Copper-catalyzed stereospecific N-allenylations of amides. Syntheses of optically enriched chiral allenamides

Article abstract of DOI:10.1021/ol051094q

(Chemical Equation Presented) Syntheses of chiral allenamides via a stereospecific amidation of optically enriched allenyl iodides using catalytic copper(I) salt and N,N′-dimethylethylene-diamine are described here.

Full text of DOI:10.1021/ol051094q

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3081-3084
Copper-Catalyzed Stereospecific
N-Allenylations of Amides. Syntheses of
Optically Enriched Chiral Allenamides
Lichun Shen, Richard P. Hsung,* Yanshi Zhang, Jennifer E. Antoline, and
Xuejun Zhang
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received May 11, 2005
ABSTRACT
Syntheses of chiral allenamides via a stereospecific amidation of optically enriched allenyl iodides using catalytic copper(I) salt and N,N
′-
dimethylethylene-diamine are described here.
Metal-catalyzed aminations and amidations of halo arenes
and alkenes have emerged in the past decade to provide a
powerful method for constructing anilines or anilides and
enamines or enamides.1-5 Amidations of 1-halo alkynes were
achieved recently.6-10 While these former processes represent
a cross-coupling of an sp2-hybridized carbon, the latter
involves sp-hybridized carbons, leading to an atom-economi-
cal synthesis of ynamides [Scheme 1].11 Intriguingly, what
has not been explored12 is the amidation of allenyl halide.
Although this amidative cross-coupling resembles amidations
of halo alkenes, it should (1) lead to an excellent synthetic
entry to allenamides,13-15 which have become attractive
synthetic building blocks,13,16,17 and (2) provide a unique
opportunity to examine the stereoselectivity issue, which has
not been possible or relevant in any of the existing investiga-
tions. Recently, Trost12 elegantly demonstrated the feasibility
(1) For a recent review on copper-mediated C-N and C-O bond
formation, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400. Also see: (b) Lindley, J. Tetrahedron 1984, 40, 1433.
(2) For reviews on the related palladium-catalyzed N-arylations of amines
and amides, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805. For an earlier account, see: (c) Kosugi, M.; Kameyama,
M.; Migita, T. Chem. Lett. 1983, 927.
(3) Recent key papers on copper-catalyzed N-arylations of amides from
the Buchwald group, see: (a) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2003, 5, 3667. (b) Klapars, A.; Huang, X.; Buchwald S. L.
J. Am. Chem. Soc. 2002, 124, 7421. (c) Kwong, F. Y.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2002, 4, 581.
(4) For an earlier account, see: Yamamoto, T.; Kurata, Y. Can. J. Chem.
1983, 61, 86 and references therein.
(5) For some recent references of copper-catalyzed aminations and
amidations: (a) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004,
126, 5680. (b) Han, C.; Shen, R.; Su, S. Porco, J. A. Jr. Org. Lett. 2004, 6,
27. (c) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A.,
Jr. J. Am. Chem. Soc. 2003, 125, 7889. (d) Evindar, G.; Batey, R. A. Org.
Lett. 2003, 5, 133. (e) Shen, R.; Porco, J. A. Jr. Org. Lett. 2002, 4, 1333.
(f) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 231.
(6) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.
(8) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang,
J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125,
2368.
(9) Zhang, Y.; Hsung R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L.
Org. Lett. 2004, 6, 1151.
(10) For an earlier documentation of copper-promoted coupling of amide
with alkyne, see: Balsamo, A.; Macchia, B.; Macchia, F.; Rossello, A.
Tetrahedron Lett. 1985, 26, 4141.
(11) For reviews on ynamides, see: (a) Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
(b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (c)
Katritzky, A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455.
(12) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117.
(13) For a review, see: Hsung, R. P.; Wei, L.-L.; Xiong, H. Acc. Chem.
Res. 2003, 36, 773.
(7) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727.
10.1021/ol051094q CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/15/2005

Scheme 1
Table 1.
concna temp time yield
X (M)
(°C) (h) (%)b
entry
metal
ligand
halide
c
1
2
3
4
5
6
7
8
9
Pd[PPh3]4 PR3
(()-2a Br 0.10
150
100
50
8
8
nd
nd
nd
16
nd
65
45
nd
64
55
69
58
CuSO4
Cul
1,10-phend (()-2a Br 0.10
1,10-phen (()-2a Br 0.10
12
8
Cul
1,10-phen (()-2b
1,10-phen (()-2b
DMEDAd (()-2b
I
I
I
I
I
I
I
I
I
0.15
0.10
0.15
0.15
0.15
0.15
0.15
50
Cul
110
50
4
Cul
4
CuSO4
CuSO4
CuCN
DMEDA
(()-2b
50
4
1,10-phen (()-2b
DMEDA (()-2b
50
18
4
50
of this amidative process using catalytic copper salts. Our
efforts have been focused on the stereoselectivity issue. We
report here a copper-catalyzed stereospecific N-allenylation
of amides.
Our work commenced prior to our knowledge of Trost’s
recent report,12 and thus, given lack of precedents at the time,
we first carefully screened various metal catalysts mainly
with palladium and copper and various ligands mostly with
phosphines, 1,10-phenanthroline, and N,N-dimethylethyl-
enediamine [DMEDA]. These results are summarized in
Table 1 specifically using Evans’ chiral oxazolidinone 1 and
10 CuCN
11 CuCN
12 CuCN
1,10-phen (()-2b
50
4
DMEDA
DMEDA
(()-2b
(()-2b
0.075 50
0.075 rt
18
18
a Concentration of 2. b Isolated yields; nd: not determined. c R ) o-tolyl
or c-hex. d 1,10-Phen: 1,10-phenanthroline. DMEDA: N,N′-dimethyleth-
ylenediamine
racemic allenyl halides 2a/b. In general, allenyl iodide 2b
[entries 4-12] worked much better than bromide 2a [entries
(14) For syntheses of allenamides, see: (a) Xiong, H.; Tracey, M. R.;
Grebe, T. P.; Mulder, J. A.; Hsung, R. P.; Wipf, P.; Smotryski, J. Org.
Synth. 2004, 81, 147. (b) Tracey, M. R.; Grebe, T. P.; Brennessel, W. W.;
Hsung, R. P. Acta Crystallogr. 2004, C60, o830. (c) Huang, J.; Xiong, H.;
Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe, T. P. Org. Lett.
2002, 4, 2417. (d) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.;
Douglas, C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459. (e) Wei, L.-L.;
Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T. Org. Lett. 1999, 1,
2145. (f) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron
Lett. 1999, 40, 6903. For some earlier syntheses of allenamides, see: (g)
Dickinson, W. B.; Lang, P. C. Tetrahedron Lett. 1967, 8, 3035. (h)
Bogentoft, C.; Ericsson, O¨ .; Stenberg, P.; Danielsson, B. Tetrahedron Lett.
1969, 10, 4745. (i) Wulff, J.; Huisgen, R. Chem. Ber. 1969, 102, 1841. (j)
Bayer, H. O.; Huisgen, R.; Knorr, R.; Schaefer, F. C. Chem. Ber. 1970,
103, 2581. (k) Balasubramanian, K. K.; Venugopalan, B. Tetrahedron Lett.
1974, 15, 2643. (l) Corbel, B.; Paugam, J.-P.; Dreux, M.; Savignac, P.
Tetrahedron Lett. 1976, 17, 835. (m) Overman, L. E.; Marlowe, C. K.;
Clizbe, L. A. Tetrahedron Lett. 1979, 20, 599. (n) Padwa, A.; Caruso, T.;
Nahm, S.; Rodriguez, A. J. Am. Chem. Soc. 1982, 104, 2865. (o) Padwa,
A.; Cohen, L. A. J. Org. Chem. 1984, 49, 399.
(15) Xiong, H.; Hsung, R. P.; Wei, L.-L.; Berry, C. R.; Mulder, J. A.;
Stockwell, B. Org. Lett. 2000, 2, 2869.
(16) For recent allenamide chemistry, see: (a) An˜orbe, L.; Poblador,
A.; Dom´ınguez, G.; Pe´rez-Castells, J. Tetrahedron Lett. 2004, 45, 4441.
(b) Achmatowicz, M.; Hegedus, L. S. J. Org. Chem. 2004, 69, 2229. (c)
Ranslow, P. D. B.; Hegedus, L. S.; de los Rios, C. J. Org. Chem. 2004, 69,
105. (d) Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M. Org. Lett.
2004, 6, 2059. (e) Bacci, J. P.; Greenman, K. L.; Van Vranken, D. L. J.
Org. Chem. 2003, 68, 4955. (f) Armstrong, A.; Cooke, R. S.; Shanahan, S.
E. Org. Biomol. Chem. 2003, 1, 3142. (g) Gaul C.; Seebach, D. HelV. Chim.
Acta 2002, 85, 963. (h) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43,
1499. (i) Le Strat, F.; Maddaluno, J. Org. Lett. 2002, 4, 2791.
(17) For our recent efforts, see: (a) Berry, C. R.; Hsung, R. P. Antoline,
J. E.; Petersen, M. E.; Rameshkumar, C.; Nielson, J. A. J. Org. Chem.
2005, 70, 4038. (b) Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775. (c)
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50. (d) Rameshkumar,
C.; Hsung, R. P. Angew. Chem., Int. Ed. 2004, 43, 615. (e) Berry, C. R.;
Hsung, R. P. Tetrahedron 2004, 60, 7629. (f) Xiong, H.; Huang, J.; Ghosh,
S.; Hsung, R. P. J. Am. Chem. Soc. 2003, 125, 12694. (g) Rameshkumar,
C.; Hsung, R. P. Synlett 2003, 1241. (h) Berry, C. R.; Rameshkumar, C.;
Tracey, M. R.; Wei, L.-L.; Hsung, R. P. Synlett 2003, 791. (i) Rameshkumar,
C.; Xiong, H.; Tracey, M. R.; Berry, C. R.; Yao, L. J.; Hsung, R. P. J.
Org. Chem. 2002, 67, 1339. (j) Xiong, H.; Hsung. R. P.; Berry, C. R.;
Rameshkumar, C. J. Am. Chem. Soc. 2001, 123, 7174.
Figure 1. Generality of the amidative cross-coupling. aUnless
otherwise indicated, all reactions were run in toluene at 50 °C using
b
10 mol% CuCN, 20 mol% DMEDA, and 2 equiv of Cs2CO3 . -
c
d
e
Isolated yields. Reaction was run at rt. Yield: 69% at 50 °C. -
Performed with 10 mol% CuTC [Cu(I) thiophenecarboxylate].
fYield: 39% using CuCN.
3082
Org. Lett., Vol. 7, No. 14, 2005

1-3].19 Cu(I) salts such as CuI and CuCN and DMEDA
appeared to be the best catalytic combination [entries 6, 7,
9, 11, 12], although 1,10-phenanthroline was also quite
feasible [entries 4, 8, and 10].
To confirm this, coupling of allenyl iodide (M)-2b21
with an enantiomeric enrichment of 70% gave allenamide 3
in 68% yield with the 3(P,R) to 3(M,R) ratio being 15:85.
An X-ray structure of pure 3(M,R) was obtained to con-
firm the absolute configuration [Scheme 2]. This phenom-
enon can be observed in other couplings that gave allena-
mides 6(M,R), 20(M,R,S), and 21(P,R,S). These reactions
collectively provide solid support that the axial stereointegrity
of allenyl iodide 2b was maintained throughout the amidation
process.
Temperature appears to be a critical factor. Despite
possessing a much improved thermal stability over allena-
mines [or 1-amino-allenes],20 not all allenamides are robust
at temperatures well over 100 °C, and they possess variable
stability at 80-90 °C. Therefore, these amidative cross-
couplings were best carried out at 50 °C or room temperature.
To demonstrate the level of stereospecificity in this
amidation, we needed an optically pure allenyl iodide.
However, our efforts were hampered by the fact that
we could not identify any useful experimental protocols
that would provide optically pure allenyl iodides such as
2b.20,21 Therefore, to support this stereospecific amidative
cross-coupling further, we pursued the following two
studies.
The generality of this cross-coupling reaction using various
amides and allenyl iodides can be distinctly illustrated as
shown in Figure 1. The scope of amides would include chiral
and achiral cyclic urethanes, cyclic urethanes containing furyl
and alkenyl functional groups, 2-oxoindole, benzimidazoli-
dinone, sulfonamide, lactams, and acyclic amides.
Allenyl iodides would include (()-2b and 1-iodo-2,2-
dimethyl-1,2-propadiene 4,21 which gave the trisubstituted
allenamides 9 and 10, respectively, and 1-iodo-2-cyclohexy-
lidene-1,2-propadiene 5,21 which gave the trisubstituted
allenamides 11. In addition, CuTC [copper(I) thiophenecar-
boxylate], used in Trost’s work,12 appeared to be superior
to or at least comparable to CuCN for specific preparations
of allenamides 8 and 17-19.
First, diastereomeric allenyl iodides 22 and 23 were
prepared22 and painstakingly separated using MPLC
[Scheme 3]. Their couplings with achiral oxazolidinone 24
Scheme 3
We then turned our attention to optically enriched chiral
allenyl iodides because we were curious whether the axial
stereointegrity of an allenyl halide would be preserved
throughout these cross-coupling conditions. As shown in
Scheme 2, coupling of optically enriched allenyl iodide (P)-
Scheme 2
led to allenamides 25 and 26, respectively, in 73 and
65% yield, as single diastereomers. More significantly, there
was no interconversion between 25 and 26 under these
conditions.
Second, as shown in Scheme 4, we employed optically
enriched allenyl iodide (P)-2b [50% ee] and (M)-2b [75%
and 66% ee] and found that their couplings with amides 27
(18) See Supporting Information for experimental procedures and
characterizations of new compounds.
(19) Trost reported some successful examples of couplings with allenyl
bromide. See ref 12.
(20) For reviews on allenes, see: (a) Krause, N.; Hashmi, A. S. K.
Modern Allene Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, 2004; Vols. 1 and 2. (b) Saalfrank, R. W.; Lurz, C. J.
Heterosubstituierte Allene and Polyallene. In Methoden Der Organischen
Chemie (Houben-Weyl); Kropf, H., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, 1993; pp 3093-3102. (c) Schuster, H. E.; Coppola, G.
M. Allenes in Organic Synthesis; John Wiley and Sons: New York, 1984.
(21) (a) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 8214. (b)
Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W. J. Org. Chem. 1985,
50, 364.
2b21 with Evans’ chiral oxazolidinone 1 gave allenamide 3
in 68% yield with the diastereomeric ratio of 3(P,R) to
3(M,R) being 77:23. This result implies that the axial chirality
of (P)-2b was retained during the amidation since the
enantiomeric enrichment of (P)-2b was only 50%.
(22) (a) Ohno, H.; Ando, K.; Hamaguchi, H.; Takeoka, Y.; Tanaka T. J.
Am. Chem. Soc. 2002, 124, 15255. (b) Ohno, H.; Toda, A.; Takemoto, Y.;
Fujii, N.; Ibuka, T. J. Chem. Soc., Perkin Trans. 1 1999, 2949.
Org. Lett., Vol. 7, No. 14, 2005
3083

Scheme 4
Scheme 5
On the basis of the generally accepted amidation
mechanism,1,2,3b this evidence strongly suggests that allenyl
copper(III) species (P)-29 and (M)-29 [Scheme 5], formed
after the oxidative addition, maintain the axial stereointegrity
that was inherited from the chiral allenyl iodide. This
integrity would persist under the reaction conditions em-
ployed here throughout the cross-coupling process that would
include transmetalation to give (P)-30 and (M)-30 followed
by reductive elimination.
and 2823 under standard conditions gave allenamides (P)-14
and (P)-15, and (M)-14 and (M)-15, respectively, with
enantiomeric excesses that are closely matched with the
initial optical enrichment in (P)-2b and (M)-2b. More
importantly, the ee of (M)-14 varied with the ee of (M)-2b.
In addition, it is noteworthy that allenamides (P)- and (M)-
14, and (P)- and (M)-15, represent the first examples of an
optically enriched allenamide with respect to its axial chirality
without any external chiral entities.
We have described here a novel stereospecific amidation
of chiral allenyl iodides. This work provides an excellent
synthetic entry to optically enriched allenamides.
Acknowledgment. The authors thank NIH-NIGMS
[GM066055] and NSF [CHE-0094005] for generous support
and Mr. Ben Kucera for X-ray analysis.
Supporting Information Available: Experimental pro-
cedures, NMR spectra and characterizations for all new
compounds, and X-ray data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) These amides were chosen because we were able to resolve their
respective enantiomeric allenamides distinctly on using HPLC on a
Chiralcel-OD chiral column with a UV detector [see Supporting Informa-
tion].
OL051094Q
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Org. Lett., Vol. 7, No. 14, 2005