Alkylation of aromatic amines by tert-enamides: Direct access to protected aminals

Article abstract of DOI:10.1080/00397911.2017.1363241

Reaction of aromatic amines with tertiary enamides was performed in n-hexane in the presence of acetic acid as an inexpensive and green catalyst at room temperature. This protocol provides the protected aminals through Markovnikov addition reaction with high to excellent yields and regiospecificity. In addition, this procedure was expanded for the synthesis of aminals from commercially available sulfa drugs such as sulfathiazole and sulfabenzamide.

Full text of DOI:10.1080/00397911.2017.1363241

Synthetic Communications
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Alkylation of aromatic amines by tert-enamides:
Direct access to protected aminals
Azim Ziyaei Halimehjani, Mehri Goudarzi & Yazdanbakhsh Lotfi Nosood
To cite this article: Azim Ziyaei Halimehjani, Mehri Goudarzi & Yazdanbakhsh Lotfi Nosood
(2017): Alkylation of aromatic amines by tert-enamides: Direct access to protected aminals,
Synthetic Communications, DOI: 10.1080/00397911.2017.1363241
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Date: 11 August 2017, At: 16:35

Alkylation of aromatic amines by tert-enamides: Direct
access to protected aminals
Azim Ziyaei Halimehjani
Faculty of Chemistry, Kharazmi University, Tehran, Iran
Mehri Goudarzi
Faculty of Chemistry, Kharazmi University, Tehran, Iran
Yazdanbakhsh Lotfi Nosood
Faculty of Chemistry, Kharazmi University, Tehran, Iran
Address correspondence to Azim Ziyaei Halimehjani, Faculty of Chemistry, Kharazmi
University, 49 Mofateh St., Tehran, Iran. Tele: +98(21)88848949. Fax: +98(21)88820992. E-
mail: ziyaei@khu.ac.ir
Supplemental data (full experimental details and characterization of title compounds) for this
article can be access on the publisher’s website. <TQ: The publisher’s website will be a live
link.>
ABSTRACT
Reaction of aromatic amines with tertiary enamides was carried out in n-hexane in the
presence of acetic acid as an inexpensive and green catalyst at room temperature. This protocol
provides the protected aminals via Markovnikov addition reaction with high to excellent yields
1

and regiospecificity. In addition, this procedure was expanded for the synthesis of aminals from
commercially available sulfa drugs such as sulfathiazole and sulfabenzamide.
GRAPHICAL ABSTRACT
KEYWORDS: aromatic amines, markovnikov addition, protected aminal, tert-enamide
Introduction
Compounds containing nitrogen atom are of great importance because of their interesting
properties and wide applications in pharmaceutical chemistry. C–N bond construction is of
significant importance as it opens windows for introducing nitrogen atom in organic
molecules.[1–3] Aminals, a category of compounds containing geminal nitrogens, are useful
intermediates in organic chemistry as surrogate of imines and were applied extensively as
efficient electrophiles for nucleophilic addition reactions.[4–8] The reactivity and stability of
aminals tolerates with the substitutions on the nitrogens and the aminal carbon atom. Although
cyclic aminals are stable and observed in the structure of many natural products,[9–12] acyclic
aminals suffer from their instability and difficulties in their production. Usually, electron
withdrawing groups on the nitrogen atoms of aminals increase their stability. Recently, several
interesting methods were reported for the synthesis of acyclic aminals including FeCl3/TBHP
catalyzed sp3C–H amination of amides and lactams with aromatic amines,[13] direct condensation
of aldehydes with amines,[14] amides[15] and lactams[16] in the presence of a catalyst, Brønsted
2

acid-catalyzed imine amidation,[17] and one-pot three-component reaction of aldehydes, aromatic
amines and lactames/amides.[18]
Enamides, as electron-riched alkenes, have been extensively applied as nucleophile in
many organic transformations.[19–21] They were widely applied in Povarov reaction.[22,23] In
addition, their applications in the synthesis of polymers were extensively investigated.[24]
Recently, especial attentions are denoted toward electrophilic properties of enamides using
Lewis or Brønsted-Lowry acid catalysts.[25,26] In the presence of an acid catalyst, enamides
usually protonated to provide the corresponding imminium ions, which are highly reactive
components toward nucleophiles.[27] Recently, reaction of enamides with in situ prepared
dithiocarbamic acids is reported by our group.[28,29] Also, Friedel-Crafts alkylation of indoles and
naphtholes with enamides in the presence of various catalysts is frequently reported by Ji,[30,31]
Hou,[32] and Zhang.[33] Furthermore, direct alkylation of amines with enamides using I2,[34]
[35]
NaHSO4
and triarylaminium salt [tris(4-bromophenyl)-aminium hexachloro-antimonate
+
-
(TBPA •SbCl6 )][36] were reported for the synthesis of aminals. However, synthesis of stable
aminals via a simple and efficient procedure provides a great potential in synthetic organic
chemistry. Here, we report an efficient and facile procedure for the synthesis of aminals from
enamides and amines in the presence of acetic acid in n-hexane (Scheme 1).
Results and discussion
Reaction of aniline 1a with N-vinylpyrrolidone 2a in the presence of acetic acid was
considered as model reaction for the optimization of the reaction conditions. Various polar and
nonpolar solvents were screened and the results are summarized in Table 1. Although good to
high yield of aminal 3aa was obtained in acetonitrile, ethylacetate, methanol, toluene, CH2Cl2
3

and THF, the best yield was obtained in n-hexane (98%) (Table 1). By using water as reaction
medium, high yield of product was obtained (65%). Also, we observed that 1 equiv. of acetic
acid in organic solvents and water gave the highest yield. By increasing or decreasing the amount
of acetic acid in water, lower yields of 3aa were obtained. In addition, we observed that the best
yield was obtained at room temperature.
After optimization of the reaction conditions, the generality of this protocol was
examined using various amines and enamides (Table 2). We observed that aromatic amines
containing an electron-withdrawing group on the phenyl ring afforded quantitative yields. Also,
excellent yield was obtained with aniline. Good to excellent yields were obtained using p-
toluidine and p-anisidine. No aminal was obtained when 1,4-phenylenediamine was applied in
the reaction. In addition, the corresponding aminals were obtained in high yields from p-
aminoacetophenone (Table 2, entries 19 and 20). Highly deactivated 2,4-dinitroaniline was also
applied in this protocol with no result (Table 2, entry 11). Aliphatic amines are not suitable
substrates in this protocol (Table 2, entry 12). Also, thiourea, benzyl carbamodithioate and
guanidine afforded no products (Table 2, entries 13–15). Electron-riched arenes such as 2-
naphthol and phenol do not react with enamides using optimized reaction conditions. In most of
the cases, the pure product was precipitated in the reaction mixture and collected by simple
filtration. Reusing the filtrate afforded the corresponding product, albeit in lower yield (60% for
3ba). Generally, higher yields were obtained for N-vinylcaprolactam in comparison to N-
vinylpyrrolidone. The products were characterized by IR, 1H NMR, 13C NMR and CHN analysis.
After successful derivatization, this protocol was applied for the synthesis of aminals
from sulfa drugs such as sulfabenzamide and sulfathiazole. We observed that the aminals of
sulfabenzamide (4a) and sulfathiazole (4b) were obtained in 79 and 89% isolated yield under
4

optimized reaction conditions, respectively (Scheme 2). Due to the unstability of the aminals in
aqueous medium for prolong times, these protected sulfa drugs may be applied for the
preparation of novel drugs with long time effect on human bodies.
A proposed mechanism for this transformation is depicted in Scheme 3. It is conceivable
that the initial event is the formation of the iminium intermediate A from N-vinyl pyrroilidone
and acetic acid.14 Subsequent nucleophilic attack of the amine to the iminium intermediate
afforded intermediate B which then provided the corresponding aminal after hydrogen transfer.
The higher yields in hexane compared to water and other solvents may be attributed to the higher
stability of the aminals in nonpolar solvents compare to polar protic and aprotic solvents. Also,
the lower yields of the aminals for electron-riched anilines can be attributed to the instability of
the product in the reaction mixture due to the high electron density on the nitrogen atom which
accelerated imine formation by elimination of the pyrrolidone ring.
Conclusion
In conclusion, an efficient procedure for the synthesis of protected aminals from
commercially available amines and tertiary enamides via Markovnikov addition reaction in n-
hexane catalyzed by acetic acid at room temperature is described. This protocol provides the
aminals containing gamma- and epsilon-lactams with high to excellent yields and
regiospecificity. Higher yields were obtained in this protocol compared to previously reported
+
-
methods using molecular iodine, NaHSO4 and TBPA •SbCl6 as catalyst. Also, this procedure
was applied successfully for the synthesis of aminals from commercially available sulfa drugs
such as sulfathiazole and sulfabenzamide. According to the known biological activities of sulfa
drugs and lactams, the presence of these functionalities in a molecule may have synergic effects
5

to provide a new family of compounds with interesting biological activities in pharmaceutical
industry.
Experimental
General procedure for the alkylation of anilines with enamides
To a magnetically stirred solution of enamide (1.2 mmol) and aromatic amines (1 mmol)
in n-hexane (3 mL), was added acetic acid (1 mmol, 0.06 mL). The reaction mixture was stirred
at room temperature for 14 h. Completion of the reaction was monitored by TLC (ethyl
acetate/petroleum ether, 1/3). The products were precipitated in the reaction mixture and
collected by simple filtration. Otherwise, evaporation of the solvent gave the crude product
which was purified by recrystallization in CH2Cl2.
Characterization data for selected compounds
2-(1-(2-oxopyrrolidin-1-yl)ethylamino)benzoic acid (3ea); White solid; m.p. 153–155°C;
1
IR (KBr): ν 3328, 1676, 1632, 1581, 1519, 754 cm ; 1H NMR (300 MHz, CDCl3) δ 1.52 (d, J =
6.4 Hz, 3H), 1.91–1.99 (m, 2H), 2.44–2.50 (m, 2H), 3.17–3.25 (m, 1H), 3.32–3.41 (m, 1H), 5.83
(q, J = 6.5 Hz, 1H), 6.70–6.75 (m, 1H), 6.82 (d, J = 8.5 Hz, 1H), 7.40–7.45 (m, 1H), 7.99–8.04
13
(m, 2H), 11.6 (brs, 1H) ppm; C NMR (75 MHz, CDCl3) δ 17.3, 18.8, 31.2, 40.4, 55.7, 109.3,
112.5, 116.0, 131.9, 135.4, 148.6, 172.4, 174.7 ppm; Anal. Calcd. (%) for C13H16N2O3: C, 62.89;
H, 6.50; N, 11.28; found: C, 62.99; H, 6.38; N, 11.08.
2-(1-(2-oxoazepan-1-yl)ethylamino)benzoic acid (3eb); White solid; m.p. 98–100°C; IR
1
(KBr): ν 2400–3600 (OH), 3317(NH), 1683, 1609, 1579, 760 cm ; 1H NMR (300 MHz, CDCl3)
δ 1.22–1.27 (m, 1H), 1.44 (d, J = 6.3 Hz, 3H), 1.53–1.71 (m, 5H), 2.52–2.64 (m, 2H), 3.19–3.33
6

(m, 2H), 6.23–6.28 (m, 1H), 6.68–6.73 (m, 1H), 6.76 (d, J = 8.5 Hz, 1H), 7.39–7.45 (m, 1H),
13
7.99 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 6.7 Hz, 1H) ppm, -OH not observed; C NMR (75 MHz,
CDCl3) δ 19.6, 23.3, 28.8, 30.0, 37.7, 41.3, 58.1, 109.6, 113.3, 116.3, 132.3, 135.7, 149.2, 172.8,
176.4 ppm; Anal. Calcd. (%) for C15H20N2O3: C, 65.20; H, 7.30; N, 10.14; found: C, 65.40; H,
7.19; N, 9.95.
1-(1-(naphthalen-2-ylamino)ethyl)pyrrolidin-2-one (3na); White solid; m.p. 149–
1
151°C; IR (KBr) ν 3310, 2970, 1652, 1593, 1520, 1480, 810 cm ; 1H NMR (300 MHz, CDCl3)
δ 1.47 (d, J = 6.4 Hz, 3H), 1.79–1.86 (m, 2H), 2.35–2.42 (m, 2H), 3.12–3.19 (m, 1H), 3.26–3.33
(m, 1H), 4.29 (brs, 1H, NH), 5.81–5.85 (m, 1H), 6.89–6.93 (m, 2H), 7.20–7.27 (m, 1H), 7.34–
7.39 (m, 1H), 7.63–7.69 (m, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 17.6, 19.2, 31.6, 40.7, 56.9,
106.1, 117.1, 122.4, 126.2, 126.3, 127.4, 127.7, 128.9, 134.9, 142.5, 174.8 ppm; Anal. Calcd.
(%) for C16H18N2O: C, 75.56; H, 7.13; N, 11.01; found: C, 75.66; H, 7.14; N, 11.20.
N-(4-(1-(2-oxopyrrolidin-1-yl)ethylamino)phenylsulfonyl)benzamide (4a); White solid;
1
1
m.p. 193–196°C; IR (KBr): ν 3363, 1680, 1646, 1599, 825, 713 cm ; H NMR (300 MHz,
DMSO-d6) δ 1.34 (d, J = 6.4 Hz, 3H), 1.84–1.86 (m, 2H), 2.20–2.26 (m, 2H), 3.02–3.08 (m, 1H),
3.27–3.38 (m, 1H), 5.47 (brs, 1H), 6.68 (d, J = 8.9 Hz, 2H), 7.20 (d, J = 7.4 Hz, 1H), 7.43–7.48
(m, 2H), 7.56–7.57 (m, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.82–7.85 (m, 2H)), 12.19 (brs, 1H) ppm;
13C NMR (75MHz, DMSO-d6) δ 17.2, 18.5, 30.9, 40.3, 55.6, 111.5, 125.6, 128.3, 128.5, 129.9,
131.7, 133.0, 150.7, 165.1, 173.7 ppm; Anal. Calcd. (%) for C19H21N3O4S: C, 58.90; H, 5.46; N,
10.85; found: C, 58.72; H, 5.33; N, 10.58.
4-(1-(2-oxopyrrolidin-1-yl)ethylamino)-N-(thiazol-2-yl)benzenesulfonamide
(4b);
1
1
White solid; m.p. 187–188°C; IR (KBr): ν 3351 (NH), 1681 (C = O), 1596, 1568, 931 cm ; H
7

NMR (300 MHz, DMSO-d6) δ 1.32 (d, J = 6.3 Hz, 3H), 1.73–1.87 (m, 2H), 2.19–2.24 (m, 2H),
2.96–3.02 (m, 1H), 3.23–3.32 (m, 1H), 5.43 (brs, 1H), 6.60 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 5.5
Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 4.6 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 12.45 (brs,
1H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 17.3, 18.5, 30.9, 40.2, 55.6, 107.6, 111.6, 124.1,
127.5, 129.6, 149.3, 168.2, 173.6 ppm; Anal. Calcd. (%) for C15H18N4O3S2: C, 49.16; H, 4.95; N,
15.29; found: C, 48.88; H, 4.81; N, 15.05.
Acknowledgment
We thank the Faculty of Chemistry of Kharazmi University for supporting this work.
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9

Table 1. Solvent effect on the Markovnikov addition reaction of aniline to N-vinylpyrrolidone.
Solvent
THF
65
H2O
CH2Cl2
88
Toluene CH3OH
n-
hexane
98
ethylacetate CH3CN
Yield
(%)a,b
65, 49c,
34d
65
78
83
49
aIsolated yield. bReaction condition: aniline (1 mmol), N-vinylpyrrolidone (1.2 mmol), solvent (3mL), acetic acid (1 equiv.), rt
and 14h. c2 equiv. of acetic acid was applied. d0.5 equiv. of acetic acid was used.
10

Table 2. Diversity in the synthesis of aminals from amines and tertiary enamides
Entry
Amine
Enamide
Product
Yield (%)a
1
2
98
2a
2b
3aa
3ab
quant.
3
4
quant.
quant.
2a
2b
3ba
3bb
5
6
7
8
quant.
quant.
47
2a
2b
2a
2b
3ca
3cb
3da
3db
quant.
9
quant.
quant.
2a
2b
3ea
3eb
10
11
12
–
–
NRb
NR
2a
2a
11

13
14
–
–
NR
NR
2a
2a
15
16
–
NR
52
2a
2b
3kb
17
18
quant.
quant.
2a
2b
3la
3lb
19
20
60
75
2a
2b
3ma
3mb
3na
3oa
21
22
53
50
2a
2a
aIsolated yield. bNR: No reaction.
12

Scheme 1. Synthesis of protected aminals from enamides
13

Scheme 2. Synthesis of aminals from sulfa drugs
14

Scheme 3. A tentative mechanism for the synthesis of aminals
15