Tandem synthesis of 2,3-dihydro-4-iminoquinolines via three-component alkyne-imine metathesis

Article abstract of DOI:10.1021/jo1013993

In the absence of any catalysts, ortho-alkynylanilines react with aldehydes and amines in HFIP to form trans-2,3-disubstituted 2,3-dihydro-4- iminoquinolines in a complete trans-selective manner via the three-component alkyne-imine metathesis.

Full text of DOI:10.1021/jo1013993

pubs.acs.org/joc
Recently, Zr- or Ti-catalyzed formation of R,β-unsaturated
Tandem Synthesis of 2,3-Dihydro-4-iminoquinolines
via Three-Component Alkyne-Imine Metathesis
imines from unactivated alkynes with imines was reported,
albeit a different route from alkyne-imine metathesis.4 Thus,
alkyne-carbonyl metathesis and the related reactions have
increasingly blossomed. We have developed a tandem synth-
esis of cyclic compounds via the alkyne-carbonyl meta-
thesis.5 For example, the SbF5-alcohol complex-catalyzed
metathesis of o-alkynylaniline derivatives and aldehydes
leads to 2,3-dihydroquinolin-4(1H)-ones (eq 2),5a,6 which
possess attractive pharmacological properties7 and also
serve as important synthetic intermediates for the prepara-
tion of biologically active compounds.8 Although the nitro-
gen analogues, 2,3-dihydro-4-iminoquinolines, are prevalent
in various biologically and medicinally important com-
pounds,9 these compounds required many synthetic steps.10
The imination of quinolinones has a limitation in the syn-
thetic scope of the quinolinones.9c,11 Our strategy inspired us
to examine the formation of 2,3-dihydro-4-iminoquinolines
from o-alkynylanilines with imines or with aldehydes and
amines. We herein describe the tandem approach to the
synthesis of 2,3-disubstituted iminoquinolines by the alkyne-
imine metathesis or by the three-component-type metathesis
without any catalysts.
Akio Saito,*,†,‡ Jun Kasai,† Tomoyo Konishi,† and
Yuji Hanzawa*,†,‡
†Laboratory of Organic Reaction Chemistry and
‡High Technology Research Center, Showa Pharmaceutical
University, 3-3165 Higashi-Tamagawagakuen,
Machida, Tokyo 194-8543, Japan
akio-sai@ac.shoyaku.ac.jp; hanzaway@ac.shoyaku.ac.jp
Received July 19, 2010
In the absence of any catalysts, ortho-alkynylanilines
react with aldehydes and amines in HFIP to form trans-
2,3-disubstituted 2,3-dihydro-4-iminoquinolines in a
complete trans-selective manner via the three-component
alkyne-imine metathesis.
Alkyne-carbonyl metathesis has received attention as a
straightforward approach to the formation of highly sub-
stituted enones through a formal [2 þ 2] cycloaddition of a
C-C triple bond with a C-O double bond and the subse-
quent cycloreversion of an oxete intermediate (eq 1, X = O).
The catalytic reaction can be used as an atom economical
process alternative to the Wittig reaction.1,2 In addition, the
catalytic metathesis of ynamides (R = NR02) or alkynylcar-
cogenides (R = SR0, SeR0) with imine (X = NTs, NAr)
provides us with the efficient synthetic procedure of R,β-
unsaturated imidates via an azetin intermediate (eq 1).3
At the outset, we focused on the screening of catalysts
(10-20 mol %) for the formation of iminoquinolines 2aa in
(4) (a) Ruck, R. T.; Zuckerman, R. L.; Krska, S. W.; Bergman, R. G.
Angew. Chem., Int. Ed. 2004, 43, 5372. (b) Aneetha, H.; Basuli, F.; Bollinger,
J.; Huffman, J. C.; Mindiola, D. J. Organometallics 2006, 25, 2402.
(5) (a) Saito, A.; Kasai, J.; Odaira, Y.; Fukaya, H.; Hanzawa, Y. J. Org.
Chem. 2009, 74, 5644. (b) Saito, A.; Umakoshi, M.; Yagyu, M.; Hanzawa, Y
Org. Lett. 2008, 10, 1783.
(6) Similar approach to 2,3-dihydrochromen-4-one from o-alkynylaniline
derivatives and aldehydes. See: Park, J. Y.; Ullapu, P. R.; Cho, H.; Lee, J. K.;
Min, S.-J.; Pae, A. N.; Kim, Y.; Baek, D.-J.; Cho, Y. S. Eur. J. Org. Chem.
2008, 5461.
(7) (a) Beifuss, U.; Feder, G.; Bes, T.; Uson, I. Synlett 1998, 649. (b) Chen,
W.; Egar, A. L.; Hursthouse, M. B.; Malik, K. M. A.; Mathews, J. E.;
Roberts, S. M. Tetrahedron Lett. 1998, 39, 8495. (c) Xia, Y.; Yang, Z.-Y.;
Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S.-C.; Hamel, E.; Hackl, T.; Lee,
K.-H. J. Med. Chem. 1998, 41, 1155. (d) Zhang, S.-X.; Kuo, S.-C.; Brossi, A.;
Hamel., E.; Tropsha, A.; Lee, K.-H. J. Med. Chem. 2000, 43, 167.
(8) (a) Nishijima, K.; Shinkawa, T.; Yamashita, Y.; Sato, N.; Nishida, H.;
Kato, K.; Onuki, Y.; Mizota, M.; Ohtomo, K.; Miyano, S. Eur. J. Med.
Chem. 1998, 33, 267. (b) Nieman, J. A.; Ennis, M. D. Org. Lett. 2000, 2, 1395.
(9) (a) Yoshitomi, Y.; Arai, H.; Makino, K.; Hamada, Y. Tetrahedron
2008, 64, 11568. (b) Cookson, J. C.; Heald, R. A.; Stevens, M. F. G. J. Med.
Chem. 2005, 48, 7198. (c) Heald, R. A.; Stevens, M. F. G. Org. Biomol. Chem.
2003, 1, 3377. (d) Read, M.; Harrison, R. J.; Romagnoli, B.; Tanious, A. A.;
Gown, S. M.; Reszka, A. P.; Wilson, W. D.; Kelland, L. R.; Neidle, S. Proc.
Natl. Acad. Sci. U.S.A. 2001, 98, 4844.
(1) Catalytic procedures for the alkyne-carbonyl metathesis: (a) Curini,
M.; Epifano, F.; Maltese, F.; Rosati, O. Synlett 2003, 552. (b) Rhee, J. U.;
Krische, M. J. Org. Lett. 2005, 7, 2493. (c) Jin, T.; Yamamoto, Y. Org. Lett.
2007, 9, 5259. (d) Jin, T.; Yang, F.; Liu, C.; Yamamoto, Y. Chem. Commun.
2009, 3533. (e) Gonzalez-Rodriguez, C.; Escalante, L.; Varela, J. A.;
Castedo, L.; Saa, C. Org. Lett. 2009, 11, 1531. (f) See also: Kurtz,
K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231.
(2) Examples of stoichiometric procedures for the alkyne-carbonyl
metathesis: (a) Harding, C. E.; Hanack, M. J. Org. Chem. 1989, 54, 3054.
(b) Sisko, J.; Balog, A.; Curran, D. P. J. Org. Chem. 1992, 57, 4341. (c)
Wempe, M. F.; Grunwell, J. R. Tetrahedron Lett. 2000, 41, 6709. (d) Hayashi,
A.; Yamaguchi, M.; Hirama, M. Synlett 1995, 195. (e) Viswanathan, G. S.;
Li, C.-J. Tetrahedron Lett. 2002, 43, 1613.
(3) (a) Abramovich, R. A.; Mavunkel, B.; Stowers, J. R.; Wegrzyn, M.;
Riche, C. J. Chem. Soc., Chem. Commun. 1985, 845. (b) Ishitani, H.;
Nagayama, S.; Kobayashi, S. J. Org. Chem. 1996, 61, 1902. (c) Ma, Y.;
Qian, C. Tetrahedron Lett. 2000, 41, 945. See also: (d) Shindo, M.; Oya, S.;
Sato, Y.; Shindo, K. Heterocycles 2000, 52, 545. (e) Shindo, M.; Oya, S.;
Sato, Y.; Shindo, K. Tetrahedron Lett. 2000, 41, 5947.
(10) (a) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem. 1995,
60, 7631. (b) Agui, H.; Nakagome, T. J. Heterocycl. Chem. 1979, 16, 1353. (c)
Boschelli, D. H.; Wang, Y. D.; Ye, F.; Wu, B.; Zhang, N.; Dutia, M.; Powell,
D. W.; Wissner, A.; Arndt, K.; Weber, J. M.; Boschelli, F. J. Med. Chem.
2001, 44, 822. (d) Zieba, A.; Suwinska, K. Heterocycles 2006, 68, 495.
6980 J. Org. Chem. 2010, 75, 6980–6982
Published on Web 09/15/2010
DOI: 10.1021/jo1013993
r
2010 American Chemical Society

Saito et al.
JOCNote
TABLE 1. Optimization for the Formation of 2aa from 1 with Imine
TABLE 2. Optimization for the Three-Component Formation of 2aa
1 þ PhCHO þ PhNH2
2aa þ 3
f
HFIP,45 °C,20 h
yield (%)a
entry
1
mixture ratio PhCHO PhNH2 additive
2aa
3
1
2
3
4
1
1
1
1
2
2
3
3
1
1
1
2
1
1
1
1
1
1
1
2
1
1
1
1
51
50
61
59
64
68
65
77
13
13
13
18
18
13
21
21
MgSO4
˚
MS 4A
5b
6b
7b
8b
˚
MS 4A
˚
MS 4A
aYields, which were based on 1, were determined by 1H NMR
analysis. bYields were based on aldehyde.
yield (%)b
Since HFIP has been known to be a hydrogen-bond donor
(pKa = 9.3) for heteroatomic functional group,13 such an
activity of HFIP would be primarily a result of the efficient
interaction with imine. This is supported by 13C NMR
studies using a 1:1 mixture of 1 and benzylideneaniline in
HFIP-CDCl3 (3:2) at rt. Compared with 13C NMR spectrum
(75 MHz) in neat CDCl3, the spectrum in HFIP-CDCl3 (3:2)
showed the larger shifts of imine-carbons of benzylideneaniline
(Δδ=5.7)14 than the other carbons such as the shift of the sp-
carbons (Δδ=2.3 and -1.0)14 of 1. Thus, the present condi-
tions would preferentially activate imine rather than alkyne,
and a similar observation has been reported in the reaction of
alkyne and aldehyde catalyzed by SbF5-alcohol complex.5
The effect of HFIP solvent was also exhibited on the three-
component formation of 2aa from 1, PhCHO, and PhNH2
entry
catalyst
Yb(OTf)3
Sc(OTf)3
solventa
DCE
DCE
DCE
DCE
DCE
conditions
2aa
3
1
2
3
4
5
6
7
8
9
90 °C, 20 h
90 °C, 20 h
90 °C, 20 h
90 °C, 43 h
90 °C, 18 h
90 °C, 18 h
90 °C, 20 h
70 °C, 44 h
70 °C, 44 h
45 °C, 20 h
41
40
43
49
46
32
43
57
57
73
70
61
24
21
21
24
25
19
17
21
13
13
17
14
13
9
c
BF3 OEt2
3
HBF4
SbF5 5MeOHd
3
TfOH 5MeOHd DCE
3
TfOH
TfOH
DCE
HFIP
HFIP
HFIP
10e
11e
12e
13e
HFIP-DCEf 45 °C, 20 h
HFIP-DCEg 45 °C, 20 h
HFIP-DCEh 45 °C, 20 h
aDCE=1,2-dichloroethane, HFIP=hexafluoroisopropanol. bYields
were determined by 1H NMR analysis. cWith 20 mol %. dCatalyst/
MeOH=1:5 mixture. e1/imine =3:1; the yield of 2aa was based on imine.
fHFIP/DCE=3:1. gHFIP/DCE=1:1. hHFIP/DCE = 1:3.
˚
(Table 2). In particular, the addition of MS 4A (entries 3, 6,
and 8) and the increasing amount of 1 (entries 5-8) brought
about good results. In the presence of MS 4A, the 3:1:1
˚
the reaction of o-alkynylaniline 1 with benzylideneaniline
(1.2 equiv) in 1,2-dichloroethane (DCE, Table 1). It turned
out that the employed Lewis acids and Brønsted acids gave
the desired 2aa in 32-49% yields (entries 1-7). In all cases,
quinoline 3, which would be considered to be formed by the
aza-Diels-Alder reaction of alkyne moiety of 1 with 2-aza-
diene part of imine,12 was detected in 13-25% yields.
mixture of 1, PhCHO, and PhNH2 in HFIP at 45 °C for 20 h
afforded 2aa as a single trans-isomer in 77% yield (entry 8).
According to the optimized conditions, we next examined
the three-component formation of various substituted 2,3-
dihydro-4-iminoquinolines (Table 3). In the absence of any
catalysts, alkyne 1 or 4 successfully reacted with various
aromatic aldehydes and various anilines to give the corre-
sponding iminoquinolines 2 or 5 in moderate to high yields.
In all cases, complete trans-selectivities were observed. In the
reaction with p-nitrobenzaldehyde or anilines bearing a strongly
electron-withdrawing group (R3 = p-NO2C6H4, p-CNC6H4),
however, ketone 6 was detected (7-15%) in place of the desired
iminoquinolines (entries 7, 12, and 13).15 Although 6 would be
expected to be formed from alkyne 1 and H2O, the reaction of 6
instead of 1 with PhCHO and PhNH2 did not yield 2aa but
yielded benzylideneaniline along with recovery of 6.
Although SbF5 5MeOH (1:5 mixture of SbF5 and MeOH)
3
was an outstanding catalyst for the formation of 2,3-
dihydroquinolin-4(1H)-ones from o-alkynylanilines and
aldehydes,5 it did not bring about a significant result in the
present reaction (entry 5). Under the trifluoromethanesulfonic
acid (TfOH)-catalyzed conditions, an addition of MeOH
was ineffective (entries 6 and 7). The use of hexafluoroisopro-
panol (HFIP) as a solvent, however, exerted a marked effect
on the formation of 2aa (entries 8-10). Thus, in HFIP,
2aa was obtained in 57% yield even without any catalysts
(entry 9). Furthermore, the increasing amount of 1 (3 equiv
to benzylideneaniline) improved the yield of 2aa up to 73%
at 45 °C within 20 h (entry 10). On the other hand, when
HFIP was used with DCE as a cosolvent, the decrease in the
ratio of HFIP caused the drop of the yield of 2aa (entries
11-13).
Under the present conditions, the treatment of o-alkyny-
laniline 7 with benzaldehyde (1 equiv) and aniline (1 equiv) in
(13) (a) Ratnikov, M. O.; Tumanov, V. V.; Smit, W. A. Angew. Chem.,
Int. Ed. 2008, 47, 9739. For review: (b) Begue, J. P.; Bonnet-Delpon, D.;
€
Crousse, B. Synlett 2004, 18. (c) Shuklov, I. A.; Dubrovina, N. V.; Borner, A.
Synthesis 2007, 2925.
(14) The chemical shift difference Δδ showed the shift to a lower field. The
shift to a higher field is stated in minus figures.
(11) (a) van Es, T.; Staskun, B. J. Chem. Soc., Perkin Trans. 1 1998, 3137.
(b) van Es, T.; Staskun, B. S. Afr. J. Chem. 2002, 55, 13.
(12) Brønsted acid-catalyzed aza-Diels-Alder reaction of alkynes with
imine: (a) Zhao, Y. L.; Zhang, W.; Wang, S.; Liu, Q. J. Org. Chem. 2007, 72,
ꢀ
4985. See also: (b) Di Salvo, A.; Spanedda, M. V.; Ourevitch; Crousse, B.;
Bonnet-Delpon, D. Synthesis 2003, 2231.
(15) The present conditions could not be applied to the reactions of
aliphatic aldehydes (R2 = n-hexyl, cyclohexyl, t-butyl) instead of aromatic
aldehydes or aliphatic amines (R3 = n-butyl, t-butyl) instead of aromatic
amines. In the absence of aniline, the reaction of 1 and PhCHO with or
without MeOH did not afford the corresponding 2,3-dihydroquinolin-
4(1H)-one and 1,2-dihydro-4-methoxyquinoline.
J. Org. Chem. Vol. 75, No. 20, 2010 6981

Saito et al.
JOCNote
TABLE 3. Three-Component Formation of Iminoquinolines
In summary, we have demonstrated the tandem prepara-
tion of 2,3-dihydro-4-iminoquinolines via three-component
metathesis of o-alkynylanilines, aromatic aldehydes, and
anilines. The effect of HFIP solvent is noteworthy in the
respect that any catalysts were not demanded. Since our
approach is a highly stereoselective procedure for the synth-
esis of trans-2,3-disubstituted iminoquinolines, the present
reaction would raise new possibilities for the construction of
quinoline frameworks. Synthetic applications and detailed
mechanistic studies of the present reaction are underway.
Experimental Section
entry alkyne
R2
R3
(h)
yield (%)a
Typical Experimental Procedure for the Formation of 2,3-
Dihydro-4-iminoquinolines (2aa): To a solution of o-alkynylani-
line 1a (316 mg, 0.4 mmol), benzaldehyde (41 μmL, 0.4 mmol),
and aniline (37.2 mg, 0.4 mmol) in HFIP (2.0 mL) was added the
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
1
1
1
1
1
1
1
1
1
1
1
4
Ph
p-MeOC6H4
m-MeOC6H4 Ph
o-MeOC6H4
p-MeC6H4
p-FC6H4
p-NO2C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20
18
20
20
21
20
42
20
18
18
18
42
42
20
2aa
2ba
2ca
2da
2ea
2fa
2ga
2ab
2ac
2ad
2ae
2af
2ag
5aa
75
68
64
56
69
67
0
32
38
70
70
0
Ph
Ph
Ph
Ph
˚
predrying MS 4A by microwave. After being stirred at 45 °C for
20 h, the reaction mixture was concentrated to dryness. The
purification of the residue by silica gel column chromatography
(hexane/AcOEt = 50/1) and the subsequent MPLC (hexane/
AcOEt=99/1) gave 2aa (136.0 mg, 77% yield) and 3 (37.1 mg,
21% yield). 2aa: yellow solid; mp 96-98 °C; IR (KBr) ν cm-1
p-MeOC6H4
p-MeC6H4
p-FC6H4
p-ClC6H4
p-NO2C6H4
p-CNC6H4
Ph
1
1635; H NMR (300 MHz, CDCl3) δ 0.75 (t, 3H, J=7.1 Hz),
1.07-1.14 (m, 4H), 1.58-1.69 (m, 2H), 2.82 (td, 1H, J = 7.4, 1.8
Hz), 4.21 (d, 1H, J = 17.1 Hz), 4.52 (d, 1H, J = 1.8 Hz), 4.80 (d,
1H, J = 17.1 Hz), 5.94-5.97 (m, 2H), 6.70-6.72 (m, 1H),
6.76-6.82 (m, 1H), 6.88-6.94 (m, 1H), 7.03-7.09 (m, 1H),
7.28-7.38 (m, 9H), 8.01 (dd, 1H, J = 7.6, 1.7 Hz); 13C NMR (75
MHz, CDCl3) δ 13.8, 22.4, 28.9, 32.2, 43.8, 53.6, 65.5, 111.0,
116.6, 119.4, 119.4, 122.5, 126.4, 127.2, 127.3, 127.6, 128.3,
128.7, 128.9, 132.6, 138.4, 141.3, 147.1, 150.8, 164.3; FAB-LM
m/z 445 (Mþ þ H); FAB-HM calcd for C32H33N2 445.2644,
found 445.265. Anal. Calcd for C32H32N2: C, 86.44; H, 7.25; N,
6.30. Found: C, 86.53; H, 7.15; N, 6.36. 3: Yellow solid; mp
147-148 °C; IR (KBr) ν cm-1 1635; 1H NMR (300 MHz,
CDCl3) δ 0.51 (t, 3H, J =7.4 Hz), 0.93 (qt, 2H, J =7.4, 7.4
Hz), 1.14-1.26 (m, 2H), 2.46-2.56 (m, 1H), 2.63-2.73 (m, 1H),
3.67 (br s, 1H), 4.29 (s, 2H), 6.75-6.78 (m, 1H), 6.83-6.89 (m,
1H), 7.04-7.07 (m, 1H), 7.17-7.34 (m, 5H), 7.41-7.58 (m, 7H),
7.65-7.71 (m, 1H), 8.18-8.19 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 13.3, 22.6, 30.0, 32.3, 47.9, 111.05, 117.2, 122.1, 125.8,
126.6, 127.0, 127.1, 128.0, 128.3, 128.5, 128.7, 129.0, 129.4,
129.6, 130.3, 133.9, 139.4, 141.6, 144.3, 145.1, 146.5, 161.7;
FAB-LM m/z 443 (Mþ þ H); FAB-HM calcd for C32H31N2
443.2487, found 443.2497.
0
80
aIsolated yield.
SCHEME 1. Three-Component Metathesis of 7, PhCHO, and
PhNH2
HFIP afforded the R,β-unsaturated imine 8 in 42% yield
along with [4 þ 2] adduct 9 and indole 10 (Scheme 1). On the
basis of the previously reported synthesis of R,β-unsaturated
imidates from alkynes and imines,3 the result suggested that
the present conditions promoted the formal alkyne-imine
metathesis of 7 with benzylideneaniline generated in situ to
afford 8. Therefore, the present pathway to 2,3-dihydro-4-
iminoquinoline derivatives from o-alkynylanilines, aldehydes,
and amines would be considered to involve the intramolecular
addition of the NH group of R,β-unsaturated imines (such as
8) generated in situ by an alkyne-imine metathesis.
Acknowledgment. This work was supported by Grant-in-
Aid for Young Scientists (B), MEXT Japan (No 21790024).
A generous donation of HFIP by Central Glass Co., Ltd is
gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures and physical data for novel compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
6982 J. Org. Chem. Vol. 75, No. 20, 2010