Copper(I)-catalyzed regioselective propargylic substitution involving Si-B bond activation

Article abstract of DOI:10.1021/ol201811d

The silicon nucleophile generated by copper(I)-catalyzed Si-B bond activation allows several γ-selective propargylic substitutions. The regioselectivity (γ:α ratio) is strongly dependent on the propargylic leaving group. Chloride is superior to oxygen leaving groups in linear substrates (γ:α > 99:1), and it is only the phosphate group that also shows promising regiocontrol (γ:α = 90:10). That leaving group produces superb γ-selectivity (γ:α > 99:1) in α-branched propargylic systems, and enantioenriched substrates react with excellent central-to-axial chirality transfer.

Full text of DOI:10.1021/ol201811d

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4462–4465
Copper(I)-Catalyzed Regioselective
Propargylic Substitution Involving SiꢀB
Bond Activation
Devendra J. Vyas,†,‡ Chinmoy K. Hazra,†,‡ and Martin Oestreich*,†
€
€
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster,
€
Corrensstrasse 40, 48149 Mu€nster, Germany
martin.oestreich@uni-muenster.de
Received July 7, 2011
ABSTRACT
The silicon nucleophile generated by copper(I)-catalyzed SiꢀB bond activation allows several γ-selective propargylic substitutions. The
regioselectivity (γ:R ratio) is strongly dependent on the propargylic leaving group. Chloride is superior to oxygen leaving groups in linear
substrates (γ:R > 99:1), and it is only the phosphate group that also shows promising regiocontrol (γ:R = 90:10). That leaving group produces
superb γ-selectivity (γ:R > 99:1) in R-branched propargylic systems, and enantioenriched substrates react with excellent central-to-axial chirality
transfer.
The ability of RhꢀO and CuꢀO complexes to activate
interelement linkages through σ-bond metathesis is a facile
entry into the chemistry of main group element nucle-
ophiles.1 The synthetic potential of both rhodium(I)-2 and
copper(I)-catalyzed3 transmetalations of the SiꢀB bond4
and subsequent CꢀSi bond-forming reactions are cur-
rently being actively explored. The copper(I) catalysis is
particularly useful as an alternative method for the forma-
tion of silicon-based cuprates.5 We recently developed a
γ-selective synthesis of branched allylic silanes from linear
allylic chlorides using that copper(I)-catalyzed SiꢀB bond
activation (γ:R g 98:2).6 The excellent regiocontrol led us
to consider the related propargylic substitution (Ifγ-II
but not R-II, Scheme 1). The Fleming group had accom-
plished the copper(I)-mediated (enantioselective) prepara-
tion of allenylic silanes from propargylic substrates with
different leaving groups.7 The corresponding catalysis is not
known,5 but there are reports of transition-metal-catalyzed
†
€
Universitat M€unster.
‡ NRW Graduate School of Chemistry.
(1) (a) Burks, H. E.; Morken, J. P. Chem. Commun. 2007, 4717–4725.
(b) Hartmann, E.; Vyas, D. J.; Oestreich, M. Chem. Commun. 2011, 47,
7917–7932. (c) Hartmann, E.; Oestreich, M. Chimica Oggi ꢀ Chemistry
Today 2011, 29, in press.
(2) (a) Walter, C.; Auer, G.; Oestreich, M. Angew. Chem., Int. Ed.
2006, 45, 5675–5677. (b) Walter, C.; Oestreich, M. Angew. Chem., Int.
€
Ed. 2008, 47, 3818–3820. (c) Walter, C.; Frohlich, R.; Oestreich, M.
Tetrahedron 2009, 65, 5513–5520. (d) Hartmann, E.; Oestreich, M.
Angew. Chem., Int. Ed. 2010, 49, 6195–6198.
(3) (a) Lee, K.-s.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 2898–
2900. (b) Welle, A.; Petrignet, J.; Tinant, B.; Wouters, J.; Riant, O.
Chem.ꢀEur. J. 2010, 16, 10980–10983. (c) Ibrahem, I.; Santoro, S.;
(5) For a review of silicon-based cuprates catalytic in copper, see:
Weickgenannt, A.; Oestreich, M. Chem.;Eur. J. 2010, 16, 402–412.
(6) Vyas, D. J.; Oestreich, M. Angew. Chem., Int. Ed. 2010, 49, 8513–
8515.
(7) Regioselective propargylic substitution by copper-mediated
CꢀSi bond formation: (a) Fleming, I.; Terrett, N. K. J. Organomet.
Chem. 1984, 264, 99–118. (b) Fleming, I.; Takaki, K.; Thomas, A. P. J.
Chem. Soc., Perkin Trans. 1 1987, 2269–2273. (c) Marshall, J. A.;
Maxson, K. J. Org. Chem. 2000, 65, 630–633.
ꢀ
Himo, F.; Cordova, A. Adv. Synth. Catal. 2011, 353, 245–252.
(d) Tobisu, M.; Fujihara, H.; Koh, K.; Chatani, N. J. Org. Chem.
2010, 75, 4841–4847. (e) Wang, P.; Yeo, X.-L.; Loh, T. P. J. Am. Chem.
€
Soc. 2011, 133, 1254–1256. (f) Vyas, D. J.; Frohlich, R.; Oestreich, M.
Org. Lett. 2011, 13, 2094–2097.
(4) For a recent summary of SiꢀB chemistry, see: Ohmura, T.;
Suginome, M. Bull. Chem. Soc. Jpn. 2009, 82, 29–49.
r
10.1021/ol201811d
Published on Web 07/25/2011
2011 American Chemical Society

propargylic displacements with silicon nucleophiles invol-
ving the transmetalation of interelement linkages. A semi-
was also high for phosphate (γ:R = 90:10). The pro-
pargylic bromide reacted, however, with poor selectivity
(γ:R = 67:33) (Table 1, entries 1ꢀ3). The remaining
common oxygen leaving groups all favor R substitution,
and γ:R ratios are in fact good for carbamate and benzoate
(Table 1, entries 4 and 6). It is noteworthy that, compared
to Sawamura’s investigations,9,12a,13 the carbonate leaving
group yielded a poor γ:R ratio (Table 1, entry 5). Chemical
yields were generally lower for oxygen leaving groups than
those for chloride and bromide (quantitative yield).
ꢀ
nal paper by Szabo et al. showed that palladium(II) pincer
complexes indeed catalyze the heterolytic cleavage of a
SiꢀSn bond (left, Scheme 1), and the thus-formed reactive
PdꢀSi intermediate participates in the γ-selective substitu-
tion of propargylic chlorides.8 Later, Sawamura et al.
adopted our rhodium(I)-catalyzed SiꢀB transmetalation
(yet without added water) and elaborated a practical
functional-group-tolerant allenylic silane synthesis with a
carbonate leaving group (middle, Scheme 1).9 In this
Letter, we demonstrate that our straightforward reaction
setup for copper(I)-catalyzed SiꢀB bond activation6 is
applicable to the γ-selective substitution of propargylic
chlorides as well as phosphates (right, Scheme 1).10ꢀ13
Table 1. Copper-Catalyzed Propargylic Substitution: Survey of
Leaving Groups
Scheme 1. Transition-Metal-Catalyzed Interelement Activation
in Propargylic Substitution with Nucleophilic Silicon
propargylic
precursor
leaving group
X
γ:R
yield
(%)b
entry
ratioa
1
2
3
4
5
6
1a
2a
3a
4a
5a
6a
Cl
100:0c
67:33
90:10
6:94
94
98
66
42
49
47
Br
OP(O)(OEt)2
OC(O)NHPh
OC(O)OMe
OC(O)Ph
24:76
5:95
a Ratio of regioisomers determined by GLC analysis prior to pur-
ification. b Combined isolated yield after flash chromatography on silica
gel. c No linear regioisomer detected by GLC analysis.
The leaving group-dependent propargylic substitution
provides an access to both allenylic (γ-selectivity) and
propargylic (R-selectivity) silanes in synthetically useful
As we continued using the protocol for the allylic
substitution,6 we immediately began with a survey of
leaving groups (Table 1). Again, CuCN (5.0 mol %) and
NaOMe (2.0 equiv) in THF at ꢀ78 °C were routinely used,
but this time, only a slight excess of Suginome’s Me2Ph-
SiꢀBpin reagent14 (1.2 equiv as opposed to 1.5 equiv) was
necessary. We were delighted to find that the γ:R ratios in
the propargylic substitution largely parallel those obtained
in the allylic transposition. The chloride leaving group
secured perfect regiocontrol (γ:R= 100:0), and γ-selectivity
0
γ:R ratios. With our focus on SN -type substitution, we
extended the substrate scope for propargylic chlorides
(1aꢀ1h, Table 2). All aryl- and alkyl-substituted precursors
were cleanly converted into allenes (Table 2, entries 1ꢀ6).
The parent compound, propargylic chloride, also yielded
the allene exclusively (Table 2, entry 7). In agreement with
our previous findings,6 the γ:R ratio was completely eroded
by a terminal Me3Si group (Table 2, entry 8).
While the chloride leaving group emerged as superior, it
would not be useful in enantioselective displacements as
enantioenriched R-chiral propargylic chlorides are not
available. Instead, R-chiral phosphates are easy to make,
and the γ:R ratio was also promising (Table 1, entry 3).
We therefore prepared the R-chiral propargylic phos-
phates (S)-3i (R = Ph) and (S)-3j (R = n-Bu) from the
known corresponding enantiopure alcohols, obtained by
enzymatic kinetic resolution. Subjecting those to our stan-
dard protocols afforded the chiral allenes with superb γ:R
ratios [(S)-3i/(S)-3jf(aR)-γ-7i/(aR)-γ-7j, Scheme 2].15
Gratifyingly, the central-to-axial chirality transfer wasalso
ꢀ
ꢀ
(8) Kjellgren, J.; Sunden, H.; Szabo, K. J. J. Am. Chem. Soc. 2005,
127, 1787–1796.
(9) Ohmiya, H.; Ito, H.; Sawamura, M. Org. Lett. 2009, 11, 5618–
5620.
(10) For an uncatalyzed reaction of terminally metalated propargyl
substrates with Me2PhSiꢀBpin, see: Shimizu, M.; Kurahashi, T.;
Kitagawa, H.; Hiyama, T. Org. Lett. 2003, 5, 225–227.
(11) We think that the current investigation is closely connected to
the recent progress in CuꢀO-mediated transmetalation of SiꢀH and
BꢀB bonds. The resultant CuꢀH and CuꢀB nucleophiles undergo
γ-selective propargylic reduction12 (with carbonate12a or acetate12b leaving
groups) and borylation13 (with carbonate leaving group).
(12) (a) Zhong, C.; Sasaki, Y.; Ito, H.; Sawamura, M. Chem. Com-
mun. 2009, 5850–5852. (b) Deutsch, C.; Lipshutz, B. H.; Krause, N. Org.
Lett. 2009, 11, 5010–5012.
(13) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130,
15774–15775.
(14) Suginome, M.; Matsuda, T.; Ito, Y. Organometallics 2000, 19,
4647–4649.
(15) It is important to note that we had also tested the cognate (R = Ph)
carbonate 5i and benzoate 6i but both showed no conversion.
Org. Lett., Vol. 13, No. 16, 2011
4463

NaOMe regenerates III thereby closing the catalytic cycle
(VIIfIII).
Table 2. Copper-Catalyzed Propargylic Substitution of Linear
Propargylic Chlorides
Scheme 3. Proposed Catalytic Cycle
propargylic
precursor
γ:R
yield
(%)b
entry
R
ratioa
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
100:0c
100:0c
100:0c
100:0c
100:0c
100:0c
100:0c
56:44
94
78
88
71
80
77
65d
88
4-MeC6H4
4-FC6H4
n-Bu
n-Pen
c-Pr
1g
1h
H
SiMe3
a Ratio of regioisomers determined by GLC analysis prior to pur-
ification. b Combined isolated yield after flash chromatography on silica
gel. c No linear regioisomer detected by GLC analysis. d Volatile
compound.
Our protocol is also applicable to tertiary propargylic
phosphates. Representative functionalized 3k and 3l yiel-
ded fully substituted allenes γ-7k and γ-7l as single regioi-
somers (Scheme 4). These results compare nicely with the
rhodium(I)-catalyzed propargylic substitutions of the cor-
responding tertiary carbonates.9
good, and regioisomerically pure (aR)-γ-7i and (aR)-γ-7j
were isolated with 92% ee and >95% ee, respectively. The
absolute configurations of the allenylic silane were as-
signed by comparison with the reported optical rotation
of (aR)-γ-7j.9
Scheme 2. Central-to-Axial Chirality Transfer in the Copper-
Catalyzed Propargylic Substitution of R-Chiral Phosphates
Scheme 4. Copper-Catalyzed Propargylic Substitution of Ter-
tiary Propargylic Phosphates
The stereochemical course, that is SfaR, is identical to
that determined by the Sawamura group in related rho-
dium(I)-9 and copper(I)-catalyzed12a,13 propargylic substi-
tutions involving interelement bond activation. That was
rationalized by syn-selective 1,2-addition of the transition
metal nucleophile across the CꢀC triple bond followed by
anti-selective β-elimination. Based on that reasonable me-
chanism, we propose the catalytic cycle depicted in Scheme
3. The CuꢀSi reagent V is generated from the CuꢀOMe
complex III through σ-bond metathesis (IIIfIVfV). The
chemoselectivity in that step is likely to be determined by
the electronegativity and/or Lewis acidity of boron over
silicon in SiꢀB. Intermediate V then reacts with I accord-
ing to the above-mentioned two-step sequence to yield γ-II
(IfVIfγ-II). Salt metathesis of CuꢀX complex VII and
In summary, we elaborated a general and practical pro-
pargylic substitution with the silicon nucleophile generated
(16) For a summary, see: Pornet, J. In Science of Synthesis; Fleming,
I., Ed.; Thieme: Stuttgart, 2002; Vol. 4, pp 669ꢀ683.
(17) Regioselective propargylic substitution by copper-mediated
CꢀC bond formation: (a) Westmijze, H.; Vermeer, P. Synthesis 1979,
390–392. (b) Guintchin, B. K.; Bienz, S. Organometallics 2004, 23, 4944–
4951 (enantioselective). By Johnson orthoester Claisen rearrangement:
(c) Brawn, R. A.; Panek, J. S. Org. Lett. 2007, 9, 2689–2692
(enantioselective).
4464
Org. Lett., Vol. 13, No. 16, 2011

from a SiꢀB precursor. The reaction setup is simple, and
only CuCN and NaOMe are needed. The new protocol is a
useful addition to the existing repertoire of regioselective
and enantioselective allenylic silane syntheses.16ꢀ19
Acknowledgment. D.J.V. and C.K.H. are indebted to
the NRW Graduate School of Chemistry for predoctoral
fellowships (2008ꢀ2011 and 2010ꢀ2013). We thank the
BASF SE (Ludwigshafen, Germany) for the generous
donation of enzymes.
(18) For selected transition-metal-catalyzed syntheses of allenylic
silanes through CꢀSi bond formation, see: (a) Kobayashi, S.; Nishio,
K. J. Am. Chem. Soc. 1995, 117, 6392–6393. (b) Suginome, M.; Matsumoto,
A.; Ito, Y. J. Org. Chem. 1996, 61, 4884–4885. (c) Han, J. W.; Tokunaga, N.;
Hayashi, T. J. Am. Chem. Soc. 2001, 123, 12915–12916.
(19) For a recent summary of the use of chiral allenylic metal
reagents, see: Marshall, J. A. J. Org. Chem. 2007, 72, 8153–8166.
Supporting Information Available. General procedure,
characterization data as well as 1H and 13C NMR spectra
for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
4465