge, the palladium-catalyzed
benzylation of sp3 CÀH bonds adjacent to a nitrogen atom
has not been described before.14 Herein we describe palla-
dium-catalyzed benzylation of anthranilic acids via (η3-
benzyl)palladium from benzyl alcohol in water and synthe-
ses of 2-(1,2-diphenylethylamino)benzoic acids using ben-
zylation of the sp3-carbon attached to the nitrogen atom.
Scheme 1. Hydration of the Hydroxyl Group
selectively in good yields. Thus, we expected an analogous
reaction for the palladium-catalyzed benzylation of benzyl
alcohols because of their structural similarity to allylic
alcohols. Water may activate the benzyl alcohol via hydra-
tion of the hydroxyl group for the generation of the
(η3-benzyl)palladium (Scheme 1). We are interested in
the development of unprotected syntheses and selective
reactions toward various reactive functional groups in
aqueous media.7À9 Thus, we began our studies of the
benzylation with benzyl alcohol 2a in water by choosing
water-soluble unprotected anthranilic acid 1a as the sub-
strate. First, we heated a mixture of anthranilic acid 1a and
benzyl alcohol 2a (5 equiv) in the presence of Pd(OAc)2
(5 mol %) and sodium diphenylphosphinobenzene-3-sul-
fonate (TPPMS, 10 mol %) in water at 120 °C for 16 h in a
sealed tube. To our surprise, dibenzylated product 3a was
obtained in good yield despite the possibility of forming
the mono-N-benzylated product 4a (Table 1, entry 1).
In general, benzylation of imines,10 hydroamination of
alkynes/reduction,11 and reductive amination of ketones12
are used for formation of N-(1,2-diphenylethyl)amines,
which are structural constituents of pharmacologically
interesting compounds.13 After 1 h, the reaction afforded
3a in 64% yield along with 4a in 24% yield (entry 2).
When 1a was consumed completely at 80 °C in 16 h,
the reaction afforded a mixture of 3a and 4a (entry 3).
Table 1. Pd-Catalyzed Benzylation of Anthranilic Acid 1aa
yield (%)b
entry
temp (°C)
time (h)
3a
4a
1
2
3
120
120
80
16
1
81
64
41
0
24
39
16
a Pd(OAc)2 (5 mol %), TPPMS (10 mol %), benzyl alcohol 2a
(5 equiv), and H2O (0.25 M) in sealed tube. b Yield of isolated product.
We next examined the effects of catalysts and solvent on
the benzylation of 1a. Since the reaction did not proceed in
the absence of the palladium catalyst and phosphine ligand
(Table 2, entry 1) or in the presence of only Pd(OAc)2
(entry 2), a SN2-type reaction mechanism was excluded in
the formation of the benzylated product. With regard to
the palladium catalyst, the use of zero- or divalent palla-
dium, Pd2(dba)3 or PdCl2, gave the product in good yields
(entry 3, 86%; entry 4, 79%). The use of a water-soluble
ligand, 4-(diphenylphosphino)benzoic acid L1, resulted in
a good yield of 3a (entry 5, 79%). In contrast, using
4-(dimethylamino)phenyldiphenylphosphine L2, diben-
zylated 3a was obtained in 27% yield along with mono-
N-benzylated 4a in 38% yield (entry 6). Since the reaction
did not occur using Pd(PPh3)4 instead of a water-soluble
ligand (entry 7) or when using DMSO (entry 8) as a
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~
´
ꢀ
Org. Lett., Vol. 13, No. 24, 2011
6513

solvent, water must play an important role in the benzyla-
tion with benzyl alcohol. With regard to the additive,
NaOH suppressed the benzylation (entry 9). In contrast,
the reaction proceeded in AcOH(aq) in good yield
(entry 10). Basset and co-workers reported that the π-allyl
palladium intermediate is unstable under strong basic
conditions.15 In contrast, Manabe16 and Yang6b reported
that carboxylic acids enhanced the formation of the π-allyl
complex in aqueous media. Since our results are consistent
with a previous report on the palladium-catalyzed ally-
lation with allylic alcohols, (η3-benzyl)palladium may be
an intermediate in analogy to the allylic substitution.
less important than for the (η3-benzyl)palladium inter-
mediate.17
Table 2. Effects of Catalysts and Solvents on Benzylation of 1aa
yield [%]b
entry
catalyst
solvent
H2O
3a
4a
1
2
none
no reaction
no reaction
Pd(OAc)2
H2O
3
Pd2(dba)3c/TPPMS
PdCl2/TPPMS
Pd(OAc)2/L1d
Pd(OAc)2/L2e
Pd(PPh3)4
H2O
86
79
79
27
0
4
H2O
0
0
5
H2O
6
H2O
38
7
H2O
no reaction
no reaction
no reaction
8
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
DMSO
1 N NaOH(aq) f
H2O/AcOHf
9
10
87
0
a Pd catalyst (5 mol %), ligand (10 mol %), benzyl alcohol 2a
(5 equiv), and solvent (0.25 M), 120 °C, 16 h in sealed tube. b Yield of
isolated product. c 2.5 mol %. d L1: 4-(diphenylphosphino)benzoic acid.
e L2: 4-(dimethylamino)phenyldiphenylphosphine. f 4 equiv was used.
Results for the benzylation of various anthranilic acids,
3-aminobenzoic acids, and 4-aminobenzoic acid using
Pd(OAc)2 and TPPMS in water are summarized in Figure 1.
All of the anthranilic acids smoothly underwent benzyla-
tion with benzyl alcohol 2a to give only the correspond-
ing dibenzylated anthranilic acids 3bÀi in overall yields
ranging from 70% to 87%. The use of methyl-substituted
benzyl alcohols also resulted in good yields of 3jÀq. To
our surprise, 2-naphthalenemethanol, which is not very
soluble in water, gave desired product 3r in 66% yield.
Legros and co-workers reported that palladium-cata-
lyzed nucleophilic substitution of naphthylmethyl esters
and the loss of resonance energy for the formation of
the (η3-naphthalenemethyl)palladium intermediate is
Figure 1. Scope of benzylation of anthranilic acids and amino-
benzoic acids. Reaction conditions: 1 (1 mmol), Pd(OAc)2
(5 mol %), TPPMS (10 mol %), benzyl alcohols 2 (5 equiv),
and H2O (4 mL) at 120 °C to 16 h in a sealed tube. Yield of
isolated product.
Thus, benzylation with 2-naphthalenemethanol can
proceed smoothly in our catalytic system. In addition to
anthranilic acids, 3- and 4-aminobenzoic acids afforded
the corresponding dibenzylated 3sÀu selectively in good
yields.
The mechanism of the formation of dibenzylated an-
thranilic acid 3a from anthranilic acid 1a and benzyl
alcohol 2a in water has not been investigated in detail
at this stage. However, on the basis of our results
ꢀ
(15) Basset, J.-M.; Bouchu, D.; Godard, G.; Karame, I.; Kuntz, E.;
Lefebvre, L.; Legagneux, N.; Lucas, C.; Michelet, D.; Tommasino, J. B.
Organometallics 2008, 27, 4300–4309.
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(16) Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5, 3241–3244.
2510.
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Org. Lett., Vol. 13, No. 24, 2011

and literature reports, the following mechanism can be
suggested (Scheme 2). First, oxidative addition of benzyl
alcohol 2a to a Pd0 species affords the (η3-benzyl)-
palladium complex 5. Water may play an important role
for the smooth generation of the (η3-benzyl)palladium
species 5 by hydration of the hydroxyl group, since the
reaction did not occur without water. Next, ligand ex-
change of the (η3-benzyl)palladium system with the amino
group of 1a takes place to generate intermediate 6, fol-
lowed by reductive elimination to give the mono-N-benzy-
lated product 4a exclusively. Ligand exchange of the (η3-
benzyl)palladium system with the amino group of 4a takes
place to generate intermediate 7, followed by β-hydride
elimination. Wang and co-workers reported that N-phenyl
benzylamines could be oxidized to the corresponding
imines using a PdCl2/PPh3 catalyst.18 Benzylation to imine
8 occurs to give the dibenzylated 3a and regenerates Pd0
throughreductiveelimination. Yamamotoandco-workers
reported palladium-catalyzed allylation of aldimines with
allylstannanes. The π-allylpalladium intermediate reacted
with imines to give the corresponding homoallylic
amines.19 Fields and co-workers reported palladium-cata-
lyzed benzylation of benzyl diphenylglycinate imines to the
corresponding homobenzylic imines.2b
3a in 90% yield (Scheme 3). In contrast, the reaction did
not proceed without Pd(OAc)2/TPPMS or with only Pd-
(OAc)2. No reaction occurred in DMSO instead of water
as a solvent. These results indicated that water plays an
important role for the C-benzylation of 4a with benzyl
alcohol in our catalytic system.
Finally, this method was applied to the benzylation of
aliphatic substrates such as anthranilic acid ethyl ester 9.
The reaction proceeded smoothly to give dibenzylated 10
in 84% yield (Scheme 4). Thus, this reaction is applicable
to the benzylation of various aliphatic substrates.
Scheme 3. Pd-Catalyzed Benzylation of 4a
Scheme 4. Pd-Catalyzed Benzylation of Ethyl Ester 9.
Scheme 2. Possible Mechanism
In conclusion, we have developed a new methodology
for achieving the palladium-catalyzed benzylation of un-
protected anthranilic acids 1 with benzyl alcohols 2 in
water. Palladium-catalyzed reactions with both allylic and
benzylic alcohols proceeded smoothly in aqueous media.
Water played an important role in the activation of the
allylic and benzylic alcohols to form the corresponding
palladium complexes. In addition, this methodology per-
forms the unique benzylation of sp3 CÀH bonds adjacent
to a nitrogen atom. We are currently investigating the
scope of various amines on the benzylation and are devel-
oping new reactions using (η3-benzyl)palladium from ben-
zyl alcohol in aqueous media.
To confirm that N-benzylanthranilic acid 4a is the
intermediate in our catalytic system, we tested benzylation
of 4a instead of anthranilic acid 1a. As expected, C-
benzylation of 4a proceeded smoothly to give dibenzylated
Supporting Information Available. Experimental pro-
cedures and characterization data; copies of H and 13
(18) Wang, J.-R.; Fu, Y.; Zhang, B.-B.; Cui, X.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2006, 47, 8293–8297.
1
C
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H.; Iwama, H.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1996,
1459–1460. (c) Nakamura, H.; Yamamoto, Y. J. Am. Chem. Soc. 1996,
118, 6641–6647.
NMR spectra of the new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
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