Synthesis of coumarins via palladium-catalyzed carbonylative annulation of internal alkynes by o-lodophenols

Article abstract of DOI:10.1021/ol0065569

(matrix presented) A variety of substituted coumarins have been prepared in good yields by the palladium-catalyzed coupling of o-iodophenols with internal alkynes and 1 atm of carbon monoxide. Unlike most of the previous work on the palladium-catalyzed carbonylation of alkynes, the insertion of the internal alkyne occurs in preference to the insertion of CO.

Full text of DOI:10.1021/ol0065569

ORGANIC
LETTERS
2
000
Vol. 2, No. 23
643-3646
Synthesis of Coumarins via
Palladium-Catalyzed Carbonylative
Annulation of Internal Alkynes by
o-Iodophenols
3
Dmitry V. Kadnikov and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received September 6, 2000
ABSTRACT
A variety of substituted coumarins have been prepared in good yields by the palladium-catalyzed coupling of o-iodophenols with internal
alkynes and 1 atm of carbon monoxide. Unlike most of the previous work on the palladium-catalyzed carbonylation of alkynes, the insertion
of the internal alkyne occurs in preference to the insertion of CO.
The propensity of unsaturated compounds, such as alkenes,
alkynes, and carbon monoxide, to undergo insertion into a
carbon-metal bond makes them some of the most versatile
substrates for transition metal-catalyzed organic transforma-
tions. It is, therefore, not surprising that many such trans-
formations have been developed over the past two decades.
For example, the palladium-catalyzed annulation of dienes
and internal alkynes has been developed in our laboratories
for the synthesis of various carbo- and heterocyclic mol-
The ability to achieve controlled insertion of two unsatur-
ated molecules into a carbon-metal bond possesses signifi-
cant advantages for organic synthesis since it should allow
rapid, efficient, and selective construction of complex
molecular structures. Palladium-catalyzed reactions involv-
ing insertion of an unsaturated hydrocarbon and carbon
monoxide into an aryl-metal bond have attracted significant
attention in the past decade. Negishi and co-workers have
studied intramolecular versions of these reactions in which
a carbon-carbon double or triple bond is tethered to the aryl
1
2
3
ecules, such as indoles, benzofurans, isocoumarins, inde-
nones,4 isoquinolines, R-pyrones, naphthalenes, and
phenanthrenes.
5
3,6
7
9
halide. Only a few examples of palladium-catalyzed three-
8
10
11
component processes have been reported. Norbornene,
1
2
13
norbornadiene, or allenes react with o-iodophenol in the
(
1) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
652.
2) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org.
Chem. 1995, 60, 3270.
presence of carbon monoxide and a palladium catalyst to
(
7
(
(9) (a) Negishi, E.; Cop e´ ret, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J.
M. J. Am. Chem. Soc. 1996, 118, 5904. (b) Negishi, E.; Ma, S.; Amanfu,
J.; Cop e´ ret, C.; Miller, J. A.; Tour, J. M. J. Am. Chem. Soc. 1996, 118,
5919. (c) Sugihara, T.; Cop e´ ret, C.; Owczarczyk, Z.; Harring, L. S.; Negishi,
E. J. Am. Chem. Soc. 1994, 116, 7923.
(
(
3) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770.
4) (a) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58,
4
579. (b) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999,
1
21, 3238.
(
(10) Satoh, T.; Itaya, T.; Okuro, K.; Miura, M.; Nomura, M. J. Org.
Chem. 1995, 60, 7267.
(11) (a) Grigg, R.; Khalil, H.; Levett, P.; Virica, J.; Sridharan, V.
Tetrahedron Lett. 1994, 35, 3197. (b) Moinet, C.; Fiaud, J.-C. Synlett 1997,
97.
5) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306. (b)
Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553.
6) Larock, R. C.; Han, X.; Doty, M. J. Tetrahedron Lett. 1998, 39,
713.
(
5
(
(
7) Larock, R. C.; Tian, Q. J. Org. Chem. 1998, 63, 2002.
8) Larock, R. C.; Doty, M. J.; Tian, Q.; Zenner, J. M. J. Org. Chem.
(12) An, Z. W.; Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1989,
371, C51.
1
997, 62, 7536.
(13) Okuro, K.; Alper, H. J. Org. Chem. 1997, 62, 1566.
1
0.1021/ol0065569 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

afford coumaranone or chromone derivatives. Palladium-
catalyzed reactions of internal alkynes with aryl halides and
coumarin (3). The isomeric 2,3-di-n-propylchromone was not
detected. However, the yield of the desired coumarin was
low. To find the optimal reaction conditions, we studied the
effect of various reaction parameters (base, phosphine,
chloride source, stoichiometry, temperature, etc.) on the
outcome of the reaction. The optimal reaction conditions thus
far achieved utilize 1 equiv of o-iodophenol, 5 equiv of
14
carbon monoxide are reported to produce furans or 2(1H)-
1
5
furanones depending on the structure of the alkyne
employed.
Our continuing interest in the palladium-catalyzed annu-
lation of internal alkynes prompted us to examine the
annulation of internal alkynes with o-iodophenols in the
presence of carbon monoxide. We envisioned that such
annulation would result in the formation of either coumarins
alkyne, 1 atm of CO, 5 mol % of Pd(OAc)
2
, 2 equiv of
pyridine, and 1 equiv of n-Bu NCl in DMF at 120 °C. The
4
use of pyridine as a base is crucial for the success of the
reaction. Only low yields of coumarin 3 have been obtained
when inorganic bases or tertiary alkylamines were employed
as the base. One atmosphere of carbon monoxide is sufficient
for the reaction. Indeed, the use of higher pressures of carbon
monoxide resulted in the formation of a large number of
unidentified products.
(1) or chromones (2) depending on the sequence of insertion
of the internal alkyne and carbon monoxide into the carbon-
palladium bond (eq 1).
Next, using the optimal reaction conditions, the annulation
of various internal alkynes has been investigated. The results
are summarized in Table 1. Both dialkyl (entry 1) and diaryl
acetylenes (entry 2) are readily annulated, although a longer
reaction time is required in the latter case to drive the reaction
to completion. Unsymmetrical alkyl aryl alkynes also afford
the desired products in good yields (entries 3 and 4).
However, the insertion of these alkynes into the aryl-
palladium bond proceeds with only modest regioselectivity,
and mixtures of regioisomers are isolated in both cases. The
regioselectivity is governed by steric factors with the larger
substituent on the triple bond ending up at the 3-position of
the coumarin. This regioselectivity is consistent with regio-
selectivity observed in our other palladium-catalyzed annu-
lations of internal alkynes. However, this reaction is con-
siderably more sensitive to steric hindrance around the triple
bond. Alkynes with bulky substituents, such as 4,4-dimethyl-
2-pentyne (entry 5), produce only very low yields of
coumarins.
Naturally occurring coumarins possess interesting biologi-
cal activity, including anticancer and HIV-1-specific reverse
16
transcriptase inhibitor properties. However, classic methods
1
7
for the synthesis of coumarins, such as the Perkin and
Pechman reactions18 and their variations, suffer major
shortcomings such as the use of stoichiometric amounts of
mineral or Lewis acids, or toxic reagents, often under high
temperatures. The scope of these processes is therefore
somewhat limited. Only a few applications of transition-metal
catalyzed reactions for the synthesis of coumarins have been
reported, and most of these are of limited scope.1 Herein,
we report that the palladium-catalyzed coupling of o-
iodophenols, internal alkynes, and carbon monoxide allows
efficient synthesis of 3,4-disubstituted coumarins bearing a
variety of functional groups.
19
2,20
The reaction of o-iodophenol and 4-octyne in the presence
of 1 atm of carbon monoxide under reaction conditions
similar to those of our previous annulation conditions (eq
We have also investigated the annulation of alkynes
bearing various functional groups. Propargylic alcohols failed
to react cleanly in this process. However, an appropriately
protected propargylic alcohol (entry 6) yielded the desired
product in 65% yield, a yield similar to that of the annulation
of 4-octyne. Again, however, a mixture regioisomers has
been obtained. Better regioselectivity has been observed in
the reactions of silyl acetylenes. The annulation of 1-trim-
ethylsilyl-1-propyne afforded exclusively coumarin 12 in
2
) resulted in the exclusive formation of 3,4-di-n-propyl-
43% yield (entry 7). The bulky trimethylsilyl group improves
the regioselectivity but simultaneously lowers the yield over
other simple alkyl or aryl groups. Note, however, the
substantial increase in yield over that obtained using 4,4-
dimethyl-2-pentyne (entry 5). Very good regioselectivity
was also observed in the annulation of an alkynone (entry
8).
(
14) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org. Chem.
992, 57, 4754.
15) Cop e´ ret, C.; Sugihara, T.; Wu, G.; Shimoyama, I.; Negishi, E. J.
Am. Chem. Soc. 1995, 117, 3422.
16) (a) Murray, R. D. H.; M e´ ndez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry, and Biochemistry; Wiley: New York,
982. (b) Naser-Hijazi, B.; Stolze, B.; Zanker, K. S. Second Proceedings
of the International Society of Coumarin InVestigators; Springer: Berlin,
994.
1
(
(
1
Coumarins bearing substituents in the 6- or 7-positions
have also been synthesized in good yields. Either an electron-
withdrawing (entry 9) or an electron-donating substituent
(entry 10) can be introduced into position 6 of the coumarin
by using the appropriate phenol. The substituents do not
affect the yields of the process, although the reaction is faster
1
(
(
(
(
17) Johnson, J. R. Org. React. 1942, 1, 210.
18) Sethna, S.; Phadke, R. Org. React. 1953, 7, 1.
19) Awasthi, A. K.; Tewari, R. S. Synthesis 1986, 1061.
20) (a) Catellani, M.; Chiusoli, G. P.; Fagnola, M. C.; Solari, G.
Tetrahedron Lett. 1994, 35, 5919. (b) Catellani, M.; Chuisoli, G. P.; Fagnola,
M. C.; Solari, G. Tetrahedron Lett. 1994, 35, 5923. (c) Trost, B. M.; Toste,
F. D. J. Am. Chem. Soc. 1996, 118, 6305
3644
Org. Lett., Vol. 2, No. 23, 2000

Table 1. Synthesis of Coumarins via Carbonylative Annulation of Internal Alkynes with o-Iodophenolsa
a
Representative experimental procedure: iodophenol (0.5 mmol), alkyne (2.5 mmol), pyridine (1.0 mmol), n-Bu4NCl (0.5 mmol), and palladium acetate
b
(
0.025 mmol, 5 mol %) in DMF (5 mL) have been stirred under a balloon pressure of carbon monoxide at 120 °C for the indicated amount of time. The
regioisomers have been separated by column chromatography. An inseparable mixture of isomers has been obtained.
c
when 2-iodo-4-methoxyphenol is employed. An electron-
withdrawing substituent has also been introduced into the
monoxide, and (5) attack of the phenolic oxygen on the
resulting acyl-palladium complex leading to formation of
the coumarin and regeneration of the Pd(0) catalyst. It is
remarkable that the insertion of an alkyne occurs in prefer-
ence to the insertion of CO. While it has been reported that
the insertion of an alkyne tethered to an aryl halide is
7-position of the coumarin (entry 11). This reaction is
significantly faster than the others, reaching completion
within 6 h. The use of an analogous phenol bearing an
electron-donating substituent, 2-iodo-5-methoxyphenol, failed
to afford the anticipated coumarin under the standard reaction
conditions. The only product isolated from the reaction is
9
c
competitive with insertion of CO, to the best of our
knowledge, this is the first example of such selectivity in an
intermolecular reaction. Moreover, this selectivity appears
to be restricted to internal alkynes. For example, the
annulation of 4,5-nonadiene under our standard conditions
resulted in the formation of 3-n-butylene-2-n-propyl-2,3-
dihydro-4H-1-benzopyran-4-one (20), in analogy with the
3
-methoxyphenol arising from deiodination of the starting
phenol.
Finally, heterocyclic analogues of o-iodophenol are also
effective in the carbonylative annulation of internal alkynes.
Thus, 3-iodo-2-pyridone 18 affords the azacoumarin 19 in
13
results reported by Alper.
70% yield.
We propose a mechanism for this carbonylative annulation
involving (1) reduction of Pd(OAc) to the actual Pd(0)
2
catalyst, (2) oxidative addition of o-iodophenol to Pd(0), (3)
insertion of the internal alkyne, (4) insertion of carbon
Org. Lett., Vol. 2, No. 23, 2000
3645

In conclusion, we have developed an efficient, palladium-
catalyzed synthesis of 3,4-disubstituted coumarins from
readily available starting materials. The synthesis employs
mild conditions and can accommodate a wide variety of
functional groups both on the alkyne and the phenol.
research and Kawaken Fine Chemicals Co., Ltd. for donation
of palladium acetate.
Supporting Information Available: General experimen-
1
13
tal procedure and H and C NMR spectra and characteriza-
tion data for compounds 3, 4, 7-17, and 19. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
OL0065569
3646
Org. Lett., Vol. 2, No. 23, 2000