Amination, aminocarbonylation, and alkoxycarbonylation of allenic/propargylic Pd intermediates derived from nonracemic propargylic mesylates: Synthesis of nonracemic propargyl amines, allenic amides, and butenolides

Full text of DOI:10.1021/jo960442m

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J . Org. Chem. 1996, 61, 3238-3239
conducted with arylamines, the allenic amides 3.2 and
the propargylic amines 3.3 were formed in high yield.
Increasing the pressure of CO led to an improvement
in the ratio of amide to amine product. Higher ratios
were also observed when the amine concentration was
decreased from 0.1 to 0.05 M. Not surprisingly, the
proportion of amine product 3.3 was found to be higher
with the more nucleophilic anilines and vice versa.
Am in a tion , Am in oca r bon yla tion , a n d
Alk oxyca r bon yla tion of Allen ic/P r op a r gylic
P d In ter m ed ia tes Der ived fr om
Non r a cem ic P r op a r gylic Mesyla tes:
Syn th esis of Non r a cem ic P r op a r gyl
Am in es, Allen ic Am id es, a n d Bu ten olid es
J ames A. Marshall* and Mark A. Wolf
Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22901
Received March 5, 1996
A key step in our recently reported total synthesis of
kallolide A (1.5) was the efficient conversion of propar-
gylic mesylate 1.1 to allenic ester 1.2 through Pd(0)-
catalyzed alkoxycarbonylation with net inversion of
configuration.1 That this initial product was formed
under kinetic control was demonstrated by its isomer-
ization to the diastereomer 1.3 with Ph3P. Butenolide
formation was effected by cleavage of 1.3 with TBAF and
treatment of the resulting acid 1.4 with catalytic AgNO3.
In the absence of CO, amines 4.2 were obtained from
the nonracemic mesylate 4.1a as the sole products of high
ee, as determined by chiral HPLC.4 The formation of
propargylic substitution products such as 4.2 from pro-
pargyl/allenyl palladium complexes has rarely been
observed.5
It was of interest to examine this chemistry in greater
detail as a possible route to nonracemic allenic acid
derivatives and butenolides. Initially, we looked into the
feasibility of preparing allenic amides 2.2 as potential
substrates for direct conversion to butenolides 2.3 in
order to bypass the relatively sensitive allenic acid
intermediates used in our previous sequence.1,2
Treatment of mesylate 4.1a 6 with aniline in the
absence of Pd(PPh3)4 afforded the propargylamine 5.1 of
opposite rotation to that of amine 4.2a secured in the
Pd(0) reaction. It can therefore be surmised that the
Pd(0)-catalyzed aminations proceed with retention of
configuration.7 In view of the ready availability of
nonracemic propargylic alcohols,6,8 the enantiodivergent
preparation of propargylic amines of high ee from a single
precursor holds significant synthetic potential.
Attempted amidocarbonylation of the racemic mesylate
3.1 with diethylamine, benzylamine, or p-fluorobenzyl-
amine in the presence of CO (1 atm) and catalytic
Pd(PPh3)4 (10 mol %) in THF at rt led to recovered
mesylate and decomposition products.3 No amide prod-
ucts could be detected. However, when the reaction was
Cyclization of the allenic carboxamide 3.2c was effected
with IBr.9 However, subsequent hydrolysis of the result-
(4) These amines were analyzed as their 3,5-dinitrobenzamide
derivatives on a (R,R)-Whelk-O column.
(5) Tsuji, J .; Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589.
(6) Marshall, J . A.; Xie, S. J . Org. Chem. 1995, 60, 7230. Ku, Y. Y;
Patel, R. R.; Elisseou, E. M.; Sawick, D. P. Tetrahedron Lett. 1995, 36,
2733.
(7) A possible pathway for this conversion would involve anti SN2′-
type oxidative addition of Pd(0) to the mesylate and subsequent anti
SN2′ attack by the amine on this allenyl Pd intermediate. Cf. Elsevier,
C. J .; Stehouwer, P. M.; Westmijze, H.; Vermeer, P. J . Org. Chem. 1983,
48, 1103. Alternatively, the amine and CO may discriminate between
equilibrating allenyl and propargyl Pd intermediates.
(8) Cf. Marshall, J . A.; Wang, X-j. J . Org. Chem. 1991, 56, 3211.
(9) Cf. Smith, A. B., III.; Duan, J . J .-W.; Hull, K. G.; Salvatore, B.
A. Tetrahedron Lett. 1991, 32, 4855.
(1) Marshall, J . A.; Wallace, E. M. J . Org. Chem. 1995, 60, 796.
(2) We have found that saponification of allenic esters generally
affords the acids in low yield. Carbonylation of propargylic mesylates
in the presence of water and Pd(PPh3)4 gives the acids directly but
proceeds in low to moderate yield.
(3) For aminations of π-allyl palladium species with aliphatic amines
see, (a) Ba¨ckvall, J -E.; Nordberg, R. E.; Zetterberg, K.; Akermark, B.
Organometallics 1983, 2, 1625. (b)Baer, H. H.; Hanna, Z. S. Can. J .
Chem. 1981, 59, 889. (c)Trost, B. M.; Keinan, E. J . Org. Chem. 1979,
44, 3451.
S0022-3263(96)00442-2 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 10, 1996 3239
ing imino lactone 6.2 could not be effected. The sole
isolable product was the interesting, but undesired,
aminofuran 6.4. The p-chloroanilide 3.2d showed analo-
gous behavior.
pendent synthesis, as outlined in eq 8, afforded buteno-
lide ent-7.4a of opposite rotation to that of 7.4a .14 Thus
the Pd(0)-catalyzed carboxylation must proceed with
inverson of configuration.15 The stereochemistry of al-
lenoates 7.1b and 7.2b is assigned by analogy.
Accordingly, we turned our attention to the allenoate
7.1a , obtained from mesylate 4.1a by Pd(0)-catalyzed
carbonylation in the presence of â-TMS ethyl alcohol, as
a possible butenolide precursor.10 Treatment with IBr
led smoothly to the iodo lactone 7.3a 11 which afforded
butenolide 7.4a in 70% yield (two steps) upon Pd(0)-
catalyzed hydrogenolysis.12 The alkoxycarbonylation of
mesylate 4.1a was effected with 5 mol % of the Pd
catalyst. The use of 10 mol % led to partially racemized
allenoate 7.1a as evidenced by the optical rotation and
chiral HPLC analysis.13 The analogous carbonylations
of propargylic mesylates 4.1b and 4.1c were effected with
less than 1 mol % of catalyst.
It is expected that these findings will be applicable to
the syntheses of a wide range of nonracemic propargylic
amines, allenic amides, and butenolides. Additional
efforts in that direction will be reported in due course.
Ack n ow led gm en t. This work was supported by
Research Grants GM39998 and GM29475 from the NIH
division of General Medical Sciences. We are indebted
to Professor M. G. Finn for providing instruction and
equipment for the HPLC analyses of the N-propargyl-
anilines.
Benzyl alcohol could also be employed in the alkoxy-
carbonylation sequence as illustrated by the formation
of allenoates 7.2b and 7.2c from mesylates 4.1b and 4.1c.
Hydrogenolysis of iodobutenolide 7.3a to 7.4a was
effected with Bu3SnH and catalytic Pd(PPh3)4. An inde-
Su p p or tin g In for m a tion Ava ila ble: Representative ex-
perimental procedures and 1H NMR spectra for all new
compounds (37 pages).
(10) The use of propargylic acetates or carbonates in these reactions
gave low conversions to propargylic esters. Cf. Tsuji, J .; Sugiura, T.;
Minami, I. Tetrahedron Lett. 1986, 27, 731. Interestingly, it has been
reported that methoxycarbonylation of (S)-diethyl-1-ethynylpentyl
phosphate affords methyl (R)-2,3-nonadienoate with retention of
configuration.5
J O960442M
(11) â-TMS ethyl esters have rarely been employed in iodolacton-
izations. Considering the facile transformation of esters 7.1a and 7.1b
to iodolactones 7.2a and 7.2b, it is likely that the methodology will be
applicable to olefinic analogues, as well.
(12) Baillargeon, V. P.; Stille, J . K. J . Am. Chem. Soc. 1986, 108,
452.
(13) For a detailed study on the effect of Pd(0) concentration on
racemization in π-allyl palladium intermediates, see Granberg, K. L.;
Ba¨ckvall, J .-E. J . Am. Chem. Soc. 1992, 114, 6858.
(14) For recent alternative routes to butenolides, Cf. Trost, B. M.;
Muller, T. J . J .; Martinez, J . J . Am. Chem. Soc. 1995, 117, 1888. Hoye,
T. R.; Humpal, P. E.; J ime´nez, J . I.; Mayer, M. J .; Tan, L.; Ye, Z.
Tetrahedron Lett. 1994, 35, 7517. Buchwald, S. L.; Fang, Q.; King, S.
M. Tetrahedron Lett. 1988, 29, 3445.
(15) An inversion pathway has been established for additions of
organozinc compounds to propargyl/allenyl Pd(II) intermediates leading
to allenes. Elsevier, C. J .; Kleijn, H.; Boersma, J .; Vermeer, P.
Organometallics 1986, 5, 716.