Synthesis of 1,2-Dihydro-Substituted Aniline Analogues Involving N -Phenyl-3-aza-Cope Rearrangement Using a Metal-Free Catalytic Approach

Article abstract of DOI:10.1155/2020/9139648

An efficient metal-free domino reaction leading to structural/electronically divergent 1,2-dihydropyridines from easily accessible propargyl vinyl anilines via N-phenyl 3-aza-Cope sigmatropic rearrangement is reported with good to excellent yields using 1,2-dichlorobenzene as solvent under thermal conditions. Spirocyclic substitution is also tolerated under the present optimized conditions.

Full text of DOI:10.1155/2020/9139648

Hindawi
Journal of Chemistry
Volume 2020, Article ID 9139648, 8 pages
https://doi.org/10.1155/2020/9139648
Research Article
Synthesisof 1,2-Dihydro-Substituted Aniline Analogues Involving
N-Phenyl-3-aza-Cope Rearrangement Using a Metal-Free
Catalytic Approach
Osamah Alduhaish,1 Ravi Varala ,2 Syed Farooq Adil ,1 Mujeeb Khan,1
Mohammed Rafiq H. Siddiqui ,1 Abdulrhman AlWarthan,1 and M. Mujahid Alam3
1Department of Chemistry, King Saud University, Riyadh 11451, Saudi Arabia
2Scrips Pharma, Mallapur, Hyderabad 500 076, Telangana, India
3Department of Chemistry, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
Correspondence should be addressed to Ravi Varala; varalaravirnd@gmail.com and Syed Farooq Adil; sfadil@ksu.edu.sa
Received 11 June 2020; Accepted 11 August 2020; Published 31 August 2020
Academic Editor: Naoki Toyooka
Copyright © 2020 Osamah Alduhaish et al. *is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
An efficient metal-free domino reaction leading to structural/electronically divergent 1,2-dihydropyridines from easily accessible
propargyl vinyl anilines via N-phenyl 3-aza-Cope sigmatropic rearrangement is reported with good to excellent yields using 1,2-
dichlorobenzene as solvent under thermal conditions. Spirocyclic substitution is also tolerated under the present
optimized conditions.
phosphate (Tamiflu), is also synthesized from 1,2-DHP via
an isoquinuclidine intermediate [5] (Figure 2).
1. Introduction
Dihydropyridine (DHP) is amongst the most attractive
molecules that have gained the attention of pharmaceutical
researchers due to its promising biological efficiency mainly
against hypertension and angina [1]. A variety of DHPs such
as amlodipine and nifedipine are presently in the market as
potent antihypertensive drugs. Literature reports on the
synthesis of easily accessible 1,2- and 1,4-dihydropyridine
intermediates, which have led to a copious library of bio-
logical active drug molecules and natural product com-
pounds including alkaloids [2].
Considerable efforts have been directed toward the
development of new and efficient methodologies for the
synthesis of 1,2-dihydropyridines since the first synthesis
started by Fowler [6]. 1,2-DHPs are prepared by hydroge-
nation involving the redox cycloisomerization approach [7]
and via 6π-azaelectrocyclization [8]. More pioneering work
particularly in this field is carried out by Tejedor et al. using
microwave-assisted domino reaction of a propargyl vinyl
ether (secondary or tertiary) and a primary amine (aliphatic
or aromatic) in toluene or methanol [9–11].
*e search for new feasible synthetic approaches for the
preparation of the derivatives of azaheterocycles, particu-
larly, 1,2-dihydropyridines (1,2-DHPs), is an important
study as these compounds can exhibit diverse biological
activities such as follows [3, 4]: 1,2-DHPs act as starting
materials for the synthesis of the 2-azabicyclo[2.2.2]octanes
(isoquinuclidines) ring system present in various alkaloids
such as ibogaine, dioscorine, and catharanthine (vinca al-
kaloids) (Figure 1). *e anti-influenza drug, oseltamivir
Harschneck and Kirsch have exploited transition metal
catalysts such as AuCl3 for preparation of 1,2-DHPs,
wherein propargyl vinyl ethers and amines were used as
starting materials [12, 13]. In another study, a four-com-
ponent synthetic approach was employed to prepare de-
rivatives of 1,2-DHPs [14] through
a
one-pot
multicomponent reaction of acetophenone, aldehyde, and
ammonium acetate with ethyl cyanoacetate or malononi-
trile, respectively. Besides these several other transition

2
Journal of Chemistry
R1
N
R
(a)
CH3
N
N
N
H3CO
O
N
H
N
H
CO2CH3
O
(b)
(c)
(d)
Figure 1: Natural product alkaloids isoquinuclidines (a), ibogaine (b), dioscorine (c), and catharanthine (vinca alkaloids) (d).
CO2Et
R1
N
Dienophile
·H3PO4
NH2
NHCH2OCH3
R2
R2
Diels–alder
O
N
R1
Reaction
(e)
Oseltamivir (Tamiflu)
Figure 2: Structures of some medicinally important compounds/cores accessible from 1,2-DHPs.
metals have also been utilized as catalysts, for example, Rh
[15], Cu/Mo [16], and low-valent Co complexes [17] for the
synthesis of 1,2-DHPs via C-H activation/6π-electro-
cyclization pathways. Furthermore, various other metal
complexes have also been evaluated, including Pt (II)-cat-
alyzed cycloisomerization of aziridinyl propargylic esters
[18], Sc(OTf)3-catalyzed imino-Aldol reactions using
vinyloxiranes as masked dienolates [19], BF3.Et2O-catalyzed
rearrangement with good to excellent yields using 1,2-
dichlorobenzene as solvent.
2. Materials and Methods
General melting points were determined on a Reichert
*ermovar apparatus and are uncorrected. *in-layer
chromatography was performed on Merck silica gel 60
F254 0.2 mm thick plates and visualized under UV light
or by exposing to iodine vapour. For preparative sepa-
ration, the plates were 0.51 mm thick. For flash chro-
matography silica Merck Kieselgel, 60 and 70–230 mesh
were used. Infrared (IR) spectra were recorded on a
6π-electrocyclization
of
enaminonitriles
with
α,β-unsaturated aldehydes [20], and N-amino-3-aza-Cope
rearrangements [21, 22]. Additionally, various other ex-
amples of the synthesis of 1,2-dihydropyridines have been
comprehensively compiled by Silva et al. in a recent review
[4]. Notably, most of the preparation methods of 1,2-
dihydropyridines are based on nucleophilic addition to N-
alkyl or N-acylpyridinium salts which often yield undesir-
able side products [23]; hence, to overcome these limitations,
various alternative reaction strategies have been designed
[24]. In most of the already reported methodologies, use of
expensive metal catalysts or harsh reaction condition
stimulates the need for further improvement in the synthesis
of 1,2-DHPs.
In this regard, sigmatropic rearrangement reactions
can be an advantageous alternative approach for the
synthesis of 1,2-dihydropyridines. *ese types of reac-
tions constitute fascinating chemical bond reorganiza-
tions reactions, which have been extensively used in
organic synthesis [25]. Herein, we present our prelimi-
nary results pertaining to an efficient domino reaction,
which led to the formation of electronically divergent 1,2-
DHPs from easily accessible propargyl vinyl anilines
involving a metal-free N-phenyl 3-aza-Cope sigmatropic
Perkin–Elmer 1000X FT-IR spectrometer. Proton and 13
C
NMR spectra were recorded in CDCl3 on a Bruker ARX
400 spectrometer (400 MHz for 1H, 100.63 MHz for 13C).
Chemical shifts are reported relative to tetramethylsilane
as the internal reference. Mass spectra were recorded on
Fisons TRIO 2000 or AEI MS-9 spectrometer. High-
resolution MS spectra (HRMS) were obtained on a FT-
ICR/MS Finnigan FT/MS 2001-DT spectrometer at 70 eV
by electron impact or on a Finnigan MAT 900 ST
spectrometer by ESI. Elemental analysis was performed in
Hewlett-Packard, model 185 (United States) (HP). Mi-
crowave reactions were conducted in sealed glass vessels
(capacity 10 mL) using a CEM Discover microwave re-
actor equipped with a surface sensor to measure the
temperature of the reaction mixture.
Usual workup implies drying the water- or brine-washed
organic extracts over anhydrous sodium sulfate or magne-
sium sulfate, followed by filtration and solvent removal

Journal of Chemistry
3
under reduced pressure. Anhydrous solvents were dried and
freshly distilled by standard methods [26].
1.0 equiv., and refluxed for 16 h (Scheme 1). *e crude
reaction mixture is purified by neutral alumina employing 1 :
1 ether: n-hexane as eluent and separated the desired
fraction D in 85% yield (81 mg) as a white solid.
2.1. Synthesis of Starting Materials (Typical Model Reaction-
Schemes 1 and 2)
2.1.6. Spectral Data for Compound D. Mp 109-110oC (Et2O).
IR (NaCl; cm−1): 3252 (C≡C-H), 3064, 2988, 2939, 2114
(C≡C), 1607 (C�C), 1586, 1493, 1369, 1296 (SO2), 1158
(SO2), 1135 (SO2), 1082, 854, 814, 695, 659. 1H NMR
(CDCl3; 400 MHz): δ 1.52 (6H, s, NC(CH3)2C≡CH), 2.37
(3H, s, Ar-CH3), 2.60 (1H, s, NC(CH3)2C≡CH), 4.51 (1H, d,
J � 12.6 Hz, NCH�CHTs), 7.11 (2H, d, J � 6.8 Hz, Ar-H), 7.21
(2H, d, J � 8.1 Hz, Ar-H), 7.34–7.40 (3H, m, Ar-H); 7.65 (2H,
d, J � 8.2 Hz, Ar-H); 8.17 (1H, d, J � 12.6 Hz, NCH�CHTs).
13C NMR (CDCl3, 100 MHz): δ 21.4 (Ar-CH3), 30.1
2.1.1. 1,1-Dimethylpropargyl Acetate (B). To a stirred solu-
tion of compound a (5 ml, 51.28 mmol, 1 equiv.) in dry DCM
(40 ml), triethyl amine (7.67 ml, 1.08 equiv.), acetic anhy-
dride (6.0 ml, 1.15 equiv.), and DMAP (325 mg, 5 mol%) are
added sequentially at room temperature and stirred over-
night (Scheme 1). After being monitored by TLC, the re-
action mixture is diluted with saturated NH4Cl solution.
Aqueous phase of the reaction mixture is extracted with
DCM (2×25 ml). Organic phase obtained is washed with
1 ml HCl twice and concentrated using vacuum, which gives
the crude compound, which is further purified by flash
column chromatography using diethyl ether: n-hexane (1 : 3)
to afford b in 91% isolated yield (5.87 g).
(NC(CH3)2C≡CH),
(NC(CH3)2C≡CH),
56.3
85.9
(NC(CH3)2C≡CH),
(NC(CH3)2C≡CH),
73.5
98.5
(NCH�CHTs), 126.3 (Ar-C), 128.6 (Ar-C), 129.3 (Ar-C),
129.6 (Ar-C), 129.7 (Ar-C), 139.3 (Ar-C), 141.5 (Ar-C),
142.2 (Ar-C), 147.8 (NCH�CHTs). m/z (EI): 324
(C19H18NO2S+, 5); 260 (45); 184 (C13H14N, 30); 110 (70); 77
(C6H5+, 100). Elemental analysis for C20H21NO2S : Calcd. C,
70.77; H, 6.24; N, 4.13; S, 9.45; found C, 70.44; H, 6.40; N,
4.04; S, 9.28.
2.1.2. Spectral Data for Compound B. Light yellow oil. IR
(NaCl): ] 3288 (C≡C-H); 2991, 2165 (C≡C), 1746 (C�O),
1
1367, 1247, 1136, 1016, 966, 844 Cm−1. H NMR (CDCl3;
400 MHz): δ 1.61 (6H, s, C(CH3)2C≡CH), 1.97 (3H, s,
CO2CH3), 2.49 (1H, s, C(CH3)2C≡CH). 13C NMR (CDCl3;
100 MHz): δ 21.7 (CO2CH3), 28.7 (C(CH3)2C≡CH), 71.4
(C(CH3)2C≡CH),
72.1
(C(CH3)2C≡CH),
84.6
(C(CH3)2C≡CH), 169.2 (CO2CH3)
2.1.7. N-Phenyl-2,2-dimethyl-5-tosyl-1,2-dihydropyridine (F).
Compound D (100 mg) is dissolved in 1,2-dichor-
obenzene (2 mL) and heated at 180°C, for 20 min, while
monitoring the reaction progress by TLC (Scheme 2).
After the starting material is almost completely con-
sumed, the crude reaction mixture is subjected to direct
flash chromatography using n -hexane as the first eluent
to remove the solvent; i.e., 1,2-DCB and then 10% ethyl
acetate : n-hexane solution is utilized as eluent to obtain
the desired compound F as colourless oil in 95% isolated
yield (95 mg).
2.1.3.
N-(1,1-Dimethylpropargyl)-aniline
(C). Aniline
(0.657 ml, 7.21 mmol, 1 equiv.) is slowly added to a stirred
solution of b (1 g, 7.93 mmol, 1.1 equiv.), CuCl (70 mg, 0.1
equiv.), and triethyl amine (1.12 ml, 1.1 equiv.) dissolved in
THF (10 ml) at room temperature (Scheme 1). *en, the
reaction mixture is refluxed for 90 min, while monitoring the
reaction mixture for the complete consumption of starting
material, and the reaction mixture is then concentrated and
then dissolved in EtOAc (10 ml). *en, the reaction mixture
is treated with saturated NH4Cl solution (10 mL) twice
followed by brine solution (10 ml). *e organic layer is then
concentrated under reduced pressure to give crude residue,
which is then subjected to flash column chromatography
using gradient elution system starting from n-hexane to 1 : 5
of ethyl acetate: n-hexane, to afford desired product c in 71%
isolated yield (0.83 g).
2.1.8. Spectral Data for Compound F. IR (NaCl; cm−1) 3060,
2972, 2924, 1630 (C�C), 1564, 1492, 1366, 1295 (SO2),
1
1150 (SO2), 1132 (SO2), 1104, 1071, 805, 706, 676. H
NMR
(CDCl3;
400 MHz):
δ
1.26
(6H,
s,
C(CH3)2CH � CH), 2.40 (3H, s, Ar-CH3), 4.95 (1H, d,
J � 9,8 Hz,
C(CH3)2CH � CH),
6.09 (1H, dd,
J � 9.8 Hz + J � 1, 4 Hz, C(CH3)2CH � CH), 7.22–7.24
(2H + 1H, m, Ar-H + NCH�CTs), 7.27 (2H, d, J � 8.1 Hz,
Ar-H), 7.33–7.41 (3H, m, Ar-H), 7.73 (2H, d, J � 8.1 Hz,
Ar-H). 13C NMR (CDCl3; 100 MHz): δ 21.5 (Ar-CH3),
29.0 (C(CH3)2CH � CH), 58.8 (C(CH3)2CH � CH), 107.6
°
2.1.4. Spectral Data for Compound C. Mp 35-36 C (ethyl
acetate). IR (NaCl; cm−1): 3402 (N-H); 3290 (C≡C-H), 3052,
2979, 2933, 2156 (C≡C), 1601, 1503, 1382, 1316, 1258, 1212,
1181, 843, 750, 694. 1H NMR (CDCl3; 400 MHz): δ 1.64 (6H,
s, NC(CH3)2C≡CH), 2.40 (1H, s, NC(CH3)2C≡CH), 3.59
(1H, sl, NH), 6.83 (1H, t, J � 7.4 Hz, Ar-H), 6.97 (2H, d,
J � 7.4 Hz, Ar-H), 7.23 (2H, t, J � 7.4 Hz, Ar-H).
(NCH�CTs),
117.6
(C(CH3)2CH � CH),
122.1
(C(CH3)2CH � CH), 126.5 (Ar-C), 128.1 (Ar-C), 129.0
(Ar-C), 129.1 (Ar-C), 129.5 (Ar-C), 140.7 (Ar-C), 142.5
(Ar-C), 142.5 (Ar-C), 144.0 (NCH�CTs). m/z (EI): 339
(M+, 25); 323 (C19H19NO2S+, 100); 168 (25); 154 (38); 91
(C7H7+, 14); 77 (C6H5+, 25). HRMS : Calcd. for
C20H21NO2S (M+): 339.129301; found: 339.129909.
2.1.5. (E)-N-(1,1-Dimethylpropargyl)-N-(enamino)-aniline
(D). To a stirred solution of compound C (45 mg, 1 equiv.)
in methanol (3 mL) is added ethynyl p-tolyl sulfone, 50 mg,

4
Journal of Chemistry
Et3N, Ac2O
DMAP, DCM (dry)
Ph-NH2
CuCl, Et3N, THF (dry)
RT, overnight
reflux, overnight
OH
HN
Ph
OAc
a
b
c
MeOH
reflux, 16h
Ts
C
Ph
N
N
Ph
Ts
e(0%)
Ts
d
Scheme 1: Synthesis of easily accessible N-propargyl vinyl anilines: (E)-N-(1,1-dimethylpropargyl)-N-vinyl-aniline as model reaction.
1, 2-Dichlorobenzene
N Ph
d
N
f
180°C, argon
Ts
Ts
Scheme 2: Metal-free propargyl aza-Cope rearrangement.
to a heteroatom (enamine) [29]. Furthermore, bands at
3. Results and Discussion
1296 cm−1, 1158 cm−1, and 1135 cm−1 corresponding to
the SO2 bonds of the tosyl group were also observed. In
the 1H NMR spectra of compound D, doublets were
displayed at δ 8.17 (d, J � 12.6 Hz, 1H) and 4.51 (d,
J � 12.6 Hz, 1H), confirming the enamine in conjugation
with trans-configuration. Both signals are characteristic
of the tosyl group. 13C NMR spectrum of D shows
characteristic peaks at δ 98.5 and 147.8, respectively,
corresponding to the double bond of enamine. Elemental
analysis of this compound further supported the pro-
posed structure D.
2-Methyl-3-butyn-2-ol (a) (dimethyl ethynyl carbinol) is
acylated using 1.1 equiv, of acetic anhydride, 1.1 equiv. of
triethyl amine, and 0.05 equiv. of DMAP in dry DCM at
ambient temperature for overnight, as shown in Scheme 1,
followed by routine workup to give 1,1-dimethylpropargyl
acetate (b) in almost quantitative yield (91%) [18, 27].
Further compound B is made to react with aniline to
yield N-(1,1-dimethylpropargyl)-aniline (c) in 71% iso-
lated yield using Imada’s protocol [28]. *e alkylation
product (c) is then made to react with one of the Michael
acceptors, ethynyl p-tolyl sulfone in methanol under
reflux conditions to yield corresponding (e)-N-(1,1-
dimethylpropargyl)-N-(enamino)-aniline (d) in 85%
yield. Interestingly, the addition reaction selectively
produces trans-enamine (d). No formation of allene (e) is
observed.
(E)-N-(1,1-Dimethylpropargyl)-N-(enamino)-aniline
(d) is refluxed in 0.1 M 1,2-dichlorobenzene (1,2-DCB)
under argon atmosphere at 180°C, and the progress of the
reaction was monitored by TLC, IR, and NMR at regular
intervals. Surprisingly, the expected rearranged product
(f) is obtained in 30 min, with an excellent yield of 95%.
Spectroscopic analysis confirmed the formation of final
product F, which is established by the disappearance of
alkynic group at 3252 cm−1 in FT-IR spectrum. Fur-
All the compounds obtained were subjected to
spectroscopic analysis. *e FT-IR of compound D
showed an absorption band of approximately 1607 cm−1,
indicating that the product has a double bond conjugated
1
thermore, the H NMR spectra of compound F yields a

Journal of Chemistry
5
R4
R4
R1
R1
1, 2-Dichlorobenzene
180°C, argon
R2
N
R2
EWG (R3)
N
R
R
EWG (R)3
(d)
(a)
R4
R4
R2
R1
R1
N
N
R2
EWG (R3)
R
R
C
EWG (R3)
H
(b)
(c)
Scheme 3: Proposed mechanism for the formation of 1,2-DHPs.
Table 1: Effect of various solvents for the synthesis of 1,2-DHP (f).
Solvent
Toluene
Condition
Time (m)
Isolated yield (%)
Inference
111°C
180 min
30 min
10 min
180 min
30 min
2 days
32
95
0
42
54
0
—
1, 2-Dichlorobenzene (1,2-DCB)
Benzene
Diphenyl ether
Chlorobenzene
Xylene
Microwave (1,2-DCB)
DMF
∗Optimized as best suitable solvent under conventional conditions.
180°C
Optimized∗
No reaction
—
80°C
265°C
140°C
—
140°C
No reaction
150 W, 120°C
30 min
120 min
78
—
Yield is less than conventional reflux
Complex mixture
155°C
doublet at δ 6.09 (dd, J � 9.8 and 1.4 Hz, 1H) and 4.95 (d,
J � 9.8 Hz, 1H), which confirms the complete electro-
cyclization. 13C NMR further confirms the formation of
the product, as propargylic peaks at δ 85.9 and δ 73.5
disappeared and new peaks at δ 117.6 and δ 122.1
appeared, representing the formation of double bond.
HRMS data further confirmed the formation of the de-
sired product F.
We propose a mechanism pathway for the above aza-
Cope rearrangement, as shown in Scheme 3, which is
quiet similar to the one reported previously [30]. In brief,
when compound (a) is heated to 180°C, it undergoes a
[3, 3]-sigmatropic rearrangement yielding the allene (b).
*is is followed by proton migration, which isomerizes to
triene (c) which through intramolecular electro-
cyclization gives the final reaction product 1,2-dihy-
dropyridine (d). However, further studies along with
experimental and spectroscopic studies must be carried
out to authenticate the claim.
Different solvents were tested for optimization, and it
was found that, among the various solvents investigated, 1,2-
DCB is the best solvent (see Table 1).
From the studies carried out, it is concluded that
conventional heating yields better results compared to
the same reaction performed employing microwave ir-
radiation under the mentioned parameters (entries 2 and
7, Table 1).
Inspired by the successful formation of F (Scheme 2), the
study is extended with electronically divergent anilines,
substituted propargyl acetates, and other Michael acceptors
such as ethynyl p-tolyl sulfone (a), methyl propargylate (b),
and dimethyl acetylene dicarboxylate (c) to synthesize
corresponding 1,2-DHPs (Table 2). *e study is extended by
utilizing five types of propargyl acetates and reacted with
electronically divergent anilines to form corresponding
propargyl vinyl amines, which in turn were subjected to the
aza-Cope sigmatropic rearrangement, yielding the corre-
sponding 1,2-DHPs.
Among the three Michael acceptors utilized in this
methodology, the addition reaction employing dimethyl
acetylene dicarboxylate (entries 11 and 12, see Table 2)
yields the lowest product. *is can be attributed to the
deactivation of the acceptor due to the presence of two
electron withdrawing groups in opposite positions,
causing a reduction in the electrophilicity of triple bond
as compared to the triple bond of the remaining acceptors
employed. Furthermore, under the optimized conditions,
cyclopentyl propargyl vinyl aniline or cyclohexyl prop-
argyl vinyl aniline also undergo aza-Cope sigmatropic
rearrangement; however, the yield is less compared to the
open chain propargyl vinyl anilines (entries 4 and 5,
Table 2). *is protocol is unsuccessful with an aniline
having electron-withdrawing group, such as NO2.
However, when propargyl acetate or 1-methyl propargyl

6
Journal of Chemistry
Table 2: Scope of the annulation reaction of N-propargyl vinyl anilines.
Entry
Propargyl acetate
Aniline
Michael acceptorsa
Propargyl vinyl amine
1,2-Dihydropyridine
Yield (%)b
95
Ts
N
1
Aniline
a
N
Ts
OAc
OCH
N
3
Ts
2
3
p-Anisidine
a
a
H CO
88
76
N
3
Ts
Br
Ts
4-Bromo aniline
Br
N
N
Ts
OCH
3
CO CH
2
3
OAc
N
H CO
4
5
p-Anisidine
p-Anisidine
b
b
3
48
56
N
CO CH
2
3
OCH
3
CO CH
2
3
N
H CO
3
N
OAc
CO CH
2
3
Ts
6
Aniline
p-Anisidine
Aniline
a
b
b
b
b
81
85
70
84
92
N
N
OAc
Ts
OCH
N
3
CO CH
2
3
H CO
3
N
Ph
Ph
7
OAc
Ph
Ph
Ph
Ph
CO CH
2
3
CO CH
2
3
8
N
N
OAc
CO CH
2
3
OCH
N
3
CO CH
2
3
9
p-Anisidine
Aniline
H CO
3
N
OAc
CO CH
2
3
CO CH
2
3
N
10
N
OAc
CO CH
2
3
H CO C
CO CH
2
3
2
3
N
CO CH
11
12
Aniline
Aniline
c
c
68
61
2
3
N
OAc
CO CH
2
3
H CO C
CO CH
2 3
3
2
N
CO CH
2
N
3
OAc
CO CH
2
3
CO CH
H CO C
CO CH
2 3
Ts
2
3
3
2
a,
; b,
; c,
; isolated yields by column chromatography.
acetate are used as precursors, the rearranged product
obtained is pyridines instead of desired 1,2-
dihydropyridines.
Observation of 13C NMR spectra shows the proximity
of all these signals presents very similar chemical devi-
ations. In the case of the proposed structures, it is possible

Journal of Chemistry
7
to draw a plane of symmetry passing along the dihy-
dropyridine ring, and that due to the planarity of all the
different functional groups, all obtained molecules extend
beyond this ring [30].
plates were 0.51 mm thick. For flash chromatography silica
Merck Kieselgel, 60 and 70–230 mesh were used. Infrared
(IR) spectra were recorded on a Perkin–Elmer 1000X FT-IR
spectrometer. Proton and 13 C NMR spectra were recorded
in CDCl3 on a Bruker ARX 400 spectrometer (400 MHz for
1H, 100.63 MHz for 13C). Chemical shifts are reported
relative to tetramethylsilane as the internal reference (δ H
0.00) for 1H NMR spectra and to CDCl3 (δ C 77.00) for 13C
NMR spectra. Ordinary mass spectra were recorded on
Fisons TRIO 2000 or AEI MS-9 spectrometer. High-reso-
lution MS spectra (HRMS) were obtained on a FT-ICR/MS
Finnigan FT/MS 2001-DTspectrometer at 70 eV by electron
impact or on a Finnigan MAT 900 ST spectrometer by ESI.
Elemental analysis was performed in Hewlett-Packard,
model 185 (United States) (HP). Microwave reactions were
conducted in sealed glass vessels (capacity 10 mL) using a
CEM Discover microwave reactor equipped with a surface
sensor to measure the temperature of the reaction mixture.
(Supplementary Materials)
4. Conclusions
In this study, we have successfully demonstrated the synthesis of
various substituted 1,2-dihydropyridines from electronically
divergent N-propargyl vinyl anilines, using metal-free aza-Cope
rearrangement. *is improved version delivers these important
heterocyclic scaffolds with a wider diversity at the ring, along
with mono- and disubstitution at the sp3 position. Spiro-
substituted 1,2-DHPs are also obtained under this reaction
conditions albeit in lesser yields. *e protocol can be extended
to secondary and tertiary propargyl vinyl ethers bearing internal
or terminal alkyne moieties and primary aromatic amines.
Extension of this protocol to aliphatic amines and other Michael
acceptors is also currently underway.
Data Availability
References
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information. Further data will be available on request to the
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