Benefits of a Dual Chemical and Physical Activation: Direct aza-Michael Addition of Anilines Promoted by Solvent Effect under High Pressure

Article abstract of DOI:10.1021/acs.joc.5b01756

The unique combination of hexafluoroisopropanol (HFIP) employed as solvent and hyperbaric conditions (10-15 kbar) allows unprecedented 1,4-addition of poor nucleophiles, such as aromatic amines, onto sluggish (cumbersome) Michael acceptors without any promoter or workup.

Full text of DOI:10.1021/acs.joc.5b01756

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Note
Benefits of a Dual Chemical and Physical Activation: direct aza-Michael
Addition of Anilines Promoted by Solvent Effect under High Pressure
Alena Fedotova, Benoit Crousse, Isabelle Chataigner,
Jacques Maddaluno, Alexander Yu. Rulev, and Julien Legros
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01756 • Publication Date (Web): 29 Sep 2015
Downloaded from http://pubs.acs.org on October 5, 2015
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Benefits of a Dual Chemical and Physical Activation:
Direct aza-Michael Addition of Anilines Promoted by Solvent Effect
under High Pressure
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Alena Fedotova,a,b Benoit Crousse,c Isabelle Chataigner,a Jacques Maddaluno,a*
Alexander Yu. Rulevb* and Julien Legrosa*
a Laboratory COBRA UMR 6014, Normandie Univ, Univ Rouen, INSA Rouen and CNRS,
IRCOF, 1 rue Lucien Tesnière, 76821 MontꢀSaintꢀAignan, France, Eꢀmail: jmaddalu@crihan.fr;
julien.legros@univꢀrouen.fr
b A. E. Favorsky Institute of Chemistry, Siberian Division of the Russian academy of sciences,
1 Favorsky Str., Irkutsk, 664033, Russia, Eꢀmail: rulev@irioch.irk.ru
c BioCIS UMR 8076, Labex LERMIT, Univ Paris Sud, and CNRS, 5 rue J. B. Clément, 92296
ChâtenayꢀMalabry, France
Abstract: The unique combination of hexafluoroisopropanol (HFIP) employed as solvent and
hyperbaric conditions (10ꢀ15 kbar) allows unprecedented 1,4ꢀaddition of poor nucleophiles such
as aromatic amines onto sluggish (cumbersome) Michael acceptors without any promoter nor
workꢀup.
Solvents often play a prominent role in the behavior of a reaction, due to specific
solute/solvent interactions susceptible to act at various stages of a chemical transformation.1
Therefore, it is possible to modulate the reactivity of chemical compounds, and thus to promote a
reaction and/or to orientate its outcome, by simple solvent tuning and at no energy expenses.
Among solvents, water and the polyfluorinated alcohols trifluoroethanol (TFE) and
hexafluoroisopropanol (HFIP) exhibit unique properties being at the top of Reichardt’s polarity
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scale ET(30) and Hꢀbonding donation scale α1.2 A notable difference between water and
polyfluorinated alcohols relies on the significant Brønsted acidity and poorer Hꢀbonding
acceptance β1 of TFE and HFIP (Table 1).3 As reaction media, these highly polar protic solvents
have been shown to have a dramatically positive impact on aromatic amines, which are generally
viewed as much poorer nucleophiles than their aliphatic counterparts.4 For example, two of us
reported that primary anilines add smoothly onto Michael acceptors, without any external
promoter, on the condition to perform the reaction in water, TFE or HFIP as solvent since no
conversion was observed in any other solvent.4a Moreover, the selectivity was also under solvent
control: monoꢀaddition took place in water whereas bisꢀadducts were obtained in fluorinated
alcohols. Unfortunately, this 1,4ꢀaddition of anilines was strictly limited to simple, βꢀ
unsubstituted, electrophilic partners, namely methyl vinyl ketone or methyl acrylate, and failed
with substituted Michael acceptors, restricting thus broad applications.
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In this context, hyperbaric conditions (>5 kbar) have been shown to dramatically
accelerate the azaꢀMichael reactions, wellꢀknown to suffer from sharp steric issues.5,6,7,8,9,10 This
technique benefits of being costꢀeffective since the energy input is limited to the initial
compression step, in contrast with a classical heating that requires continuous energy
consumption during the entire reaction course. Thus, challenging nucleophiles/electrophiles,
such as cumbersome aliphatic amines, or secondary amines, amides toward αꢀ or βꢀsubstituted
Michael acceptors, become reactive under high pressure,5ꢀ9 whereas a single report described a
sluggish addition of aniline onto an αꢀacrylate derivative (34% yield after 24 h at 15 kbar and 25
°C in THF). 5h While these reactions are commonly performed in organic solvents (such as THF
and EtOH), the 1,4ꢀaddition of aliphatic amines onto acrylates6 and that of azoles onto enones7
have been described in water at 3ꢀ6 kbars. However, the improvement brought by water is either
modest when compared to classical solvents,7 or unpredictable6 due to the poor solubility of
many chemicals in this solvent and the absence of stirring means in high pressure devices.
Moreover, it should be noted that water freezes at 27 °C at approximately 10 kbar.11 We thus
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imagined that combining the unique promoter effect of an adequate polyfluorinated alcohol to
hyperbaric activation could facilitate the reaction between anilines and cumbersome Michael
acceptors. The results below show that we have been nicely rewarded.
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Investigations began with Nꢀmethylaniline 1a and methyl crotonate 2a in various solvents
at room temperature and under 10 kbar (Table 1). In aprotic solvents (CH2Cl2, THF, MeCN), no
conversion was observed after 24 h and starting material was recovered unchanged (entries 1ꢀ3).
The use of isopropyl alcohol was also unsuccessful (entry 4), whereas small conversion into
expected adduct 3a was observed in ethanol and methanol (9% and 12%; entries 5 and 6). The
use of halogenated analogues of ethanol allowed to reach fair conversion: 40% in
trichloroethanol (TCE) and 55% in TFE (entries 7 and 8).
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Table 1. Solventꢀpromoted AzaꢀMichael addition between Nꢀmethylaniline 1a and methyl crotonate
2a under high pressure.a,b
c
Entry
Solvent
ET(30) pKa
α1
β1
P (kbar)
Time (h) Conversion
(%)d
1
2
CH2Cl2
THF
40.7
37.4
45.6
0.10
0.00
0.23
0.00
0.58
0.37
0.68
0.62
0.54
0.20
0.23
0.37
0.16
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10
10
10
10
10
10
10
5
24
24
24
24
24
24
24
24
24
24
24
24
17
24
17
0
0
3
MeCN
iPrOH
EtOH
MeOH
TCE
0
4
5e
48.4
51.8
55.4
54.1
59.8
63.1
65.3
16.5 0.53
15.9 0.75
15.5 1.00
12.2 0.92
12.5 1.36
15.7 1.54
9.3 1.86
0
9
6
12
40
55
0
7
8
TFE
9
H2O
10
11
12f
13g
14
15h
HFIP
5
73
90
20
100
8
HFIP
10
10
14
0.5
1·10ꢀ3
HFIP/CH2Cl2
HFIP
HFIP
HFIP
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a Reaction conditions: 1a (1 mmol), 2a (2 mmol) in the solvent (0.5ꢀ1.5 mL) at rt. b Physicoꢀchemical
values (at atmospheric pressure) taken from references 2a,b,3a,b,12. c Values in H2O. d Conversion based
on 1H NMR; only Michael adduct was observed. e Performed with ethyl crotonate. f HFIP/ CH2Cl2 1:1
(V/V) g Isolated yield: 81%. h The reaction was performed at 58 °C.
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Water was also tested under high pressure. However, at 5 kbar: chemicals were insoluble
and no conversion could be detected. In contrast, HFIP gave excellent results under pressure:
73% at 5 kbar and 90% at 10 kbar (entries 10 and 11). It must be mentioned that HFIP has to be
used as solvent since halving its quantity (by performing the reaction in a 1:1 mixture of
HFIP/CH2Cl2) induced only moderate activation with a low conversion (20%) at 10 kbar (entry
12). Full conversion was attained at 14 kbar after 17 h, and the product 3a was obtained in 81%
yield (entry 13). Due to the absence of any external promoter, the pure product was recovered by
simple removal of the volatiles: HFIP (bp 58 °C) and methyl crotonate (bp 120 °C) that can be
recovered and recycled. In order to assess the promotion potency of the HFIP/high pressure
combination, two test reactions were performed (entries 14 and 15). In a first attempt a moderate
pressure of 0.5 kbar was exerted and only 8% conversion was reached after 24h (entry 14).
Another experiment was done at atmospheric pressure in refluxing HFIP (58 °C), affording only
18% conversion after 17h heating (entry 15). These experiments highlight the outstanding effect
of HFIP when under hyperbaric conditions.13 It is very important to note that, in contrast to
regular alcohols, no transesterification occurs with the βꢀaminoester when HFIP is used as a
reaction medium, while no βꢀelimination is observed that could reverse the reaction.
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On a mechanistic standpoint, a plain correlation between physicoꢀchemical parameters of
the alcohol solvents (iPrOH, EtOH, MeOH, TCE, TFE and HFIP) and conversions obtained
under 10 kbar clearly highlight the role of Brønsted acidity (or Hꢀbond donation ability) with a
correlation factor R2 = 0.966 (Figure 1). Thus, the acidity of HFIP seems to stand at the
appropriate point where it is sufficient to activate the Michael acceptor but incapable of
deactivating the aniline by protonation (Scheme 1).2c,d It has been reported that Ka of protic
compounds increases according to pressure,5i reinforcing thus the effect of HFIP. Moreover, high
pressure positively affects reactions with a negative activation volume (∆V‡ < 0): due to
electrostriction, the azaꢀMichael reaction goes through a highly favorable zwitterionic compact
transition state (Scheme 1).
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Figure 1. Yield (%) of the addition product of Nꢀmethylaniline onto methyl crotonate vs.
Brønsted acidity (pKa) in various alcohols at 10 kbar.
Scheme 1. Solvent and pressure effect on the reaction between Nꢀmethyl aniline and methyl
crotonate.
The scope of this addition was next examined and anilines or their Nꢀmethyl homologues
were reacted with challenging Michael acceptors (esters and nitriles) bearing substituent(s) in the
α or β position (Table 2). The optimized conditions determined above were retained (HFIP, P ≥
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10 kbar, 12 h). If aniline itself added quantitatively to crotonate (entry 3), 4ꢀchloroꢀNꢀ
methylaniline behaved also as a powerful nucleophile (90% yield, entry 2). In contrast, the
reaction with 4ꢀchloroaniline was more sluggish 53% yield, entry 4).
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To our delight, the sterically hindered 2,6ꢀxylidine behaved very well (73% yield, entry 5).
With the cumbersome trifluorocrotonate as Michael acceptor, however, aniline only afforded a
moderate 45% yield (entry 6). The case of the very challenging senecioate (β,βꢀdimethylacrylate
or βꢀmethylcrotonate) is to be noted, the addition leading to the creation of a quaternary center in
54% yield (entry 7).14 It is well established that αꢀsubstituted acrylates are sluggish electrophiles
in heteroꢀMichael reactions,15,16 and examination of the reaction of methyl methacrylate with Nꢀ
methylaniline and aniline afforded βꢀaminoesters in poor to moderate yields (9% and 40%,
respectively; entries 8 and 9). The scope of Michael acceptors was then extended to acrylonitriles
(entries 10ꢀ17). With simple acrylonitrile, Nꢀsubstituted anilines (methyl, cyclohexyl) afforded
the corresponding products in >99% yield (entries 10 and 11). Crotonitrile also appeared to be an
excellent partner since the 1,4ꢀaddition with Nꢀmethylaniline proceeded very well (81% yield,
entry 12). The last reactions were performed with 2ꢀchloroacrylonitrile (entries 13ꢀ17): the
reaction occurred smoothly with primary and secondary aromatic amines and the corresponding
αꢀchloroꢀβꢀaminonitriles were obtained as sole products in medium to good yields (60ꢀ86%).
One of the salient points of this procedure is that the product can be recovered by simple
distillation of the reaction solvent, conversely to most protocols that require hydrolysis and
multiple extractions with an organic solvent, even if the reaction is conducted neat.17
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Table 2. HFIPꢀpromoted azaꢀMichael addition of anilines under hyperbaric
conditionsa
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5
6
7
8
9
Entry
1
P (kbar)
14
Product
Yield (%)b
81
3a
3b
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2
14
90
3
4
10
14
100
53
3c
3d
5
10
73
3e
6c
7
15
10
14
45
54
40
3f
3g
3h
8
9d
10
11
15
14
14
9
3i
3j
100
99
Cy
N
3k
CN
12
13
14
14
81
65
3l
3m
14
15
14
14
86
83
3n
3o
16
17
14
14
73
60
3p
3q
[a] Conditions: 1 (1 mmol), 2 (2 mmol) in HFIP (0.5ꢀ1.5 mL) at rt under
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presure. [b] Isolated yield. [c] The reaction was performed for 24h. [d] 20%
conversion into product was observed by 1H NMR.
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In conclusion, the unprecedented combination of hyperbaric conditions and HFIP solvent
promoted the challenging 1,4ꢀaddition of poorly nucleophilic aromatic amines (primary and
secondary anilines) onto Michael acceptors when one of the reagents exhibits a sterically
hindered reaction center. Notably, the first addition of an aniline onto a β,βꢀdisubstituted Michael
acceptor, leading to the creation a quaternary center is reported. This dual physical/chemical
activation leads to a procedure sober in energy for the facile synthesis of βꢀaminoacid derivatives
(esters and nitriles) without any external promoter or workꢀup/extraction; beyond the wellꢀ
appreciated interest of βꢀaminoesters in biosciences,18 it has been recently reported that 2ꢀ
(alkoxycarbonyl)ethyl moieties are attractive removable Nꢀprotecting groups.19 The effectiveness
of the HFIP/pressure combination in the azaꢀMichael addition possibly rests on an increase of
the acidity of HFIP under high pressure affording an enhanced activation the Michael acceptor,
as well as a favorable compact transition state in the transformation. As a perspective, it is
planned to combine the organizing properties of high pressure with chiral fluorinated alcohols
(eg (S)ꢀ or (R)ꢀtrifluoroisopropanol or phenyltrifluoroethanol) in order to perform
enantioselective transformations in chiral media. This strategy initiated by Seebach 40 years
ago,20 and which led to significant ee’s in a few cases,21 could benefit from being reꢀexamined in
a wellꢀorganized medium such as that resulting from the application of hyperbaric conditions.
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Experimental Section
General methods
Highꢀpressure reactions were performed in a pistonꢀcylinder type apparatus U101 and U22
(Unipress, Warsaw, Poland), designed for pressures up to 12 kbar and up to 15 kbar, respectively
and a pistonꢀcylinder type apparatus (Ollivaud/Lebas, France) for pressures from 12 to 14 kbar.
1
The silica gel used for flash chromatography was 230ꢀ400 mesh. H, 19F and 13C spectra were
recorded at 300, 282 and 75 MHz, respectively, for solution in CDCl3. Chemical shift (δ) in ppm
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are reported using residual chloroform (7.26 for 1H and 77.16 for 13C) as internal reference. The
coupling constants (J) are given in Hertz (Hz). Highꢀresolution mass data were recorded on a
Micromass QꢀTOF (Quadrupole timeꢀofꢀflight) instrument with an electrospray source in the EI
or ESI mode.
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General Procedure for the reaction of Michael acceptors with anilines: The mixture of amine
(1 mmol) and Michael acceptor (2 mmol) in HFIP (0.5ꢀ1.5 mL) was placed in a Teflon reaction
vessel and kept under 0.5ꢀ15 kbar at room temperature overnight (17 h). After the pressure was
released and the mixture was concentrated in vacuo. The crude product was purified by column
chromatography over silica gel (cyclohexane/AcOEt, from 90:10 to 60:40). The compounds 3a-q
were prepared according to this procedure.
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3-(Methyl(phenyl)amino)butanoate 3a: brown oil, 230 mg, 81% yield; H NMR (CDCl3, 300
MHz): δ 1.22 (d, J = 6.6 Hz, 3H), 2.46 (dd, J = 14.4, 7.2 Hz, 1H), 2.66 (dd, J = 14.4, 7.2Hz, 1H),
2.75 (s, 3H), 3.63 (s, 3H), 4.48 (m, 1H), 6.73ꢀ6.93 (m, 3H), 7.21ꢀ7.30 (m, 2H); 13C NMR
(CDCl3, 75 MHz): δ 17.2, 30.2, 39.0, 51.6, 51.9, 114.2, 117.5, 129.1, 150.0, 172.2; IR (neat) ν
(cmꢀ1): 1730 (C=O). HRMS (ES+) m/z [M + H]+ calcd for C12H18NO2 208.1338; found
208.1332.
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Methyl 3-((4-chlorophenyl)(methyl)amino)butanoate 3b: brown oil, 217 mg, 90% yield; H
NMR (CDCl3, 300 MHz): δ 1.18 (d, J = 6.9 Hz, 3H), 2.43 (dd, J = 14.7, 6.9 Hz, 1H), 2.62 (dd, J
= 14.7, 7.8 Hz, 1H), 2.69 (s, 3H), 3.61 (s, 3H), 4.39 (m, 1H), 6.77 (d, J = 9.0 Hz, 2H), 7.16 (d, J
= 9.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz): δ 17.2, 30.4, 39.0, 51.8, 52.2, 115.3, 122.2, 128.9,
148.7, 172.2; IR (neat) ν (cmꢀ1): 810 (CꢀCl), 1732 (C=O); (ES+) m/z [M + H]+ calcd for
C12H17ClNO2 242.0949; found 242.0948.
1
Methyl 3-(phenylamino)butanoate 3c:22a brown oil, 192 mg, quantitative yield; H NMR
(CDCl3, 300 MHz): δ 1.29 (d, J = 9.6 Hz, 3H), 2.44 (dd, J = 22.5, 10.5 Hz, 1H), 2.68 (dd, J =
22.5, 7.8 Hz, 1H), 3.70 (s, 4H, CH3), 3.89ꢀ4.07 (m, 1H), 6.60ꢀ6.80 (m, 3H), 7.15ꢀ7.27 (m, 2H);
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13C NMR (CDCl3, 75 MHz): δ 20.7, 40.8, 46.0, 51.6, 113.6, 117.7, 129.4, 146.8, 172.3; IR (neat)
ν (cmꢀ1): 1726 (C=O), 3387(NH).
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Methyl 3-((4-chlorophenyl)amino)butanoate 3d:22b brown oil, 121 mg, 53% yield; H NMR
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(CDCl3, 300 MHz): δ 1.25 (d, J = 6.3 Hz, 3H), 2.43 (dd, J = 15.0, 6.6, Hz, 1H), 2.60 (dd, J =
15.0, 5.1 Hz, 1H), 3.67 (s, 3H), 3.50ꢀ3.75 (mask, 1H), 3.88 (m, 1H), 6.53 (d, J = 9.0 Hz, 2H),
7.10 (d, J = 9.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz): δ 20.5, 40.6, 46.2, 51.7, 114.7, 122.2,
129.2, 145.5, 172.2; IR (neat) ν (cmꢀ1): 815 (CꢀCl), 1725 (C=O), 3390 (NH).
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Methyl 3-((2.6-dimethylphenyl)amino)butanoate 3e: brown oil, 161 mg, 73% yield; H NMR
(CDCl3, 300 MHz): δ 1.18 (d, J = 6.6 Hz, 3H), 2.27 (s, 6H), 2.44 (dd, J = 15.0, 6.6 Hz, 1H), 2.51
(dd, J = 15.0, 6.0 Hz, 1H), 3.22 (br.s, 1H), 3.65 (s, 3H), 4.48 (m, 1H), 6.75ꢀ6.84 (m, 1H), 6.95ꢀ
7.00 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 19.0, 21.2, 42.1, 49.8, 51.7, 121.9, 129.1, 129.7,
144.3, 172.6; IR (neat) ν (cmꢀ1): 1731 (C=O), 3378 (NH); HRMS (ES+) m/z [M + H]+ calcd for
C13H20NO2 222.1494; found 222.1489.
Ethyl 4,4,4-trifluoro-3-(phenylamino)butanoate 3f:22c brown oil, 118 mg, 45% yield; 1H NMR
(CDCl3, 300 MHz): δ 1.20 (t, J = 7.2 Hz, 3H), 2.62 (dd, J = 15.6, 8.7 Hz, 1H), 2.84 (dd, J = 15.6,
4.5 Hz, 1H), 3.90 (br.s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 4.40ꢀ4.60 (m, 1H), 6.70ꢀ6.85 (m, 3H),
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7.17ꢀ7.25 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 14.1, 35.2, 53.5 (q, JCF = 30.2 Hz), 61.5,
125.7 (q, J = 282 Hz), 114.1, 119.6, 129.5, 145.9, 169.6; 19F NMR (CDCl3, 300 MHz): ꢀ76.10 (d,
J = 7.2 Hz); IR (neat) ν (cmꢀ1): 1117 (CF), 1728 (C=O), 3391 (NH).
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Ethyl 3-methyl-3-(phenylamino)butanoate 3g: brown oil, 119 mg, 54% yield; H NMR
(CDCl3, 300 MHz): δ 1.24 (m, 4H, NH), 1.40 (s, 6H), 2.56 (s, 2H), 4.13 (q, J = 7.2 Hz, 2H),
6.80ꢀ6.85 (m, 3H), 7.10ꢀ7.25 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 14.4, 28.7, 45.4, 53.5,
60.5, 119.6, 119.9, 129.0, 146.3, 171.9; IR (neat) ν (cmꢀ1): 1722(C=O), 3395 (NH); HRMS
(ES+) m/z [M + H]+ calcd for C13H20NO2 222.1494; found 222.1492.
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Methyl 2-methyl-3-(methyl(phenyl)amino)propanoate 3h: brown oil, 83 mg, 40% yield; H
NMR (CDCl3, 300 MHz): δ 1.21 (d, J = 6.0 Hz, 3H), 2.89ꢀ3.01 (m, 4H, CH), 3.35 (dd, J = 14.7,
6.6 Hz, 1H), 3.72 (dd, J = 14.7, 7.8 Hz, 1H), 3.66 (s, 3H), 6.70ꢀ6.77 (m, 3H), 7.23ꢀ7.30 (m, 2H);
13C NMR (CDCl3, 75 MHz): δ 15.2, 38.4, 39.2, 51.8, 56.4, 112.3, 116.6, 129.3, 149.0, 172.1; IR
(neat) ν (cmꢀ1): 1732 (C=O); HRMS (ES+) m/z [M + H]+ calcd for C12H18NO2 208.1338; found
208.1341.
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Methyl 2-methyl-3-(phenylamino)propanoate 3i:22d brown oil, 17 mg, 9% yield; H NMR
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(CDCl3, 300 MHz): δ 1.24 (d, J = 6.0 Hz, 3H), 2.74ꢀ2.85 (m, 1H), 3.23 (dd, J = 13.2, 5.7 Hz,
1H), 3.42 (dd, J = 13.2, 8.1 Hz, 1H), 3.70 (s, 3H), 3.98 (br.s, 1H), 6.60ꢀ6.75 (m, 3H), 7.14ꢀ7.21
(m, 2H); 13C NMR (CDCl3, 75 MHz): δ 15.2, 39.3, 47.0, 52.0, 113.0, 117.7, 129.4, 147.9, 176.0;
IR (neat) ν (cmꢀ1): 1724 (C=O), 3408 (NH).
3-(Methyl(phenyl)amino)propanenitrile 3j:22e brown oil, 160 mg, quantitative yield; H NMR
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(CDCl3, 300 MHz): δ 2.57 (t, J = 6.9 Hz, 2H), 3.03 (s, 3H), 3.72 (t, J = 6.9 Hz, 2H), 6.70ꢀ6.85
(m, 3H), 7.25ꢀ7.33 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 15.3, 38.7, 49.0, 112.7, 117.8, 118.6,
129.6, 147.7; IR (neat) ν (cmꢀ1): ν 2247 (C≡N).
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3-(Cyclohexyl(phenyl)amino)propanenitrile 3k: brown oil, 225 mg, 99% yield; H NMR
(CDCl3, 300 MHz): δ 1.10ꢀ2.00 (m, 10H), 2.54 (t, J = 6.9 Hz, 2H), 3.48ꢀ3.68 (m, 3H), 6.75ꢀ6.85
(m, 3H), 7.23ꢀ7.33 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 17.6, 25.8, 26.1, 31.0, 58.8, 41.1,
114.7, 118.4, 118.5, 129.5, 147.3; IR (neat) ν (cmꢀ1): 2247 (C≡N); HRMS (ES+) m/z [M + H]+
calcd for C15H21N2 229.1705; found 229.1709.
3-(Methyl(phenyl)amino)butanenitrile 3l:22f brown oil, 141 mg, 81% yield; H NMR (CDCl3,
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300 MHz): δ 1.40 (d, J = 6.6 Hz, 3H), 2.49 (dd, J = 16.8, 7.2 Hz, 1H), 2.57 (dd, J = 16.8, 6.0 Hz,
1H), 2.80 (s, 3H), 4.30 (m, 1H), 6.75ꢀ6.87 (m, 3H), 7.25ꢀ7.35 (m, 2H); 13C NMR (CDCl3, 75
MHz): δ 17.3, 21.9, 30.5, 51.7, 114.4, 118.3, 118.5, 129.4, 149.3; IR (neat) ν (cmꢀ1): 2248
(C≡N).
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2-Chloro-3-(methyl(phenyl)amino)propanenitrile 3m: brown oil, 126 mg, 65% yield; H
NMR (CDCl3, 300 MHz): δ 3.18 (s, 3H), 3.92ꢀ4.00 (m, 2H), 4.62 (t, J = 6.9 Hz, 1H), 6.70ꢀ6.95
(m, 3H), 7.30ꢀ7.40 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 39.2, 39.8, 57.8, 112.2, 116.8, 118.3,
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129.7, 147.0; IR (neat) ν (cmꢀ1): 2247 (C≡N); HRMS (EI+) m/z [M]ꢀ calcd for
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C10H11ClN2 194.06108; found 194.05992.
2-Chloro-3-(phenylamino)propanenitrile 3n:22g brown oil, 155 mg, 86% yield; H NMR
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(CDCl3, 300 MHz): δ 3.64ꢀ3.86 (m, 2H), 4.30 (br.s, 1H), 4.57 (t, J = 6.6 Hz, 1H), 6.60ꢀ6.90 (m,
3H), 7.21ꢀ7.30 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 41.1, 48.6, 113.3, 116.4, 119.4, 129.7,
145.2; IR (neat) ν (cmꢀ1): 2249 (C≡N), 3407 (NH).
2-Chloro-3-((4-chlorophenyl)(methyl)amino)propanenitrile 3o: brown oil, 190 mg, 83%
yield; 1H NMR (CDCl3, 300 MHz): δ 3.11 (s, 3H), 3.85ꢀ3.95 (m, 2H), 4.57 (dd, J = 7.5, 6.9 Hz,
1H), 6.64 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz): δ 39.1, 39.9,
57.9, 113.5, 116.6, 123.4, 129.5, 145.8; IR (neat) ν (cmꢀ1): 809 (CꢀCl), 2247 (C≡N); HRMS
+
(EI+) m/z [M]ꢀ calcd for C10H10Cl2N2 228.02210; found 228.02156.
2-Chloro-3-((4-chlorophenyl)amino)propanenitrile 3p:22g brown oil, 157 mg, 73% yield; H
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NMR (CDCl3, 300 MHz): δ 3.60ꢀ3.83 (m, 2H), 4.33 (br.s, 1H), 4.55 (dd, J = 6.9, 6.6 Hz, 1H),
6.58 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz): δ 41.1, 48.5,
114.4, 116.3, 123.9, 129.5, 143.9; IR (neat) ν (cmꢀ1): 802 (CꢀCl), 2247(C≡N), 3424 (NH).
2-Chloro-3-((2.6-dimethylphenyl)amino)propanenitrile 3q: brown oil, 125 mg, 60% yield; 1H
NMR (CDCl3, 300 MHz): δ 2.36 (s, 6H), 3.46ꢀ3.72 (m, 3H), 4.44 (dd, J = 6.0, 5.7 Hz, 1H), 6.90ꢀ
7.10 (m, 3H); 13C NMR (CDCl3, 75 MHz): δ 18.6, 42.5, 52.2, 116.4, 123.4, 129.3, 130.1, 142.5;
IR (neat) ν (cmꢀ1): 2254 (C≡N), 3402 (NH); HRMS (EI+) m/z [M]ꢀ calcd for
+
C11H13ClN2 208.07673; found 208.07716.
Supporting Information
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The Supporting Information contains copies of 1H and 13C NMR spectra for all compounds.
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Acknowledgements
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Authors are grateful to the French Ministry of Foreign Affairs for the fellowship of AF
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(programme Metchnikov), the CNRS (PICS 6293) and RFBR (Grant N14ꢀ03ꢀ91051) through a
joint programme HP2O. Labex SynOrg (ANRꢀ11ꢀLABXꢀ0029), the Région HauteꢀNormandie
and the European France (Manche) – England crossꢀborder cooperation program INTERREG IV
A “AIꢀCHEM CHANNEL” and coꢀfinanced by ERDF are also thanked for financial support.
References and Footnotes
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