Ring opening/C-N cyclization of activated aziridines with carbon nucleophiles: Highly diastereo- and enantioselective synthesis of tetrahydroquinolines

Article abstract of DOI:10.1021/ol2016077

A simple strategy for the synthesis of substituted tetrahydroquinolines through regio- and stereoselective ring opening of N-tosyl aziridines with carbon nucleophiles generated from 2-(bromoaryl)acetonitriles followed by palladium-catalyzed intramolecular

Full text of DOI:10.1021/ol2016077

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4256–4259
Ring Opening/CÀN Cyclization of
Activated Aziridines with Carbon
Nucleophiles: Highly Diastereo- and
Enantioselective Synthesis of
Tetrahydroquinolines
Manas K. Ghorai,* Y. Nanaji, and A. K. Yadav
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
mkghorai@iitk.ac.in
Received June 15, 2011
ABSTRACT
A simple strategy for the synthesis of substituted tetrahydroquinolines through regio- and stereoselective ring opening of N-tosyl aziridines with
carbon nucleophiles generated from 2-(bromoaryl)acetonitriles followed by palladium-catalyzed intramolecular CÀN cyclization is reported in
excellent yields (up to >99%) and stereoselectivity (ee and de up to >99%).
Tetrahydroquinolinesand their derivativesareprevalent
in a number of naturally occurring and biologically active
compounds. Some of the important natural products con-
taining a tetrahydroquinoline ring system are Sumanirole
maleate (PNU95666E) 1,1a Angustureine 2a,1b Galipinine
2b,1c Cuspareine 2c,1d (S)-flumequine 31e (Figure 1), Dis-
corhabdin C,1f Dynemycin A,1g and Virantmycin.1h Several
of them have been found to exhibit a wide range of phar-
macological acitivities such as analgesic, antiarrhythmic,
cardiovascular, immunosuppresent, antitumor, antiallergenic,
anticonvulsant, antifertility, NMDA antagonist activities,
etc.2,3 Pyrrolo[3,2,l-ij]quinoline derivatives 4 are the basic
skeleton of compounds possessing 5-lipoxygenase inhibitor
properties and used for the treatment of asthma (Figure 1).4
Tetrahydroquinoline based inhibitors are also shown as one
of the most potent protein farnesyltransferase inhibitors.5
(1) (a) Heier, R. F.; Dolak, L. A.; Duncan, J. N.; Hyslop, D. K.;
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r
10.1021/ol2016077
Published on Web 07/18/2011
2011 American Chemical Society

Weanticipated thattetrahydroquinolinescouldeasilybe
synthesized from the ring opening of N-tosyl aziridines by
C-nucleophiles generated from bromoarylacetonitriles fol-
lowed by Pd-catalyzed intramolecular CÀN cyclization.
Several reports are known for the ring opening of azir-
idines with heteroatoms;13 yet, ring opening of aziridines
with C-nucleophiles is still limited.14,15
Recently, we have reported the Lewis acid (LA)
mediated SN2-type ring opening of enantiopure 2-aryl-N-
tosylaziridines and azetidines by a number of nucleophiles
to provide nonracemic products in high enantiomeric
excess.16 In continuation of our research in this area, we
have developed a simple strategy for the synthesis of
tetrahydroquinolines with excellent yields (up to 99%)
and stereoselectivity (ee and de up to >99%) via the regio-
and stereoselective ring opening of aziridines by C-nucleo-
philes generated from 2-bromoarylacetonitriles followed
by Pd-catalyzed intramolecular CÀN cyclization. Herein,
we report our preliminary results.
Figure 1. Some biologically active tetrahydroquinolines.
Immense synthetic and pharmacological utilities of such
tetrahydroquinolines have inspired synthetic organic and
medicinal chemists to develop new strategies for their
syntheses. A number of methodologies have been developed
for this purpose2,6,7 including synthesis from either aniline
precursors using electrophilic aromatic substitution,8 Aza
DielsÀAlder reaction,9 or nucleophilic displacement10 or
reduction of a quinolone precursor.11 Palladium-catalyzed
amination reactions allow for facile construction of CarylÀN
bonds to form both activated and nonactivated aryl
halogenides.12
Our study began with the ring opening of 2-phenyl-N-
tosylaziridine 5a with a C-nucleophile generated from
2-bromo-3,4-dimethoxyphenylacetonitrile6abytreatment
t
of BuOK as the base in THF at 0 °C to afford the
corresponding ring opening product 7a (Scheme 1). Other
bases were studied; yet the best results (yield and reaction
time) wereobtainedusingtBuOK (Scheme1;see TableS1).
Product 7a was characterized by 1H, 13C NMR and mass
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Org. Lett., Vol. 13, No. 16, 2011
4257

Scheme 1. Regioselective Ring Opening of 6a with Carbon
Nucleophile of 2-Bromo-3,4-dimethoxyphenylacetonitrile
Scheme 3. Synthesis of Tetrahydroquinolines 8aÀi
spectral data. Next, 7a was subjected to Pd-catalyzed
cyclization to obtain tetrahydroquinoline 8a (Scheme 2).
To find the optimum reaction conditions, 7a was subjected
to different Pd-catalysts, solvents, ligands, and a number
of bases. These optimization results are summarized in
Table 1 (Scheme 2). The best result was obtained with
Pd(OAc)2, (()-BINAP, and K2CO3 as the base in toluene
at 110À115 °C (Table 1, entry 8), and this condition was
employed for further studies as the optimum reaction
Table 2. Regioselective Ring Opening of 6 and Pd-Catalyzed
Intramolecular CÀN Cyclization of 7aÀia
7
time
8
entry
5 (Ar)
5a (Ph)
6 (R1 = R2) yield (%)b,c (h) yield (%)b
1
2
3
4
5
6
7
8
9
6a (OMe)
7a, >99
7b, 99
7c, 99
10
12
6
8a, 83
8b, 90
8c, 86
8d, 98
8e, 95
8f, 86
8g, 91
8h, 87
8i, 94
conditions. 8a was characterized by H, 13C NMR, H
COSY, and mass spectral data. The structure of 8a was
unequivocally confirmed by X-ray crystallographic analy-
sis. In some cases, we also observed the formation of
quinoline 9a (Scheme 2, Table 1), and its structure was
1
1
5b (4-ClC6H4) 6a (OMe)
5c (t-BuC6H4) 6a (OMe)
5a (Ph)
6b (H)
7d, >99
7e, >99
7f, >99
7g, 99
7h, 99
7i, 99
5
5b (4-ClC6H4) 6b (H)
5c (t-BuC6H4) 6b (H)
5
10
5
5a (Ph)
6c (OCH2O)
1
confirmed by H, 13C NMR and mass spectral data. To
5b (4-ClC6H4) 6c (OCH2O)
5c (t-BuC6H4) 6c (OCH2O)
5
5
generalize this approach, several N-[3-(2-bromoaryl)-3-
cyano-2-arylpropyl]-4-methylbenzene sulfonamides 7aÀi
were prepared from aziridines 5aÀc and nitriles 6aÀc.
Compounds 7aÀi were cyclized under optimized conditions
a All reactions were carried out with 7aÀi (1.0 mmol), Pd(OAc)2
(20 mol %), (()BINAP (40 mmol %), K2CO3 (2.5 equiv) in toluene
(8 mL) under argon for 4À10 h under refluxed at 110À115 °C. b Yields of
isolated products (%), c de >99% in all the cases.
to afford the corresponding tetrahydroquinolines 8aÀi in
excellent yields (Scheme 3, Table 2). The strategy was
extended further for the synthesis of cyclopenta- and
cyclohexa-fused tetrahydroquinolines 12aÀf via the ring
opening of bicyclic aziridines 10aÀb. Aziridines 10aÀb
were reacted with different arylacetonitriles 6aÀc in the
Scheme 2. Pd-Catalyzed CÀN Cyclization of 7a
t
presence of BuOK in THF at 0 °C to afford the corre-
sponding ring-opening products 11aÀf in almost quanti-
tative yields. 11aÀf were cyclized under optimized
conditions to afford the corresponding fused tetrahydro-
quinolines 12aÀf in excellent yields (Scheme 4, Table 3).
After the successful demonstration of our strategy for the
synthesis of a variety of racemic tetrahydroquinolines8aÀi
and 12aÀf via the ring opening of racemic aziridines, the
scope of the methodology was extended to the synthesis of
nonracemic tetrahydroquinolines 15aÀe. Chiral N-tosyla-
ziridines (S)-13a and (2S,3S)-13bÀc (ee/de > 99%) were
Table 1. Pd-Catalyzed Intramolecular CÀN Cyclization of 7a
8a
9a
yield yield
entry
1b Pd(PPh3)4, K2CO3, toluene, 12 h
reaction conditionsa
(%)c
(%)c
À
À
À
À
62
58
61
57
2
Pd(PPh3)4, K2CO3, CH3CN, reflux, 12 h
3b Pd(OAc)2, Xantphos, K2CO3, toluene, 10 h
4
Pd(OAc)2, (o-tolyl)3P, K2CO3, DMF,
120 °C, 10 h
5
6
7
Pd(OAc)2, PPh3, K2CO3, toluene, reflux, 8 h
Pd(OAc)2, dppb, toluene, K2CO3, reflux, 8 h
Pd(OAc)2, dpp, toluene, K2CO3, reflux, 8 h
À
66
12
10
À
58
56
99
62
Scheme 4. Synthesis of Cyclopenta[b]- and Cyclohexa[b]-Fused
Tetrahydroquinolines 12aÀf
8b Pd(OAc)2, (()-BINAP, K2CO3, toluene, 8 h
9b Pd(OAc)2, (()-BINAP, Cs2CO3, toluene, 3 h
10 Pd(OAc)2, dppb, toluene, t-BuOK, reflux, 8 h 60
À
11
a All reactions were carried out with 7a (1.0 mmol), Pd-catalyst
(20 mol %), ligand (40 mmol %), base (2.5 equiv) in solvent (8 mL)
under argon. b These reactions were reflexed at 110À115 °C for 3À12 h.
c Yields of isolated products (%).
4258
Org. Lett., Vol. 13, No. 16, 2011

Table 3. Synthesis of Cyclopenta[b]- and Cyclohexa[b]-Fused
Tetrahydroquinolines 12aÀfa
Table 4. One-Pot Ring Opening CÀN Cyclization of Activated
Aziridines with Carbon Nucleophilesa
11
time
12
yield (%)b
time
(h)
yield
(%)b
de
(%)c
entry
10 (n)
6 (R1 = R2)
yield (%)b
(h)
entry
6 (R1= R2)
13 (R)
15
1
2
3
4
5
6
10a (0)
10b (1)
10a (0)
10b (1)
10a (0)
10b (1)
6b (H)
11a, 99
11b, 98
11c, >99
11d, >99
11e, 94
11f, >99
6
6
12a, 97
12b, 93
12c, 90
12d, 98
12e, 98
12f, 96
1
2
3
4
5
6
7
8
9
6b (H)
6b (H)
13a (H)
5
18
12
7
15a
15f
98
92
97
94
93
94
97
71
85
>99d
99
6b (H)
13c (nBu)
6a (OMe)
6a (OMe)
6c (OCH2O)
6c (OCH2O)
10
15
12
13
6c (OCH2O) 13b (nPr)
6c (OCH2O) 13c (nBu)
15g
15h
15i
99
99
6a (OMe)
6b (H)
13b (nPr)
13b (nPr)
13c (nBu)
13b (nPr)e
13c (nBu)e
11
12
10
8
99
15d
15e
15i
99
6a (OMe)
6a (OMe)
6a (OMe)
99
a All reactions were carried out with 11aÀf (1.0 mmol), Pd(OAc)2
(20 mol %), (()BINAP (40 mmol %), and K2CO3 (2.5 equiv) in toluene
(8 mL) under argon for 4À10 h refluxed at 110À115 °C. b Yields of
isolated products.
99
11
15e
99
a All reactions were carried out with 13aÀc (1.0 mmol), 6aÀc (1.1
mmol), t-BuOK (1.1 equiv), toluene (8 mL), 0 °C, 25 min, Pd(OAc)2 (20
mol %), (()BINAP (40 mol %), K2CO3 (2.5 equiv), under reflux at
110À115 °C, 5À18 h. b Yields of isolated products (%). c Determined by 1H
NMR. d The enantiomeric excess determined by chiral HPLC using ADÀH
column. e These two reactions were carried out under domino conditions.
reacted with C-nucleophiles derived from various bro-
moarylacetonitriles 6aÀc followed by Pd-catalyzed intra-
molecular CÀN cyclization to produce the nonracemic
tetrahydroquinolines (3R,4S)-15aÀb, (7R,8S)-15c, and
(2S,3R,4S)-15dÀe in excellent yields (up to 99%) and
stereoselectivity (ee, de up to >99%) as shown in Scheme 5.
Scheme 5. Synthesis of Nonracemic Tetrahydroquinolines 15
Figure 2. Proposed reaction mechanism.
A probable mechanism for the formation of chiral
tetrahydroquinolines 15aÀi is described in Figure 2. SN2-
type ring opening of chiral N-tosylaziridines 13aÀc by the
C-nucleophiles derived from 6aÀc at the benzylic position
generate the corresponding bromoamines 14 which under-
go Pd-catalyzed intramolecular CÀN coupling to produce
the corresponding tetrahydroquinolines 15aÀi.12
To make our strategy more attractive and straightfor-
ward as a synthetic methodology, domino and one-pot
(stepwise) protocols for the synthesis of chiral tetrahydro-
quinolines 15 via ring opening of enantiopure mono- and
trans-disubstituted aziridines 13aÀc were explored. When
(S)-13a and (2S,3S)-13bÀc were reacted with C-nucleo-
philes generated from 6aÀc followed by cyclization under
one-pot or domino reaction conditions,17 the corresponding
substituted tetrahydroquinolines (3R,4S)-15a, (2S,3R,4S)-
15dÀi, and (6S,7R,8S)-15gÀh were obtained as the only
diastereomer de (>99%) with excellent yields (up to 98%)
(Scheme 6 and Table 4).
In conclusion, we have developed a simple protocol for
the synthesis of substituted nonracemic tetrahydroquino-
lines through a tBuOK-mediated SN2-type ring opening of
N-activated aziridines with arylacetonitriles followed by
Pd-catalyzed CÀN cyclization in excellent yields and
stereoselctivity (de and ee up to >99%).
Acknowledgment. M.K.G. is grateful to DST, India for
financial support. Y.N. and A.K.Y. thank CSIR, India for
research fellowships.
Scheme 6. Synthesis of Nonracemic Tetrahydroquinolines 15
Supporting Information Available. Experimental pro-
cedure, characterization data, and NMR spectra for all
new compounds and X-ray crystallographic data of 8a,
12a, 14e, and 15d. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) See Supporting Information for details.
Org. Lett., Vol. 13, No. 16, 2011
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