Three distinct reactions of 3,4-dihydroisoquinolines with azlactones: Novel synthesis of imidazoloisoquinolin-3-ones, benzo[a]quinolizin-4-ones, and benzo[d]azocin-4-ones

Article abstract of DOI:10.1021/ol062429m

(Diagram presented) A facile and direct synthetic entry to tricyclic imidazoloisoquinolin-3-ones and benzo[a]quinolizin-4-ones is reported based on the ring annulation of 1-unsubstituted and 1-substituted dihydroisoquinolines with azlactones under neutral

Full text of DOI:10.1021/ol062429m

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5845-5848
Three Distinct Reactions of
3,4-Dihydroisoquinolines with
Azlactones: Novel Synthesis of
Imidazoloisoquinolin-3-ones,
Benzo[a]quinolizin-4-ones, and
Benzo[d]azocin-4-ones
Rattana Worayuthakarn,† Nopporn Thasana,‡ and Somsak Ruchirawat*,†,‡,§
Chulabhorn Research Institute, VipaVadee Rangsit Highway, Bangkok 10210,
Thailand, Department of Chemistry, Mahidol UniVersity, Rama 6 Road, Bangkok,
Thailand, and Programme on Research and DeVelopment of Synthetic Drugs, Institute
of Science and Technology for Research and DeVelopment, Mahidol UniVersity,
Salaya Campus, Nakornpathom, Thailand
somsak@cri.or.th
Received October 3, 2006
ABSTRACT
A facile and direct synthetic entry to tricyclic imidazoloisoquinolin-3-ones and benzo[a]quinolizin-4-ones is reported based on the ring annulation
of 1-unsubstituted and 1-substituted dihydroisoquinolines with azlactones under neutral conditions in a one-step procedure. Bicyclic 2,3-
dihydrobenzo[d]azocin-4-ones were also prepared using simple azlactone and 1-substituted dihydroisoquinolines in a one-pot reaction.
Azlactones1 are versatile precursors for the asymmetric
syntheses of R-amino acid derivatives, lactam, and arylpyru-
vic acid units which have been used for the synthesis of
tetrahydro-â-carbolines2 and lamellarin alkaloids.3 Schulzeines
A-C, new R-glucosidase inhibitors, isolated from the marine
sponge Penares schulzei, were the first three benzo[a]-
quinolizin-4-ones containing an amide moiety at the C-3
position.4
(1) (a) MacDonald, S. F. J. Chem. Soc. 1948, 376. (b) Crawford, M.;
Little, W. T. J. Chem. Soc. 1959, 729. (c) Gelmi, M. L.; Clerici, F.; Melis,
A. Tetrahedron 1997, 53, 1843. (d) Wang, Y.; Shi, D.; Lu, Z.; Dai, G.
Synth. Commun. 2000, 30, 707. (e) Monk, K. A.; Sarapa, D.; Mohan, R. S.
Synth. Commun. 2000, 30, 3167. (f) Paul, S.; Nanda, P.; Gupta, R.; Loupy,
A. Tetrahedron Lett. 2004, 45, 425.
† Mahidol University.
‡ Chulabhorn Research Institute.
§ Mahidol University, Salaya Campus.
10.1021/ol062429m CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/07/2006

Within the class of ring-fused isoquinolines, there have
been no reports on the synthesis and biological activity of
imidazoloisoquinolines. However, the related triazoloiso-
quinolines were reported to have some interesting pharma-
ceutical and agricultural properties.5 The berberine,6 emetine,
and related ipecac alkaloids,7 all containing benzo[a]quino-
lizine moieties,8 are reported to possess interesting biological
activities. Several methods for the preparation of the benzo-
[a]quinolizine ring system have been reported in the litera-
ture.9 Benzazocine was found as a structural component of
pentacyclic alkaloids which exhibited highly potent cyto-
toxicity.10 It was also synthesized for biological study as an
eight-membered B-ring of colchicine analogues.11
convenient synthesis of tricyclic imidazoloisoquinolin-3-ones
1, benzo[a]quinolizin-4-ones 2, and benzo[d]azocin-4-ones
3 (Figure 1). To generate heterocyclic structures relevant to
Various 1-substituted dihydroisoquinolines have been used
for the synthesis of benzazocine,12 benzo[a]quinolizines,13
and thiazolo[2,3-a]isoquinolin-3-ones14 related to imidazo-
loisoquinolin-3-ones.
Figure 1. Structures of imidazoloisoquinolin-3-ones 1, benzo[a]-
quinolizin-4-ones 2, and benzo[d]azocin-4-ones 3.
the alkaloid targets, we have investigated the cycloconden-
sation of azlactones with various dihydroisoquinolines, both
unsubstituted and 1-substituted.
Our group has been interested in the synthesis of some
pyrroloisoquinoline alkaloid derivatives.15 We now report a
(2) Audia, J. E.; Drost, J. J.; Nissen, J. S.; Murdoch, G. L.; Evrard, D.
A. J. Org. Chem. 1996, 61, 7937.
(3) (a) Peschko, C.; Winklhofer, C.; Steglich, W. Chem.-Eur. J. 2000,
6, 1147. (b) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int. Ed.
Engl. 1997, 36, 155.
(4) Takada, K.; Uehara, T.; Nakao, Y.; Matsunaga, S.; van Soest, R. W.
M.; Fusetani, N. J. Am. Chem. Soc. 2004, 126, 187.
(5) Awad, E. M.; Elwan, N. M.; Hassaneen, H. M.; Linden, A.;
Heimgartner, H. HelV. Chim. Acta 2002, 85, 320.
Azlactones 4 were prepared directly from the reaction of
benzaldehydes and N-acetylglycine or hippuric acid in the
presence of sodium acetate and acetic anhydride.1a They were
obtained in moderate yields after recrystallization from
ethanol. The required 3,4-dihydroisoquinolines 5 and 6 were
synthesized by the well-established Bischler-Napieralski
reaction starting from the arylethylamine derivatives which
were converted to the corresponding amide derivatives and
then cyclized to imines 5 and 6 using POCl3.16
(6) (a) Jeffs, P. W. In The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, London, 1967; p 41. (b) Singh, K. N. Tetrahedron Lett.
1998, 39, 4391. (c) Memetzidis, G.; Stambach, J. F.; Jung, L.; Schott, C.;
Heitz, C.; Stocklet, J. C. Eur. J. Med. Chem. 1991, 26, 605. (d) Suan, R.;
Lo´pez-Romero, J. M.; Ruiz, A.; Rico, R. Tetrahedron 2000, 56, 993.
(7) (a) Sza´ntay, C.; To¨ke, L.; Kolonits, P. J. Org. Chem. 1966, 31, 1447.
(b) Buzas, A.; Cavier, R.; Cossais, F.; Finet, J.-P.; Jacquet, J.-P.; Lavielle,
G.; Platzer, N. HelV. Chim. Acta 1977, 60, 2122.
With both key starting materials in hand, the reaction of
the simple dihydroisoquinolines with azlactones in acetoni-
trile was investigated. When 3,4-dihydroisoquinoline 5a was
treated with azlactone 4a (entry 1, Table 1) in acetonitrile
under reflux for 12 h, a single product was obtained in good
yield (88%). The product was characterized as imidazolo-
isoquinolin-3-one 1a on the basis of spectroscopic and
(8) Reviews: (a) Saraf, S. D. Heterocycles 1981, 16, 803. (b) Popp, F.
D.; Watts, R. F. Heterocycles 1977, 6, 1189.
(9) (a) Kirschbaum, S.; Waldmann, H. Tetrahedron Lett. 1997, 38, 2829.
(b) Kirschbaum, S.; Waldmann, H. J. Org. Chem. 1998, 63, 4936. (c) Van
der Eycken, E.; Deroover, G.; Toppet, S. M.; Hoornaert, G. J. Tetrahedron
Lett. 1999, 40, 9147. (d) Yamaguchi, R.; Otsuji, A.; Utimoto, K. J. Am.
Chem. Soc. 1988, 110, 2186. (e) Itoh, N.; Sugasawa, S. J. Org. Chem. 1959,
24, 2042. (f) Osbond, J. M. J. Chem. Soc. 1961, 4711. (g) Bosch, J.;
Domingo, A.; Linares, A. J. Org. Chem. 1983, 48, 1075. (h) Rubiralta, M.;
Diez, A.; Balet, A.; Bosch, J. Tetrahedron 1987, 43, 3021. (i) Rubiralta,
M.; Diez, A.; Bosch, J. Heterocycles 1988, 27, 1653.
(10) For a review of these compounds, see: Scott, J. D.; Williams, R.
M. Chem. ReV. 2002, 102, 1669. (a) Chan, C.; Heid, R.; Zheng, S.; Guo,
J.; Zhou, B.; Furuuchi, T.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127,
4596. (b) Pettit, G. R.; Knight, J. C.; Collins, J. C.; Herald, D. L.; Pettit, R.
K.; Boyd, M. R.; Young, V. G. J. Nat. Prod. 2000, 63, 793.
(11) (a) Bergemann, S.; Brecht, R.; Bu¨ttner, F.; Gue´nard, D.; Gust, R.;
Seitz, G.; Stubbs, M. T.; Thoret, S. Bioorg. Med. Chem. 2003, 11, 1269.
(b) Brecht, R.; Gunther, S.; Gue´nard, D.; Thoret, S. Bioorg. Med. Chem.
2000, 8, 557. (c) Berg, U.; Bladh, H.; Svensson, C.; Wallin, M. Bioorg.
Med. Chem. Lett. 1997, 7, 2771.
1
analytical data with a singlet at δ 6.56 (C-10b) in the H
NMR spectrum and the amide groups at 1713 and 1668 cm-1
in the IR spectrum. To further demonstrate the scope of this
cyclocondensation reaction, the reaction of various azlactones
4a-d and dihydroisoquinolines 5a-c was investigated and
the corresponding imidazoloisoquinolin-3-ones 1b-h were
obtained in yields ranging from 4 to 94% as shown in Table
1.
The mechanism for the formation of 1 is proposed to
involve the acyl iminium salt 7 formed by the reaction of
the imine group of the dihydroisoquinoline with the carbonyl
group of azlactone followed by subsequent C-N bond
formation to provide the imidazoloisoquinolin-3-ones 1
(Scheme 1).
(12) Lal, B.; Bhedi, D. N.; Gidwani, R. M.; Sankar, C. Tetrahedron 1994,
50, 9167.
(13) (a) Abdallah, T. A.; Abdelhadi, H. A.; Ibrahim, A. A.; Hassaneen,
H. M. Synth. Commun. 2002, 32, 581. (b) Roy, A.; Nandi, S.; Ila, H.;
Junjappa, H. Org. Lett. 2001, 3, 229. (c) Nemes, P.; Bala´zs, B.; To´th, G.;
Scheiber, P. Synlett 2000, 1327. (d) Nemes, P.; Bala´zs, B.; To´th, G.;
Scheiber, P. Synlett 1999, 222. (e) Mikhal’chuk, A. L.; Gulyakevich, O.
V.; Akhrem, A. A. Russ. J. Org. Chem. 1997, 33, 582. (f) Mikhal’chuk, A.
L.; Gulyakevich, O. V. Zh. Obshch. Khim. 1996, 66, 163. (g) Mikhal’chuk,
A. L.; Gulyakevich, O. V.; Akhrem, A. A. Khim. Geterotsikl. Soedin. 1996,
235. (h) Naito, T.; Katsumi, K.; Tada, Y.; Ninomiya, I. Heterocycles 1983,
20, 775. (i) Shono, T.; Hamaguchi, H.; Sasaki, M.; Fujita, S.; Nagami, K.
J. Org. Chem. 1983, 48, 1621. (j) Lenz, G. R. J. Heterocycl. Chem. 1979,
16, 433. (k) Ninomiya, I.; Kiguchi, T.; Tada, Y. Heterocycles 1977, 6, 1799.
(l) Kametani, T.; Suzuki, Y.; Terasawa, H.; Ihara, M. J. Chem. Soc., Perkin
Trans. I 1979, 1211.
(14) Rozwadowska, M. D.; Sulima, A. Tetrahedron 2001, 57, 3499.
(15) (a) Ruchirawat, S.; Mutatapat, T. Tetrahedron Lett. 2001, 42, 1205.
(b) Namsaaid, A.; Ruchirawat, S. Org. Lett. 2002, 4, 2633. (c) Ploypradith,
P.; Jinaglueng, W.; Pavaro, C.; Ruchirawat, S. Tetrahedron Lett. 2003, 44,
1363. (d) Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.; Wongbundit, S.;
Ruchirawat, S. Angew. Chem., Int. Ed. 2004, 43, 866. (e) Ploypradith, P.;
Kagan, R. K.; Ruchirawat, S. J. Org. Chem. 2005, 70, 5119.
(16) (a) Pabuccuoglu, V.; Hesse, M. Heterocycles 1997, 45, 1751. (b)
Barbier, D.; Marazano, C.; Das, B. C.; Potier, P. J. Org. Chem. 1996, 61,
9596. (c) Marsden, R.; MacLean, D. B. Can. J. Chem. 1984, 62, 1392.
5846
Org. Lett., Vol. 8, No. 25, 2006

Scheme 2. Preparation of Imidazoloisoquinolin-3-ones 8
Table 1. Preparation of Imidazoloisoquinolin-3-ones 1
entry
azlactones
isoquinolines
time (h)
yield of 1 (%)
1
2
3
4
5
6
7
8
4a
4a
4b
4a
4c
4c
4d
4c
5a
5b
5a
5c
5a
5b
5a
5c
12
3
24
48
24
3
1a (88)
1b (94)
1c (78)
1d (17)a
1e (44)
1f (64)
1g (47)
1h (4)b
Furthermore, a completely different pathway was observed
when azlactones 4 were treated with various 1-alkyl-
substituted 3,4-dihydroisoquinolines 6a-c where an imine-
enamine equilibrium is possible. For example, when 1-methyl
dihydroisoquinoline 6a (R1 ) H) was treated with azlactone
4a in acetonitrile under reflux for 2 h, the benzo[a]-
quinolizine-4-one 2a was obtained in 89% yield as shown
in entry 1, Table 2. The structure of the product was fully
24
48
a 78% recovery of imine 5c and 77% recovery of azlactone 4a. b 80%
recovery of imine 5c and 50% recovery of azlactone 4c.
The following observations were made from the above
reaction. The presence of an electron-donating group at
position 6 of the dihydroisoquinoline 5 (R2) increased the
rate of the reaction presumably by increasing the nucleo-
philicity of the imine group, as shown in entries 2 and 6
where the reaction went to completion within 3 h. However,
the presence of an electron-donating group on the aromatic
ring of the azlactone deactivated the carbonyl reactivity
resulting in a much slower rate of reaction as shown in entries
3 and 7 where a longer reaction time (24 h) was required.
As expected, when the 1-position of the dihydroisoquinoline
5 is substituted with a phenyl group, only a low yield of the
product was obtained as in entries 4 and 8. In general,
azlactones 4 with a methyl side chain (R ) Me) instead of
a phenyl group gave lower yields of the product.
We next turned our attention toward the synthesis of other
imidazoloisoquinolin-3-ones 8a-c by treatment of 3,4-
dihydroisoquinolines 5d-f with a simple azlactone 9 in
refluxing acetonitrile for 1 h. As indicated in Scheme 2, the
low yield of products 8a-c was observed. This could be
due to the formation of other byproducts and decomposition
of the simple azlactone 9.
Table 2. Preparation of Benzo[a]quinolizin-4-ones 2
yield of 2
entry
azlactones
isoquinolines
(%, cis/trans)a
1
2
3
4
5
6
7
8
4a
4a
4a
4e
4e
4e
4f
6a
6b
6c
6a
6b
6c
6a
6b
2a (89, 74:26)
2b (67, 39:61)
2c (83, 24:76)
2d (91, 78:22)
2e (77, 48:52)
2f (88, 44:56)
2g (74, 51:49)
2h (80, 36:64)
4f
a All reaction times are 2 h.
supported by spectroscopic data with absorption in the IR
spectrum at 1683 and 1654 cm-1 for the two amide groups.
The ratio of the cis/trans isomers was found to be 74:26 as
judged by 1H NMR (J ) 7.6 Hz for the cis isomer and 14.3
Hz for the trans isomer).
Scheme 1. Proposed Mechanism for the Formation of 1
The reaction was found to proceed well with other 1-ethyl
and 1-benzyl dihydroisoquinoline derivatives (6b,c) and
differently substituted azlactones 4 giving yields varying from
67 to 91% as shown in Table 2 entries 2-8. It was found
that in the case where R1 ) H in 6a the cis product
predominated. When the steric bulk of the substituents
increased (R1 ) Me, Ph), the trans isomer became the major
product.
The formation of 2 is proposed to involve the acyliminium
salt 10, analogous to compound 7, formed by the ring-
Org. Lett., Vol. 8, No. 25, 2006
5847

opening reaction at the carbonyl of azlactone 4 with C-N
bond formation. With the alkyl substitution at the C-1
position, the acyliminium salt 10 will be readily converted
to the corresponding enamide intermediate 11 which under-
goes C-C bond formation to give the product 2 via the
intermediate 12 as shown in Scheme 3.
by the lone pair of an electron on oxygen could lead to
intermediate 16 which could aromatize to give the benzo-
[d]azocin-4-one derivatives 3 (Scheme 5). All compounds
Scheme 5. Proposed Mechanism for the Formation of 3
Scheme 3. Proposed Mechanism for the Formation of 2
were fully characterized, and for compound 3a, the amide
absorptions were observed at 1666 and 1631 cm-1. Dihy-
droisoquinolines with a phenyl substituent at C-1 (5C) seem
to work slightly better than the C-1 alkyl-substituted dihy-
droisoquinolines (6a and 6c).
A completely different pathway was observed when
various 1-substituted 3,4-dihydroisoquinolines 5c, 6a, and
6c were treated with the azlactone 9 in acetonitrile at reflux
for 2 h, and benzo[d]azocin-4-one derivatives 3 were instead
obtained in moderate yield as shown in Scheme 4. The
In summary, we have devised a direct, highly efficient
route with very simple reaction conditions to imidazoloiso-
quinolin-3-ones 1, benzo[a]quinolizine-4-ones 2, and benzo-
[d]azocin-4-ones 3. The imidazoloisoquinolin-3-ones 1 could
be readily obtained by the cyclocondensation reaction of
azlactones 4 with C-1 unsubstituted 3,4-dihydroisoquinolines
5. However, under similar conditions, the C-1 substituted
3,4-dihydroisoquinolines 6 led directly to benzo[a]quinoliz-
ine-4-ones 2 and benzo[d]azocin-4-ones 3 depending on the
nature of C-1 substituents and azlactone substrates. Com-
pounds 2 lend themselves to conversion to various products,
and we are applying this methodology to the synthesis of
related alkaloids and other biologically important benzo[a]-
quinolizin-4-one derivatives.
Scheme 4. Preparation of Benzo[d]azocin-4-ones 3
Acknowledgment. We acknowledge the Thailand Re-
search Fund (TRF) for the award of Senior Research Scholar
to S.R. and the TRF Research Scholar (RMU4980048) to
N.T. We also acknowledge the facilities in the Department
of Chemistry provided by the Postgraduate Education and
Research Program in Chemistry (PERCH) Program. We are
grateful to one of the reviewers for useful comments.
mechanism of the reaction was proposed to involve acyl
iminium salt 13 which could lead to imidazoloisoquinolin-
3-ones 8, similar to the conversion of intermediate 7 to
imidazoloisoquinolin-3-ones 1, when 3,4-dihydroisoquino-
lines are unsubstituted. However, in the 1-substituted 3,4-
dihydroisoquinolines, the formation of imidazoloisoquinolin-
3-one was not favorable, and the iminium salt 13 could
undergo proton transfer to generate enolate 14 followed by
the â lactam ring formation to form lactam 15. Alternatively,
the lactam could be envisaged to form by the addition of
the amido ketene, derived from the azlactones 9, to imine.
Cleavage of the C-N bond in the strained lactam assisted
Supporting Information Available: Synthetic procedures
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL062429M
5848
Org. Lett., Vol. 8, No. 25, 2006