Heterocycles by PtCl2-catalyzed intramolecular carboalkoxylation or carboamination of alkynes

Article abstract of DOI:10.1021/ja055659p

PtCl₂ constitutes a convenient catalyst for intramolecular hydroalkoxylation, carboalkoxylation, hydroamination, and carboamination reactions of alkynes, effecting the formation of substituted benzo[b]furan, indole-, and isochromene-1-one derivatives, respectively. This procedure allows for the transfer of (substituted) allyl, methoxymethyl (MOM), benzyloxymethyl (BOM), and (trimethylsilyl)ethoxymethyl (SEM) groups from oxygen to carbon and is compatible with functional groups that are susceptible to oxidative insertion of low valent metal species previously used for similar purposes. Although some of the reactions can even be carried out in air, the rates are significantly increased when conducted under an atmosphere of CO. A mechanistic rationale is proposed, implying activation of the alkyne by the carbophilic Pt(2+) template as the primary step of the catalytic cycle. Copyright

Full text of DOI:10.1021/ja055659p

Published on Web 10/08/2005
Heterocycles by PtCl2-Catalyzed Intramolecular Carboalkoxylation or
Carboamination of Alkynes
Alois Fu¨rstner* and Paul W. Davies
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
Received August 18, 2005; E-mail: fuerstner@mpi-muelheim.mpg.de
Scheme 1. PtCl2-Catalyzed Carboalkoxylation2
During the course of our studies on noble metal catalyzed skeletal
rearrangements,1 it was found that alkynes bearing lateral allyl ether
moieties form tetrahydrofuran rings with concomitant O f C allyl
transfer on treatment with PtCl2 (Scheme 1).2 In an attempt to
explore the scope of this net carboalkoxylation of the triple bond,2,3
we now present a versatile and convenient entry into aromatic
heterocycles and extend the concept of carboalkoxylation beyond
the original allyl shift reaction.
Table 1. PtCl2-Catalyzed Synthesis of 2-Substituted Benzofurans
Given the efficient activation of alkynes by late transition metal
species toward nucleophilic attack,4 it comes as no surprise that
phenol derivatives 1 bearing an alkyne moiety at the ortho-position
Entry
R
PtCl2
t (h)
Yield
smoothly convert into the corresponding benzofurans on exposure
to catalytic amounts of PtCl2 in toluene. The reaction proceeds at
ambient temperature, although it is significantly faster when
performed at 80 °C. Low catalyst loadings (0.5-1 mol %) usually
suffice to obtain almost quantitative yields with an assortment of
examples (Table 1). In contrast to most other catalysts used for
similar purposes,5 no external base is necessary to promote the
reaction. Workup is therefore greatly simplified with only filtration
of the crude mixture through a plug of silica necessary. The fact
that the cyclization even proceeds in air using an easy-to-handle,
nonhygroscopic salt constitutes an additional bonus in practical
terms.
1
2
3
4
5
6
7
8
-C3H7
-C5H11
cyclopropyl
-CH2CH2Ph
-CH2CH(COOMe)2
-C6H5
5 mol %
0.5 mol %
1 mol %
1 mol %
5 mol %
5 mol %
0.5 mol %
0.5 mol %
1
5
1
5
1
1.5
2
88% (83%)a
98%
98%
98%
92%
97%
95%
94%
p-MeO-C6H4-
m-F3C-C6H4-
5
a Under air at ambient temperature, 3 h.
Table 2. PtCl2-Catalyzed Benzofuran Synthesis by Intramolecular
Carboalkoxylation (Allyl/Benzyl Shift Reactions)
Gratifyingly, protection of the phenolic -OH in 1 as the
corresponding allyl ethers 3 does not preclude the heteroannulation.
Rather, the allyl substituent is transferred to the 3-position of the
resulting benzofuran 4 via an efficient intramolecular “endo-mode”
trans-carboalkoxylation (Table 2). The reaction is best performed
under an atmosphere of CO, which we have recently shown to
accelerate certain PtCl2-catalyzed skeletal rearrangements to a
significant extent.6,7 Entries 9-12 witness that benzyl ether
derivatives are also well behaved substrates. Furthermore, Scheme
2 shows that related reactions can be achieved with suitable aniline
derivatives 5, thus opening a novel entry into substituted indoles 6
by intramolecular (hydro)carboamination.8
At first sight, the overall transformation formally resembles the
benzofuran (indole) synthesis pioneered by Cacchi and Balme using
Pd(PPh3)4 cat. (Scheme 3).9,10 It is important to note, however, that
this palladium-based methodology generates the actual catalyst in
situ by oxidative addition into the allyl ether group and hence relies
on a redox cycle, whereas the PtCl2-catalyzed procedure does not.
This particular feature pays off in dealing with substrates containing
additional sites prone to oxidative insertion as evident from entry
7 (Table 2). In this case, the PtCl2-catalyzed reaction proceeds
without affecting the vinyl bromide entity, thus leaving options for
subsequent manipulation.
The proposed catalytic cycle (Scheme 4) implies activation of
the alkyne by the electrophilic metal species which enables
nucleophilic attack by the heteroelement, resulting in trans-
alkoxyplatination. This process formally generates an allyl cation
fragment11 that shifts to the most nucleophilic position on the
a Using 10 mol % of PtCl2. b Linear cinnamyl entity in the product.
incipient ring to give the product and regenerate the catalyst. This
notion suggests that other entities R3, able to stabilize positive
charge, might transfer in a similar fashion.
To probe this concept, a series of appropriate phenolic MOM-
acetals was subjected to the PtCl2-catalyzed rearrangement. All of
them afforded the corresponding 2,3-disubstituted benzofuran
derivatives in good to excellent yield after short reaction times
9
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J. AM. CHEM. SOC. 2005, 127, 15024-15025
10.1021/ja055659p CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 6. Carboalkoxylation of a Benzoate
Scheme 2. PtCl2-Catalyzed Indole Synthesis
Scheme 3. Heterocycle Synthesis by Oxidative Insertion9,10
intramolecular etherification,12 affording the polycyclic skeleton 11
of the pterocarpane family of phytoalexins.13 Furthermore, pre-
liminary experiments indicate that PtCl2-catalyzed carboalkoxylation
reactions are not limited to phenolic substrates. The successful
cyclization of the benzoic acid ester 12 to isochromene-1-one 13
illustrates this point (Scheme 6). In any case, it is important to
note that none of the acetalic substrates described in this paper is
amenable to heteroannulation using Pd(PPh3)49,10 because they are
unable to generate a catalytically competent species by oxidative
addition. Therefore, the PtCl2-catalyzed protocol is not only more
convenient but also significantly broader in scope and constitutes
a useful supplement to existing methodology for the preparation
of physiologically relevant heterocycles.14
Scheme 4. Proposed Reaction Mechanism
Acknowledgment. Financial support by the MPG and the Fonds
der Chemischen Industrie is gratefully acknowledged. We thank
Umicore, Hanau, for a gift of noble metal salts.
Supporting Information Available: Experimental part and spec-
troscopic data of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Table 3. PtCl2-Catalyzed Benzofuran Synthesis by Intramolecular
Carboalkoxylation (MOM/BOM/SEM Shift Reactions)
References
(1) (a) Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc.
1998, 120, 8305. (b) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J.
Am. Chem. Soc. 2004, 126, 8654. (c) Fu¨rstner, A.; Hannen, P. Chem.
Commun. 2004, 2546. (d) Mamane, V.; Hannen, P.; Fu¨rstner, A. Chem.s
Eur. J. 2004, 10, 4556. (e) Fu¨rstner, A.; Mamane, V. J. Org. Chem. 2002,
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(2) (a) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122,
6785. (b) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001,
123, 11863.
(3) For other carboalkoxylations catalyzed by PtCl2, see: Nakamura, I.;
Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima, Y.; Gridnev, I. D.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423 and references cited
therein.
(4) Reviews: (a) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002,
102, 813. (b) Me´ndez, M.; Echavarren, A. M. Eur. J. Org. Chem. 2002,
15. (c) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215. (d) Me´ndez,
M.; Mamane, V.; Fu¨rstner, A. Chemtracts 2003, 16, 397. (e) Pioneering
study: Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics
1996, 15, 901.
(5) (a) Leading reference: Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi,
G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280 and references cited therein.
(b) Review: Larock, R. C. J. Organomet. Chem. 1999, 576, 111.
(6) (a) Fu¨rstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005, 127,
8244. (b) For another noble metal catalyzed rearrangement under CO
atmosphere, see: Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Am.
Chem. Soc. 1994, 116, 6049.
Entry
R2
R3
t (h)
Yield
1
2
3
4
5
6
7
8
9
-C5H11
-CH2CH2Ph
Me
Me
Bn
2
91%
84%
78%
81%
84%
95%
62%
74%
84%
94%
0.5
0.5
0.5
2
0.5
2
2
0.5
2
CH2CH2SiMe3
cyclopropyl
-C6H5
m-MeO-C6H4-
m-F3C-C6H4-
Me
Me
Me
Me
Bn
Bn
10
o-(i-PrO)-C6H4-
Scheme 5. Preparation of the Pterocarpane Skeletona
(7) PtCl2 is by far the most effective catalyst among the metal salts screened;
cf. Supporting Information.
(8) (a) For related N f C acyl migrations, see: Shimada, T.; Nakamura, I.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546. (b) See also: Arcadi,
A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 610.
(9) (a) Cacchi, S.; Fabrizi, G.; Moro, L. Synlett 1998, 741. (b) Cacchi, S.;
Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998, 39, 5101. (c) Battistuzzi,
G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671.
(10) (a) Monteiro, N.; Balme, G. Synlett 1998, 746. (b) Balme, G.; Bouyssi,
D.; Lomberget, T.; Monteiro, N. Synthesis 2003, 2115.
(11) Although we assume that the allyl fragment remains bound to the transition
metal template, further investigation of this point is ongoing.
(12) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 12202.
(13) Representative examples: (a) Engler, T. A.; Reddy, J. P.; Combrink, K.
D.; Vander Velde, D. J. Org. Chem. 1990, 55, 1248. (b) Miki, Y.;
Kobayashi, S.; Ogawa, N.; Hachiken, H. Synlett 1994, 1001.
(14) After completion of this study, we became aware of closely related results.
Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 15022.
a Conditions: (a) PtCl2 (5 mol %), CO (1 atm), toluene, 80 °C, 3 h,
75%; (b) (i) HF, pyridine; (ii) Pd(OAc)2 cat., Cs2CO3, (tBu)2P(2-biphenyl).
(Table 3). Analogous transfer of the BOM group (entries 3, 9, and
10) opens further options for subsequent manipulation of the
protected hydroxymethyl substituent at C-3 of the heterocycle, either
by oxidative (CAN) or hydrogenolytic cleavage of the benzyloxy
entity. Along the same lines, SEM-ethers are valuable substituents
susceptible to selective cleavage with fluoride after O f C transfer
(entry 4). The application in Scheme 5 illustrates this point. Since
the aryl bromide group of substrate 9 is compatible with the PtCl2-
catalyzed cyclization, the resulting product 10 allows for subsequent
JA055659P
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