A Radical Pathway for Direct Substitution of Benzyl Alcohols with Water-Soluble Copper Catalyst in Water

Article abstract of DOI:10.1002/adsc.201500835

We have developed a novel strategy for the direct substitution of benzyl alcohols with anthranilic acids using water-soluble copper catalysts through a radical pathway in water, which offers efficient and environmentally friendly N-, S-, and C-benzylations under neutral conditions. Radical scavengers strongly inhibited the benzylation. Radical clock experiments using α-cyclopropylbenzyl alcohol were conducted to observe the rapid isomerization of the cyclopropylmethyl radical to the allylmethyl radical. Hammett plots could be fitted to a two-parameter Hammett relationship containing both radical and polar contributions [log (k_X/k_H)=-1.24 σ^.-0.38 σ, R²=0.99]. The relative parameter ρ^./ρ of 3.3 suggested that these reactions involved a strong radical character with minor polar influence at the transition state.

Full text of DOI:10.1002/adsc.201500835

FULL PAPERS
DOI: 10.1002/adsc.201500835
A Radical Pathway for Direct Substitution of Benzyl Alcohols
with Water-Soluble Copper Catalyst in Water
Hidemasa Hikawa,a,* Yuki Mori,a Shoko Kikkawa,a and Isao Azumayaa,*
a
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Fax: (+81)-47-472-1595, phone: (+81)-47-472-1591; e-mail: hidemasa.hikawa@phar.toho-u.ac.jp or
isao.azumaya@phar.toho-u.ac.jp
Received: September 7, 2015; Revised: November 28, 2015; Published online: February 8, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500835.
Abstract: We have developed a novel strategy for radical. Hammett plots could be fitted to a two-pa-
the direct substitution of benzyl alcohols with anthra- rameter Hammett relationship containing both radi-
nilic acids using water-soluble copper catalysts cal and polar contributions [log (kX/kH)=À1.24sC–
through a radical pathway in water, which offers effi- 0.38s, R2 =0.99]. The relative parameter 1C/1 of 3.3
cient and environmentally friendly N-, S-, and C- suggested that these reactions involved a strong radi-
benzylations under neutral conditions. Radical scav- cal character with minor polar influence at the tran-
engers strongly inhibited the benzylation. Radical sition state.
clock experiments using a-cyclopropylbenzyl alcohol
were conducted to observe the rapid isomerization Keywords: anthranilic acids; benzyl alcohols; benzy-
of the cyclopropylmethyl radical to the allylmethyl lation; copper; radicals
Introduction
The direct substitution of hydroxy groups has become
an atom-economical and environmentally benign
À
À
À
methodology for the formation of C C, C S, and C
N bonds.[1] However, direct substitutions of alcohols
are challenging because hydroxides are poor leaving
groups compared to halides, thus requiring activating
agents such as Lewis and Brønsted acids. Recently, N-
monoalkylations using alcohols have been demon-
strated under transition metal catalysis, which are usu-
ally achieved by the borrowing hydrogen method.[2,3]
We have been developing a unique strategy for the
direct substitution of benzyl alcohols using water-solu-
ble transition metal catalysts [M/TPPMS: M=Pd(0)[4]
or Au(III)[5] and TPPMS=sodium diphenylphosphi-
nobenzene-3-sulfonate] in water (Scheme 1). We be-
Scheme 1. Water-soluble transition metal-catalyzed direct
substitution of hydroxyl groups.
lieve that water activates the sp C O bond by a hy- droxy group of the alcohol.[7] On the basis of our pre-
drogen bond between water and the hydroxy group of vious results, the hydrophobic effect also enhances
the alcohol, which enhances the formation of an the reaction in water, since water-insoluble substrates
active metal ion species by hydration. Theoretical cal- could be adapted to these strategies.[4a,5a] Therefore,
culations by Shinokubo and Oshima have elucidated no reaction or lower yield occurred when using co-
the importance of hydration of the hydroxy group for solvents such as alcohols or polar organic solvents in
the smooth generation of p-allylpalladium species.[6] water. Since water molecules have unusual chemical
Cozzi et al. proposed that the direct generation of car- and physical properties compared to organic solvents,
bocations in water from alcohols is driven by the for- water should play an important role in the develop-
mation of hydrogen bonds between water and the hy- ment of new and efficient reactions.
3
À
Adv. Synth. Catal. 2016, 358, 765 – 773
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
765

FULL PAPERS
Hidemasa Hikawa et al.
Table 1. Effects of catalysts and solvents.[a]
It is well known that alkyl radicals are generated
from the radical deoxygenation of alcohols (Barton–
McCombie reaction[8] and Marko–Lam reaction[9]).
Other concepts for the metal-catalyzed radical reac-
tion of benzyl halides based on a single electron trans-
fer (SET)[10] or atom transfer[11]-mediated pathway
have been developed. Watson and co-workers report-
ed that Cu(I) catalysts initiate radical reactions of ni-
troalkanes with benzyl bromides.[10b] However, to the
best of our knowledge, there are no examples of the
direct substitution of benzyl alcohols instead of
benzyl halides via benzyl radicals.[12]
En- Catalyst
try
Solvent
Conv.
[%][b]
On the basis of our previous results and literature
reports, we hypothesize that the activation of the sp3
À
C O bond of alcohols by hydration in the presence of
1
CuBr/TPPMS
H2O
H2O
H2O
H2O
H2O
28
a radical initiator could directly generate benzyl radi-
cals, which have the potential to be powerful tools in
direct transformations in water. Consequently, we
herein report a radical pathway for direct substitution
of benzyl alcohols initiated by a water-soluble copper
catalyst (Scheme 1).[13,14] This new strategy should pro-
vide a mechanistic alternative to traditional nucleo-
philic substitution reactions or borrowing hydrogen
methodology.
2
3
4
5
Cu2O/TPPMS
CuBr2/TPPMS
CuCl2/TPPMS
CuSO4/TPPMS
trace
69 (80)[c]
53
50
12
35
43
12
trace
8
6
7
Cu(OAc)2/TPPMS H2O
CuO/TPPMS H2O
8
9
Cu(OTf)2/TPPMS H2O
Cu(acac)2/TPPMS H2O
10
11
12
Sc(OTf)3 or HCl
CuBr2
CuBr2/TPPMS
H2O
H2O
toluene, DMF, EtOH trace
or dioxane
Results and Discussion
13
CuBr2/TPPMS
DMF/H2O (1:1)
trace
[a]
Reaction conditions: anthranilic acid (1a) (1 mmol), cata-
lysts (5 mol%), TPPMS (10 mol%), benzhydrol (2a)
(1.2 mmol), solvent (4 mL), 808C, 16 h under air.
The conversion was determined by H NMR analysis of
the crude product using p-nitroanisole as an internal
Effects of Catalysts and Solvents
[b]
[c]
1
We began by examining the reaction of anthranilic
acid (1a) and benzhydrol (2a, 1.2 equiv.) in the pres-
ence of CuBr (5 mol%) and TPPMS (10 mol%) in
water. Unfortunately, N-monobenzylated product 3a
was obtained in only 28% yield (Table 1, entry 1).
The use of Cu2O resulted in no reaction (entry 2). In
standard.
At 1008C.
contrast, the use of CuBr2 instead of a Cu(I) catalyst thranilic acids with bromo, iodo, and chloro groups
afforded 3a in good yield (entry 3). When the reaction produced N-benzylated products 3b–d in excellent
was performed at 1008C, the yield of 3a was increased yields with the carbon-halogen moiety left intact,
to 80% despite the possibility of forming the N,N-di- which could be employed for further manipulation.
benzylated product, benzyl ester or decarboxylated N-Benzylation of 5-bromoanthranilic acid (1b) with
product. With regard to the Cu(II) catalyst, CuBr2 benzhydrol (2a) could be performed up to a 10-mmol
gave the best result (entries 3–9). Use of Lewis and scale, with product 3b purified only by recrystalliza-
Brønsted acids was ineffective (entries 10). Since the tion in 88% isolated yield. Anthranilic acids with
benzylation did not proceed in the presence of only fluoro groups also resulted in excellent yields (3e,
Cu(II) catalyst (entry 11) or using organic solvents 90%; 3f, 85%). Strong electron-withdrawing nitro and
(entry 12), water must play an important role in our trifluoromethyl groups were tolerated in the N-benzy-
catalytic system. In a biphasic system such as DMF/ lation through the radical pathway (3g, 65%; 3h,
H2O (1:1), the reaction also did not proceed 86%). The anthranilic acids with electron-donating
(entry 13).
methyl and methoxy groups resulted in moderate to
good yields (3i, 58%; 3j, 62%; 3k, 58%). The use of
benzhydrol with methyl, chloro and fluoro groups re-
sulted in moderate to good yields (3l, 66%; 3m, 54%;
3n, 61%). The reaction of a-alkylbenzyl alcohols af-
Reaction Scope
Results for the reactions of several anthranilic acids forded N-monobenzylated products (3o, 50%; 3p,
1 with benzyl alcohols 2 using CuBr2 and TPPMS in 41%). The reaction of 3-aminobenzoic acid or 4-nitro-
H2O are summarized in Scheme 2. The reaction of an- aniline also gave the desired products (3q, 57%; 3r,
766
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 765 – 773

FULL PAPERS
A Radical Pathway for Direct Substitution of Benzyl Alcohols
Scheme 2. Scope of anilines 1 and benzyl alcohols 2. Reaction conditions: 1 (1 mmol), CuBr2 (5 mol%), TPPMS (10 mol%),
2 (1.2 or 5 mmol), H2O (4 mL), 1208C, 16 h under air in a sealed tube. Yield of isolated product.
79%). Mercaptobenzoic acid could be used for the S- and TEMPO strongly inhibited the radical reaction
benzylation despite sulfur poisoning of the copper (Scheme 3), while the reaction using an Au(III) cata-
catalysts (3s, 67%). The reaction of cinnamyl alcohol lyst with BHT proceeded through a benzyl cation
afforded N-monoallylated product 3t in 67% yield.
pathway (Scheme 3). Next, radical clock experiments
using a-cyclopropylbenzyl alcohol were conducted to
observe the rapid isomerization of the cyclopropyl-
methyl radical to the allylmethyl radical, which is well
known in free-radical chemistry (Scheme 4).[15] If the
Control Experiments
To gain insight into the radical reaction mechanism, cyclopropylmethyl radical 4 is generated, ring opening
we carried out the following control experiments. As of cyclopropane 5 must be observed. The correspond-
expected, radical scavengers such as BHT, galvinoxyl ing cyclopropyl ring fragmentation product 7 was only
Adv. Synth. Catal. 2016, 358, 765 – 773
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
767

FULL PAPERS
Hidemasa Hikawa et al.
reactions, a Hammett study was conducted on the re-
action of 1a with 5-substituted anthranilic acids 1 (F,
1
Me, OMe, Cl, and Br groups) followed by H NMR
spectroscopy to obtain the ratio of rate constants (Fig-
ure 1A). The Hammett plot shows no correlation of
the typical polar substituent constant parameter (R2 =
0.1 for s). The fit was improved by employing the
Creary scale of sC parameter (R2 =0.63).[17] The exper-
imental data could be fitted to a two-parameter Ham-
mett relationship containing both radical and polar
contributions [log (kX/kH)=À1.24sCÀ0.38s, R2 =
0.99].[18] The relative parameter 1C/1 of 3.3 suggested
that these reactions involved a strong radical charac-
ter with minor polar influence at the transition state.
Wallentin and co-workers reported that various
s scales could be combined with sC to account for
polar influences in radical reactions of iron-catalyzed
cross-coupling.[18a] Next, a Hammett study based on
para-substituted benzhydryl alcohols 2 (Me, F, and Cl
Scheme 3. Experiments with radical scavengers.
Scheme 4. A: Radical clock experiments and B: reaction
using HCl as catalyst.
obtained, while the reaction using HCl instead of
copper catalyst afforded not the ring-opened product
7 but 8 via cyclopropylmethyl cation 6, which could
be stabilized by the cyclopropyl group.[16]
Hammett Studies
Figure 1. Hammett plot of experimental log (kX/kH) vs. cal-
culated 1s+1sC in the benzylation of 5-substituted anthra-
nilic acids 1 (A), and the rate constants of benzylation by
To demonstrate the effect of substituents on the rates
À
À
of the C O bond cleavage and C N bond formation various substituted benzhydrols 2 (B).
768
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 765 – 773

FULL PAPERS
A Radical Pathway for Direct Substitution of Benzyl Alcohols
groups) resulted in a good correlation (R2 =0.99 in
Figure 1B) between the log(kX/kH) and the s+ value
of the respective substituents that resulted in a nega-
À
tive 1 value of 3.39, suggesting that the C O bond
cleavage process involved a polar transition state.
Mechanistic Considerations
On the basis of our results and literature reports, the
following mechanism can be suggested. First, anthra-
nilic acid 1 coordinates to the Cu(II)/TPPMS catalyst
to form Cu(II) intermediate A,[19] which is in equilib-
rium with amine radical B (Scheme 5A).[20] The Ham-
mett study suggests that there is build-up of the
Scheme 6. Effect of carboxyl group.
Scheme 7. Cross-over experiment using different benzyl al-
cohols.
terated 9-d, and 3-methylbenzyl alcohol (2c) afforded
the corresponding 10, which was not labelled with
deuterium. This result excluded the borrowing hydro-
gen mechanism in our catalytic system, since H/D
scrambling products were not formed.
Scheme 5. Proposed mechanism.
amine radical in the transition state (see Figure 1A).
The carboxyl group of B would enhance the benzyla-
tion by chelation to the copper catalyst, and allow for C-Benzylation
spin-delocalization. Indeed, N-benzylations of anthra-
nilic acid methyl ester or 3-aminobenzoic acid result- 4,4’-Dimethoxybenzhydrol (2c) afforded only C-ben-
ed in no reaction (Scheme 6). Next, an atom-transfer zylated product 11 in 90% yield with the amino group
event initiated by the Cu(I) complex B generates left intact (Scheme 8), while the addition of BHT
amine radical C along with benzyl radical D, followed (1 equiv.) inhibited this reaction significantly. Anthra-
by subsequent radical coupling to afford desired prod- nilic acids 1 have been used as building blocks for me-
uct 3 (Scheme 5B). The Hammett study also suggests dicinal purposes, e.g., mefenamic acid, which has non-
that there is a build-up of positive charge in the tran- steroidal anti-inflammatory and analgesic properties.
sition state TS (see Figure 1B).
Furthermore, anthranilic acids are important for the
synthesis of benzo-fused heterocycles or the biosyn-
thesis of tryptophan and several types of alkaloids.
Borrowing Hydrogen Pathway
To exclude the possibility of the borrowing hydrogen Conclusions
pathway, we carried out a cross-over experiment
using different benzyl alcohols (Scheme 7).[21] Deuter- In summary, we have developed an atom-transfer ini-
ated benzyl alcohol-d7 2b-d was converted into deu- tiated radical pathway for copper-catalyzed direct
Adv. Synth. Catal. 2016, 358, 765 – 773
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
769

FULL PAPERS
Hidemasa Hikawa et al.
Scheme 8. Chemoselective C-benzylation of anthranilic acid 1a.
6.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=60.72,
106.1, 113.0, 115.6, 127.3, 127.9, 129.4, 133.9, 137.1, 143.0,
149.2, 169.5; FAB-MS: m/z=382 [M+H]+, 384 [M+H+
2]+.
substitution of benzyl alcohols, which is an environ-
mentally benign method. This reaction could be ap-
plied to various anthranilic acids in moderate to ex-
cellent yields. Water plays an important role in the ac-
tivation of the benzyl alcohols to form the corre-
sponding benzyl radicals. Mechanistic studies on radi-
cal reactions supported this hypothesis. The strategy
presented here should provide greater insights for the
design of several new direct uses of benzyl alcohols.
2-(Benzhydrylamino)-5-iodobenzoic acid (3c):[5a] Follow-
ing the general procedure, 3c was obtained as a pale yellow
solid; yield: 395 mg (92%); mp 223–2258C; IR (KBr): n=
1
3356, 3029, 1671 cmÀ1; H NMR (400 MHz, DMSO-d6): d=
5.85 (d, J=6.4 Hz, 1H), 6.45 (d, J=9.2 Hz, 1H), 7.22–7.42
(m, 11H), 7.52 (dd, J=9.2, 6.8 Hz, 1H), 8.05 (d, J=2.4 Hz,
1H), 8.68 (d, J=6.0 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6): d=60.7, 75.8, 113.9, 116.0, 127.3, 127.9, 129.4, 139.9,
142.5, 143.0, 149.5, 169.4; FAB-MS: m/z=430 [M+H]+.
2-(Benzhydrylamino)-5-chlorobenzoic acid (3d): Follow-
ing the general procedure, 3d was obtained as a pale yellow
solid; yield: 289 mg (86%); mp 210–2128C; IR (KBr): n=
Experimental Section
General Procedure
1
3379, 3029, 1671 cmÀ1; H NMR (400 MHz, DMSO-d6): d=
A mixture of anthranilic acid 1 (1 mmol), CuBr2 (11 mg,
5.85 (d, J=6.0 Hz, 1H), 6.63 (d, J=9.2 Hz, 1H), 7.23–7.40
(m, 12H), 7.76 (d, J=2.8 Hz, 1H), 8.64 (d, J=6.4 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=60.72, 112.4, 115.2,
118.9, 127.3, 127.9, 129.4, 131.0, 134.5, 143.0, 148.9, 169.6;
FAB-MS: m/z=338 [M+H]+, 340 [M+H+2]+; anal. calcd.
for C20H16ClNO2: C 71.11, H 4.77, N 4.15; found: C 71.08, H
4.83, N 4.15.
0.05 mmol), sodium diphenylphosphinobenzene-3-sulfonate
(TPPMS, 38 mg, 0.1 mmol) and benzhydryl alcohol
2
(1.2 mmol) in H2O (4 mL) was heated at 1208C for 16 h in
a sealed tube under air. After cooling, the reaction mixture
was poured into water and extracted with EtOAc. The or-
ganic layer was washed with brine, dried over MgSO4 and
concentrated under vacuum. The residue was washed with
hexanes, then purified by flash column chromatography
(silica gel, hexanes/EtOAc) to give the desired product 4.
2-(Benzhydrylamino)benzoic acid (3a):[5a] Following the
general procedure, 3a was obtained as a white solid; yield:
222 mg (73%); mp 202–2048C; IR (KBr): n=3362, 3027,
2-(Benzhydrylamino)-5-fluorobenzoic acid (3e):[5a] Follow-
ing the general procedure, 3e was obtained as a white solid;
yield: 289 mg (90%); mp 194–1958C; IR (KBr): n=3369,
3029, 1670 cmÀ1 1H NMR (400 MHz, CDCl3): d=5.60 (s,
;
1H), 6.50 (dd, J=9.2, 4.4 Hz, 1H), 7.00–7.05 (m, 1H), 7.22–
7.41 (m, 11H), 7.66 (dd, J=9.6, 3.2 Hz, 1H), 8.12 (s, 1H);
13C NMR (100 MHz, DMSO-d6): d=61.12, 111.5 (d, J=
5.7 Hz), 114.7 (d, J=6.6 Hz), 117.1 (d, J=21.9 Hz), 122.3 (d,
J=22.9 Hz), 127.3, 127.8, 129.3, 143.3, 147.2, 153.0 (d, J=
231.7 Hz), 169.7, (d, J=2.8 Hz); FAB-MS: m/z=322 [M+
H]+.
1
1661 cmÀ1; H NMR (400 MHz, DMSO-d6): d=5.84 (d, J=
6.4 Hz, 1H), 6.57 (t, J=7.2 Hz, 1H), 6.59 (d, J=8.4 Hz,
1H), 7.25 (tt, J=6.8, 1.2 Hz, 3H), 7.33–7.41 (m, 9H), 7.82
(dd, J=8.4, 2.0 Hz, 1H), 8.67 (d, J=6.0 Hz, 1H); 13C NMR
(100 MHz, acetone-d6): d=62.88, 112.0, 114.4, 116.6, 128.7,
128.9, 130.4, 133.5, 136.0, 144.7, 152.0, 171.5; FAB-MS:
m/z=304 [M+H]+.
2-(Benzhydrylamino)-4-fluorobenzoic acid (3f):[5a] Follow-
ing the general procedure, 3f was obtained as a white solid;
yield: 273 mg (85%); mp 200–2018C; IR (KBr): n=3355,
2-(Benzhydrylamino)-5-bromobenzoic acid (3b);[5a] Scale-
up experiment: A mixture of 2-amino-5-bromobenzoic acid
(1.08 g, 5 mmol), CuBr2 (56 mg, 0.25 mmol), TPPMS
(182 mg, 0.5 mmol), and benzhydrol 2a (1.1 g, 6 mmol) in
H2O (20 mL) was heated at 908C for 16 h under air. After
cooling, the reaction mixture was poured into water and ex-
tracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4 and concentrated under vacuum.
The residue was recrystallized from hexane/AcOEt to give
desired product 3b as a pale yellow solid; yield: 1.64 g
(4.4 mmol, 88%); mp 215–2168C; IR (KBr): n=3380, 3033,
3029, 1665 cmÀ1 1H NMR (400 MHz, DMSO-d6): d=5.87
;
(d, J=6.8 Hz, 1H), 6.35–6.41 (m, 2H), 7.26 (tt, J=6.0,
1.2 Hz, 2H), 7.34–7.41 (m, 9H), 7.88 (t, J=7.6 Hz, 1H), 8.88
(d, J=5.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=
60.7, 99.3 (d, J=25.8 Hz), 102.9 (d, J=22.8 Hz), 108.3 (d,
J=1.9 Hz), 127.3, 127.9, 129.4, 135.0 (d, J=11.5 Hz), 142.9,
152.4 (d, J=12.4 Hz), 166.6 (d, J=247.0), 169.9; FAB-MS:
m/z=322 [M+H]+.
2-(Benzhydrylamino)-5-nitrobenzoic acid (3g): Following
the general procedure, 3g was obtained as a white solid;
yield: 226 mg (65%); mp 198–1998C; IR (KBr): n=3334,
1
1670 cmÀ1; H NMR (400 MHz, DMSO-d6): d=5.86 (d, J=
6.0 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 7.24–7.28 (m, 2H),
7.34–7.42 (m, 10H), 7.89 (d, J=2.8 Hz, 1H), 8.66 (d, J=
3019, 1672 cmÀ1 1H NMR (400 MHz, CDCl3): d=5.74 (d,
;
770
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 765 – 773

FULL PAPERS
A Radical Pathway for Direct Substitution of Benzyl Alcohols
J=5.6 Hz, 1H), 6.60 (d, J=10.0 Hz, 1H), 7.21–7.37 (m,
10H), 8.12 (dd, J=9.2, 2.0 Hz, 1H), 8.95 (d, J=2.8 Hz, 1H),
9.06 (d, J=5.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d=60.73, 110.7, 113.3, 127.3, 128.2, 128.9, 129.5, 129.8, 136.1,
142.1, 154.1, 169.4; FAB-MS: m/z=349 [M+H]+; anal.
calcd. for C20H16N2O4: C 68.96, H 4.63, N 8.04; found: C
68.44, H 4.76, N 7.93.
CDCl3): d=5.62 (d, J=4.8 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H),
6.62–6.66 (m, 1H), 7.25–7.37 (m, 11H), 7.99 (dd, J=8.0,
1.2 Hz, 1H), 8.27 (d, J=5.2 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): d=60.10, 111.5, 113.2, 115.7, 127.4, 127.9, 129.2,
129.3, 129.4, 132.2, 132.3, 134.8, 142.4, 143.0, 150.0, 170.6;
FAB-MS: m/z=338 [M+H]+, 340 [M+H+2]+.
2-[Bis(4-fluorophenyl)methylamino]benzoic acid (3n):[5a]
Following the general procedure, 3k was obtained as a white
solid; yield: 207 mg (61%); mp 198–1998C; IR (KBr): n=
2-(Benzhydrylamino)-4-(trifluoromethyl)benzoic
acid
(3h):[5a] Following the general procedure, 3h was obtained as
a white solid; yield: 320 mg (86%); mp 184–1868C; IR
1
3362, 3029, 1663 cmÀ1; H NMR (400 MHz, CDCl3): d=5.62
(KBr): n=3358, 3030, 1673 cmÀ1
;
1H NMR (400 MHz,
(d, J=5.2 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 6.65 (t, J=
8.0 Hz, 1H), 7.03 (dt, J=8.8, 2.4 Hz, 5H), 7.22–7.35 (m,
5H), 7.99 (dd, J=8.0, 1.6 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=59.3, 111.5, 113.2,
115.8, 116.0 (d, J=20 Hz), 129.3, 129.4, 132.2, 134.8, 139.4
(d, J=3.8 Hz), 150.0, 161.8 (d, J=240 Hz), 170.6; FAB-MS:
m/z=340 [M+H]+.
DMSO-d6): d=5.97 (d, J=6.0 Hz, 1H), 6.86 (s, 1H), 6.87 (d,
J=8.0 Hz, 1H), 7.26 (t, J=7.2 Hz, 2H), 7.34–7.43 (m, 9H),
8.01 (d, J=8.4 Hz, 1H), 8.85 (d, J=6.0 Hz, 1H); 13C NMR
(100 MHz, acetone-d6): d=62.75, 111.0 (q, J=4.7 Hz), 112.4
(q, J=3.8 Hz), 114.9, 125.5 (q, J=270.8 Hz), 128.7, 129.1,
130.5, 134.6, 136.5 (q, J=31.5 Hz), 144.1, 151.8, 170.7; FAB-
MS: m/z=372 [M+H]+.
5-Bromo-2-(1-phenylethylamino)benzoic acid (3o): Fol-
lowing the general procedure, 3o was obtained as a white
solid; yield: 159 mg (50%); mp 174–1758C; IR (KBr): n=
2-(Benzhydrylamino)-4-methylbenzoic acid (3i):[5a] Follow-
ing the general procedure, 3i was obtained as a white solid;
yield: 184 mg (58%); mp 190–1938C; IR (KBr): n=3370,
1
3373, 3029, 1669 cmÀ1; H NMR (400 MHz, CDCl3): d=1.60
1
3029, 1654 cmÀ1; H NMR (400 MHz, DMSO-d6): d=2.11 (s,
(d, J=6.8 Hz, 3H), 4.57 (q, J=9.2 Hz, 1H), 6.35 (d, J=
9.2 Hz, 1H), 7.22–7.36 (m, 7H), 8.06–8.09 (m, 2H);
13C NMR (100 MHz, DMSO-d6): d=25.0, 52.1, 105.5, 112.7,
115.4, 126.2, 127.4, 129.2, 133.9, 137.0, 145.0, 149.4, 169.4;
FAB-MS: m/z=320 [M+H]+, 322 [M+H+2]+; anal. calcd.
for C15H15BrNO2: C 56.27, H 4.41, N 4.37; found: C 56.57, H
4.48, N 4.39.
3H), 5.84 (d, J=6.8 Hz, 1H), 6.40 (d, J=8 Hz, 1H), 6.46 (s,
1H), 7.19–7.39 (m, 11H), 7.70 (d, J=8 Hz, 1H), 8.64 (d, J=
6.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=22.2, 60.7,
108.9, 113.2, 116.8, 127.3, 127.7, 129.3, 132.2, 143.6, 144.9,
150.3, 170.6; FAB-MS: m/z=318 [M+H]+.
2-(Benzhydrylamino)-5-methylbenzoic acid (3j):[5a] Fol-
lowing the general procedure, 3j was obtained as a white
solid; yield: 197 mg (62%); mp 224–2278C; IR (KBr): n=
5-Bromo-2-[(1-phenylpropyl)amino]benzoic acid (3p):
Following the general procedure, 3p was obtained as
a yellow solid; yield: 137 mg (41%); mp 152–1548C; IR
1
3383, 3025, 1669 cmÀ1; H NMR (400 MHz, DMSO-d6): d=
2.13 (s, 3H), 5.79 (d, J=5.2 Hz, 1H), 6.52 (d, J=8.4 Hz,
1H), 7.06 (dd, J=8.8, 2 Hz, 1H), 7.23 (tt, J=6.4, 1.6 Hz,
2H), 7.31–7.38 (m, 8H), 7.62 (d, J=1.6 Hz, 1H), 8.46 (d, J=
5.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=20.3, 60.8,
111.3, 113.4, 124.0, 127.3, 127.7, 129.3, 132.0, 135.6, 143.6,
148.3, 170.6; FAB-MS: m/z=318 [M+H]+.
(KBr): n=3357, 3029, 1670 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=1.02 (t, J=7.6 Hz, 3H), 1.91 (quin, J=7.2 Hz,
2H), 4.33 (t, J=6.4 Hz, 1H), 6.35 (d, J=9.2 Hz, 1H), 7.22–
7.35 (m, 7H), 8.08 (d, J=2.4 Hz, 1H), 8.17 (brs, 1H);
13C NMR (100 MHz, DMSO-d6): d=10.9, 31.4, 58.1, 105.4,
112.6, 115.3, 126.8, 127.5, 129.0, 133.9, 137.0, 143.6, 149.8,
169.5; FAB-MS: m/z=334 [M+H]+, 336 [M+H+2]+; anal.
calcd. for C16H16BrNO2: C 57.50, H 4.83, N 4.19; found: C
57.62, H 4.86, N 4.17.
2-(Benzhydrylamino)-5-methoxybenzoic acid (3k): Fol-
lowing the general procedure, 3k was obtained as a yellow
solid; yield: 193 mg (58%); mp 231–2338C; IR (KBr): n=
1
3381, 3029, 1672 cmÀ1; H NMR (400 MHz, DMSO-d6): d=
3-(Benzhydrylamino)benzoic acid (3q):[22] Following the
general procedure, 3q was obtained as a white solid; yield:
173 mg (57%); mp 175–1768C; IR (KBr): n=3394, 3027,
3.65 (s, 3H), 5.78 (s, 1H), 6.58 (d, J=9.2 Hz, 1H), 6.95 (dd,
J=8.8, 3.2 Hz, 1H), 7.23 (tt, J=6.4, 1.6 Hz, 2H), 7.31–7.39
(m, 10H), 8.26 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d=
56.0, 61.3, 111.6, 114.7, 115.3, 112.8, 127.3, 127.7, 129.3,
143.7, 145.2, 149.7, 170.3; FAB-MS: m/z=334 [M+H]+;
anal. calcd. for C21H19NO3·0.1H2O: C 75.25, H 5.77, N 4.18;
found: C 75.15, H 5.78, N 4.10.
1671 cmÀ1 1H NMR (400 MHz, CDCl3): d=5.56 (s, 1H),
;
6.74 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H),
7.24–7.46 (m, 12H), 7.41 (dt, J=7.6, 1.2 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d=61.4, 114.5, 117.7, 117.8, 127.4,
127.8, 128.9, 129.2, 131.8, 143.7, 148.5, 168.3; FAB-MS: m/
z=304 [M+H]+.
2-[Phenyl(p-tolyl)methylamino]benzoic acid (3l):[5a] Fol-
lowing the general procedure, 3l was obtained as a white
solid; yield: 224 mg (66%); mp 192–1938C; IR (KBr): n=
N-Benzhydryl-4-nitroaniline (3r):[23] Following the general
procedure, 3r was obtained as a yellow solid; yield: 241 mg
1
3358, 3025, 1662 cmÀ1; H NMR (400 MHz, CDCl3): d=2.32
(79%); mp 182–1838C; IR (KBr): n=3405, 1508 cmÀ1
;
(s, 3H), 5.61 (s, 1H), 6.56 (d, J=8.8 Hz, 1H), 6.58–6.62 (m,
1H), 7.14 (d, J=8.0 Hz, 2H), 7.23–7.37 (m, 9H), 7.98 (dd,
J=8.0, 1.6 Hz, 1H), 8.30 (brs, 1H); 13C NMR (100 MHz,
DMSO-d6): d=21.11, 60.60, 111.3, 113.2, 115.4, 127.3, 127.6,
129.3, 129.9, 132.1, 134.7, 136.9, 140.5, 143.6, 150.2, 170.6;
FAB-MS: m/z=318 [M+H]+.
1H NMR (400 MHz, CDCl3): d=4.98 (d, J=4.4 Hz, 1H),
5.63 (d, J=4.8 Hz, 1H), 6.51 (d, J=7.2 Hz, 2H), 7.22–7.40
(m, 10H), 8.03 (d, J=7.2 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6): d=60.8, 112.5, 126.4, 127.8, 127.9, 129.1, 137.0,
142.5, 154.1; FAB-MS: m/z=305 [M+H]+.
2-(Benzhydrylthio)benzoic acid (3s):[24] Following the gen-
eral procedure, 3s was obtained as a white solid; yield:
216 mg (67%); mp 202–2048C; IR (KBr): n=3014,
2-[(4-Chlorophenyl)(phenyl)methylamino]benzoic
acid
(3m):[5a] Following the general procedure, 3j was obtained as
a white solid; yield: 184 mg (54%); mp 205–2078C; IR
1682 cmÀ1 1H NMR (400 MHz, CDCl3): d=5.65 (s, 1H),
;
(KBr): n=3357, 3027, 1669 cmÀ1
;
1H NMR (400 MHz,
7.12–7.49 (m, 14H), 8.07 (dd, J=7.6, 1.2 Hz, 1H); 13C NMR
Adv. Synth. Catal. 2016, 358, 765 – 773
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
771

FULL PAPERS
Hidemasa Hikawa et al.
(100 MHz, DMSO-d6): d=53.7, 124.8, 127.7, 127.7, 128,8,
129.2, 131.2, 132.4, 140.4, 141.4, 168.0; FAB-MS: m/z=321
[M+H]+.
[2] Reviews: a) G. Guillena, D. J. Ramn, M. Yus, Chem.
Rev. 2010, 110, 1611–1641; b) G. E. Dobereiner, R. H.
Crabtree, Chem. Rev. 2010, 110, 681–703.
5-Bromo-2-(cinnamylamino)benzoic acid (3t): Following
the general procedure, 3t was obtained as a white solid;
yield: 222 mg (67%); mp 188–1908C; IR (KBr): n=3377,
[3] Iron catalysis through SN1 type pathway: Y. Zhao, S. W.
Foo, S. Saito Angew. Chem. 2011, 123, 3062–3065;
Angew. Chem. Int. Ed. 2011, 50, 3006–3009.
3021, 1666 cmÀ1 1H NMR (400 MHz, DMSO-d6): d=4.05
;
[4] a) H. Hikawa, K. Izumi, Y. Ino, S. Kikkawa, Y. Yokoya-
ma, I. Azumaya, Adv. Synth. Catal. 2015, 357, 1037–
1048; b) H. Hikawa, N. Matsuda, H. Suzuki, Y. Yo-
koyama, I. Azumaya, Adv. Synth. Catal. 2013, 355,
2308–2320; c) H. Hikawa, Y. Ino, H. Suzuki, Y. Yo-
koyama, J. Org. Chem. 2012, 77, 7046–7051; d) H.
Hikawa, Y. Yokoyama, Org. Lett. 2011, 13, 6512–6515.
[5] a) H. Hikawa, H. Suzuki, I. Azumaya, J. Org. Chem.
2013, 78, 12128–12135; b) H. Hikawa, H. Suzuki, Y. Yo-
koyama, I. Azumaya, J. Org. Chem. 2013, 78, 6714–
6720.
(d, J=6.0 Hz, 2H), 6.38 (dt, J=16.0, 5.6 Hz, 1H), 5.58 (d,
J=16.0 Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 7.23 (tt, J=7.2,
1.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 2H), 7.42 (d, J=7.2 Hz,
2H), 7.49 (dd, J=9.2, 2.4 Hz, 1H), 7.86 (d, J=2.8 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=44.1, 104.7, 111.8,
114.2, 126.2, 126.7, 127.5, 128.6, 130.6, 133.4, 136.4,136.7,
149.7, 168.8; EI-MS: m/z (%)=333 (M+ +2, 16.4), 331 (M+,
17.0), 59 (100); anal. calcd. for C16H14BrNO2: C 57.85, H
4.25, N 4.22; found: C 58.12, H 4.48, N 4.18.
(E)-2-[(4-Phenylbut-3-en-1-yl)amino]-4-(trifluoromethyl)-
benzoic acid (7): Following the general procedure, 7 was ob-
tained as a white solid; yield 83 mg (25%); mp 150–1518C;
[6] H. Kinoshita, H. Shinokubo, K. Oshima, Org. Lett.
2004, 6, 4085–4088.
IR (KBr): n=3347, 3029, 1670 cmÀ1 1H NMR (400 MHz,
;
[7] P. G. Cozzi, L. Zoli, Angew. Chem. 2008, 120, 4230–
4234; Angew. Chem. Int. Ed. 2008, 47, 4162–4166.
[8] a) H. S. Park, H. Y. Lee, Y. H. Kim, Org. Lett. 2005, 7,
3187–3190; b) D. Crich, L. Quintero, Chem. Rev. 1989,
89, 1413–1432.
[9] K. Lam, I. E. Marko, Org. Lett. 2008, 10, 2773–2776.
[10] a) N. Zhang, S. R. Samanta, B. M. Rosen, V. Percec,
Chem. Rev. 2014, 114, 5848–5958; b) P. G. Gildner,
A. A. S. Gietter, D. Cui, D. A. Watson, J. Am. Chem.
Soc. 2012, 134, 9942–9945.
CDCl3): d=2.63 (ddd, J=13.7, 6.7, 1.3 Hz, 2H), 3.39 (t, J=
6.8 Hz, 2H), 6.23 (td, J=15.6, 6.8 Hz, 1H), 6.57 (d, J=
16.4 Hz, 1H), 6.83 (dd, J=8.0, 1.6 Hz, 1H), 6.93 (s, 1H),
7.22 (tt, J=6.0, 1.2 Hz, 1H), 7.26 (m, 1H), 7.30 (dt, J=7.6,
1.2 Hz, 2H), 7.38 (d, J=7.2 Hz, 2H), 7.83 (s, 1H), 8.00 (d,
J=8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=32.6,
42.2, 108.1 (d, J=4.8 Hz), 110.4 (d, J=3.8 Hz), 113.6, 124.4
(q, J=271.8 Hz), 126.5, 127.7, 128.0, 129.0, 132.3, 133.4,
134.7 (q, J=31.4 Hz), 137.6, 151.1, 169.6; EI-MS: m/z (%)=
335 (M+, 13.4), 200 (100); HR-MS (EI): m/z=335.12, calcd.
for C18H16F3NO2 [M+]: 335.11; anal. calcd. for C18H16F3NO2:
C 64.47, H 4.81, N 4.18; found: C 64.24, H 4.81, N 4.23.
2-[(Cyclopropylphenylmethyl)amino]-4-(trifluoromethyl)-
benzoic acid (8): Following the general procedure, 8 was ob-
tained as a white solid; yield: 118 mg (70%); mp 170–
[11] Reviews: a) A. A. Isse, G. Visona, F. Ghelfi, F. Ronca-
glia, A. Gennaro, Adv. Synth. Catal. 2015, 357, 782–
792; b) T. Pintauer, K. Matyjaszewski, Chem. Soc. Rev.
2008, 37, 1087–1097.
À
[12] Direct generation of benzyl radical by C H bond acti-
1728C; IR (KBr): n=3366, 3009, 1671 cmÀ1
;
1H NMR
vation of toluenes using Et3B as a radical initiator was
reported: M. Ueda, E. Kondo, Y. Ito, H. Shono, M. Ka-
kiuchi, Y. Ichii, T. Kimura, T. Miyoshi, T. Naito, O.
Miyata, Org. Biomol. Chem. 2011, 9, 2062–2064.
[13] Synthesis and characterization of CuI complexes of
water-soluble phosphine ligands was reported: a) M.
Pellei, G. G. Lobbia, C. Santini, R. Spagna, M. Camalli,
D. Fedeli, G. Falcioni, Dalton Trans. 2004, 17, 2822–
2828; b) F. Tisato, F. Refosco, G. Bandoli, G. Pilloni, B.
Corain, Inorg. Chem. 2001, 40, 1394–1396; c) S. Sakaki,
H. Mizutani, Y.-i. Kase, T. Arai, T. Hamada, Inorg.
Chim. Acta 1994, 225, 261–267.
(400 MHz, CDCl3): d=0.39–0.75 (m, 4H), 1.24–1.36 (m,
1H), 3.91 (d, J=7.2 Hz, 1H), 6.63 (s, 1H), 6.76 (dd, J=8.8,
1.6 Hz, 1H), 7.22–7.37 (m, 6H), 8.09 (d, J=8 Hz, 1H), 8.45
(s, 1H); 13C NMR (100 MHz, DMSO-d6): d=3.4, 4.7, 19.3,
60.8, 109.4 (d, J=3.3 Hz), 110.7 (d, J=3.8 Hz), 114.0, 124.2
(q, J=271.8 Hz), 126.8, 127.6, 129.1, 133.3, 134.1 (q, J=
31.4 Hz), 143.1, 150.2, 169.7; FAB-MS: m/z=336 [M+H]+;
anal. calcd. for C18H16F3NO2: C 64.47, H 4.81, N 4.18;
found: C 64.54, H 4.77, N 4.26.
2-Amino-5-[bis(4-methoxyphenyl)methyl]benzoic
acid
(11):[5b] Following the general procedure, 11 was obtained as
a white solid; yield: 327 mg (90%); mp 190–1918C; IR
[14] The reactions of free radicals are not affected by
water: a) M. Ueda, H. Miyabe, A. Nishimura, O.
Miyata, Y. Takemoto, T. Naito, Org. Lett. 2003, 5,
3835–3838; b) H. Miyabe, A. Nishimura, M. Ueda, T.
Naito, Chem. Commun. 2002, 1454–1455.
[15] a) M. I. Lipschutz, T. D. Tilley, Angew. Chem. 2014,
126, 7418; Angew. Chem. Int. Ed. 2014, 53, 7290; b) B.
Paul, D. Das, B. Ellington, E. N. G. Marsh, J. Am.
Chem. Soc. 2013, 135, 5234–5237; c) M. J. B. Aulia,
Y. M. Badiei, T. H. Warren, J. Am. Chem. Soc. 2013,
135, 9399–9406; d) J. M. R. Narayanam, J. W. Tucker,
C. R. J. Stephenson, J. Am. Chem. Soc. 2009, 131, 8756–
8757.
1
(KBr): n=3475, 3364, 3015, 1656 cmÀ1; H NMR (400 MHz,
DMSO-d6): d=3.71 (s, 6H), 5.30 (s, 1H), 6.67 (d, J=8.8 Hz,
1H), 6.84 (td, J=9.6, 3.2 Hz, 4H), 6.95–7.00 (m, 5H), 7.41
(d, J=2.0 Hz, 1H), 8.46 (brs, 1H); 13C NMR (100 MHz,
DMSO-d6) d=53.8, 55.5, 109.8, 114.2, 117.0, 130.3, 131.1,
131.4, 135.1, 137.1, 150.4, 158.0, 170.0; FAB-MS: m/z=364
[M+H]+.
References
[1] Reviews: E. Emer, R. Sinisi, M. G. Capdevila, D. Pet-
ruzziello, V. F. De, P. G. Cozzi, Eur. J. Org. Chem. 2011,
647–666.
[16] A. Brown, G. H. Schmid, Can. J. Chem. 1972, 50, 2432–
2436.
772
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 765 – 773

FULL PAPERS
A Radical Pathway for Direct Substitution of Benzyl Alcohols
[17] X. Creary, M. E. M-Mohammadi, S. McDonald, J. Org.
Chem. 1987, 52, 3254–3263.
[20] W. Si, S. Lu, M. Bao, N. Asao, Y. Yamamoto, T. Jin,
Org. Lett. 2014, 16, 620–623.
[21] a) S. Liao, K. Yu, Q. Li, H. Tian, Z. Zhang, X. Yu, Q.
Xu, Org. Biomol. Chem. 2012, 10, 2973–2978; b) Marti-
nez-Asencio, D. J. Ramon, M. Yus, Tetrahedron 2011,
67, 3140–3149; c) T. Miura, O. Kose, F. Li, S. Kai, S.
Saito, Chem. Eur. J. 2011, 17, 11146–11151.
[22] S. Takemura, H. Terauchi, Y. Miki, K. Nakano, Y. Ina-
mori, K. Miyazeki, H. Nishimura, Yakugaku Zasshi
1979, 99, 779–781.
[23] V. Terrasson, S. Marque, M. Georgy, J.-M. Campagne,
D. Prim, Adv. Synth. Catal. 2006, 348, 2063–2067.
[24] H. Hikawa, I. Azumaya, Org. Biomol. Chem. 2014, 12,
5964–5972.
[18] Two-parameter Hammett relationship: a) A. Hed-
stroem, Z. Izakian, I. Vreto, C.-J. Wallentin, P. -O.
Norrby, Chem. Eur. J. 2015, 21, 5946–5953; b) L. Maes-
tre, W. M. C. Sameera, M. M. Diaz-Requejo, F. Mase-
ras, P. J. Perez, J. Am. Chem. Soc. 2013, 135, 1338–1348;
c) S. S. Kim, Y. Zhu, K. H. Lee, J. Org. Chem. 2000, 65,
2919–2923; d) X.-K. Jiang, Acc. Chem. Res. 1997, 30,
283–289; e) X.-K. Jiang, G.-Z. Ji, J. Org. Chem. 1992,
57, 6051–6056; f) J. M. Dust, D. R. Arnold, J. Am.
Chem. Soc. 1983, 105, 1221–1227.
[19] T. Inomata, T. Moriwaki, Bull. Chem. Soc. Jpn. 1973,
46, 1148–1154.
Adv. Synth. Catal. 2016, 358, 765 – 773
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
773