Rhodium(III)-Catalyzed Direct Cyanation of Aromatic C-H Bond to Form 2-(Alkylamino)benzonitriles Using N-Nitroso As Directing Group

Article abstract of DOI:10.1021/acs.joc.5b01666

2-(Alkylamino)benzonitriles were synthesized via a rhodium-catalyzed cyanation on the aryl C-H bond and subsequent denitrosation of N-nitrosoarylamines using a removable nitroso as the directing group, in which N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) was used as the "CN" source. Various substituents on the aryl ring and amino group of N-nitrosoarylamines tolerated the reaction, and the corresponding products were achieved in moderate to good yields.

Full text of DOI:10.1021/acs.joc.5b01666

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Note
Rhodium(III)-Catalyzed Direct Cyanation of Aromatic C-H Bond to
Form 2-(Alkylamino)benzonitriles Using N-Nitroso As Directing Group
Jiawei Dong, Zhongjie Wu, Zhengyi Liu, Ping Liu, and Peipei Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01666 • Publication Date (Web): 05 Nov 2015
Downloaded from http://pubs.acs.org on November 10, 2015
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Rhodium(III)ꢀCatalyzed Direct Cyanation of Aromatic C−H Bond to
Form 2ꢀ(Alkylamino)benzonitriles Using NꢀNitroso As Directing
Group
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Jiawei Dong,a Zhongjie Wu,a Zhengyi Liu,a Ping Liu,a,b and Peipei Sun*a,b
aCollege of Chemistry and Materials Science, Jiangsu Provincial Key Laboratory of Material
Cycle Processes and Pollution Control, Nanjing Normal University, Nanjing 210097, China
bJiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing 210023,
China
sunpeipei@njnu.edu.cn
[RhCp*Cl2]2
Ts
N
CN
Ar
AgSbF6
acetone, H2O, 120 oC
N
Ar
+
R
O
N
R
Ph
CN
N
H
ABSTRACT: 2ꢀ(Alkylamino)benzonitriles were synthesized via a rhodiumꢀcatalyzed cyanation on
the aryl C−H bond and subsequent denitrosation of Nꢀnitrosoarylamines using a removable nitroso
as the directing group, in which NꢀcyanoꢀNꢀphenylꢀpꢀmethylbenzenesulfonamide (NCTS) was
used as the “CN” source. Various substituents on the aryl ring and amino group of
Nꢀnitrosoarylamines tolerated the reaction and the corresponding products were achieved in
moderate to good yields.
Benzonitriles are versatile and important structural motifs in organic synthesis, as well as in
agrochemicals, pharmaceuticals, and natural products.1 For example, 2ꢀaminobenzonitrile
derivatives have favourable antiꢀinflammatory effects.2 Cyano group can be converted into a
variety of useful functional groups, such as carboxyl, carbamoyl, aminomethyl, carbonyl, and
heterocycles.3 The transitionꢀmetalꢀcatalyzed cleavage of C−CN bond can also form various other
important chemical bonds.4 Thus, efficient and selective synthesis of benzonitriles is highly
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desirable in both organic and medicinal chemistry. There are numerous ways to be developed for
the preparation of benzonitriles, e.g., by the Rosenmundꢀvon Braun reaction from aryl halides,5 or
by the diazotization of anilines and a subsequent Sandmeyer reaction.6 In recent years,
transitionꢀmetalꢀcatalyzed cyanation of aryl halides provided an effective approach for the
synthesis of these compounds.3b,7 Significantly, in last decade, the direct C−CN bond formation
via transitionꢀmetalꢀcatalyzed C−H bond activation brought about a new insight, which provided a
straightforward and economical sequences to prepare benzonitriles from nonꢀprehalogenated
arenes. By using nitromethane, K3[Fe(CN)6], DMF, CuCN, AIBN, Nꢀcyanosuccinimide and
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NꢀcyanoꢀNꢀphenylꢀpꢀmethylbenzenesulfonamide (NCTS) as the “CN” source,
a series
of regioselective cyanation of aromatic or alkenyl C(sp2)−H bond were developed, in which
pyridyl,8 carbamyl,9 azo,10 Oꢀmethyl oxime11 were employed as the directing groups. Other
reports referred to transitionꢀmetalꢀcatalyzed cyanation of activated arenes and heteroarenes
without coordinating directingꢀgroups.12 Considering the importance of the benzonitrile
derivatives in many fields, putting the direct cyanation strategy into more kinds of arene
derivatives is still a urgent need and challenge. Because of the moderate coordination effect of
nitroso to transition metals,13 the application of this group as a favorable directing group to carry
out the functionalization of inert C−H bond has been concerned.14 In our previous works, a
palladiumꢀcatalyzed direct orthoꢀalkoxylation of NꢀalkylꢀNꢀnitrosoarylamines was developed, and
a series of oꢀalkoxyꢀNꢀalkylanilines were finally obtained.15 In continuation of our longstanding
interest in the directed C−H functionalization, herein we want to describe a RhIIIꢀcatalyzed
orthoꢀC(sp2)−H bond cyanation of NꢀalkylꢀNꢀnitrosoarylamines directed by nitroso group to form
2ꢀ(alkylamino)benzonitriles.
An easily accessible and userꢀfriendly reagent NCTS was selected as the “CN” source in our
investigations. We initially studied the cyanation conditions by employing
NꢀmethylꢀNꢀphenylnitrous amide (1a) as the reactant (Table 1). Without catalyst, the reaction
could not take place at all (entry 1). Thus, a series of transitionꢀmetal catalysts, such as palladium,
ruthenium and rhodium were tested. Unfortunately, they did not show catalytic activity to this
transformation (entries 2ꢀ4). However, to our delight, in the presence of [RhCp*Cl2]2 combined
with an additive AgSbF6, the cyanation took place successfully. Surprisingly, the denitrosation
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occurred at the same time and the product 2ꢀ(methylamino)benzonitrile (2a) was obtained in 54%
yield (entry 5). Subsequently, we agreeably found out that the presence of 2 equiv water promoted
the reaction efficiently and improved the yield to 77% (entry 6). Nevertheless, when 10 equiv
water was added, a lower yield of 35% was obtained. Furthermore, some acids or bases could
completely inhibit the reaction (entries 8ꢀ11). Solvent was then screened. In trifluorotoluene, the
reaction also proceeded smoothly and gave a good yield as that in acetone (entries 6, 12). In
toluene, however, only a lower yield of 22% was obtained (entry 13). If the reaction carried out in
DMF, acetonitrile, dioxane or DCE, almost no desired product was found (entries 14ꢀ17).
Considering the economic reason, in our following research, acetone was used as the solvent. The
appropriate reaction temperature was 120 oC. A lower temperature of 100 oC brought a measurable
decrease of the yield (entry 18).
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Table 1. Optimization of Reaction Conditionsa
entry
catalyst (mol %)
ꢀ
additive (equiv)
solvent
acetone
acetone
acetone
acetone
acetone
acetone
yield (%)
1
2
3
4
5
6
ꢀ
0
Pd(OAc)2 (5)
ꢀ
0
[RuCl2(pꢀcymene)]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
ꢀ
0
ꢀ
0
AgSbF6 (0.15)
AgSbF6
54
77
(0.15)/H2O (2)
AgSbF6
7
8
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
acetone
acetone
35
0
(0.15)/H2O (10)
AgSbF6
(0.15)/PivOH (2)
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[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
AgSbF6
acetone
acetone
acetone
trifluorotoluene
toluene
CH3CN
dioxane
DMF
0
(0.15)/AcOH (2)
AgSbF6
10
11
12
13
14
15
16
17
18b
0
(0.15)/PivONa (2)
AgSbF6
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0
(0.15)/NaOAc (2)
AgSbF6
79
22
trace
0
(0.15)/H2O (2)
AgSbF6
(0.15)/H2O (2)
AgSbF6
(0.15)/H2O (2)
AgSbF6
(0.15)/H2O (2)
AgSbF6
0
(0.15)/H2O (2)
AgSbF6
DCE
0
(0.15)/H2O (2)
AgSbF6
acetone
62
(0.15)/H2O (2)
a1a (0.3 mmol), NCTS (1.5 equiv), catalyst, AgSbF6 (15 mol %), additive and solvent (2 mL) at
120 °C under N2 atmosphere for 24 h. All yields are isolated ones. bAt 100 oC .
With the optimized reaction conditions in hand, we then explored the substrate scope of this
cyanation and subsequent denitrosation reaction. The results are summarized in Table 2.
NꢀAlkylꢀNꢀnitrosophenylamines with several different alkyls substituted on amino group were
first examined. For Nꢀmethyl, ethyl, propyl and isopropylꢀsubstituted derivatives, the reaction
proceeded smoothly and afforded the cyanated products in good yields (2aꢀ2d). Larger alkyl such
as butyl, isobutyl or cyclohexyl on amino group affected the reaction in a manner and led to the
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decrease of the yields (2eꢀ2g), which was obviously due to the steric hindrance of these groups.
Specially, Nꢀaromatic group seemed unfavorable to this process. For these cases, the products with
lower yields were obtained and the cyanation strictly occurred on the electronꢀrich side (2hꢀ2j).
NꢀAlkylꢀNꢀnitrosoarylamines with a series of substituent groups on benzene ring were then
employed for this cyanation/denitrosation reaction. The electronꢀdonating groups seemed
favorable for this transformation. For the substrates with alkyl, aryl, as well as alkoxy, the reaction
gave the corresponding cyanated and denitrosated products in good yields (2kꢀ2r). It is interesting
that for most of the reactants with metaꢀsubstituent, the cyanation selectively took place on the
side with smaller steric hindrance (2l, 2p, 2t, 2y). But when the mꢀmethoxy substituted substrate
NꢀpropylꢀNꢀnitrosoꢀ3ꢀmethoxyaniline was used, a mixture of 2r and 2r’ was obtained with a ratio
of 2.3/1, and the exact reason was not clear. The electronꢀwithdrawing groups such as chloro,
bromo and ester were also tolerated in this process and the reaction afforded the desired products
in moderate yields (2tꢀ2w). However, the fluorꢀsubstituted substrate only gave a yield of 22% (2s).
The presence of strong electronꢀwithdrawing group nitro restrained the reaction evidently and only
trace product was found (2x). From the disubstituted arylamine derivative
N,4ꢀdimethylꢀ3ꢀ(trifluoromethyl)aniline, a yield of 38% was obtained (2y).
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Table 2. Cyanation and Subsequent Denitrosation of NꢀNitroso Arylaminesa
2d, 70%
2h, 31%
2b, 79%
2f, 59%
2a, 77%
2e, 63%
2c, 80%
2g, 42%
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2l, 89%
2p, 90%
2s, 22%
2w, 57%
2i, 38%
2j, 30%
2k, 86%
2o, 69%
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2m, 87%
2n, 80%
2q, 73%
2t, 63%
2x, trace
2r, 2r’, 74% (2.3 : 1)
2u, 41%
2v, 42%
2y, 38%
aThe reaction was carried out with 1 (0.3 mmol), NCTS (1.5 equiv), [RhCp*Cl2]2 (2.5 mol %),
AgSbF6 (15 mol %) and H2O (2.0 equiv) in acetone (2 mL) at 120 °C under N2 atmosphere for
24 h. All yields are isolated ones.
Dissolving the cyanated product 2ꢀ(methylamino)benzonitrile (2a) in methol, in the presence
of H2SO4, 2a could be transformed into methyl 2ꢀ(methylamino)benzoate (3a) after heating the
mixture for 24 h. And also, 2a could be conveniently reduced to 2ꢀ(aminomethyl)ꢀNꢀmethylaniline
(4a) by LiAlH4 (Scheme 1). Both 3a and 4a are important compounds in pharmaceutical
synthesis.16
Scheme 1. Transformation of Cyanated Product
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O
NH
4
O
5
6
NH
CN
%
d 67
3a, yiel
7
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NH
2a
NH2
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4a, yield 93%
The isotope effect was investigated by using an equimolar mixture of
NꢀmethylꢀNꢀphenylnitrous amide (1a) and NꢀmethylꢀNꢀ(phenylꢀd5)nitrous amide (1aꢀd5) to take
place the reaction (Scheme 2, Eq. a). From this reaction system, a mixture of 2a and 2aꢀd4 was
obtained with a ratio of 3.1 after a reaction time of 3 h, which indicated that the rhodiumꢀcatalyzed
C–H bond cleavage of benzene ring might occur in the rate determining step. And also, when
NꢀmethylꢀNꢀ(phenylꢀd5)nitrous amide (1aꢀd5) was used as the reactant, in the absence of NCTS,
about 16% of orthoꢀdeuterium in 1aꢀd5 was substituted by hydrogen under the standard reaction
conditions (Scheme 2, Eq. b). This result showed that the orthoꢀC(sp2)−H bond activation was a
reversible process.
Scheme 2. Kinetic Isotope Effect
Based on our present experimental results and the related reports,8f,10,11,14a we proposed a
possible mechanism for this direct cyanation of the aryl C−H bond and denitrosation reaction
(Scheme 3). First, treatment of [RhCp*Cl2]2 with AgSbF6 generated the active cationic
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rhodium(III) species A, which reacted with NꢀalkylꢀNꢀphenylnitrous amide (1) to afford the cyclic
rhodium species B. Then insertion of the CN group of NCTS into the C–Rh bond of B occurred
and provided intermediate C. For the electronꢀdeficient nitrogen atom of nitroso in the
intermediate C was attacked by a nucleophile H2O, the N−N bond in the intermediate C was
cleaved, a new intermediate D was formed and the nitrous acid was released as well. Finally, the
rearrangement of D led to the producing of cyanated product (2) along with the regeneration of
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active
rhodium
species
A
to
carry
on
the
next
catalytic
cycle.
4ꢀMethylꢀNꢀphenylbenzenesulfonamide was also separated from the reaction mixture.
Scheme 3. Plausible Reaction Mechanism
In summary, we have successfully developed an efficient and mild rhodiumꢀcatalyzed
cyanation/denitrosation of Nꢀnitrosoarylamines, using a removable nitroso as the directing group,
to obtain 2ꢀ(alkylamino)benzonitriles. A range of corresponding products were synthesized by this
strategy with moderate to good yields. Various active functional groups were compatible in this
catalytic system. The result presented here should be of considerable interest for constructing
valuable synthetic building blocks in organic synthesis.
Experimental Section
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General
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All reactions were run in a sealed tube with a Teflon lined cap under nitrogen atmosphere.
NꢀAlkylꢀNꢀnitrosoarylamines were prepared according to the literature;17 other reagents were
commercially available and were used without purification. NMR spectra were recorded at 400
MHz (1H) and 100 MHz (13C) using TMS as an internal standard. Chemical shifts are given
relative to CDCl3 (7.28 ppm for 1H NMR, 77.16 ppm for 13C NMR). The following abbreviations
were used to explain the multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t = triplet,
q = quartet, m = multiplet, brs = broad, dt = doublet of triplet, ddd = doublet of doublet of doublet,
td = triplet of doublet, dq = doublet of quartet, dhept = doublet of heptet, tdt = triplet of doublet of
triplet, sepd = septet of doublet, sept = septet of triplet. Melting points are uncorrected. For the
HRMS measurements, QꢀTOF was used.
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General procedures for the rhodiumꢀcatalyzed cyanation and subsequent denitrosation of
Nꢀnitroso arylamines
NꢀAlkylꢀNꢀnitrosoarylamine (0.3 mmol), NCTS (122 mg, 0.45 mmol), [RhCp*Cl2]2 (4.6 mg,
2.5 mol %), AgSbF6 (15.5 mg, 15 mol %) and H2O (0.01 mL, 2.0 equiv) and acetone (2 mL) were
added in a 25 mL sealed tube with a Teflon lined cap. The mixture was stirred at 120 °C (oil bath
temperature) under N2 for 24 h. After the reaction finished, the mixture was cooled to room
temperature and diluted with dichloromethane then washed with water and dried. The solution was
concentrated by vacuum and separated on a silica gel column using hexane/EtOAc (10:1, v/v) as
eluent to give the corresponding pure 2ꢀ(alkylamino)benzonitrile products. For the solid products,
the melting points were obtained after further recrystallization from hexane.
Preparation of methyl 2ꢀ(methylamino)benzoate (3a)
To a solution of 2ꢀ(methylamino)benzonitrile (2a, 66.1 mg, 0.5 mmol) in MeOH (4 mL) in a
sealing tube was added H2O (4 drops) and H2SO4 (conc., 1.5 mL). The reaction mixture was
o
heated at 90 C for 24 h. After cooling to room temperature, the reaction mixture was slowly
quenched with saturated aqueous NaHCO3 to pH 8 and extracted with DCM (10 mL × 3). The
combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by silica gel chromatography using hexane/ethyl
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acetate eluent (8:1) to afford the pure product 3a.
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Preparation of 2ꢀ(aminomethyl)ꢀNꢀmethylaniline (4a)
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To a solution of 2ꢀ(methylamino)benzonitrile (2a, 66.1 mg, 0.5 mmol) in dry THF (2.5 mL)
was added lithium aluminum hydride (56.9 mg, 1.5 mmol) under iceꢀcooling in an argon gas
atmosphere. The solution was then heated and refluxed with stirring for 8 h. After cooling to room
temperature, the reaction mixture was quenched with water until foaming ceased and diluted with
DCM. Thereafter, the insolubles were filtered off and the filtrate was concentrated to give
2ꢀ(aminomethyl)ꢀNꢀmethylaniline (4a).
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o
1
2ꢀ(Methylamino)benzonitrile (2a)18 Brown solid (30.5 mg, 77% yield). Mp: 69ꢀ70 C. H NMR
(400 MHz, CDCl3) δ 7.46–7.36 (m, 2H), 6.72–6.63 (m, 2H), 4.68 (brs, 1H), 2.93 (d, J = 2.7 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 151.2, 134.3, 132.6, 118.0, 116.3, 110.1, 95.5, 30.0.
2ꢀ(Ethylamino)benzonitrile (2b)19 Brown oil (34.6 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ
7.43–7.36 (m, 2H), 6.71–6.64 (m, 2H), 4.49 (brs, 1H), 3.26 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 150.3, 134.3, 132.7, 118.0, 116.3, 110.5, 95.5, 37.9, 14.5.
2ꢀ(Propylamino)benzonitrile (2c)20 Yellow oil (38.4 mg, 80% yield). 1H NMR (400 MHz, CDCl3)
δ 7.42–7.36 (m, 2H), 6.70–6.64 (m, 2H), 4.57 (brs, 1H), 3.19 (td, J = 10.8, 7.1 Hz, 2H), 1.76–1.65
(m, 2H), 1.04 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.4, 134.2, 132.7, 118.0, 116.2,
110.6, 95.5, 45.1, 22.4, 11.5.
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2ꢀ(Isopropylamino)benzonitrile (2d)21 Yellow oil (33.6 mg, 70% yield). H NMR (400 MHz,
CDCl3) δ 7.42–7.35 (m, 2H), 6.71–6.62 (m, 2H), 4.38 (brs, 1H), 3.74 (sepd, J = 12.6, 6.4 Hz, 1H),
1.29 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 149.5, 134.2, 132.9, 118.1, 116.0, 111.0,
95.6, 44.1, 22.7.
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2ꢀ(Butylamino)benzonitrile (2e) Yellow oil (32.9 mg, 63% yield). H NMR (400 MHz, CDCl3) δ
7.47–7.35 (m, 2H), 6.75–6.61 (m, 2H), 4.54 (brs, 1H), 3.21 (t, J = 7.1 Hz, 2H), 1.75–1.58 (m, 2H),
1.47 (qt, J = 14.5, 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.4,
134.2, 132.7, 118.0, 116.2, 110.5, 95.4, 43.0, 31.2, 20.2, 13.8; HRMSꢀESI (m/z): calcd for
C11H14N2Na [M + Na]+ 197.1050, found 197.1055.
2ꢀ(Isobutylamino)benzonitrile (2f)22 Yellow oil (30.8 mg, 59% yield). 1H NMR (400 MHz, CDCl3)
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δ 7.44–7.34 (m, 2H), 6.71–6.61 (m, 2H), 4.64 (brs, 1H), 3.03 (d, J = 6.8 Hz, 2H), 1.95 (sept, J =
13.4, 6.7 Hz, 1H), 1.03 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 150.5, 134.2, 132.7,
118.0, 116.2, 110.6, 95.5, 51.0, 28.0, 20.3.
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2ꢀ(Cyclohexylamino)benzonitrile (2g)23 Yellow oil (25.2 mg, 42% yield). H NMR (400 MHz,
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CDCl3) δ 7.35 (dd, J = 12.4, 4.6 Hz, 2H), 6.74–6.58 (m, 2H), 4.46 (br, 1H), 3.36 (tdt, J = 11.1, 7.6,
3.7 Hz, 1H), 2.04 (dd, J = 8.5, 4.2 Hz, 2H), 1.85–1.76 (m, 2H), 1.72–1.63 (m, 1H), 1.45–1.34 (m,
2H), 1.33–1.20 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 149.5, 134.1, 132.9, 118.1, 115.9, 111.0,
95.5, 51.4, 32.9, 25.6, 24.8.
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2ꢀ(Phenylamino)benzonitrile (2h)24 White solid (18.1 mg, 31% yield). Mp: 50ꢀ51 C. H NMR
(400 MHz, CDCl3) δ 7.52 (dd, J = 7.8, 1.3 Hz, 1H), 7.43–7.35 (m, 3H), 7.27–7.19 (m, 3H),
7.19–7.12 (m, 1H), 6.86 (td, J = 7.8, 0.9 Hz, 1H), 6.42 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ
147.4, 139.9, 133.9, 133.1, 129.6, 124.2, 121.7, 119.2, 117.6, 114.2, 98.5.
o
2ꢀ(4ꢀFluorophenylamino)benzonitrile (2i)24 White solid (24.2 mg, 38% yield). Mp: 104ꢀ105 C.
1H NMR (400 MHz, CDCl3) δ 7.53–7.47 (m, 1H), 7.40–7.33 (m, 1H), 7.23–7.16 (m, 2H),
7.12–6.99 (m, 3H), 6.83 (td, J = 7.8, 0.9 Hz, 1H), 6.43 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ
159.8 (d, J = 244.9 Hz), 148.1, 135.8 (d, J = 2.8 Hz), 134.0, 133.1, 124.6 (d, J = 8.2 Hz), 119.0,
117.7, 116.4 (d, J = 22.7 Hz), 113.5, 97.9.
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2ꢀ(4ꢀChlorophenylamino)benzonitrile (2j)24 White solid (20.6 mg, 30% yield). Mp: 128ꢀ129 C.
1H NMR (400 MHz, CDCl3) δ 7.56–7.50 (m, 1H), 7.41 (ddd, J = 8.8, 7.4, 1.6 Hz, 1H), 7.36–7.30
(m, 2H), 7.20–7.10 (m, 3H), 6.89 (td, J = 7.8, 1.0 Hz, 1H), 6.38 (brs, 1H); 13C NMR (100 MHz,
CDCl3) δ 146.9, 138.6, 134.0, 133.2, 129.7, 129.1, 122.8, 119.7, 117.4, 114.3, 98.9.
o
5ꢀMethylꢀ2ꢀ(methylamino)benzonitrile (2k) Brown solid (37.7 mg, 86% yield). Mp: 121ꢀ122 C.
1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 8.5, 2.1 Hz, 1H), 7.20 (dd, J = 1.5, 0.6 Hz, 1H), 6.59
(d, J = 8.5 Hz, 1H), 4.49 (brs, 1H), 2.92 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
149.3, 135.3, 132.4, 125.7, 118.1, 110.3, 95.4, 30.2, 19.9; HRMSꢀESI (m/z): calcd for C9H10N2Na
[M + Na]+ 169.0736, found 169.0739.
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4ꢀMethylꢀ2ꢀ(methylamino)benzonitrile (2l) Brown solid (39.0 mg, 89% yield). Mp: 69ꢀ70 C. H
NMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.9 Hz, 1H), 6.54–6.49 (m, 1H), 6.47 (s, 1H), 4.59 (brs,
1H), 2.93 (d, J = 4.6 Hz, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.2, 145.3, 132.4,
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118.3, 117.7, 110.6, 92.8, 30.0, 22.4; HRMSꢀESI (m/z): calcd for C9H10N2Na [M + Na]+ 169.0736,
found 169.0738.
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5ꢀEthylꢀ2ꢀ(methylamino)benzonitrile (2m) Brown oil (41.8 mg, 87% yield). H NMR (400 MHz,
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CDCl3) δ 7.28 (dd, J = 8.2, 2.5 Hz, 1H), 7.23 (dd, J = 2.1, 0.4 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H),
4.51 (brs, 1H), 2.93 (d, J = 4.9 Hz, 3H), 2.55 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 149.5, 134.2, 132.3, 131.3, 118.2, 110.3, 95.4, 30.2, 27.4, 15.6;
HRMSꢀESI (m/z): calcd for C10H12N2Na [M + Na]+ 183.0893, found 183.0898.
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5ꢀtButylꢀ2ꢀ(propylamino)benzonitrile (2n) Yellow oil (51.9 mg, 80% yield). H NMR (400 MHz,
CDCl3) δ 7.44 (dd, J = 8.9, 2.4 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.45
(brs, 1H), 3.17 (td, J = 7.1, 5.6 Hz, 2H), 1.74–1.65 (m, 2H), 1.28 (s, 9H), 1.03 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 148.4, 139.2, 131.8, 129.1, 118.5, 110.6, 95.0, 45.2, 33.8, 31.2,
22.5, 11.5; HRMSꢀESI (m/z): calcd for C14H20N2Na [M + Na]+ 239.1519, found 239.1516.
4ꢀ(Methylamino)ꢀ[1,1'ꢀbiphenyl]ꢀ3ꢀcarbonitrile (2o) Brown solid (43.1 mg, 69% yield). Mp:
155ꢀ156 oC. 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 8.7, 2.3 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H),
7.54–7.49 (m, 2H), 7.47–7.41 (m, 2H), 7.33 (t, J = 7.3 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 4.73 (brs,
1H), 3.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.4, 139.3, 133.1, 130.8, 129.7, 128.9, 127.0,
126.2, 117.9, 110.6, 96.0, 30.2; HRMSꢀESI (m/z): calcd for C14H12N2Na [M + Na]+ 231.0893,
found 231.0895.
3ꢀ(Methylamino)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀcarbonitrile (2p) Yellow solid (56.2 mg, 90% yield). Mp:
115ꢀ116 oC. 1H NMR (400 MHz, CDCl3) δ 7.63–7.58 (m, 2H), 7.52–7.45 (m, 3H), 7.45–7.40 (m,
1H), 6.92 (dd, J = 8.0, 1.6 Hz, 1H), 6.84 (d, J = 1.5 Hz, 1H), 4.74 (brs, 1H), 3.01 (d, J = 1.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 151.4, 147.4, 140.4, 133.0, 128.9, 128.4, 127.2, 115.7, 108.7,
94.4, 30.1; HRMSꢀESI (m/z): calcd for C14H12N2Na [M + Na]+ 231.0893, found 231.0891.
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5ꢀMethoxyꢀ2ꢀ(methylamino)benzonitrile (2q)25 Brown oil (35.5 mg, 73% yield). H NMR (400
MHz, CDCl3) δ 7.08 (dd, J = 9.1, 3.0 Hz, 1H), 6.93 (d, J = 3.0 Hz, 1H), 6.64 (d, J = 9.1 Hz, 1H),
4.35 (brs, 1H), 3.76 (s, 3H), 2.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.5, 146.5, 122.5,
117.9, 115.8, 111.8, 95.4, 56.0, 30.6.
2ꢀMethoxyꢀ6ꢀ(propylamino)benzonitrile (2r) & 4ꢀmethoxyꢀ2ꢀ(propylamino)benzonitrile (2r’)
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Yellow oil (42.2 mg, 74% yield, 2.3 : 1). H NMR (400 MHz, CDCl3) δ 7.36–7.25 (m, 1H),
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6.33–6.11 (m, 2H), 4.55 (brs, 1H), 3.88 (s, 3H × 0.7), 3.83 (s, 3H × 0.3), 3.16 (q, J = 7.0 Hz, 2H),
1.77–1.60 (m, 2H), 1.03 (dt, J = 13.3, 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6, 162.3,
152.1, 151.8, 134.7, 134.3, 118.5, 115.9, 103.2, 103.0, 98.3, 95.8, 88.3, 85.5, 55.8, 55.3, 45.2, 45.1,
22.4, 22.3, 11.5, 11.4; HRMSꢀESI (m/z): calcd for C11H14N2ONa [M + Na]+ 213.1009, found
213.1004.
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5ꢀFluoroꢀ2ꢀ(methylamino)benzonitrile (2s) Yellow solid ( 9.9 mg, 22% yield). Mp: 78ꢀ80 C. 1H
NMR (400 MHz, CDCl3) δ 7.19 (ddd, J = 9.1, 8.1, 3.0 Hz, 1H), 7.13 (dd, J = 7.9, 3.0 Hz, 1H),
6.62 (dd, J = 9.2, 4.2 Hz, 1H), 4.54 (brs, 1H), 2.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.6
(d, J = 238.0 Hz), 148.2, 139.3, 122.1 (d, J = 22.6 Hz), 118.2 (d, J = 25.1 Hz), 111.3 (d, J = 7.5
Hz), 95.4 (d, J = 3.9 Hz), 30.4; HRMSꢀESI (m/z): calcd for C8H7FN2Na [M + Na]+ 173.0486,
found 173.0490.
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4ꢀChloroꢀ2ꢀ(methylamino)benzonitrile (2t) Brown solid (31.5 mg, 63% yield). Mp: 97ꢀ98 C. H
NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.1 Hz, 1H), 6.71–6.62 (m, 2H), 4.77 (brs, 1H), 2.94 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 151.8, 141.0, 133.6, 117.2, 116.8, 110.3, 94.1, 30.0;
HRMSꢀESI (m/z): calcd for C8H7ClN2Na [M + Na]+ 189.0190, found 189.0195.
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5ꢀChloroꢀ2ꢀ(methylamino)benzonitrile (2u) Brown solid (20.4 mg, 41% yield). Mp: 97ꢀ99 C. 1H
NMR (400 MHz, CDCl3) δ 7.40–7.34 (m, 2H), 6.63–6.58 (m, 1H), 4.69 (s, 1H), 2.94 (d, J = 4.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 149.8, 134.5, 131.6, 120.8, 116.7, 111.4, 96.5, 30.1;
HRMSꢀESI (m/z): calcd for C8H7ClN2Na [M + Na]+ 189.0190, found 189.0198.
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5ꢀBromoꢀ2ꢀ(methylamino)benzonitrile (2v) Brown solid (26.6 mg, 42% yield). Mp: 119ꢀ120 C.
1H NMR (400 MHz, CDCl3) δ 7.52–7.47 (m, 2H), 6.59–6.53 (m, 1H), 4.70 (brs, 1H), 2.93 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 150.1, 137.2, 134.4, 116.6, 111.8, 107.1, 97.1, 30.1; HRMSꢀESI
(m/z): calcd for C8H7BrN2Na [M + Na]+ 232.9685, found 232.9684.
Methyl 3ꢀcyanoꢀ4ꢀ(methylamino)benzoate (2w) Orange solid (32.5 mg, 57% yield). Mp: 152ꢀ153
oC. H NMR (400 MHz, CDCl3) δ 8.13–8.03 (m, 2H), 6.66 (d, J = 8.9 Hz, 1H), 5.17 (brs, 1H),
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3.88 (s, 3H), 3.00 (d, J = 4.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 153.6, 135.7, 135.1,
118.2, 117.0, 109.4, 95.3, 52.0, 30.0; HRMSꢀESI (m/z): calcd for C10H10N2O2Na [M + Na]+
213.0634, found 213.0637.
5ꢀMethylꢀ2ꢀ(methylamino)ꢀ4ꢀ(trifluoromethyl)benzonitrile (2y) Orange solid (24.4 mg, 38% yield).
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Mp: 147ꢀ149 oC. 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 6.90 (s, 1H), 4.70 (br s, 1H), 2.97 (d,
J = 5.0 Hz, 3H), 2.35 (d, J = 1.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 149.1, 135.4, 134.2 (q, J
= 30.0 Hz), 123.8 (q, J = 274.7 Hz), 123.6, 116.8, 107.8 (q, J = 6.0 Hz), 98.1, 30.1, 17.9 (d, J = 2.1
Hz); HRMSꢀESI (m/z): calcd for C10H9F3N2Na [M + Na]+ 237.0611, found 237.0609.
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Methyl 2ꢀ(methylamino)benzoate (3a)18 Yellow oil (55.4 mg, 67% yield). H NMR (400 MHz,
CDCl3) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.67 (brs, 1H), 7.40 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 6.69
(d, J = 8.6 Hz, 1H), 6.61 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 3.87 (s, 3H), 2.93 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 169.1, 152.0, 134.6, 131.6, 114.3, 110.7, 109.9, 51.4, 29.6.
2ꢀ(Aminomethyl)ꢀNꢀmethylaniline (4a)16d Light yellow oil (63.2 mg, 93% yield). H NMR (400
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MHz, DMSO) δ 7.08 (td, J = 7.7, 1.6 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.54 (td, J = 7.3, 1.1 Hz,
1H), 6.50 (d, J = 8.0 Hz, 1H), 5.85 (brs, 1H), 3.66 (s, 2H), 2.72 (s, 3H), 1.96 (brs, 2H); 13C NMR
(100 MHz, CDCl3) δ 149.0, 128.8, 128.6, 125.6, 116.2, 109.8, 45.4, 30.3.
ASSOCIATED CONTENT
■ AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: sunpeipei@njnu.edu.cn.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (Project 21272117,
21502097) and the Priority Academic Program Development of Jiangsu Higher Education
Institutions. The authors also thank Mr. Zilie Liu for the determination of HRMS.
Supporting Information
Copies of 1H NMR and 13C NMR spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
■ REFERENCES
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