Primary amino acid catalyzed asymmetric intramolecular Mannich reaction for the synthesis of 2-aryl-2,3-dihydro-4-quinolones

Article abstract of DOI:10.1039/c4ob02146k

Primary amino acids are found to be good enantioselective catalysts for the direct asymmetric Mannich reaction between 2-amino acetophenone and aldehydes. The 2-aryl-2,3-dihydro-4-quinoline products are obtained in moderate to good yields and good to high enantioselectivities with 10 mol% of the primary amino acid catalyst under mild reaction conditions.

Full text of DOI:10.1039/c4ob02146k

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DOI: 10.1039/C4OB02146K
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ARTICLE TYPE
Primary amino acid catalyzed asymmetric intramolecular Mannich
reaction for the synthesis of 2-aryl-2,3-dihydro-4-quinolones
Buddhadeb Mondal and Subhas Chandra Pan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Primary amino acids are found to be good enantioselective
catalysts for the direct asymmetric Mannich reaction between
are biological molecules their modification is difficult.
O
2
-amino acetophenone and aldehydes. The 2-aryl-2,3-
dihydro-4-quinoline products are obtained in moderate to
good yields and good to high enantioselectivities with 10
mol% of primary amino acid catalyst under mild reaction
condition.
10
N
R
O
PG
O
R
+
RM
Quinolones have wide spectrum antibacterial properties and
they have been used in pharmaceutical chemistry not only
N
Ref . 5
CO tBu
2
PG
NH
PG
1
2
2
3
3
4
4
5
0
5
0
5
0
5
because of their availability orally and parentally but also for
1
O
N
their favourable pharmacokinetics.
In particular, 2-aryl-2,3-
dihydro-4-quinolones have attracted attention because of their
2
activities as anticancer, antimalarial as well as antibiotic agents
3
and as potent cross-species micro RNA inhibitors. These
R
Ref. 8
important biological properties have stimulated interest for the
synthesis of 2-aryl-2,3-dihydro-4-quinolones from different
research groups, particularly in enantioselective fashion as two
individual stereoisomers behave in totally different ways.
and this work
Most direct,
no PG
PG
O
O
There are five different routes to access enantiopure 2-
4
aryl/alkyl-2,3-dihydro-4-quinolones (Figure 1). The first one is
-8
+
RCHO
NH
2
the asymmetric intermolecular 1,4-Michael addition of
4
organometallic reagents to 4-quinolones. Here, handling of air
NH
PG
R
sensitive catalysts and reagents is required. The second method is
50
the kinetic resolution of 2-substituted 2,3-dihydro-4-quinolones
5
by palladium catalyzed allylic alkylation. As this is a kinetic
Figure 1 Synthetic approaches to 2-aryl-2,3-dihdro-4-quinolones
resolution, the starting material was recovered in less than 50%
Recently, Yang, Luo and co-workers reported amino acid
derived sulfonamide catalyzed asymmetric synthesis of 2-aryl-
yield. The third strategy is the 6-endo-trig cyclization of amino
6
alkylidene β-keto esters. One drawback of this method is the 55 2,3-dihydro-4-quinolones; though the products were obtained in
8c
requirement of the ester functionality which makes this approach
moderate enantioselectivities (maximum 74% ee). Taking all
these facts into account and realizing the importance of 2-aryl-
2,3-dihydro-4-quinolones we thought that a high enantioselective
synthesis by intramolecular Mannich reaction using simple
non atom-economical. The fourth approach is 6-endo aza-
7
Michael addition of aminochalcone derivatives. Here also like
previous methods, protection of amino group is required and the
substrate has to be synthesized in a couple of steps. The fifth and 60 organocatalysts is well desirable. Herein, we describe primary
10
the most direct approach is the asymmetric intramolecular
8
amino acid catalyzed one pot asymmetric synthesis of 2-aryl-
2,3-dihydro-4-quinolones and also employ a variety of 2-
aminoacetophenones for the first time.
,9
Mannich reaction
aldehydes.
between 2-aminoacetophenone and
Chandrasekhar et al first shown that 2-amino acetophenone
We started our investigation by screening different primary
could react with arylaldehydes in the presence of proline catalyst 65 amino acids I-VIII for the reaction between 2-
to furnish 2-aryl-2,3-dihydro-4-quinolones in good yields;
aminoacetophenone (1a) and benzaldehyde (2a). The reactions
were performed in the presence of 10 mol% of catalyst in
methanol solvent at room temperature. After stirring for 4 days
with valine (I) catalyst, the product 3a was obtained in 40% yield
8a
however poor enantioselectivity (<10% ee) was attained.
Pitchumani and Kanagaraj have developed enantioselective
synthesis of 2-aryl-2,3-dihydro-4-quinolones using per-6-amino-
8
b
β-cyclodextrin as chiral base catalyst. However as cyclodextrins 70 with 77:23 er (Table 1, entry 1).
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DOI: 10.1039/C4OB02146K
o
Table 1 Catalyst screening and optimization of reaction condition
after lowering the reaction temperature to 0 C and increasing the
catalyst loading did not enhance the enantioselectivity or yield of
the product.
H
2
N
2
CO H
CO
2
2
H
30
CO
2
H
H
3
C
CO
2
2
H
HO
Table 2 Substrate scope of the catalytic enantioselective
NH
2
NH
NH
III
intramolecular Mannich reaction
I
II
IV
O
O
R
R
catalyst VIII (10 mol%)
t
O Bu
+
ArCHO
(1.5 equiv)
2
OTBS
OTBDPS
CO
MeOH (0.5 M)
RT, 4 d
N
H
Ar
CO
2
2
H
CO
H
H
NH
2
2
2
CO
2
2
H
NH
1
3a-y
NH
2
NH
2
NH
VIII
V
VI
VII
b
c
entry
a
1
R
H
Ar
Ph
3
yield
51
75
61
45
62
60
69
70
52
49
58
55
32
46
67
38
35
73
er
3a
3b
3c
3d
3e
3f
90.5:9.5
93:7
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-OMeC H4
6
O
O
4-MeC H4
6
89.5:10.5
89:11
89:11
90:10
87:13
92:8
catalyst (10 mol%)
4-tBuC H4
6
+
PhCHO
solvent (0.5 M)
RT, 4 d
4-FC H4
6
NH
2
N
H
Ph
4-ClC H4
6
4-BrC H4
6
3g
3h
3i
1
a
2a
3a
4-OHC H4
6
a
b
c
4-OEtC
6
H
4
92:8
entry
catalyst
solvent
yield
40
46
44
35
50
45
42
55
50
51
er
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
4-OnPrC H4
6
3j
92:8
1
2
3
4
5
6
7
8
9
I
II
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
TFE
77:23
67:33
76:24
85:15
85:15
4-OiBuC H4
6
3k
3l
93:7
4-OAllC H4
6
91:9
III
IV
V
4-OnOctC H4 3m
6
92:8
4-OAcC H4
6
3n
3o
3p
3q
3r
90:10
90:10
82:18
83:17
96:4
3-OMeC H4
6
VI
VII
VIII
VIII
V
81.5:18.5
79:21
3-ClC H4
6
3-BrC H4
6
87:13
4-OH-3-
85:15
OMeC H3
6
1
0
TFE
90.5:9.5
H
H
3,4-
3s
3t
61
61
92:8
a
19
20
Reaction condition: 0.2 mmol of 1a with 0.3 mmol of 2a in 0.4
b
mL solvent using 10 mol% catalyst. Isolated yield after silica gel
c
column chromatography. Determined by HPLC using stationary
(OMe)
3,4,5-
OMe) C H
C
H
3
2
6
89:11
5
0
5
0
5
(
3
6
2
phase chiral column.
2
2
2
2
2
1
2
3
4
5
H
H
2-furyl
3u
3v
23
28
43
71
33
82:18
86.5:13.5
92:8
_
___________________________________________________
2-pyrrolyl
5-Cl
4-OMeC H4 3w
6
A little less enantioselectivity was observed with L-serine (II)
(entry 2). L-isoleucine (III) could not change the
enantioselectivity much and the product was obtained in similar
yield (entry 3). A higher enantioselectivity was achieved with 1-
adamantyl(amino)acetic acid (IV) albeit in less yield (entry 4). L-
tert-leucine (V) provided the product in similar enantioselectivity
but a higher yield of 50% was obtained (entry 5). Then we found
5-Me
4-OMeC H4
6
3x
3y
91:9
1
1
2
2
3,5-(Me)2 4-OMeC H4
6
84.5:15.5
a
Reaction was carried out with catalyst V in TFE solvent
b
(condition A). Isolated yield after silica gel column
35
c
chromatography. Determined by HPLC using stationary phase
chiral.column.
____________________________________________________
1
1
that O-protected L-threonine derivatives (VI-VIII) are quite
effective for our reaction. Though TBS protected L-threonine
With the optimized reaction condition in hand we ventured in
the scope of the reaction. Except for benzaldehyde (2a), condition
B was followed for all substituted benzaldehydes as we failed to
achieve similar enantioselectivities for other aldehydes using
(
VI) and TBDPS protected L-threonine (VII) could not change
40
much the enantioselectivity of the reaction (entries 6-7), a higher
t
enantioselectivity was attained with O Bu-L-threonine catalyst
(
VIII) (entry 8). A change of the solvent from methanol to
trifluoroethanol did not alter the enantioselectivity with catalyst
VIII, but surprisingly higher enantioselectivity was attained with 45 were obtained (Table 2). As can be seen, a variety of 4-
condition A. Gratifyingly, condition
B was suitable for
substituted benzaldehydes and good to high enantioselectivities
catalyst V (entry 10). Future experiments were carried out either
with catalyst V in trifluoroethanol (condition A) or with catalyst
VIII in methanol (condition B). A sluggish reaction was observed
substituted benzaldehydes can be employed in our reaction and
incorporation of electron withdrawing or electron rich groups did
not affect the outcome of the reaction (entries 1-14). p-
Anisaldehyde provided the product 3b in 75% yield with 93:7 er
2
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DOI: 10.1039/C4OB02146K
a
(
entry 2). 4-Alkylsubstituted benzaldehydes delivered the
products with fairly good level of enantioselectivities (entries 3-
). Different halo-substitutions at the 4-position of benzaldehyde
Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati 781039, India. Fax: 91-361-2582349; Tel: 91-361-2583304; E-
mail: span@iitg.ernet.in
4
†
Electronic Supplementary Information (ESI) available: [Experimental
13
were also tolerated and the products were obtained in similar
enantioselectivities (entries 5-7). 4-Hydroxybenzaldehyde can
also be employed and product 3h was observed in satisfactory
yield with 92:8 er (entry 8). Encouraged by this result and that of
entry 2, we screened different 4-alkoxybenzaldydes for our
reaction and acceptable yields with high enantioselectivities
(>90:10 er) were attained in all cases (entries 9-13). Good
enantioselectivity was also achieved with 4-acetoxybezaldehyde
1
5
6
6
7
5
0
5
0
procedures and H, C NMR and HPLC data of all products]. See
DOI: 10.1039/b000000x/
1
5
a) B. E. Evans, K. E. Rittle, M. G. Bock, R. M. Dipardo, R. M.
Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S.
Anderson, R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J.
Kling, K. A. Kunkel, J. P. Springer, J. Hirshfield, J. Med. Chem.,
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O. Sterner, Bioorg. Med. Chem. Lett., 2008, 18, 5713; c) M. E.
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2012, 15, 52.
1
1
2
2
0
5
0
5
(entry 14). Then different 3-substituted benzaldehydes were
screened (entries 15-17). Though, m-anisaldehyde afforded
product 3o in good enantioselectivity (entry 15), diminished
yields and enantioselectivities were observed for products 3p and
2
a) Y. Xia, Z. –Y. Yang, P. Xia, K. F. Bastow, Y. Tachibana, S. –C.
Kuo, E. Hamel, T. Hackle, K. –H. Lee, J. Med. Chem., 1998, 41,
3
q (entries 16-17). Pleasingly, our reaction condition is suitable
1
155.; b) S. –X. Zhang, J. Feng, S. –C. Kuo, A. Brossi, E. Hamel, A.
for the employment of different di and tri-substituted
benzaldehydes (entries 18-20) and vanillin proved to be the best
aldehyde with 96:4 er (entry 18). Different heteroaromatic
aldehydes can also be engaged in our reaction albeit poor yields
were observed (entries 21-22). Additionally, different substituted
Tropsha, K. –H. Lee, J. Med. Chem., 2000, 43, 167; c) A. E. Nibbs,
K. A. Scheidt, Eur. J.Org. Chem., 2012, 449; d) A. Patti, S. Pedotti,
T. Grassi, A. Ido lo, M. Guido, A. De Donno, J. Organomet. Chem.,
2
012, 716, 216.
3
4
S. Chandrasekhar, S. N. C. V. L. Pushpavalli, S. Chatla, D.
Mukhopadyay, B. Ganganna, K. Vijeender, P. Srihari, C. R. Reddy,
M. J. Ramaiah, U. Bhadra, Bioorg. Med. Chem. Lett., 2012, 22, 645.
a) R. Shintani, T. Yamagami, T. Kimura, T. Hayashi, Org. Lett.
2
-amino acetophenones were also employed for the first time in
this reaction (entries 23-25). 5-Chloro-2-aminoacetophenone (1b)
provided product 3w in moderate yield with 92:8 er but a higher
yield was attained for product 3x in similar enantioselectivity.
75
2005, 7, 5317; b) X. Zhang, J. Chen, F. Han, L. Cun, J. Liao, Eur. J.
Org. Chem., 2011, 1443.
5
6
B. –L. Lei, C. –H. Ding, X. –F. Yang, X. –L. Wan, X. –L. Hou, J.
Am. Chem. Soc., 2009, 131, 18250.
a) Z. Feng, Q. L. Xu, L. X. Dai, S. L. You, Heterocycles 2010, 80,
A proposed transition state model has been shown in Figure 2 and
it dictates that the primary amino group of the catalyst generates
an enamine intermediate. Also only Si face of the newly
generated imine double bond is exposed for enamine addition.
We also assume that the carboxylic acid group of catalyst
simultaneously activates the imine from the Re face for the
addition. The absolute configuration of the product could be
envisaged as “R” by this model and it was also confirmed by the
comparison of the optical rotation with literature value (see
supporting information for details).
8
8
9
9
0
5
0
5
7
65; b) X. Liu, Y. Lu, Org. Lett., 2010, 12, 5592; c) X. Xiao, X. Liu,
S. Dong, Y. Cai, L. Lin, X. Feng, Chem. Eur., J. 2012, 18, 15922.
a) M. Rueping, S. A. Moreth, M. Z. Bolte, Z. Naturforsch B 2012,
67b, 1021; b) S. Cheng, L. Zhao, S. Yu, Adv. Synth. Catal., 2014,
356, 982.
a) S. Chandrasekhar, K. Vijeender, C. Sridhar, Tetrahedron Lett.,
2007, 48, 4935; b) K. Kanagaraj, K. Pitchumani, J. Org Chem. 2013,
78, 744; c) H. Zheng, Q. Liu, S. Wen, H. Yang, Y. Luo,
Tetrahedron: Asymmetry 2013, 24, 875. For a recent report on copper
(II) catalyzed asymmetric [1,6]-aza-electrocyclization of 1,3
dicarbonyl compounds having related structures, see: P. C. Knipe, M.
D. Smith, Org. Biomol. Chem., 2014, 12, 5094.
For reviews on organocatalytic asymmetric Mannich reactions, see:
a) A. Córdova, Acc. Chem. Res. 2004, 37, 102; b) A.Ting, S. E.
Schaus, Eur. J. Org. Chem., 2007, 5797; c) M. M. B. Marques,
Angew. Chem. Int. Ed., 2006, 45, 348; d) J. M. M. Verkade, L. J. C.
van Hemert, P. J. L. M. Quaedflieg, F. P. J. T. Rutjes, Chem. Soc.
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Organocatalysis 1: Lewis base and acid catalysis, B. List, Ed.
Thieme Verlag: Stuttgart, 2012, pp 73-134; f) X. –H. Cai, B. Xie,
ARKIVOC 2013, 264.
For a review on primary amino acids as privileged catalysts in
enantioselective organocatalysis, see: L. –W. Xu, Y. Lu, Org.
Biomol. Chem., 2008, 6, 2047.
For selected recent reports on O-protected-L-threonine catalyzed
asymmetric transformations, see: a) S. S. V. Ramasastry, H. Zhang,
F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc., 2007, 129, 288; b) S.
S. V. Ramasastry, K. Albertshofer, N. Utsumi, F.Tanaka, C. F.
Barbas III, Angew. Chem. Int. Ed., 2007, 46, 5572; c) N. Utsumi, M.
Imai, F.Tanaka, S. S. V. Ramasastry, C. F. Barbas III, Org. Lett.,
30
7
8
35
t
O Bu
O
HN
O
9
O
H
N
R
N
H
Ph
Ph
3a
Figure 2 Proposed transition state
1
00
Conclusions
1
1
0
1
In summary, we have developed primary α-amino acid
catalyzed asymmetric intramolecular Mannich reaction between
1
05
40
2
-aminoacetophenones and aryl aldehydes. This report shows that
primary α-amino acids are better catalysts than secondary α-
amino acid such as proline for this particular reaction. Future
applications of primary amino acids in related reactions are in 110
progress in our laboratory.
45
2
007, 9, 3445; d) H. Zhang, S. S. V. Ramasastry, F.Tanaka, C. F.
Barbas III, Adv. Synth. Catal., 2008, 350, 791; e) X. Wu, Z. Jiang, H.
M. Shen, Y. Lu, Adv. Synth. Catal., 2007, 349, 812; f) L. Cheng, X.
Acknowledgements
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Han, H. Huang, M. W. Wong, Y. Lu, Chem. Commun., 2007, 4143;
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52; h) T. C. Nugent, A. Sadiq, A. Bibi, T. Heine, L. L. Zeonjuk, N.
Vankova, B. S. Bassil, Chem. Eur. J., 2012, 18, 4088.
This work was supported by DST-MPI partner programme. We
thank CIF, Indian Institute of Technology Guwahati for the
instrumental facility.
50
Notes and references
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