One-step synthesis of the tricyclic core of martinellic acid from 2-(cyanomethyl)-3-oxo-N-arylbutanamides

Article abstract of DOI:10.1021/jo701551f

(Chemical Equation Presented) A SnCl4·5H₂O-mediated facile and efficient one-step synthesis of the tricyclic core of martinellic acid from readily available 2-(cyanomethyl)-3-oxo-N-arylbutanamides was developed and a mechanism involving consecu

Full text of DOI:10.1021/jo701551f

One-Step Synthesis of the Tricyclic Core of
Martinellic Acid from
2-(Cyanomethyl)-3-oxo-N-arylbutanamides
Zhiguo Zhang, Qian Zhang,* Zihong Yan, and Qun Liu*
Department of Chemistry, Northeast Normal UniVersity,
Changchun 130024, China
zhangq651@nenu.edu.cn; liuqun@nenu.edu.cn
ReceiVed July 16, 2007
FIGURE 1. Structures of martinellic acid and martinelline.
approaches.9,10 Among these methods, the simplicity of the core
connectivity of martinellic acid produced in two steps from
arylthio-substituted succinic anhydrides and imines deserves
special mention although some limitations in terms of the
starting materials and efficiency exist (Scheme 1).9j
Domino reactions are highly efficient processes that allow
the synthesis of complex molecules starting from simple,
inexpensive starting materials, in a straightforward fashion.11
In the last two decades, various types of domino reactions have
been developed and employed in the synthesis of heterocyclic
compounds.12 During our research on syntheses of carbocyclic13
and heterocyclic compounds14 by domino reactions, we devel-
A SnCl4‚5H2O-mediated facile and efficient one-step syn-
thesis of the tricyclic core of martinellic acid from readily
available 2-(cyanomethyl)-3-oxo-N-arylbutanamides was de-
veloped and a mechanism involving consecutive hydrolysis
of a cyano group and a double annulation process is
proposed.
(9) Selected examples of synthesis of the pyrroloquinoline core: (a)
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Tetrahedron 2001, 57, 5615-5624. (g) Batey, R. A.; Powell, D. A. Chem.
Commun. 2001, 2362-2363. (h) Hara, O.; Sugimoto, K.; Makino, K.;
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Naito, T. Synlett 2006, 893-896. (e) Takeda, Y.; Nakabayashi, T.; Shirai,
A.; Fukumoto, D.; Kiguchi, T.; Naito, T. Tetrahedron Lett. 2004, 45, 3481-
3484. (f) Hadden, M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.;
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Y.; Mahmud, H.; Moningka, R.; Lovely, C. J.; Dias, H. V. R. Tetrahedron
2006, 62, 8755-8769. (h) Ikeda, S.; Shibuya, M.; Iwabuchi, Y. Chem.
Commun. 2007, 504-506.
The pyrrolo[3,2-c]quinoline ring system is known as a core
structure unit of bioactive molecules of either synthetic1 or
natural source2 for many years. Several derivatives of such a
tricyclic angular heterocycle possess a wide spectrum of
biological activities,3 including most notably antitumor proper-
ties,4 gastric (H+/K+)-ATPase inhibitor,5 hypotensive,6 anti-
inflammatory activities,7 and others. The relatively recent
isolation of martinella alkaloids (Figure 1) from the organic
extracts of Martinella iquitosensis roots,2 which evidenced
antagonist properties against bradykinin receptors,8 renewed
interest from several research groups to plan new synthetic
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Int. Ed. 2007, 46, 1570-1581.
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Chem. 1990, 33, 527-533. (b) Escolano, C.; Jones, K. Tetrahedron Lett.
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B. F.; Winterstein, A.; Bickerton, R. K.; Halliday, R. P.; Pals, D. T. J.
Med. Chem. 1971, 14, 1060-1066.
(7) Skonicki, J. S.; Kearney, R. M. U.S. patent 5,216,162, and references
cited therein.
(12) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341-5378 and
references cited therein.
(13) (a) Zhang, Q.; Sun, S.; Hu, J.; Liu, Q.; Tan, J. J. Org. Chem. 2007,
72, 139-143. (b) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J.
Am. Chem. Soc. 2005, 127, 4578-4579.
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10.1021/jo701551f CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/14/2007
9808
J. Org. Chem. 2007, 72, 9808-9810

TABLE 1. Synthesis of Pyrrolo[3,2-c]quinolines 2 from 1a
SCHEME 1
substrate
time
(h)
product
yieldb
(%)
SCHEME 2. Synthesis of Pyrrolo[3,2-c]quinoline 2a from 1a
entry
1
R1
R2
R3
2
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
OMe
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6.0
7.5
7.0
7.0
22
24
6.0
77
2a
2b
2c
2d
2e
2f
2g
2h
92
88
83
93
85
85
82
71
68
94c
Me
H
OMe
OEt
Me
Cl
oped new strategies for the preparation of furo[2,3-b]quinolines
and highly substituted pyridin-2(1H)-ones through a novel
SnCl4-mediated tandem ring-opening/recyclization reaction and
the Vilsmeier-Haack reaction, respectively, starting from the
easily available 1-acetyl N-aryl cyclopropanecarboxamides.15
The successful synthesis of furo[2,3-b]quinolines15a prompted
us to pay special attention to the development of new synthetic
strategies for the preparation of fused quinoline derivatives by
suitably selecting the substituents on the active methylene group
of 1-acetyl N-arylcarboxamides. In this paper, we describe a
one-step, atom economical procedure for the preparation of the
tricyclic core of martinellic acid 2 from the readily available
2-(cyanomethyl)-3-oxo-N-arylbutanamides 1.
Cl
Me
H
H
72
8.0
2i
10
1j
2j + 3jc
a Reactions were carried out with SnCl4‚5H2O (1.2 equiv) and 1 (2.0
mmol) in xylene at 60 °C. b Isolated yield. c 3j is the regioisomer of 2j and
the ratio of the two regioisomers (2j:3j) is about 5:1 (estimated by 1H NMR
spectrum).
Our initial studies were focused on the SnCl4‚5H2O-mediated
reaction of 2-(cyanomethyl)-N-(2-methoxyphenyl)-3-oxobu-
tanamide (1a), which was obtained in 88% yield from N-(2-
methoxyphenyl)-3-oxobutanamide and 2-bromoacetonitrile based
on known methods.15a,16 After the optimization of the reaction
conditions, including the reaction temperature, the solvent, and
the amount of SnCl4‚5H2O, we were pleased to discover that
in the presence of 1.2 equiv of SnCl4‚5H2O, 1a could be
efficiently transformed into a pyrrolo[3,2-c]quinoline derivative
2a in 92% yield at 60 °C in xylene for 6.0 h (Scheme 2, Table
1, entry 1). The structure of 2a was confirmed by the X-ray
single crystal analysis, showing the expected cis ring fusion
(Figure 2). It is noteworthy that the above transformation from
1a to 2a represents one of the simplest routes to the tricyclic
core of martinellic acid.9,10
FIGURE 2. ORTEP drawing of 2a.
SCHEME 3
high regioselectivity is observed in the transformation from 1i
to 2i (Table 1, entry 9). However, for the substrate 1k with a
strongly electron-withdrawing COOEt group on the aryl ring,
no desired 2k was observed. Instead, an annulation product 4k
was produced in 61% yield (Scheme 3).
Next, a series of 2-(cyanomethyl)-3-oxo-N-arylbutanamide
substrates 1 were prepared (in yields of 64-90% by alkylation
of the commercially available 3-oxo-N-arylbutanamides with
2-bromoacetonitrile15,16) and subjected to the above optimal
reaction conditions with the aim to determine its scope. Some
of the results are summarized in Table 1. It is clear that the
substrates 1 with one or two electron-donating groups on the
aryl ring are reactive and lead to the corresponding pyrrolo-
[3,2-c]quinoline derivatives 2 in excellent yields (Table 1, entries
1-3, 5-7, and 10). In the case of precursors 1h and 1i with an
electron-withdrawing chloro group on the aryl ring, the desired
products 2h and 2i are also obtained in high yields with
prolonged reaction times (Table 1, entries 8 and 9). In addition,
On the basis of all of the above results and our previous
work,15 the overall transformation may involve the hydrolysis
of the cyano group of 2-(cyanomethyl)-3-oxo-N-arylbutanamide
1,17 followed by proton (generated from the hydrolysis of
SnCl418) catalyzed aza-annulation and dehydration to form the
pyrrolinone intermediate 4. The next SnCl4 mediated Micheal
addition of a water to the intermediate 4 provides a cis-fused
ring intermediate 7, which undergoes an intramolecular annu-
lation to produce the pyrroloquinolines 2 (Scheme 4). In our
research, the above proposed mechanism was proven by some
further experiments. Under otherwise identical conditions as
described in Table 1, entry 1, but with catalytic quantity of
(15) (a) Zhang, Z.; Zhang, Q.; Sun, S.; Xiong, T.; Liu, Q. Angew. Chem.,
Int. Ed. 2007, 46, 1726-1729. (b) Pan, W. Dong, D. Wang, K.; Zhang, J.;
Wu, R.; Xiang, D.; Liu, Q. Org. Lett. 2007, 9, 2421-2423.
(16) For reaction procedure in detail please see the Supporting Informa-
tion.
(17) Demir, A. S.; Emrullahoglu, M.; Ardahan, G. Tetrahedron 2007,
63, 461-468.
(18) The constitution of aqueous Tin(IV) chloride has been studied in
detail, please see: Taylor, M. J.; Coddinfton, J. M. Polyhedron, 1992, 11,
1531-1544 and references cited therein.
J. Org. Chem, Vol. 72, No. 25, 2007 9809

SCHEME 4. The Proposed Mechanism for the Synthesis of
Pyrrolo[3,2-c]quinolines 2
the ready availability of substrates from cheap starting materials,
make this new method very powerful. The extension of the
scope of the methodology including the introduction of a
hydrogen atom instead of the angular methyl group in the
tricyclic core and the examination of biological activity of the
pyrrolo[3,2-c]quinolines are currently under investigation in our
laboratory.
Experimental Section
General procedure for the preparation of pyrrolo[3,2-c]-
quinoline 2 from 2-(cyanomethyl)-3-oxo-N-arylbutanamide 1 (2a
as an example): A mixture of 2-(cyanomethyl)-N-(2-methoxyphe-
nyl)-3-oxobutanamide (1a) (492 mg, 2.0 mmol) and SnCl4‚5H2O
(840 mg, 2.4 mmol) was well stirred for 6.0 h at 60 °C in xylene
(2 mL). Cooling the reaction mixture to 0 °C was followed by
basification with 5 mL of sodium hydroxide solution (15%). Then
the mixture was filtrated and washed with water (10 mL) and
dichloromethane (3 mL) and dried in vacuum to afford compound
2a as a white solid (450 mg, 92%).
SCHEME 5. Reaction of 1a in the Presence of 0.2 or 0.5
equiv of SnCl4‚5H2O
1
Selected data for 2a: mp 140-141 °C; H NMR (500 MHz,
DMSO) δ 1.43 (s, 3H), 2.26 (q, J ) 10.5 Hz, 1H), 2.51 (q, J )
10.5 Hz, 1H), 3.05 (t, J ) 10.0 Hz, 1H), 3.79 (s, 3H), 6.91-6.93
(m, 1H), 7.01-7.05 (m, 2H), 8.79 (s, 1H), 9.33 (s, 1H); 13C NMR
(125 MHz, DMSO) δ 29.4, 35.1, 47.9, 56.5, 59.9, 111.1, 119.0,
123.8, 124.2, 128.0, 146.2, 168.6, 174.0; MS calcd m/z 246.1, found
247.1 [(M + 1)]+; IR (KBr, neat) ν 3206, 3073, 2973, 2852, 1689,
1497, 1422, 1265, 1181, 1053, 985, 867, 787, 738 cm-1. Anal.
Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.33; H, 5.61; N, 11.48.
SnCl4‚5H2O (0.2 equiv) for 12 h, the reaction of 1a gave a
pyrrolinone 4a16 in 66% yield and a trace amount of 2a (Scheme
5). Furthermore, with 0.5 equiv of SnCl4‚5H2O for 6 h, 39%
4a and 38% 2a were obtained from 1a, respectively. In addition,
the quantitative transformation from 4a to 2a was achieved with
1.0 equiv of SnCl4‚5H2O at 60 °C for 6 h. However, upon
treatment of 4a with 1.0 equiv of anhydrous SnCl4 at 60 °C for
12 h, no reaction occurred. These above results suggest that 4
is involved as the intermediate in the transformation from 1
into 2, and during the transformation from 4 into 2, water plays
an important role and a stoichiometric amount of SnCl4‚5H2O
is also required.
In conclusion, we have developed a new strategy for the
synthesis of the tricyclic core of martinellic acids 2 through a
SnCl4-mediated domino reaction of the 2-(cyanomethyl)-3-oxo-
N-arylbutanamides 1. The advantages of this method, which
include high yields, mild conditions, high regioselectivity, and
Acknowledgment. Financial support of this research by the
NNSFC (20772015), Science foundation for young teachers of
Northeast Normal University (20060301), and analysis and
testing foundation of Northeast Normal University is greatfully
acknowledged.
Supporting Information Available: Experimental procedures,
1
full characterization data, and copies of H and 13C NMR spectra
for all the new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO701551F
9810 J. Org. Chem., Vol. 72, No. 25, 2007