(NHC)CuH-catalyzed entry to alienes via propargylic carbonate s n2'-reductions

Article abstract of DOI:10.1021/ol901868m

The copper hydride-catalyzed S_N2'-reduction of propargylic carbonates provides an efficient route to functionalized alienes. The method takes advantage of the stabilizing effect of NHC llgands on CuH and combines high reactivity and stereoselec

Full text of DOI:10.1021/ol901868m

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5010-5012
(NHC)CuH-Catalyzed Entry to Allenes
via Propargylic Carbonate
SN2′-Reductions
Carl Deutsch,† Bruce H. Lipshutz,‡ and Norbert Krause*,†
Organic Chemistry, Dortmund UniVersity of Technology, Otto-Hahn-Strasse 6,
D-44227 Dortmund, Germany, and Department of Chemistry and Biochemistry,
UniVersity of California, Santa Barbara, California 93106
norbert.krause@tu-dortmund.de
Received August 11, 2009
ABSTRACT
The copper hydride-catalyzed SN2′-reduction of propargylic carbonates provides an efficient route to functionalized allenes. The method takes advantage
of the stabilizing effect of NHC ligands on CuH and combines high reactivity and stereoselectivity with excellent tolerance toward reactive functionalities.
The combination of isolation of allenic natural products (e.g.,
bromoallene laurallene; Figure 1), industrial development of
biologically active allenes (e.g., prostaglandin analogue enpros-
til),1 and the potential use of highly reactive cumulated double
bonds in synthesis have catapulted allenes into focus.2 Their
synthetic utility has been acknowledged by an abundance of
regio- and stereoselective C-C and C-heteroatom bond-
forming transformations now available, perhaps most notewor-
thy being their efficient transfer of allenic axial chirality to the
creation of sp3 stereogenic centers. New inroads for the
syntheses of allenes that reflect their growing value continue
† Dortmund University of Technology.
‡ University of California, Santa Barbara.
(1) Review : Hoffmann-Ro¨der, A.; Krause, N. Angew. Chem., Int. Ed.
2004, 43, 1196–1216, and references cited therein.
Figure 1. Naturally occurring and biologically active allenes.
(2) (a) Cumulenes and Allenes; Krause, N., Ed.; Science of Synthesis,
Vol. 44; Thieme: Stuttgart, 2007. (b) Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004. (c) Krause, N.;
Belting, V.; Deutsch, C.; Erdsack, J.; Fan, H.-T.; Gockel, B.; Hoffmann-
Ro¨der, A.; Morita, N.; Volz, F. Pure Appl. Chem. 2008, 80, 1063–1069.
(d) Brummond, K. M.; DeForest, J. E. Synthesis 2007, 795–818. (e) Ma, S.
Pure Appl. Chem. 2006, 78, 197–208. (f) Ma, S. Chem. ReV. 2005, 105,
2829–2871. (g) Krause, N.; Hoffmann-Ro¨der, A. Tetrahedron 2004, 60,
11671–11694.
to be disclosed, often taking advantage of copper-mediated or
-catalyzed nucleophilic addition or substitution reactions.2
One alternative to C-C bond construction is the synthesis
of allenes through underutilized carbon-hydrogen bond
formation. Other than two reports featuring allene syntheses
10.1021/ol901868m CCC: $40.75
Published on Web 10/05/2009
 2009 American Chemical Society

mediated by stoichiometric copper hydride3 (Stryker’s
reagent [(Ph3PCuH)6]4) on propargylic acetates,5 there is only
a single catalytic method6 known leading to highly func-
tionalized allenes involving in situ generation of CuH and
reactions with propargylic oxiranes in the presence of
polymethylhydridosiloxane (PMHS).7 This shortage of syn-
thetic methods stands in stark contrast to the rich and highly
developed catalysis by CuH applied to both 1,2- and 1,4-
reductions of carbonyl compounds.3 While CuH-catalyzed
SN2′-reduction of propargylic oxiranes offers access to a
variety of R-hydroxyallenes,7 extension to other propargylic
electrophiles would have advantages, such as (i) greater
substrate reactivity, (ii) improved stereoselectivity, and (iii)
better insight as to ligand effects in CuH catalysis. Impor-
tantly, the limitation of Stryker’s reagent to SN2′-reductions
of terminal propargylic acetates5 might be overcome.
Table 1. Copper-Catalyzed SN2′-Reduction of Propargylic
Electrophiles 1
entry
1
LG
ligand
1/2 (yield, %)
1
2
3
4
5
6
7
8
9
a
b
b
c
d
e
e
f
Ac
Piv
Piv
3c
3c
3a
3c
3c
3b
3c
3a
3c
35/40
25/70
0/0a
0/trace
60/20
trace/88
0/95
To establish the optimal combination of leaving group and
stabilizing ligand for the CuH catalyst, various propargylic
electrophiles 18 were treated in toluene at room temperature
with a mixture of CuCl, NaO-t-Bu and NHC-carbene
precursors 3a-c9 in the presence of PMHS as stoichiometric
hydride source10 (Table 1).
ClCH2CO
3-O2NC6H4CO
MeOCO
MeOCO
Boc
25/33
trace/75
Whereas acetate 1a and pivalate 1b in the presence of
IBiox12 (3c) afforded the desired allene 2 (albeit in a slow
reaction that did not go to completion; entries 1, 2), no
product was formed when 1b was exposed to SIMes ligand
3a (entry 3). Unexpectedly, more electron-deficient esters
are not suitable for this SN2′-reduction as well (entries 4 and
5). Best results were achieved with carbonates 1e and 1f,
which afforded allene 2 in up to 95% isolated yield (entries
6-9). Again, the Glorius ligands 3b/c performed in a far
superior fashion to the Arduengo carbene 3a (entries 6, 7, 9
vs 8). The bulkier IBiox12 carbene 3c11 relative to analogue
3b gave a slightly higher yield of the allene (entry 6 vs 7).12
f
Boc
a No conversion.
The proposed mechanistic model (Scheme 1) provides an
explanation for the pronounced leaving group effect.
Scheme 1
(3) Reviews: (a) Lipshutz, B. H. Copper(I)-Mediated 1,2- and 1,4-
Reductions. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: Weinheim, 2002; pp 167-187. (b) Rendler, S.; Oestreich, M. Angew.
Chem., Int. Ed. 2007, 46, 498–504. (c) Deutsch, C.; Krause, N.; Lipshutz,
B. H. Chem. ReV. 2008, 108, 2916–2927. (d) Lipshutz, B. H. Synlett 2009,
509–524.
(4) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291–293. (b) Brestensky, D. M.; Huseland, D. E.;
McGettigan, C.; Stryker, J. M. Tetrahedron Lett. 1988, 29, 3749–3752.
(5) (a) Daeuble, J. F.; McGettigan, C.; Stryker, J. M. Tetrahedron Lett.
1990, 31, 2397–2400. (b) Brummond, K. M.; Lu, J. J. Am. Chem. Soc.
1999, 121, 5087–5088.
(6) For a reductive allene synthesis using stoichiometric amounts of
Schwartz’s reagent, see: (a) Pu, X.; Ready, J. M. J. Am. Chem. Soc. 2008,
130, 10874–10875. (b) For the synthesis of allenic hydrocarbons using
catalytic CuH stabilized by phosphines, see: Zhong, C.; Sasaki, Y.; Ito, H.;
Sawamura, M. Chem. Commun. 2009, 5850-5852.
(7) Deutsch, C.; Lipshutz, B. H.; Krause, N. Angew. Chem., Int. Ed.
2007, 46, 1650–1653.
Thus, the in situ formed copper hydride species A likely
reacts with the propargylic electrophile B to form π-com-
plex C, which is then converted into the σ-copper(III)
species D.13 Reductive elimination affords allene E and
the copper salt F. The key to efficiency of the catalytic
cycle is regeneration of the copper hydride catalyst A by
reaction of F with PMHS. It has been shown that the rate
of this transmetalation step depends strongly on the
(8) Substrates 1aa-ad: Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew.
Chem., Int. Ed. Engl. 1978, 17, 569–583. Substrates 1ae and 1af: Mandai,
T.; Matsumoto, T.; Tsujiguchi, Y.; Matsuoka, S.; Tsuji, J. J. Organomet.
Chem. 1994, 473, 343–352.
(9) (a) Arduengo, A. J.; Krafczyk, R.; Schmutzler, R. Tetrahedron 1999,
55, 14523–14534. (b) Jafarpour, L.; Stevens, E. D.; Nolan, S. P. J.
Organomet. Chem. 2000, 606, 49–54. (c) Altenhoff, G.; Goddard, R.;
Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc. 2004, 126, 15195–15201.
(10) Besides PMHS, also (Me2HSi)2O, Et3SiH, and (EtO)3SiH were used
as hydride source, but these silanes afforded diminished reactivities.
(11) Wu¨rtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523–1533.
(12) Treatment of 1ae with stoichiometric amounts of Stryker’s reagent
led to decomposition of the substrate.
(13) For a recent review on the mechanism of copper-mediate reactions,
see: Gschwind, R. M. Chem. ReV. 2008, 108, 3029–3053.
Org. Lett., Vol. 11, No. 21, 2009
5011

The scope of this allene synthesis was explored by
reacting various propargylic carbonates (Table 2) under
the newly established optimal conditions (Table 1, entry
7). A wide variety of functional groups is tolerated in the
substrate, such as electron-rich (Table 2, entries 1-3, 6)
or electron-deficient aromatics (entries 8, 10, 11), free
hydroxyl groups (entries 6-8, 10-12), silyl ethers (entry
5), acetals (entries 2, 4, 5), cyclopropanes (entries 7, 12),
halogens (entries 8, 11), and CF3 groups (entry 10).
Moreover, the method also applies to cyclic carbonates
(entries 9-12). In these SN2′-reductions (as well as for
chiral oxazolidine 10, entry 5), each allene was obtained
as a single diastereomer, indicating complete transfer of
axis-to-center chirality. Comparison of the relative con-
figuration of allenes 19, 23, and 25 with those obtained
from propargylic oxiranes7 reveals that propargylic car-
bonates react with SN2′ anti-stereoselectivity (as expected
for the mechanism depicted in Scheme 1).13 It is worth
noting that allene 25 (entry 12) was obtained in diaste-
reomerically pure form from carbonate 24, while the
corresponding oxirane led to only 86% ds.7 Thus, the
method presented herein offers the additional advantage
of improved diastereoselectivity, as well as the opportunity
to access enantiomerically enriched or pure precursors to
propargylic carbonates, e.g., by Sharpless dihydroxylation.
In summary, we have developed a mild and efficient
copper hydride-catalyzed SN2′-reduction of propargylic
carbonates which provides a highly chemo- and stereose-
lective route to functionalized allenes. Products of this type
are valuable precursors for further transformations;2 for
example, Garner aldehyde-derived allene 11 can be used for
the synthesis of derivatives of the antibiotic amino acid
furanomycin by gold-catalyzed cycloisomerization.14 We are
continuing to expand the repertoire of CuH technology and
to apply these methods to target-oriented synthesis.
Table 2. Copper-Catalyzed SN2′-Reduction of Propargylic
Carbonatesa
a Conditions: CuCl (3 mol %), 3c (3 mol %), NaO-t-Bu (9 mol %),
PMHS (2 equiv), rt, 8-24 h, workup with satd aq NaHCO3. b 8 was used
as a 1:1 mixture of diastereomers; 3b was used instead of 3c. c Substrate
and product are enantiomerically pure. d 37% of starting material 16
recovered. e Relative configuration assigned by comparison with allenes
obtained by SN2′-reduction of propargyl oxiranes.7
Acknowledgment. Support by the Deutsche Forschungs-
gemeinschaft, the European Community, and the U.S. NSF
is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and selected NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
basicity of the copper salt.3 Thus, we assume that this
step is slow for copper carboxylates, whereas a fast
hydride transfer occurs with copper alkoxides which are
presumably formed in situ from the corresponding carbon-
ate.
OL901868M
(14) Erdsack, J.; Krause, N. Synthesis 2007, 3741–3750, and references
cited therein.
5012
Org. Lett., Vol. 11, No. 21, 2009