The synthesis of allenes by Cu(i)-catalyzed regio- and stereoselective reduction of propargylic carbonates with hydrosilanes

Article abstract of DOI:10.1039/b910192f

Cu(i)-catalyzed anti-S_N2′-type reduction of internal propargylic carbonates with hydrosilanes affords various di- and trisubstituted allenes with high regioselectivities; the reactions are compatible with functional groups and work efficiently

Full text of DOI:10.1039/b910192f

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The synthesis of allenes by Cu(I)-catalyzed regio- and stereoselective
reduction of propargylic carbonates with hydrosilanesw
Chongmin Zhong,a Yusuke Sasaki,a Hajime Ito*ab and Masaya Sawamura*a
Received (in Cambridge, UK) 26th May 2009, Accepted 23rd July 2009
First published as an Advance Article on the web 11th August 2009
DOI: 10.1039/b910192f
Cu(I)-catalyzed anti-SN20-type reduction of internal propargylic
carbonates with hydrosilanes affords various di- and trisubstituted
allenes with high regioselectivities; the reactions are compatible
with functional groups and work efficiently for the synthesis of
optically-active allenes.
The development of efficient synthetic methods for the
production of allenes has received considerable attention
Scheme
carbonates.
1
Copper-catalyzed SN20-type reactions of propargylic
because they have widespread applications in the synthesis
of biologically- and pharmacologically-active compounds.1
The highly selective reduction of propargylic alcohols or their
derivatives with transition metal catalysts is an attractive
method for allene synthesis. However, there are only a few
examples of transition metal-catalyzed reactions that fulfil
the following requirements: high SN20/SN2 selectivity in the
introduction of hydride, high reactivity towards substrates
with bulky substituents, good functional group compatibility
and high enantiomeric purity of the product in reactions of
optically pure substrates.
can serve as an attractive method for the synthesis of allenes
through an SN20-type selective reduction of propargylic
alcohol derivatives (Scheme 1, from 1 to 3).
To obtain the optimal reaction conditions, we used
propargylic carbonate 1a and polymethylhydrosiloxane (PMHS)
as the substrate and reducing agent, respectively (Table 1).
The palladium-catalyzed reduction of formate derivatives of
propargylic alcohols was first reported by Tsuji and co-workers
in 1993.2 These reactions suffer from low SN20/SN2 selectivity,
and their applicability to bulky trisubstituted substrates
remains unresolved. The highly regioselective reduction of
Initial experiments utilized the Cu(O–t-Bu)/Xantphos
catalyst, which is quite effective for the borylation of
propargylic esters with
a stoichiometric Cu(I) hydride
([HCuPPh3]6, Stryker’s reagent) is known.3 A catalytic method
for this reaction was first reported by Krause and co-workers
using a Cu(I)–NHC/hydrosilane (NHC: nitrogen-containing
heterocyclic carbene) catalyst system. Here, propargylic
oxiranes were converted to their corresponding a-hydroxyallenes
in a highly regio- and stereoselective manner.4 Lipshutz and
co-workers also mentioned a Cu(I)–NHC-catalyzed reduction
of propargylic esters in a review paper;5 however, only two
examples were reported. Despite these pioneering research
efforts, the scope of the Cu(I)/hydrosilane catalytic system
has not been fully explored in the regioselective reduction of
propargylic esters.
Table 1 The Cu(I)-catalyzed SN20 selective reduction of propargylic
carbonate 1a with PMHSa
Mol%
Cu
Yield
Solvent T/1C t/h (%)b
Entry Ligand
1
2
3
Xantphos
5
5
2
2
5
5
5
5
5
5
5
THF
THF
THF
THF
23
50
50
50
4
1
66
69
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
dppp
We recently reported a Cu(I)/Xantphos-catalyzed highly
SN20-selective borylation of propargylic carbonates with
diboron (Scheme 1, from 1 to 2).6 Here, we report that a
similar reaction using a hydride compound instead of diboron
1.5 73
1
4
4c,d
5
73 (68)
Toluene 23
62
20
6
2
7
6
7
8
9
10
11
DMI
THF
THF
THF
THF
THF
23
23
23
23
23
23
4
12
12
12
12 20
12
dppe
dppf
a Department of Chemistry, Faculty of Science, Hokkaido University,
Sapporo 060-0810, Japan. E-mail: hajito@sci.hokudai.ac.jp;
Fax: +81 11-706-3749; Tel: +81 11-706-4647
PPh3
1,10-Phenanthroline
1
a
b PRESTO Science and Technology Agency (JST), Honcho,
Kawaguchi, Saitama 332-0012, Japan
Reaction conditions: carbonate 1a (0.5 mmol), solvent (1.0 mL),
PMHS (4.0 equiv., 2.0 mmol), Cu(OAc)2 (0.01–0.025 mmol) and
b
ligand (0.01–0.025 mmol). Determined by GC.
d
Xantphos was used. Isolated yield in parentheses.
c
w Electronic supplementary information (ESI) available: Detailed
synthetic procedures and analytical data for all new compounds are
available. See DOI: 10.1039/b910192f
3 mol% of
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Table 2 SN20 selective reduction of propargylic carbonates 1 with
improve the yield of the present reactions (Table 1, 66%, entry 1).
Consequently, the reaction conditions were optimized using
Cu(OAc)2. Higher reaction temperatures led to a faster reaction
rate and a slightly improved yield (69%; Table 1, entry 2). We
found that the best yields were achieved with a low catalyst
loading (2 mol% Cu(OAc)2/Xantphos, 1.5 h, 73%; Table 1,
entry 3) and when 1.5 equiv. of ligand relative to the copper salt
was employed (2 mol% Cu(OAc)2, 3 mol% Xantphos, 1 h, 73%;
Table 1, entry 4). Toluene and the coordinating solvent DMI
afforded lower yields (Table 1, entries 5 and 6). Other bidentate
phosphines (dppp, dppe and dppf; Table 1, entries 7–9),
monophosphines (PPh3; Table 1, entry 10; PCy3 and PBu3
not shown) and 1,10-phenanthroline (Table 1, entry 11) were
examined. None of these ligands provided 3a in a yield of
420%. No SN2 reduction product (alkyne) was detected
by 1H NMR in these Cu(OAc)2/Xantphos-catalyzed reduc-
tions of 1a. The best results were obtained when the reaction
was terminated at an appropriate reaction time. Excessively
long reaction times led to further side reactions of the allene
products to form unidentified compounds.
PMHSa
Yield
t/min (%)b
Carbonate
Allene
Entry
1
105 86
2
3
45
50
51
56
Having identified the optimal conditions for the copper-
catalyzed regioselective reduction of propargylic carbonates
(Table 1, entry 4), the generality of this reduction was
evaluated (Table 2).8 Both tri- and disubstituted allenes were
obtained in moderate to good yields from the corresponding
tertiary and secondary propargylic carbonates (50–86%;
Table 2, entries 1, 2 and 5–7). Generally, allenes from
propargylic carbonates with bulky substituents at the
g-position were obtained in higher yields than those from
carbonates with less bulky substituents (cf. 3a (68%) vs. 3b
(86%) and 3f (50%) vs. 3g (86%)). The bulky substituents in
the products probably prevent these compounds from reacting
further and so are responsible for the observed higher yields.
The carbonates involving five- and six-membered rings
(1d and 1e) were converted into allenes containing vinylidene-
cyclopentane (3d) and vinylidenecyclohexane (3e) structures,
respectively (Table 2, entries 3 and 4). The reactions also
showed good functional group tolerance. Benzoate ester,
carbamate and CQC double bonds were compatible under
the reaction conditions employed (Table 2, entries 8–10).
Unfortunately, complex mixtures were obtained in reactions
using substrates with a phenyl group at the a- or g-carbon.
Our results obtained with 1l and (S)-1h provide evidence for
the anti-SN20 pathway in these reactions (Scheme 2). The
diastereomeric ratio of (1R,4R)-(+)-camphor-based allene 3l
was 495 : 5 (by 1H NMR).9,10 Optically-active propargylic
carbonate (S)-1h (99.5% ee)11 was converted into chiral allene
(S)-(+)-3h at 0 1C with complete 1,3-chirality transfer.12
These regio- and stereochemical results are explained by the
plausible reaction mechanism shown in Scheme 3. In the
presence of Xantphos, Cu(OAc)2 is reduced by the hydrosilane
to Cu(I) hydride species A, which is then coordinated by the
triple bond of the substrate. syn-Addition of the Cu–H bond
to the triple bond produces alkenyl copper intermediate B.
anti-b-Elimination of B gives the allene product, with the
release of CO2, forming copper alkoxide C. s-Bond metathesis
between C and the hydrosilane regenerates Cu(I) hydride A.
In summary, we have found a useful method for the
synthesis of di- and trisubstituted allenes through a highly
4
5
6
90
60
90
46
50
86
7
8
9
180 78
70
90
77
44
10
600 82
a
Reaction conditions: Cu(II) acetate (2 mol%, 0.01 mmol), Xantphos
(3 mol%, 0.015 mmol), THF (1.0 mL), PMHS (4.0 equiv, 2.0 mmol)
b
and 1 (0.5 mmol). Isolated yield.
propargylic carbonates,6a affording 60% of allene 3a after
4 h at room temperature (data not shown). Yun et al. have
reported that easy-to-handle Cu(OAc)2 can be used instead of
Cu(O–t-Bu) in copper-catalyzed hydrosilylation and reduction
reactions.7 The use of Cu(OAc)2 rather than Cu(O–t-Bu) did
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Notes and references
1 K. M. Brummond and H. Chen, in Modern Allene Chemistry, ed.
N. Krause and A. S. K. Hashmi, Wiley-VCH, Weinheim, 2004,
vol. 2, ch. 19, pp. 1041–1089.
2 T. Mandai, T. Matsumoto, M. Kawada and J. Tsuji, Tetrahedron
Lett., 1993, 34, 2161–2164.
3 J. F. Daeuble, C. McGettigan and J. M. Stryker, Tetrahedron Lett.,
1990, 31, 2397–2400.
4 C. Deutsch, B. H. Lipshutz and N. Krause, Angew. Chem., Int. Ed.,
2007, 46, 1650–1653.
5 (a) C. Deutsch, N. Krause and B. H. Lipshutz, Chem. Rev., 2008,
108, 2916–2927; For Cu(I)-catalyzed reductions, see also:
(b) S. Rendler and M. Oestreich, Angew. Chem., Int. Ed., 2007,
46, 498–504; (c) B. H. Lipshutz, Synlett, 2009, 509–524.
6 (a) H. Ito, Y. Sasaki and M. Sawamura, J. Am. Chem. Soc., 2008,
130, 15774–15775; (b) H. Ito, C. Kawakami and M. Sawamura,
J. Am. Chem. Soc., 2005, 127, 16034–16035; (c) H. Ito, S. Ito,
Y. Sasaki, K. Matsuura and M. Sawamura, J. Am. Chem. Soc.,
2007, 129, 14856–14857; For a Cu(I)/Xantphos/hydrosilane catalyst
system, see also: (d) H. Ito, A. Watanabe and M. Sawamura,
Org. Lett., 2005, 7, 1869–1871.
Scheme 2 The synthesis of optically-active allenes via the regio-
selective and stereoselective reduction of propargylic carbonates with
PMHS.
7 (a) D. Lee and J. Yun, Tetrahedron Lett., 2004, 45, 5415–5417;
(b) D. Kim, B.-M. Park and J. Yun, Chem. Commun., 2005,
1755–1757.
8 Experimental procedures: Cu(II) acetate (1.8 mg, 0.01 mmol) and
Xantphos (8.6 mg, 0.015 mmol) were placed in a screw-capped
reaction vial. The vial was connected to an argon line through a
needle and was evacuated and back-filled with argon three times.
After the addition of de-gassed anhydrous THF (1.0 mL), the
mixture was stirred for about 20 min. PMHS (130 mL, 4.0 equiv.)
was then added dropwise with a microsyringe. The solution was
stirred for an additional 30 min until the mixture had assumed a
characteristic yellow-orange colour. Carbonate 1 (0.5 mmol) was
then added at 50 1C. The reaction mixture was stirred for a
specified period of time. The reaction mixture was subsequently
transferred to
a 50 mL round-bottomed flask using Et2O.
Unreacted PMHS was hydrolyzed using a 1 M NaOH aqueous
solution (3.0 mL). The products were purified by silica gel
chromatography with hexane as the eluent.
Scheme 3 A plausible catalytic cycle.
9 3l was also prepared from the corresponding propargylic alcohol
by reduction with stoichiometric amounts of LiAlH4 and AlCl3.10
Products prepared by these two methods showed identical 1H and
13C NMR spectra.
regio- and stereoselective copper/Xantphos-catalyzed reduction
of propargylic carbonates. The catalyst system works
efficiently for the synthesis of bulky substituted allenes and
shows good functional group compatibility.
10 S.-C. Hung, Y.-F. Wen, J.-W. Chang, C.-C. Liao and B.-J. Uang,
J. Org. Chem., 2002, 67, 1308–1313.
11 K. Matsumura, S. Hashiguchi, T. Ikariya and R. Noyori, J. Am.
Chem. Soc., 1997, 119, 8738–8739.
This work was supported by the PRESTO program (JST),
Grant-in-Aid for Scientific Research (B) (JSPS). C. Z. was
supported by GCOE (Catalysis as the Basis for Innovation
in Materials Science, Hokkaido University). We also
acknowledge Daicel Chemical Industries for chiral HPLC
analysis.
12 The enantiomeric excess (ee) of (S)-(+)-3h was determined by
chiral HPLC analysis (DAICEL CHIRALCELs OJ-RH,
H2O : MeOH = 20 : 80, 0.5 mL minꢁ1, 220 nm). The reaction
with (S)-1h at a high temperature (50 1C) produced (S)-(+)-3h in a
yield of 78% with a decreased enantioselectivity of 87% ee. This
decrease is probably due to a side reaction of the allene product
with the Cu(I) hydride species.
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This journal is The Royal Society of Chemistry 2009
5852 | Chem. Commun., 2009, 5850–5852