Synthesis of isoquinolines and naphthyridines by electrophilic ring closure of iminoalkynes.

Article abstract of DOI:10.1021/ol010136h

Substituted isoquinolines and naphthyridines have been prepared in good to excellent yields by the reaction of iminoalkynes with a variety of electrophiles under mild reaction conditions. Reaction: see text.

Full text of DOI:10.1021/ol010136h

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ORGANIC
LETTERS
2001
Vol. 3, No. 19
2973-2976
Synthesis of Isoquinolines and
Naphthyridines by Electrophilic Ring
Closure of Iminoalkynes
Qinhua Huang, Jack A. Hunter, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received June 19, 2001
ABSTRACT
Substituted isoquinolines and naphthyridines have been prepared in good to excellent yields by the reaction of iminoalkynes with a variety
of electrophiles under mild reaction conditions.
The isoquinoline backbone appears in numerous natural
products. Thus, the synthesis of isoquinolines has received
much recent attention.1 Although classical methods2 have
been frequently employed in the total synthesis of isoquino-
line alkaloids, these approaches often have drawbacks.
Recently, substituted isoquinolines have been synthesized
by employing palladium chemistry.3 We have reported the
formation of numerous 3,4-disubstituted isoquinolines by the
palladium-catalyzed annulation of internal alkynes (eq 1).4
During the course of this latter study, we discovered an
interesting reaction which utilizes an external electrophile,
I2, to cyclize an iminoalkyne to a 3,4-disubstituted isoquino-
line in modest yield (eq 4). The requisite iminoalkynes can
be easily prepared by the Sonogashira reaction of a 2-halo-
benzaldehyde and a terminal alkyne, followed by reaction
(1) (a) Buske, A.; Busemann, S.; Mu¨hlbacker, J.; Schmidt, J.; Porzel,
A.; Bringmann, G.; Adam, G. Tetrahedron 1999, 55, 1079. (b) Bringmann,
G.; Holenz, J.; Weirich, R.; Ru¨benacker, M.; Funke, C. Tetrahedron 1998,
54, 497. (c) Xu, X.-Y.; Qin, G.-W.; Xu, R.-S.; Zhu, X.-Z. Tetrahedron
1998, 54, 14179. (d) Brossi, A. Heterocycles 1988, 12, 2905. (e) Fitzgerald,
J. J.; Michael, F. E.; Olofson, R. A. Tetrahedron Lett. 1994, 49, 9191.
(2) (a) Whaley, W. M.; Govindachari, T. R. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 74-150. (b) Kohno,
H.; Yamada, K. Heterocycles 1999, 51, 103. (c) Flippin, L. A.; Muchowski,
J. M. J. Org. Chem. 1993, 58, 2631. (d) Aubert, T.; Farnier, M.; Hanquet,
B.; Guilard, R. Synth. Commun. 1987, 17, 1831. (e) Bobbitt, J. M.; Bourque,
A. J. Heterocycles 1987, 25, 601.
(3) (a) Diederen, J. J. H.; Sinkeldam, R. W.; Fru¨hauf, H.-W.; Hiemstra,
H.; Vrieze, K. Tetrahedron Lett. 1999, 40, 4255. (b) Wu, G.; Geib, S. J.;
Rheingold, A. L.; Heck, R. F. J. Org. Chem. 1988, 53, 3238. (c) Maassarani,
F.; Pfeffer, M.; Le Borgne, G. J. Chem. Soc., Chem. Commun. 1987, 565.
(d) Wu, G.; Rheingold, A. L.; Geib, S. J.; Heck, R. F. Organometallics
1987, 6, 1941.
3-Substituted isoquinoline derivatives can be prepared by the
palladium- and copper-catalyzed cross coupling of terminal
alkynes and subsequent ring closure by catalytic CuI (eq 2)5
or by the reaction of o-(1-alkynyl)benzaldehydes with NH3
(eq 3).6a
(4) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306.
10.1021/ol010136h CCC: $20.00 © 2001 American Chemical Society
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cyclization had little effect on the product yield. PhSCl has
also been employed as an electrophile. The results are
summarized in Table 1, entries 9 and 15. In general, these
reactions take 24 h and afford only modest yields of the
corresponding sulfides.
Scheme 1
In earlier work, we reported that catalytic amounts of CuI
would close these same iminoalkynes to isoquinolines with
a hydrogen in the 4 position.5 We now wish to report that
catalytic amounts of AgNO3 will effect the same transforma-
tion and the reaction occurs under milder reaction conditions,
is more general, and the yields are higher. Thus, 0.25 mmol
of iminoalkyne 1 has been allowed to react with 2 equiv of
AgNO3 in 7 mL of CHCl3 at 50 °C. After 1 day, isoquinoline
4 was obtained in 90% yield. Further study indicated that 5
mol % of AgNO3 is enough to close the six-membered ring
in good yield. Thus, the following standard conditions have
been employed in all subsequent experiments: 0.25 mmol
of the iminoalkyne and 5 mol % of AgNO3 were stirred at
50 °C in 7 mL of CHCl3 for the appropriate reaction time.
The reaction takes approximately 24 h at 50 °C and gives
decent yields of the corresponding cyclization products
(entries 4, 10, and 11).
A variety of isoquinolines and naphthyridines have been
prepared by this electrophilic ring closure reaction. The
results are summarized in Table 1. Iodine and ICl close the
six-membered ring the fastest. These reactions are complete
in 0.5 h, although the yields from iminoalkyne 1 are
somewhat less than those of PhSeCl (entry 3) and AgNO3
(entry 4). PhSCl and p-O2NC6H4SCl are the least efficient
electrophiles for this reaction. Their reactions are still
incomplete after 3 days, and yields of sulfides are generally
low.
The introduction of electron-donating groups onto the
phenyl group directly attached to the triple bond of the alkyne
increased the yield using PhSeCl from 76% (entry 3) to 95%
(entry 6). This indicates that electron-rich aryl groups
facilitate cyclization. From entries 7-9, one can see that
imine 8 containing an enyne moiety reacts well with PhSeCl,
I2, and PhSCl, affording the desired products in fair to good
yields.
To further test the scope of this electrophilic ring closure,
alkyl-substituted acetylenes such as iminoalkynes 12 and 14
have been allowed to react with some of these same
electrophiles. Cacchi8 has reported that alkyl-substituted o-(1-
alkynyl)phenols can react with I2 to give substituted benzo-
furans. However, in our chemistry, I2 does not react with
either iminoalkyne 12 or 14, and neither do PhSeCl or PhSCl.
Since a phenyl group is a better electron donor than an alkyl
group, the reaction of I2 with the carbon-carbon triple bond
in iminoalkynes such as 12 and 14 most likely forms a
cationic intermediate such as A, where the positive charge
is located on the carbon next to the aromatic ring. Obviously,
with tert-butylamine (Scheme 1).5 This efficient approach
to a 4-iodoisoquinoline encouraged us to investigate this
process, improve the reaction conditions, and extend the
reaction to other electrophiles. Herein we report the results
of that study.
First, we studied the reaction of iminoalkyne 1 and I2. A
variety of bases, such as NaHCO3, Na2CO3, K2CO3, NaOCO2-
CH3,7 pyridine, 2,4,6-trimethylpyridine, and triethylamine,
different solvents, and different amounts of I2 have been
examined. This work has afforded a general procedure for
the preparation of 4-iodoisoquinolines and 4-iodonaphthy-
ridines. The following are the optimal reaction conditions:
0.25 mmol of the iminoalkyne, 6 equiv of I2, and 3 equiv of
NaOCO2CH3 in 7 mL of CH3CN are stirred at room
temperature for an appropriate amount of time. The results
of these I2 cyclization reactions are summarized in Table 1,
entries 1, 8, and 12. The reaction is complete in 0.5 h and
affords good to excellent yields of 4-iodonaphthalenes and
8-iodonaphthyridines.
ICl, a stronger electrophile, has also been employed, and
the corresponding cyclization products have been observed
in yields comparable to those obtained using I2. The reaction
times are also essentially identical to those of I2. The results
are summarized in Table 1, entries 2, 13, and 16.
The next electrophile studied was PhSeCl. Very similar
yields, 74% and 78%, respectively, of isoquinoline 3 were
obtained from iminoalkyne 1 using 1 or 2 equiv of PhSeCl.
The concentration of the reactants seems to play a role in
this reaction. A more concentrated reaction gave a slightly
lower yield. Thus, we chose 0.25 mmol of the iminoalkyne
and 2 equiv of PhSeCl in 7 mL of CH2Cl2 at room
temperature as our standard reaction conditions for the
reaction of PhSeCl. The results from various cyclizations
using this procedure are summarized in Table 1, entries 3,
6, 7, and 14. In general, the reaction of iminoalkynes and
PhSeCl requires 1-3 days, and good to excellent yields of
selenium-containing isoquinolines and naphthyridines are
obtained.
The electrophile p-O2NC6H4SCl has been examined under
the optimum reaction conditions for PhSeCl. The isoquino-
line product 5 expected from iminoalkyne 1 was obtained
in a rather low yield of 47%. An increase in the reaction
temperature or the addition of a Lewis acid to induce the
(5) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553.
(6) (a) Sakamoto, T.; Kondo, Y.; Miura, N.; Hayashi, K.; Yamanaka,
H. Heterocycles 1986, 24, 2311. (b) Sun, Q.; LaVoie, E. J. Heterocycles
1996, 43, 737. (c) Anderson, C. D.; Sharp, J. T. J. Chem. Soc., Perkin
Trans. 1 1980, 1331.
(7) Brillon, D.; Sauve´, G. J. Org. Chem. 1990, 55, 2246.
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Org. Lett., Vol. 3, No. 19, 2001

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Table 1. Synthesis of Substituted Isoquinolines and Naphthyridinesa
a The reactions were run under the following conditions, unless otherwise specified: 0.25 mmol of the iminoalkyne and 2 equiv of electrophile in 7 mL
of CH2Cl2 at room temperature. b 0.25 mmol of the iminoalkyne, 6 equiv of I2, and 3 equiv of NaOCO2CH3 in 7 mL of CH3CN at room temperature. c 4
equiv of ICl was used. d 0.25 mmol of the iminoalkyne and 5 mol % of AgNO3 in 7 mL of CHCl3 at 50 °C.
the formation of isoquinolines from such an intermediate is
impossible. However, AgNO3 reacts with iminoalkynes 12
and 14 to give the expected monosubstituted isoquinolines
in good yields (entries 10 and 11). The success of the silver-
catalyzed cyclization suggests that silver forms a complex
in which the silver simply coordinates to the triple bond,
rather than forming a carbon-bearing cation.
From entries 12 and 13, one can see that the introduction
of a pyridine ring into the starting material results in relatively
high yields when either I2 or ICl is employed as the
(8) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
1999, 1432.
Org. Lett., Vol. 3, No. 19, 2001
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electrophile. This might be explained by an intermediate such
as B. The pyridine nitrogen being close to the phenylethynyl
not react with PhSeCl, I2, or PhSCl. However, imine 18
(entries 14-16) can be cyclized by I2, PhSeCl, and PhSCl
in yields ranging from 40% to 76%. Again, we believe that
the key is either coordination of the electrophile to the
pyridine nitrogen and formation of an intermediate, such as
C, or destabilization of a cation closer to the pyridine ring.
In conclusion, efficient syntheses of isoquinolines and
naphthyridines using mild reaction conditions have been
developed. This methodology accommodates a variety of
iminoalkynes and affords the anticipated substituted iso-
quinolines in moderate to excellent yields. Further studies
into the scope and limitations of this electrophilic cyclization
reaction are underway.
group might first coordinate to the electrophile to form an
ammonium cation. Because of this coordination, electrophilic
attack of the triple bond might then occur in an intra-
molecular fashion. Alternatively, the presence of an electron-
deficient pyridine ring may simply be disfavoring a structure
such as A and favoring formation of the cationic intermediate
on the carbon necessary for formation of the six-membered
ring. Whatever the reason, the presence of the pyridine ring
significantly increases the yields from the reactions of I2 and
ICl from 68% and 67% for iminoalkyne 1 (entries 1 and 2)
to 90% and 92% for iminoalkyne 16 (entries 12 and 13),
respectively. This is very encouraging, since it broadens the
potential applications of this cyclization and improves its
efficiency.
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
research.
Supporting Information Available: General experimen-
tal procedures and characterization data for all starting
materials and products. This material is available free of
charge via the Internet at http://pubs.acs.org.
As described above, iminoalkynes derived from o-iodo-
benzaldehyde and acetylenes bearing simple alkyl groups do
OL010136H
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Org. Lett., Vol. 3, No. 19, 2001