Borrowing Hydrogen Methodology for N-Benzylation using a π-Benzylpalladium System in Water

Article abstract of DOI:10.1002/adsc.201501041

We demonstrate a borrowing hydrogen methodology using the unique reactivity of the π-benzylpalladium system in water, which offers an efficient and environmentally friendly N-monobenzylation of electron-deficient anilines or 2-aminopyridine with non-activated benzylic alcohols under neutral conditions. The crossover experiment using benzyl-α,α-d₂ alcohol and 3-methylbenzyl alcohol afforded H/D scrambling products, suggesting that the borrowing hydrogen pathway occurred in our catalytic system. Our simple protocol can accomplish a gram scale reaction of 2-aminobenzonitrile (76 % isolated yield), and is performed with the use of only 1 mol % Pd(OAc)₂ and 2 mol % TPPMS without other additives in water.

Full text of DOI:10.1002/adsc.201501041

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DOI: 10.1002/adsc.201501041
Borrowing Hydrogen Methodology for N-Benzylation using a p-
Benzylpalladium System in Water
Hidemasa Hikawa,a,* Toshitaka Koike,a Kyoko Izumi,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: November 13, 2015; Revised: December 1, 2015; Published online: February 18, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501041.
Abstract: We demonstrate a borrowing hydrogen rowing hydrogen pathway occurred in our catalytic
methodology using the unique reactivity of the p- system. Our simple protocol can accomplish a gram
benzylpalladium system in water, which offers an ef- scale reaction of 2-aminobenzonitrile (76% isolated
ficient and environmentally friendly N-monobenzyla- yield), and is performed with the use of only
tion of electron-deficient anilines or 2-aminopyridine 1 mol% Pd(OAc)2 and 2 mol% TPPMS without
with non-activated benzylic alcohols under neutral other additives in water.
conditions. The crossover experiment using benzyl-
a,a-d2 alcohol and 3-methylbenzyl alcohol afforded Keywords: benzyl alcohol; benzylation; borrowing
H/D scrambling products, suggesting that the bor- hydrogen methodology; palladium; water
Introduction
monoalkylation of amino derivatives with poor nucle-
ophilic character.[5b] Seayad et al. reported that PdCl2/
The borrowing hydrogen methodology is gaining in- dppe is an efficient catalyst for the N-alkylation of
creasing interest for the formation of carbon–carbon, various primary and cyclic secondary amines under
carbon–sulfur and carbon–nitrogen bonds.[1] This neat conditions.[5a] Although these are simple, conven-
method generally can be performed using stable, ient and highly efficient homogeneous palladium cata-
available, and non-toxic alcohols instead of halides or lytic systems, further progress is needed to find more
aldehydes. The mechanism for N-alkylation proceeds environmentally friendly conditions. Water can be an
as follows: 1) the metal-catalyzed in situ oxidation of attractive tool for new transition metal-catalyzed re-
alcohol generates the aldehyde; 2) the aldehyde actions. However, most borrowing hydrogen methods
reacts with an amine to form the corresponding are usually conducted in organic solvents where the
imine; 3) the imine is reduced by the metal hydride extrusion of moisture is essential.[6]
complex to give the N-monoalkylated amine. There-
We have been developing a unique strategy for
À
fore, these reactions occur through an attractive salt- benzylation and C H activation by the p-benzylpalla-
free and atom-economic process, which affords the dium(II) species A[7] from Pd(0)/TPPMS (TPPMS:
desired products along with water as the sole co-prod- sodium diphenylphosphinobenzene-3-sulfonate) and
uct. While Ru[2] and Ir[3] catalysts are usually used for non-activated benzyl alcohol in water (Scheme 1).[8,9]
this method, a few efficient palladium catalysts have Recently, the palladium-catalyzed N-benzylation/ben-
been developed.[4] For example, using heterogeneous zylic C–H benzylation cascade of anilines with benzyl
palladium catalysts, Murahashi and co-workers re- alcohols in water was reported (Scheme 2A).[8a] The
ported the N-benzylation of primary and secondary
amines from their Pd/C-catalyzed reactions with ben-
zylic alcohols.[4c] However, homogeneous palladium
catalysts are extremely rare compared with heteroge-
neous palladium catalysts for the borrowing hydrogen
method.[5] Ramón and co-workers reported that
Pd(OAc)2 is a versatile catalyst for the selective N- Scheme 1. p-Benzylpalladium(II) species A.
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Borrowing Hydrogen Methodology for N-Benzylation
(Scheme 2B). Thus, the reaction of electron-deficient
anilines such as 1a might proceed, not through nucle-
ophilic substitution to complex A, but by another
pathway. Notably, benzaldehyde was formed along
with desired 3a, suggesting that p-benzylpalladium(II)
A oxidizes the benzyl alcohol via b-hydride elimina-
tion of intermediate B. Therefore, the N-benzylation
of 1a with 2a might involve a hydrogen transfer
mechanism. Consequently, we herein report the N-
monobenzylation of electron-deficient anilines with
benzylic alcohols catalyzed by Pd(OAc)2/TPPMS in
water. To our knowledge, there is no precedent of the
borrowing hydrogen method by the p-benzylpalladiu-
m(II) system. Mechanistic studies supported this hy-
pothesis of the borrowing hydrogen pathway. Further-
more, this new strategy should provide a mechanistic
alternative to nucleophilic substitution reactions.
Scheme 2. Our strategy via a p-benzylpalladium system.
N-monobenzylated intermediate coordinates with p-
benzylpalladium(II) A to form a cationic N-palladat-
ed intermediate, which is favored by electron-donat- Results and Discussion
ing X groups that stabilize the positive charge (Ham-
À
mett 1 value of C H activation for N-benzyl anilines 1. Effects of catalysts and solvents
is À2.75). Thus, this pathway should be favored using
electron sufficient anilines as starting materials. How- First, a mixture of 2-aminobenzonitrile (1a) and
ever, N-monobenzylation of 2-aminobenzonitrile (1a) benzyl alcohol (2a, 5 equiv) in the presence of
with benzyl alcohol (2a) at 608C proceeded in 78% Pd(OAc)2 (5 mol%) and TPPMS (10 mol%) in water
yield, while no reaction occurred using simple aniline was heated at 608C for 16 h under air. The desired N-
Table 1. Effects of catalysts and solvents.[a]
[b]
Entry
Catalyst (mol%)
Ligand (mol%)
Additive (equiv)
Solvent
Conv. (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5) or Sc(OTf)3 (5)
TsOH·H2O (10)
–
TPPMS (10)
TPPMS (10)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
toluene
EtOH
1,4-dioxane
H2O
78 (74)[c]
95[d]
0
0
–
TPPMS (10)
TPPMS (10)
TPPMS (10)
TPPMS (10)
TPPMS (10)
TPPMS (10)
TPPMS (10)
PPh3 (10)
TPPMS (10)
TPPMS (10)
TPPMS (10)
TPPMS (10)
TPPMS (10)
trace
0
0
0
PdCl2 (5)
Pd(acac)2 (5)
Pd(OTf)2 (5)
[PdCl(allyl)]2 (5)
PdCl2(MeCN)2 (5)
Pd2(dba)3 (2.5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
9
0
10
11
12
13
14
15
16
17
0 (85)[d]
0
0
0
0
0
0
85
K2CO3 (1)
AcOH (1)
H2O
[a]
Reaction conditions: 2-aminobenzonitrile (1a) (1 mmol), Pd catalyst (5 mol%), TPPMS (10 mol%), benzyl alcohol (2a)
(5 mmol), solvent (4 mL), 608C, 16 h under air.
The conversion was determined by H NMR analysis of the crude product using p-nitroanisole as an internal standard.
Benzyl alcohol (2a) (3 equiv) was used.
At 808C.
[b]
[c]
[d]
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Hidemasa Hikawa et al.
monobenzylated product 3a was obtained in 78%
yield selectively despite the possibility of forming the
N,N- or C,N-dibenzylated products (Table 1, entry 1).
The use of 3 equiv of 2a resulted in 74% yield. When
the reaction was performed at 808C, the yield of 3a
was increased to 95% (entry 2). Since no reaction oc-
curred in the presence of Lewis and Brønsted acids
(entries 3 and 4), an SN2 type reaction mechanism was
excluded in the formation of the N-monobenzylated
3a. The Mitsunobu type reaction mechanism via
phosphonium intermediates was also excluded be-
cause the use of only TPPMS ligand resulted in no re-
action (entry 5). With regard to the palladium cata-
lyst, Pd(OAc)2 gave the best result (entry 1 vs. en-
tries 6–11). When the reaction was performed at 808C
using the PdCl2(MeCN)2/TPPMS catalyst, the desired
Scheme 4. Crossover experiment.
3a was obtained in 85% yield (entry 10). Using PPh3 the reaction of 1a with benzyl-a,a-d2 alcohol 2b-d
instead of a water-soluble ligand (entry 12) or using and 3-methylbenzyl alcohol (2c) afforded H/D scram-
organic solvents such as toluene, EtOH, or 1,4-diox- bling products 2-(benzylamino)benzonitrile (3a-d and
ane instead of H2O (entries 13–15) resulted in no re- 3a-d2 mixture) and 2-[(3-methylbenzyl)amino]benzo-
action. Therefore, water must play an important role nitrile (3 f and 3 f-d mixture) in 26% and 30% isolat-
in our catalytic system. While K2CO3 as an additive ed yields, respectively. In the mixture of 3a-d and 3a-
suppressed N-benzylation in our catalytic system d2, the ratio of the integration values of the methylene
(entry 16), AcOH enhanced the reaction (entry 17, doublet at 4.4 ppm to the doublet at 6.6 ppm is
85%). Basset and co-workers reported that the p-al- 0.63:1.00 in the 1H NMR spectrum (Figure 1A). In
lylpalladium intermediate is unstable under basic con- the mass spectrum, the mixture of 3a-d and 3a-d2
ditions.[10] In contrast, Kobayashi et al.[11] reported shows two lines as the molecular ion peaks at m/z=
that the use of a carboxylic acid such as 1-AdCO2H 209 and 210, respectively (see SI).
accelerates the palladium-catalyzed allylic substitu-
Additionally, a control experiment was performed
tion. Since our results are consistent with these re- to exclude the possibility of other borrowing hydro-
ports on the palladium-catalyzed allylation with allylic gen pathways. If the Pd(0)/TPPMS follows the Pd di-
alcohols, p-benzylpalladium would be an intermediate hydride pathway, H/D scrambling should occur and
here, analogous to the allylic substitution reaction.
Additionally, the imine formation process should be
favored under the weak acidic conditions.
2. Control experiments
To gain insight into the mechanism of the borrowing
hydrogen method using the p-benzylpalladium(II)
system, we carried out control experiments. If the oxi-
dation of benzyl alcohol (2a) to benzaldehyde (4)
proceeds, toluene should be formed through b-hy-
dride elimination of intermediate B (Scheme 3). We
were delighted to observe toluene 5 (34%) and ben-
zaldehyde 4 (34%) from 2a in the reaction mixture.
Next, we carried out a crossover experiment using
different benzyl alcohols (Scheme 4). As expected,
Figure 1. 1H NMR spectrum for mixture of 3a-d and 3a-d2
(A) and authentic sample 3a (B).
Scheme 3. Disproportionation of benzyl alcohol 2a.
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Borrowing Hydrogen Methodology for N-Benzylation
Table 2. Scope of anilines 1 and alcohols 2.[a]
Scheme 5. N-Benzylation in D2O to exclude the palladium
dihydride pathway.
N-benzylated 3a-d should show D incorporation
(Scheme 5). As expected, treatment of 2-aminobenzo-
nitrile (1a) with benzyl alcohol (2a) in D2O showed
0% deuterium incorporation at the benzylic position,
excluding the possibility of this pathway.
3. Hammett study
To demonstrate the effect of substituents on the rates
of the N-benzylation, a Hammett study was conduct-
ed on the reaction of 2-aminobenzonitrile (1a) with
4- or 6-substituted 2-aminobenzonitrile 1 (Me, F and
CF3 groups) to obtain the ratio of rate constants fol-
1
lowed by H NMR. Figure 2 shows good correlation
(R2 =0.99) between the log(kX/kH) and the s values of
the respective substituents that resulted in a negative
1 value of 0.71, suggesting that there is a build-up of
positive charge in the transition state.
[a]
1 (1 mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%), 2
(5 mmol), H2O (4 mL), 1208C, 16 h under air. Yield of
isolated product.
tion (3g, 73%). 2-Naphthalenemethanol and a-meth-
Figure 2. Hammett plot for the rate constants of N-benzyla- ylbenzyl alcohol also resulted in good yields (3h,
tion by various substituted 2-aminobenzonitrile 2.
81%; 3i, 67%). The reaction of 2-aminobenzonitriles
with electron-donating methyl and dimethoxy groups
afforded desired 3j–l in excellent to good yields (3j,
76%; 3k, 96%; 3l, 70% along with imine 13%). The
reaction of 2-aminobenzonitriles with electron-with-
4. Reaction scope
Results for the reactions of several anilines 1 with drawing fluoro and trifluoromethyl groups afforded
benzyl alcohols 2 using Pd(OAc)2 and TPPMS in 3m–n in moderate to good yields (3m, 75%; 3n,
water are summarized in Table 2. The use of benzyl 64%). The reaction of 4-amino-3-fluorobenzonitrile,
alcohols with electron-donating methoxy, n-butoxy 2-aminophenyl phenyl sulfone, and 2-aminopyridine
and methyl groups resulted in moderate to excellent resulted in excellent to good yields (3o, 85%; 3p,
yields (3b, 62%; 3c, 80%; 3d, 70%; 3e, 85%; 3 f, 75%; 3q, 90%). No reaction occurred using 4-fluoro-
78%). A sterically demanding methyl group at the benzyl alcohol (2b) and phenethyl alcohol (2e) in our
ortho position was tolerated in the N-monobenzyla- catalytic system.
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Hidemasa Hikawa et al.
5. Mechanistic considerations
6. Comparison of palladium-catalyzed borrowing
hydrogen
Based on these results and previous reports, we favor
a catalytic system for the N-benzylation of 2-amino- To compare our p-benzylpalladium system with other
benzonitrile (1a) with benzyl alcohol (2a) in water, as efficient homogeneous palladium catalytic systems,
illustrated in Scheme 6. First, oxidative addition of 2a the reaction of substrate 1a with alcohol 2a at 608C
to water-soluble Pd(0)/TPPMS catalyst affords the was carried out (Scheme 7). While our catalytic
cationic p-benzylpalladium(II) complex A (step 1). system proceeded smoothly to give desired product
3
À
Water activates the sp C O bond by hydrogen bonds 3a in 74% yield, 3a was not obtained using the prior
between water and the hydroxyl group of the alcohol methods [PdCl2/dppe (5 mol%) with LiOH·H2O
under neat conditions,[5a] or Pd(OAc)2 (5 mol%) with
CsOH in toluene[5b]], clearly showing the superiority
of the p-benzylpalladium system for the N-monoben-
zylation of 1a. Furthermore, our simple protocol
could be achieved under neutral conditions, which
should be advantageous for organic synthesis.
Scheme 7. Comparison of palladium-catalyzed borrowing
hydrogen of 2-aminobenzonitrile (1a) with benzyl alcohol
(2a). Reaction conditions: 1a (1 mmol), Pd cat. (5 mol%),
Ligand (5 or 10 mol%), 2a (2 or 3 mmol), solvent (4 mL),
Scheme 6. Proposed mechanism.
for formation of the p-benzylpalladium complex.[12] 608C, 16 h under air. NMR yield.
This process should be favored by electron-donating
groups on intermediate A, since these will stabilize
the positive charge on PdII. Indeed, no reaction oc-
Recently, efficient methods for the direct use of un-
curred using benzyl alcohols with electron-withdraw- activated benzylic alcohols 2 for the N-monobenzyla-
ing groups (see Table 2). Additionally, phenethyl alco- tion of 2-aminobenzonitriles 1 have been reported uti-
hol also resulted in no reaction since the p-benzylpal- lizing a Brønsted acid,[13] copper-aluminum hydrotal-
ladium(II) species could not be formed. Next, the p- cite (CuAl-HT)/K2CO3,[14] and TaF5.[15] However,
benzylpalladium(II) cation species activates the hy- these methods suffer from disadvantages such as the
droxide of 2a, and then the hydroxyl anion acts as use of toxic and moisture sensitive reagents or haz-
a base to remove the proton of the cationic alcohol- ardous organic solvents. To enable efficient synthesis
PdII intermediate, followed by formation of a palladi- for the improvement of organic chemistry, it is essen-
um alkoxide species B (step 2). Seayad et al. reported tial to develop green chemistry methods. To demon-
that reaction of the in situ-formed lithium alkoxide strate the utility of our environmentally benign, effi-
with palladium catalyst generates the palladium alk- cient and simple protocol, a gram scale reaction of 1a
oxide species.[5a] In the oxidation step, b-hydride elim- (10 mmol) with 2a in the presence of Pd(OAc)2
ination of intermediate B affords benzaldehyde (4) (1 mol%) and TPPMS (2 mol%) was carried out at
along with palladium(II) hydride C. The aldehyde 4 908C under ambient air (Scheme 8). The resulting
reacts with amine 1a to form the corresponding imine crude 3a could be purified simply by recrystallization
6 (step 3), which is reduced by the palladium(II) hy- to give the desired product 3a in 76% (1.59 g) isolat-
dride complex C to give N-monobenzylated 3a and
regenerate the p-benzylpalladium(II) species A (step
4). Indeed, an imine intermediate was observed (see
Table 2, 3l). Simple aniline would be ineffective due
to poisoning of palladium catalysts by nitrogen, when
the reaction was carried out at 608C (see
Scheme 2B).
Scheme 8. Scale-up experiment.
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Borrowing Hydrogen Methodology for N-Benzylation
2-[(3,4-Dimethoxybenzyl)amino]benzonitrile 3c.[15] Fol-
lowing the general procedure, 3c was obtained as a white
solid. 214 mg (80%); mp 83–858C; IR (KBr) (cmÀ1) 3378,
ed yield. Notably, this protocol avoids using column
chromatography.
1
2215; H NMR (400 MHz, CDCl3): d 3.88 (s, 6H), 4.36 (d,
J=5.2 Hz, 2H), 4.95 (brs, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.69
(dt, J=7.6, 0.8 Hz, 1H), 6.83–6.93 (m, 3H), 7.35 (d, J=8.8,
6.0, 2.0 Hz, 1H), 7.42 (d, J=8.0, 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 47.4, 55.9, 56.0, 95.9, 110.4, 111.1,
111.3, 116.9, 117.9, 119.5, 130.1, 132.7, 134.3, 148.5, 149.3,
150.1; MS (EI): m/z (%) 268 (M+, 17.7), 151 (100); Anal.
calcd. for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44; found: C,
71.58; H, 5.96; N, 10.19.
Conclusions
In summary, the p-benzylpalladium(II) species has
been shown to be an active catalyst for the borrowing
hydrogen methodology in water. This strategy could
achieve N-benzylation of electron-deficient anilines
or 2-aminopyridine in moderate to excellent yields.
Mechanical studies supported the borrowing hydro-
gen pathway. The reaction conditions are neutral and
base is not required. We are currently investigating
the scope of various nucleophiles using the p-benzyl-
palladium(II) system from benzylic alcohols in aque-
ous media.
2-[(4-n-Butoxybenzyl)amino]benzonitrile 3d. Following
the general procedure, 3d was obtained as a white solid.
196 mg (70%); mp 78–808C; IR (KBr) (cmÀ1) 3380, 2213;
1H NMR (400 MHz, CDCl3): d 0.98 (t, J=7.2 Hz, 3H), 1.45–
1.55 (m, 2H), 1.70–1.80 (m, 2H), 3.96 (t, J=6.4 Hz, 2H),
4.35 (d, J=5.6 Hz, 2H), 4.92 (brs, 1H), 6.65 (d, J=8.4 Hz,
1H), 6.68 (dt, J=8.0, 1.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H),
7.25 (m, 2H), 7.31–7.37 (m, 1H), 7.40 (dd, J=8.0, 0.4 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 13.9, 19.2, 31.3, 47.0,
67.7, 95.8, 111.0, 114.8, 116.7, 128.5, 129.3, 132.7, 134.3,
150.1, 158.7; MS (EI): m/z (%) 280 (M+, 21.3), 14 (100);
HRMS (EI): m/z calcd. for C17H18N2O (M+) 280.1576;
found: 280.1575.
2-[(4-Methylbenzyl)amino]benzonitrile 3e.[15] Following
the general procedure, 3e was obtained as a white solid.
188 mg (85%); mp 118–1208C; IR (KBr) (cmÀ1) 3377, 2213;
1H NMR (400 MHz, CDCl3): d 2.35 (s, 3H), 4.39 (d, J=
5.6 Hz, 2H), 4.97(brs,1H), 6.64 (d, J=8.4 Hz, 1H), 6.68 (dt,
J=7.6, 0.8 Hz, 1H), 7.17 (d, J=8.0 Hz, 2H), 7.23 (d, J=
8.0 Hz, 2H), 7.34 (ddd, J=9.2, 7.2, 1.6 Hz, 1H), 7.41 (dd,
J=7.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.0,
47.1, 95.9, 111.0, 116.8, 127.2, 129.6, 132.8, 134.3, 134.6,
137.4, 150.1; MS (EI): m/z (%) 222 (M+, 42.8), 105 (100);
Anal. calcd. for C15H14N2: C, 81.05; H, 6.35; N, 12.60; found:
C, 80.80; H, 6.25; N, 12.37.
Experimental Section
General procedure: A mixture of 1 (1 mmol), Pd(OAc)2
(11 mg, 0.05 mmol), sodium diphenylphosphinobenzene-3-
sulfonate (TPPMS, 38 mg, 0.1 mmol) and benzylic alcohols 2
(5 mmol) in H2O (4 mL) was heated at 80–1208C 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 in vacuo. The residue was washed with hex-
anes, then purified by flash column chromatography (silica
gel, hexanes/EtOAc) to give desired product 4.
2-(Benzylamino)benzonitrile 3a.[16] Scale-up experiment:
A mixture of 2-aminobenzonitrile (1a) (1.18 g, 10 mmol),
Pd(OAc)2 (22 mg, 0.1 mmol), sodium diphenylphosphino-
benzene-3-sulfonate (TPPMS, 73 mg, 0.2 mmol) and benzyl
alcohol (2a) (5.1 mL, 50 mmol) in H2O (40 mL) was heated
at 908C for 16 h under air. After cooling, the reaction mix-
ture 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 recrystallized from
hexane/AcOEt to give desired product 3a (1.59 g, 7.6 mmol,
76%) as a white solid. IR (KBr) (cmÀ1) 3377, 2213;
1H NMR (400 MHz, CDCl3): d 4.43 (d, J=5.6 Hz, 2H), 5.02
(brs, 1H), 6.63 (d, J=8.8 Hz, 1H), 6.69 (dt, J=7.2, 0.8 Hz,
1H), 7.27–7.40 (m, 6H), 7.42 (dd, J=7.6, 1.2 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 47.3, 95.8, 111.0, 116.8,
117.9, 127.1, 127.6, 128.8, 132.7, 134.2, 137.7, 150.0; MS (EI):
m/z (%) 238 (M+, 59.3), 91 (100).
2-[(3-Methylbenzyl)amino]benzonitrile 3 f. Following the
general procedure, 3 f was obtained as a white solid. 173 mg
1
(78%); mp 80–828C; IR (KBr) (cmÀ1) 3371,2213; H NMR
(400 MHz, CDCl3): d 2.35 (s, 3H), 4.38 (d, J=4.8 Hz, 2H),
4.97 (brs, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.68 (ddd, J=7.6,
7.6, 0.8 Hz, 1H), 7.08–7.16 (m, 3H), 7.24 (dd, J=6.8, 6.8 Hz,
1H), 7.33 (ddd, J=7.6, 7.6, 0.8 Hz, 1H), 7.40 (ddd, J=7.6,
7.6, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.53,
47.57, 95.90, 111.0, 116.9, 124.4, 128.0, 128.5, 128.8, 132.8,
134.4, 137.7, 138.7, 150.2, 207.1; MS (EI): m/z (%) 222 (M+,
47.6), 105 (100); Anal. calcd. for C15H14N2: C, 81.05; H,
6.35; N, 12.60; found: C, 80.96; H, 6.38; N, 12.53.
2-[(2-Methylbenzyl)amino]benzonitrile 3g.[17] Following
the general procedure, 3g was obtained as a white solid.
162 mg (73%); mp 123–1258C; IR (KBr) (cmÀ1) 3382, 2214;
1H NMR (400 MHz, CDCl3): d 2.37 (s, 3H), 4.37 (d, J=
5.2 Hz, 2H), 4.80 (brs, 1H), 6.65 (d, J=8.8 Hz, 1H), 6.70
(ddd, J=7.6, 1.2 Hz, 1H), 7.15–7.31 (m, 4H), 7.37 (t, J=
8.2 Hz, 1H), 7.42 (dd, J=8.0, 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 18.98, 45.70, 95.76, 110.9, 116.8, 117.9,
126.4, 127.8, 127.9, 130.7, 132.8, 134.3, 135.2, 136.1, 150.1,
207.1; Anal. calcd. for C15H14N2: C, 81.05; H, 6.35; N, 12.60;
found: C, 81.24; H, 6.24; N, 12.45.
2-[(4-Methoxybenzyl)amino]benzonitrile 3b.[15] Following
the general procedure, 3b was obtained as a white solid.
148 mg (62%); mp 88–908C; IR (KBr) (cmÀ1) 3410, 2210;
1H NMR (400 MHz, CDCl3): d 3.81 (s, 3H), 4.35 (d, J=
4.8 Hz, 2H), 4.93 (brs, 1H), 6.65 (t, J=8.8 Hz, 1H), 6.68 (dt,
J=7.6, 0.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 7.27 (d, J=
8.4 Hz, 2H), 7.35 (ddd, J=8.8, 7.6, 1.6 Hz, 1H), 7.41 (dd,
J=7.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 47.1,
55.4, 95.9, 110.1, 114.3, 116.9, 128.6, 129.7, 132.8, 134.4,
150.1, 159.1; MS (EI): m/z (%) 238 (M+, 15.3), 121 (100).
Adv. Synth. Catal. 2016, 358, 784 – 791
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FULL PAPERS
Hidemasa Hikawa et al.
2-[(Naphthalen-2-ylmethyl)amino]benzonitrile 3h. Fol-
lowing the general procedure, 3h was obtained as a yellow
solid. 209 mg (81%); mp 150–1528C; IR (KBr) (cmÀ1) 3379,
2214; 1H NMR (400 MHz, CDCl3): d 4.61 (d, J=5.6 Hz,
2H), 5.16 (brt, J=5.6 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.69
(dt, J=8.4, 0.8 Hz, 1H), 7.28–7.34 (m, 1H), 7.41–7.52 (m,
4H), 7.76–7.81 (m, 4H); 13C NMR (100 MHz, CDCl3): d
47.6, 96.0, 111.2, 117.0, 117.9, 125.1, 125.7, 126.0, 126.4,
127.7, 127.8, 128.8, 132.8, 132.9, 133.4, 134.3, 135.2, 150.1;
MS (EI): m/z (%) 258 (M+, 29.6), 141 (100); HRMS (EI):
m/z calcd. for C18H14N2 (M+), 258.1157; found: 258.1157.
Anal. calcd. for C14H11FN2: C, 74.32; H, 4.90; N, 12.38;
found: C, 74.38; H, 4.98; N, 12.32.
2-(Benzylamino)-4-(trifluoromethyl)benzonitrile 3n. Fol-
lowing the general procedure, 3n was obtained as a white
solid. 177 mg (64%); mp 118–1208C; IR (KBr) (cmÀ1) 3370,
2221; 1H NMR (400 MHz, CDCl3): d 4.46 (d, J=5.2 Hz,
2H), 5.17 (brs, 1H), 6.89 (s, 1H), 6.93 (d, J=8.0 Hz, 1H),
7.31–7.42 (m, 5H), 7.53 (d, J=8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 98.9, 107.6 (q, J=3.8 Hz), 113.2 (q, J=
3.8 Hz), 116.6, 123.2 (q, J=268 Hz), 127.4 128.1, 129.1,
133.5, 135.9 (q, J=32.4 Hz), 136.6; MS (EI): m/z (%) 276
(M+, 40.6), 91 (100); Anal. calcd. for C15H11F3N2: C, 65.22;
H, 4.01; N, 10.14; found: C, 65.22; H, 4.09; N, 10.11.
2-{[1-(4-Methoxyphenyl)ethyl]amino}benzonitrile 3i. Fol-
lowing the general procedure, 3i was obtained as a colorless
1
oil. 170 mg (67%); IR (KBr) (cmÀ1) 3379, 2200; H NMR
4-(Benzylamino)-3-fluorobenzonitrile 3o. Following the
general procedure, 3o was obtained as a white solid. 192 mg
(400 MHz, CDCl3): d 1.56 (d, J=6.8 Hz, 3H), 3.78 (s, 3H),
4.53 (quin, J=5.2 Hz, 2H), 4.86 (brd, J=5.2 Hz, 1H), 6.44
(dd, J=8.8 Hz, 1H), 6.62 (dt, J=7.6, 0.8 Hz, 1H), 6.87 (d,
J=8.8 Hz, 2H), 7.18–7.30 (m, 3H), 7.38 (ddd, J=7.6, 1.6,
0.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 24.9, 52.7, 55.3,
95.8, 112.0, 114.2, 116.6, 118.0, 126.7, 132.6, 134.1, 135.7,
149.3, 158.8; MS (EI): m/z (%) 252 (M+, 8.7), 135 (100);
HRMS (EI): m/z calcd. for C16H16N2O (M+), 252.1263;
found: 252.1264.
1
(85%); mp 81–828C; IR (KBr) (cmÀ1) 3248, 2216; H NMR
(400 MHz, CDCl3): d 4.43 (d, J=5.6 Hz, 2H), 4.87 (brs,
1H), 6.63 (t, J=8.4 Hz, 1H), 7.20–7.42 (m, 7H); 13C NMR
(100 MHz, CDCl3): d 47.1, 98.3, 99.9, 111.5 (d, J=30.8 Hz),
117.6 (d, J=21.9 Hz), 119.2, 127.3, 127.9, 129.0, 130.1 (d, J=
3.8 Hz), 137.2, 140.5 (d, J=11.4 Hz), 149.9 (d, J=240.3 Hz);
MS (EI): m/z (%) 226 (M+, 53.3), 91 (100); HRMS (EI): m/
z calcd. for C14H11N2F (M+), 226.0906; found: 226.0907.
N-Benzyl-2-(phenylsulfonyl)aniline 3p. Following the gen-
eral procedure, 3p was obtained as a white solid. 241 mg
(75%); mp 97–998C; IR (KBr) (cmÀ1) 3406, 1335, 1286,
2-(Benzylamino)-4-methylbenzonitrile 3j. Following the
general procedure, 3j was obtained as a white solid. 170 mg
(76%); mp 98–1008C; IR (KBr) (cmÀ1) 3369, 2210;
1H NMR (400 MHz, CDCl3): d 2.28 (s, 3H), 4.42 (d, J=
5.6 Hz, 2H), 4.91 (brs, 1H), 6.46 (s, 1H), 6.52 (d, J=7.2 Hz,
1H), 7.26–7.40 (m, 6H); 13C NMR (100 MHz, CDCl3): d
22.5, 47.6, 93.2, 111.5, 118.3, 118.3, 127.3, 127.7, 129.0, 132.6,
137.9, 145.4, 150.2; MS (EI): m/z (%) 222 (M+, 64.7), 91
(100); Anal. calcd. for C15H14N2: C, 81.05; H, 6.35; N, 12.60;
found: C, 81.51; H, 6.36; N, 12.08.
2-(Benzylamino)-6-methylbenzonitrile 3k.[18] Following
the general procedure, 3k was obtained as a white solid.
214 mg (96%); mp 112–1148C; IR (KBr) (cmÀ1) 3385,2207;
1H NMR (400 MHz, CDCl3): d 2.45 (s, 3H), 4.43 (s, 2H),
5.00 (brs, 1H), 6.45 (d, J=8.0 Hz, 1H), 6.56 (d, J=7.2 Hz,
1H), 7.10–7.40 (m, 6H); 13C NMR (100 MHz, CDCl3): d
20.8, 47.6, 96.8, 108.2, 118.1, 127.2, 127.6, 128.8, 133.6, 137.9,
142.6, 150.4; MS (EI): m/z (%) 222 (M+, 58.6), 91 (100);
Anal. calcd. for C15H14N2: C, 81.05; H, 6.35; N, 12.60; found:
C, 81.51; H, 6.36; N, 12.08.
2-(Benzylamino)-4,5-dimethoxybenzonitrile 3l.[18] Follow-
ing the general procedure, 3l was obtained as a white solid.
188 mg (70%); mp 96–988C; IR (KBr) (cmÀ1) 3369, 2200;
1H NMR (400 MHz, CDCl3): d 3.76 (s, 3H), 3.79 (s, 3H),
4.83 (brs, 1H), 6.13 (s, 1H), 6.85 (s, 1H), 7.27–7.40 (m, 5H);
13C NMR (100 MHz, CDCl3): d 48.1, 55.8, 56.6, 85.6, 95.6,
114.3, 118.5, 127.2, 127.7, 128.9, 138.0, 140.8, 147.3, 154.7;
MS (EI): m/z (%) 268 (M+, 80.3), 91 (100); HRMS (EI): m/
z calcd. for C16H16N2O2 (M+), 268.1212; found: 268.1213.
1
1147; H NMR (400 MHz, [D6]DMSO): d 4.45 (d, J=5.2 Hz,
2H), 6.63 (d, J=8.0 Hz, 1H), 6.73 (dt, J=7.6, 0.8 Hz, 1H),
6.86 (t, J=5.6 Hz, 1H), 7.09 (d, J=6.4 Hz, 2H), 7.15–7.25
(m, 3H), 7.33 (dt, J=6.8, 1.6 Hz, 1H), 7.62 (t, J=7.2 Hz,
2H), 7.72 (tt, J=7.6, 1.2 Hz, 1H), 7.83 (dd, J=8.0, 1.6 Hz,
1H), 7.98 (d, J=8.4 Hz, 2H); MS (FAB): m/z (%) 324 [M+
H]+; Anal. calcd. for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33;
found: C, 70.65; H, 5.36; N, 4.37.
N-Benzylpyridin-2-amine 3q.[20] Following the general
procedure, 3q was obtained as a white solid. 165 mg (90%);
mp 90–918C; IR (KBr) (cmÀ1) 3232; 1H NMR (400 MHz,
CDCl3): d 4.50 (d, J=5.6 Hz, 2H), 4.95 (brs, 1H), 6.36 (dt,
J=8.4, 1.2 Hz, 1H), 6.58 (ddd, J=7.2, 5.2, 1.2 Hz, 1H),
7.23–7.29 (m, 1H), 7.30–7.36 (m, 2H), 7.39 (dd, J=8.8, 7.2,
1.6 Hz, 1H), 8.09 (ddd, J=5.2, 2.0, 1.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d 46.3, 106.8, 113.1, 127.0, 127.2, 127.4,
128.6, 137.5, 139.2, 148.2, 158.6; MS (FAB): m/z (%) 185
[M+H]+.
Acknowledgements
This work was supported by JSPS KAKENHI Grant
Number 25460026.
2-(Benzylamino)-6-fluorobenzonitrile 3m.[19] Following
the general procedure, 3m was obtained as a white solid.
169 mg (75%); mp 121–1238C; IR (KBr) (cmÀ1) 3369, 2221;
1H NMR (400 MHz, CDCl3): d 4.44 (d, J=5.6 Hz, 2H), 5.10
(brs, 1H), 6.40 (d, J=8.4 Hz, 1H), 6.43 (dt, J=8.4, 0.8 Hz,
1H), 7.20–7.40 (m, 6H); 13C NMR (100 MHz, CDCl3): d
47.8, 85.9, 103.5 (d, J=19.1 Hz), 106.6 (d, J=2.9 Hz), 113.5,
127.2, 127.9, 129.0, 135.4 (d, J=10.5 Hz), 137.3, 151.4 (d, J=
2.9 Hz), 162.8; MS (EI): m/z (%) 226 (M+, 48.6), 91 (100);
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