Unprecedented hydrothermal reaction of o-phenylaniline and related derivatives with cyclic ketones. A novel approach to the construction of phenanthridine and quinoline ring systems

Article abstract of DOI:10.1021/ol0300120

(Matrix presented) A new method for synthesizing phenanthridine and its related compounds was developed using the condensation of o-phenylaniline and its homologues with cyclic ketones under hydrothermal conditions.

Full text of DOI:10.1021/ol0300120

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1605-1608
Unprecedented Hydrothermal Reaction
of O-Phenylaniline and Related
Derivatives with Cyclic Ketones. A
Novel Approach to the Construction of
Phenanthridine and Quinoline Ring
Systems†
,|
Barun K. Mehta,‡ Kazumichi Yanagisawa,‡ Motoo Shiro,§ and Hiyoshizo Kotsuki*
Research Laboratory of Hydrothermal Chemistry, Faculty of Science,
Kochi UniVersity, Akebono-cho, Kochi 780-8520, Japan, Rigaku Corporation,
Matsubara-cho, Akishima, Tokyo 196-8666, Japan, and Laboratory of Natural
Products Synthesis, Faculty of Science, Kochi UniVersity, Akebono-cho,
Kochi 780-8520, Japan
kotsuki@cc.kochi-u.ac.jp
Received January 27, 2003
ABSTRACT
A new method for synthesizing phenanthridine and its related compounds was developed using the condensation of o-phenylaniline and its
homologues with cyclic ketones under hydrothermal conditions.
There is a growing requirement for the development of
“green” process reactions that avoid the use of potentially
harmful organic solvents.1 Hence, over the past decade,
considerable effort has been directed toward developing a
method for extending synthetic organic reactions to an
aqueous environment. As part of our study of organic
synthesis in hydrothermal reaction media, we recently
reported a novel synthesis of fully substituted pyridines via
the self-condensation of cyclic ketones in hot aqueous
ammonium chloride.2 The mechanism proposed for this
transformation involves aza-triene-type electrocyclization,3
followed by irreversible cycloalkane ring-fission, as crucial
steps (Scheme 1). As an extension of this work, we became
aware that incorporation of an aza-triene moiety into an
aromatic ring would provide a novel entry to 6-substituted
phenanthridine derivatives (Scheme 1).4 In this paper, we
report a realization of this expectation.
* Corresponding author.
† Hydrothermal Organic Reactions. Part 2. For Part 1, see ref 2.
‡ Research Laboratory of Hydrothermal Chemistry, Kochi University.
§ Rigaku Corporation.
| Laboratory of Natural Products Synthesis, Kochi University.
(1) Green Chemistry. Designing Chemistry for the EnVironment; Anastas,
P. T., Williamson, T. C., Eds.; American Chemical Society: Washington,
DC, 1996. Green Chemistry: Frontiers in Benign Chemical Syntheses and
Processes; Anastas, P. T., Williamson, T. C., Eds.; Oxford University
Press: New York, 1999.
(2) Kotsuki, H.; Mehta, B. K.; Yanagisawa, K. Synlett 2001, 1323.
(3) Thermal Electrocyclic Reactions; Marvell, E. N.; Academic Press:
New York, 1980.
10.1021/ol0300120 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/19/2003

Scheme 1
Phenanthridines are an important class of heterocyclic
structures of these products were unequivocally determined
by their X-ray crystallographic analyses.14 Our proposed
compounds in materials science and in medicinal chemistry
due to their significant biological activities.5 Although there
have been several studies on the synthesis of these molecules,
most of them require multistep syntheses or strictly anhy-
drous conditions.6 Thus, there is a need for more versatile
and simpler methods that can serve as safe and environmen-
tally friendly processes. As one promising approach, we were
particularly interested in reactions in hot water, since it has
been shown that the solvent properties of water at higher
temperatures are roughly equivalent to those of acetone at
25 °C.7
(8) All reactions were conducted in a Teflon autoclave reaction vessel
(for higher temperature reactions, a Hasteloy-C reaction vessel was used)
with cone and thread fittings and an internal volume of 20 mL, designed to
withstand temperatures up to 250 °C. Typical Experimental Procedure
for the Reaction of 1a with 2a (entry 1). A mixture of o-phenylaniline‚
HCl (1a, 144 mg, 0.7 mmol) and cyclohexanone (2a; 151 mg, 1.54 mmol)
in 15 mL of H2O was placed in an autoclave reaction vessel and allowed
to react at 250 °C for 24 h. After basification with saturated NaHCO3, the
mixture was extracted with AcOEt. The crude product was purified by
preparative TLC (hexane/AcOEt ) 9:1) to afford 3a (126 mg, 72%) and
3b (28 mg, 12%). Compound 3a: colorless oil; UV (C6H6) λmax (ꢀ) 344.0
(680), 329.0 (810), 293.0 (1780); FTIR (neat) ν 1613, 1586, 1487, 1462,
1
758, 725 cm-1; H NMR (400 MHz, CDCl3) δ 0.93 (3H, t, J ) 7.3 Hz),
First, we examined the reaction of o-phenylaniline‚HCl
(1a) with various cyclic ketones (see Table 1).8 When a
mixture of 1a and 2.2 equiv of cyclohexanone (2a) in water
(0.04 M solution) was heated at 250 °C for 24 h, 6-pen-
tylphenanthridine (3a) was obtained in 72% yield along with
a small amount (12%) of byproduct 3b (entry 1).9 The latter
compound may be formed by a quite unusual cyclohexyla-
tion10 of 1a at the para-position, followed by annulation with
2a.11 Under similar conditions, cycloheptanone (2b) and
cyclooctanone (2c) gave the desired 6-substituted phenan-
thridine derivatives 3c and 3e in moderate yields (entries 2
and 3). In these examples, 3d and 3f could be detected as
only very minor byproducts.12 Again, as in our previous
observation,2 increasing the hydrophobicity of the substrates
tends to retard the reaction progress, probably due to their
reduced solubility in the hot water system.
1.43 (2H, sextet, J ) 7.3 Hz), 1.47-1.56 (2H, m), 1.88-1.96 (2H, m),
3.36 (2H, dd, J ) 8.1, 6.0 Hz), 7.61 (1H, ddd, J ) 8.3, 7.1, 1.5 Hz), 7.68
(1H, ddd, J ) 8.1, 7.1, 1.2 Hz), 7.70 (1H, ddd, J ) 8.1, 7.1, 1.5 Hz), 7.82
(1H, ddd, J ) 8.3, 7.1, 1.2 Hz), 8.13 (1H, dd, J ) 8.1, 1.5 Hz), 8.25 (1H,
dd, J ) 8.2, 1.2 Hz), 8.53 (1H, dd, J ) 8.3, 1.5 Hz), 8.63 (1H, dt, J ) 8.3,
1.2 Hz); 13C NMR (100 MHz, CDCl3) δ 14.05, 22.60, 29.35, 32.18, 36.41,
121.88, 122.46, 123.62, 125.22, 126.23, 126.35, 127.19, 128.54, 129.51,
130.25, 132.94, 143.71, 162.50. Compound 3b: colorless oil; FTIR (neat)
ν 1613, 1584, 1495, 1449, 831, 787, 764 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.92 (3H, t, J ) 7.2 Hz), 1.26-1.67 (9H, m), 1.79-2.02 (7H, m), 2.76
(1H, tt, J ) 11.7, 3.4 Hz), 3.33 (1H, dd, J ) 8.1, 7.8 Hz), 7.58 (1H, dd, J
) 8.3, 1.7 Hz), 7.65 (1H, ddd, J ) 8.0, 7.8, 1.2 Hz), 7.79 (dt, J ) 7.8, 1.2
Hz), 8.05 (1H, d, J ) 8.3 Hz), 8.22 (1H, dd, J ) 8.0, 1.2 Hz), 8.34 (1H,
d, J ) 1.7 Hz), 8.65 (1H, dd, J ) 7.8, 1.2 Hz); 13C NMR (100 MHz, CDCl3)
δ 14.03, 22.58, 26.16, 26.91 (×2), 29.48, 32.13, 34.67 (×2), 36.20, 44.94,
119.23, 122.41, 123.40, 125.15, 126.35, 126.98, 128.13, 129.10, 130.09,
132.99, 142.04, 146.21, 161.54.
(9) We found that the product ratio was highly dependent upon the molar
concentration of 1a: at 0.04 M, 3a (72%) and 3b (12%) (Table 1, entry 1);
at 0.07 M, 3a (54%) and 3b (16%); at 0.1 M, 3a (46%) and 3b (23%); at
0.2 M, 3a (40%) and 3b (40%); and at 0.4 M, 3a (32%) and 3b (42%).
(10) There is only one precedent for this type of cycloalkylation of
anilines: Gataullin, R. R.; Kazhanova, T. V.; Fatykhov, A. A.; Spirikhin,
L. V.; Abdrakhmanov, I. B. Russ. Chem. Bull. 2000, 49, 174. Mechanistic
studies on this unusual reaction are currently in progress and will be reported
in the future.
Unexpectedly, when cyclobutanone (2d) and cyclopen-
tanone (2e) were used as ketone components, completely dif-
ferent types of ring-fused compounds 3g and 3i, respectively,
were obtained as the major product (entries 4 and 5).13 The
(11) In a separate reaction, we confirmed that no detectable amount of
3b was formed by the treatment of 3a with 2a under the same conditions.
(12) Compound 3f could only be detected by GCMS analysis of the crude
sample.
(4) For a related work on the synthesis of phenanthridines from
o-phenylanilines via radical cyclization, see: Leardini, R.; Tundo, A.;
Zanardi, G. Synthesis 1985, 107.
(13) Compound 3g: oil; FTIR (neat) ν 1597, 1574, 1478, 1458, 760
1
cm-1; H NMR (400 MHz, CDCl3) δ 2.22 (2H, quint, J ) 6.1 Hz), 3.15
(5) Keene, B. R. T.; Tissington, P. AdV. Heterocycl. Chem. 1971, 13,
315. Troll, T. In Houben-Weyl-Methods of Organic Chemistry; Georg
Thieme Verlag: Stuttgart, 1992; Vol. E7b, pp 157-204.
(6) Lyse´n, M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org. Lett. 2002,
4, 257. Pawlas, J.; Begtrup, M. Org. Lett. 2002, 4, 2687 and references
therein.
(7) For reviews see: Siskin, M.; Katritzky, A. R. Science 1991, 254,
231. Katritzky, A. R.; Allin, S. M.; Siskin, M. Acc. Chem. Res. 1996, 29,
399. Bro¨ll, D.; Kaul, C.; Kra¨mer, A.; Krammer, P.; Richter, T.; Jung, M.;
Vogel, H.; Zehner, P. Angew. Chem., Int. Ed. 1999, 38, 2998. Savage, P.
E. Chem. ReV. 1999, 99, 603. Akiya, N.; Savage, P. E. Chem. ReV. 2002,
102, 2725.
(2H, t, J ) 6.1 Hz), 3.30 (2H, t, J ) 6.1 Hz), 7.41 (1H, dd, J ) 7.1, 1.0
Hz), 7.56 (1H, dd, J ) 8.0, 1.2 Hz), 7.66-7.70 (2H, m), 8.08 (1H, d, J )
8.0 Hz), 8.39 (1H, d, J ) 8.3, 1.0 Hz), 8.47 (1H, d, J ) 8.1, 1.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 23.26, 30.84, 35.31, 119.74, 122.18, 123.17,
123.85, 125.95, 126.31, 128.54, 129.06, 130.28, 132.80, 139.64, 143.48,
160.15. Compound 3i: mp 92.0-94.0 °C; FTIR (KBr) ν 2943, 1572, 1460,
1
1313, 763 cm-1; H NMR (400 MHz, CDCl3) δ 2.00-2.13 (4H, m), 3.30
(2H, dd, J ) 6.4, 5.1 Hz), 3.49 (2H, dd, J ) 6.8, 4.9 Hz), 7.45 (1H, d, J
) 7.3 Hz), 7.58 (1H, ddd, J ) 8.3, 7.3, 1.2 Hz), 7.65-7.70 (2H, m), 8.04
(1H, d, J ) 8.3 Hz), 8.49 (2H, dd, J ) 8.3, 1.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 23.90, 25.95, 34.42, 38.33, 120.42, 122.16, 123.81, 126.16, 126.59,
128.52, 128.97, 129.23, 129.95, 134.38, 143.07, 143.18, 163.69.
1606
Org. Lett., Vol. 5, No. 10, 2003

Table 1. Reaction of Aniline‚HCl Salts with Cyclic Ketones under Hydrothermal Conditionsa
a Unless otherwise noted, all reactions were performed with 1 (0.7 mmol) and 2 (1.54 mmol) in water (15 mL). b Used 3.0 equiv of 2. c 2,4-Dimethylquinoline
was also isolated in 5% yield. d Trace amount of 2-butyl-4-methylquinoline was detected.
mechanism for the formation of these compounds is outlined
in Scheme 2. At the initial stage, 1a should condense with
2d or 2e to provide imine 4, which is further converted to
the spiro-compound 5 via thermal 6-π electrocyclization. This
compound is then aromatized to afford cyclobutylamine 6,
which undergoes spontaneous [1,3]-migrative ring expan-
sion15 followed by aromatization in the air, thus giving the
corresponding ring-fused phenanthridines 3g and 3i. In
contrast to the case with 2a-c, the remarkably different mode
of reactivity for 2d and 2e can be understood by invoking
their inherent ring strain at the stage from 6 to 7.
(15) Berson, J. A. In Rearrangements in Ground and Excited States; de
Mayo, P., Ed.; Academic Press: New York, 1980; Vol. 1, pp 311-390.
Wong, H. N. C.; Lau, K.-L.; Tam, K.-F. In Small Ring Compounds in
Organic Synthesis I; de Meijere, A., Ed.; Springer-Verlag: Berlin, 1986;
pp 138-141.
(14) See Supporting Information.
Org. Lett., Vol. 5, No. 10, 2003
1607

Scheme 2
Scheme 3
3p, implies the possibility of equilibration like that shown
in Scheme 3 under these conditions.
In conclusion, we have described for the first time a novel
and simple method for preparing a variety of phenanthridines
and related compounds via the condensation of o-phenyl-
aniline or 2-isopropenylaniline with cyclic ketones under
hydrothermal conditions.17 The results illustrate the potential
utility of this method as an environment-friendly process,
and further studies to elucidate the reaction mechanism and
extend the scope of this reaction are now in progress.
We extended this methodology to the reaction of
2-isopropenylaniline‚HCl (1b) to obtain quinoline deriva-
tives. As expected, the reaction with 2a proceeded quite
smoothly through a normal pathway to afford quinoline 3k
in 64% yield (entry 6). Although the yields were not always
so high, the reactions with 2d and 2e again gave an
unpredictable mixture of products, and we found that their
product distributions were strongly dependent upon the
reaction temperature. Thus, heating 1b and 2d at 200 °C for
24 h resulted in 3l, 3m, and 3n in a combined yield of 28%
and in a ratio of 64:13:23 (entry 7),16 while the same reaction
at 100 °C gave mostly 3l (27% yield) (entry 9). On the other
hand, the use of 2e led to a different mixture, from which
3o, 3p, and p-cyclopentylaniline (3q) could be isolated
(entries 10-12). Among these products, 3o was always a
major product and 3p and 3q were isolated as minor
components. The formation of tricyclic compounds, 3n and
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research from the Japan Society
for the Promotion of Science and by a Research Grant from
the Research Institute of Innovative Technology for the Earth
(RITE) (H.K.). We also thank Prof. Y. Fukuyama of
Tokushima Bunri University for MS/HRMS measurements.
Supporting Information Available: Experimental pro-
cedures and spectral data for compound 3 as well as X-ray
data for the picrate salt of compound 3i. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0300120
(16) In this case 2,4-dimethylquinoline was also detected as a minor
byproduct (5% yield). This might be formed by condensation of 1b with
acetone, formed by decomposition of 1b (see Scheme 3), followed by
electrocyclization and aromatization.
(17) Similar reactions using acyclic ketones such as 3-pentanone and
benzophenone gave only a complex mixture of products.
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Org. Lett., Vol. 5, No. 10, 2003