Silver-catalyzed allenylation and enantioselective propargylation reactions of ketones

Article abstract of DOI:10.1002/anie.201206971

More than a silver lining: Certain silver complexes are capable of selective catalysis of either allenylation or asymmetric propargylation reactions of ketones. Ligand-free conditions lead to allenyl alcohols as the major product, whereas ligation with Walphos-8 gives enantioenriched homopropargyl alcohols. This method can be applied to reactions of prochiral diarylketones to provide optically enriched tertiary diaryl alcohols. Copyright

Full text of DOI:10.1002/anie.201206971

Angewandte
Chemie
DOI: 10.1002/anie.201206971
Asymmetric Catalysis
Silver-Catalyzed Allenylation and Enantioselective Propargylation
Reactions of Ketones**
Benjamin L. Kohn, Naoko Ichiishi, and Elizabeth R. Jarvo*
Homopropargylic alcohols have garnered significant interest
as useful building blocks for complex molecule synthesis.[1]
This structural motif is frequently formed through the
addition of propargylic nucleophiles to the corresponding
aldehyde or ketone.[2,3] Early advances focused on the
development of stoichiometric addition reactions of chiral
allenylboron reagents to aldehydes. In the early 1990s, the
first catalytic asymmetric methods to form chiral secondary
alcohols were reported, spurring renewed interest in the
field.[2] Additions to aldehydes have been extensively studied
and new asymmetric catalysts have recently been identified
for enantioselective propargylation reactions of ketones,
which employ propargyl- or allenylboron reagents or prop-
argyl bromide as starting materials, to form the corresponding
tertiary alcohols.[4,5] Several of these catalyst systems provide
high enantioselectivity in additions to methyl ketones.
Enantioselective propargylation reactions of prochiral diaryl
ketones have not been reported, however.[6] Herein, we report
silver-catalyzed allenylation and propargylation reactions on
a wide range of ketones (Scheme 1). Allenylation predom-
first report of catalytic enantioselective propargylation reac-
tions of prochiral benzophenones.
In previous work, our group has investigated the metal-
catalyzed reactions of allenylboronic acid pinacol ester with
a series of electrophiles, using both palladium and silver
catalysts.[7] We found that silver complexes ligated by
phosphine ligands catalyze the enantioselective propargyl-
ation reaction of imines to provide enantioenriched homo-
propargyl amines.[8,9] We hypothesized that a silver catalyst
could also facilitate the enantioselective propargylation
reactions of ketones.[10,11]
We sought to identify suitable silver catalysts for alleny-
lation and propargylation reactions of ketones with control of
chemo- and enantioselectivity. As the formation of either
allenyl or propargylic products could stem from isomerization
of allenyl and propargylmetal intermediates (Scheme 1),[12]
we hypothesized that controlling the relative reactivity of
these intermediates would be essential in achieving highly
selective reactions. We first examined reactions of a-ketoest-
ers using silver catalysts in the absence of exogenous ligands.
In contrast to our studies with imines, where Walphos-1 (see
Table 2 for structure) was required, we determined that silver
fluoride alone provided good yield and chemoselectivity,
giving allenyl alcohol as the major product (Table 1, entries 1
Table 1: Propargylation and allenylation reactions of a-ketoesters.
Scheme 1. Silver-catalyzed allenylation and enantioselective propargyl-
ation reactions of ketones.
Entry
Base
Additive
Yield [%][a]
Ratio (2a/3a)[b]
inates in the absence of exogenous ligands, whereas enantio-
selective propargylation takes place in the presence of a chiral
phosphine ligand. To the best of our knowledge, this is the
1[c]
2[c]
3
KOtBu
–
–
LiCl
nBu4Cl
nBu4Br
nBu4I
61
75
65
78
79
77
1:11
1:5.8
1.8:1
8.8:1
6.2:1
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
4[c]
5
[*] B. L. Kohn, N. Ichiishi, Prof. E. R. Jarvo
Department of Chemistry, University of California, Irvine
Irvine, CA 92697 (USA)
6
14.4:1
[a] Determined by 1H NMR spectroscopy using PhSiMe3 or 1,4-dime-
thoxybenzene as an internal standard. [b] Ratio determined by 1H NMR
spectroscopic analysis of the purified mixture of 2 and 3 after silica gel
column chromatography. [c] 18 h reaction time.
E-mail: erjarvo@uci.edu
Homepage: http://chem.ps.uci.edu/~erjarvo/
[**] This work was supported by an NSF CAREER Award (CHE-0847273),
Vertex Graduate Fellowship, UCI Regents Dissertation Fellowship
(B.L.K.), and UROP, NSF-REU, and Allergan Undergraduate
Fellowships (N.I.). Charlotte A. Osborne is acknowledged for
Table 2, entry 4. Chanel R. Easley is acknowledged for preliminary
studies of related transformations. We thank Solvias and Frontier
Scientific for donations of chemicals. Dr. John Greaves is acknowl-
edged for mass spectrometry data.
and 2).[8] To our surprise, upon addition of a halide, the
selectivity of the reaction switched to favor propargylation as
the major pathway (entries 3–6).[13] Therefore, under opti-
mized conditions, either allene 3a (entry 2) or alkyne 2a
(entry 6) can be accessed as the major product using the same
starting materials, depending upon the presence or absence of
nBu4NI. The ability to form either product supports a mech-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206971.
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anism that includes the opportunity for isomerization of
allenyl– and propargyl–metal intermediates.
We hypothesized that the halide additives promoting the
propargylation reaction act as ligands for the silver catalyst.[14]
Therefore, replacing the halide with a chiral ligand, such as
a phosphine, could result in the formation of enantioenriched
products. Based on the knowledge gained from our identifi-
cation of enantioselective catalysts for propargylation reac-
tions of imines, we examined a series of bidentate phosphine
ligands.[8] As expected, propargylation was favored in the
presence of phosphine ligands (Table 2). This is consistent
Table 2: Enantioselective propargylation reactions of a-ketoesters.
Entry
Ligand
R
Yield [%][a]
Ratio (2/3)[b]
ee [%] 2[c]
Scheme 2. Ketoester and ketone scope. [a] Reaction run with AgF
(10 mol%), Walphos-8 (11 mol%), and NaOtBu (30 mol%). [b] Prod-
uct 2h was isolated as an inseparable mixture with 1h; see the
Supporting Information for details. Pin=pinacolyl.
1
2
3
Walphos-1
Walphos-2
Walphos-8
Walphos-8
Walphos-8
Walphos-8
Walphos-8
Me
Me
Me
Me
tBu
tBu
tBu
87
58
79
74
95
88
67
3.3:1
6.5:1
4:1
13:1
3.2:1
3.0:1
2.5:1
45
15
72
63
79
86
91
4[d]
5
6[e]
7[e,f ]
(2e–2h). A heterocyclic ketone and an aliphatic ketone also
performed well under the reaction conditions (2i and 2j). In
all reactions with ketones, no aldol-type products are
observed.[18] After consumption of the allenylboronic acid
pinacol ester, only ketone and desired product remain in the
reaction mixture.
[a] Yield determined after isolation of 2 and 3 by flash column
chromatography. [b] Ratio determined by 1H NMR spectroscopic analy-
sis of the purified mixture of 2 and 3 after silica gel column
chromatography. [c] Enantioselectivity determined by analysis of purified
reaction mixture by SFC analysis on a chiral stationary phase. [d] nBu4NI
(50 mol%) added (we acknowledge Charlotte A. Osborne for this data).
[e] Reaction performed at À208C. [f] Reaction performed in tert-butyl
methyl ether as solvent.
Asymmetric addition to ketones typically requires a large
steric difference between the two carbon fragments in order
to differentiate the re and si faces. We were intrigued by the
challenge presented by prochiral diaryl ketones, as few
methods for the asymmetric addition to this class of ketones
exist.[19–21] In 2006, the Leighton group reported the highly
enantioselective allylation of prochiral 2’-hydroxyphenyl-
ketones, where the phenol directing group accelerates reac-
tion rates and differentiates the arenes.[6] To the best of our
knowledge, however, enantioselective propargylation of pro-
chiral benzophenones has not been demonstrated. The ability
of the silver catalyst to distinguish between two aromatic rings
would lead to enantioenriched diaryl carbinols, which are
present in a variety of drugs[22] and medicinal agents.[23]
We were pleasantly surprised to find that ortho-substi-
tuted benzophenones provide the desired products in high
enantioselectivity (Scheme 3).[24] Various substituents are
tolerated in the ortho-position, including methyl groups (5a
and 5e) and halogens (5b, 5c, and 5d). Substrate 5e is
structurally similar to escitalopram, currently used clinically
for treatment of major depressive and generalized anxiety
disorders.[21,25]
with our findings for imines, the Walphos ligand scaffold
provided the highest levels of enantioselectivity.[15] Whereas
Walphos-1 gave an initial promising result of 45% ee,
Walphos-8, which combines a more electron-rich phosphine
with the electron-poor phosphine found in Walphos-1,
provided higher enantioselectivities (entries 3–6). Increasing
the steric bulk of the ester and cooling the reaction to À208C
further improved the ee to 86% (entry 6). Examining alter-
native solvents gave an additional increase in enantioselec-
tivity to afford the tertiary homopropargylic alcohol in 91%
ee (entry 7).
After a brief reaction optimization to increase the yield,
a selection of pyruvates was examined (Scheme 2). Overall,
a-ketoesters afford the tertiary alcohols in high yield, with
good enantioselectivity for the propargylic products (2b–2d).
These substrates provided modest selectivity of propargyl
over allenyl products, ranging from 2:1 to 4:1. We next
examined reactions of simple ketones and found that
acetophenone derivatives furnished homopropargyl tertiary
alcohols with good enantioselectivities,[17] high selectivity for
propargylation over allenylation (> 30:1), and good yield
In summary, we have developed silver-catalyzed addition
reactions of allenylboronic acid pinacol esters to ketones, to
provide tertiary alcohols. The reaction conditions can be
easily modified to selectively promote either allenylation or
propargylation reactions. Asymmetric synthesis of homopro-
pargylic tertiary alcohols using a chiral silver complex has
been achieved. Diverse substrates, including ortho-substi-
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Yamaguchi, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2008,
130, 10078.
[4] For examples of allenylation and progargylation of a-keto esters,
see: T. Hameury, J. Guillemont, L. V. Hijfte, V. Bellosta, J. Cossy,
Org. Lett. 2009, 11, 2397, and references therein.
[5] a) For chiral boranes, see: E. Hernandez, C. H. Burgos, E.
Alicea, J. A. Soderquist, Org. Lett. 2006, 8, 4089; b) for propargyl
bromide with a titanacene catalyst, see: J. Justicia, I. Sancho-
Sanz, E. ꢀlvarez-Manzaneda, J. E. Oltra, J. M. Cuerva, Adv.
Synth. Catal. 2009, 351, 2295; c) for allenyl boronate with
a copper catalyst, see: S. L. Shi, L.-W. Xu, K. Oisaki, M. Kanai,
M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 6638; d) for
propargyl boronate with a copper catalyst, see: K. R. Fandrick,
D. R. Fandrick, J. T. Reeves, J. Gao, S. Ma, W. Li, H. Lee, N.
Grinberg, B. Lu, C. H. Senanayake, J. Am. Chem. Soc. 2011, 133,
10332; e) for allenyl boronate with a diol catalyst, see: D. S.
Barnett, S. E. Schaus, Org. Lett. 2011, 13, 4020; f) for propargyl
bromide with a chromium catalyst, see: K. C. Harper, M. S.
Sigman, Science 2011, 333, 1875.
Scheme 3. Asymmetric propargylation reactions of benzophenones.
The 5/6 ratio in all reactions is >30:1, as determined by 1H NMR
spectroscopic analysis of the purified mixture of 5 and 6 after silica gel
column chromatography. [a] Reaction run in THF solvent. [b] Enantio-
mers of 5a were not separable by supercritical fluid chromatography
(SFC) on a chiral stationary phase; ee was determined after Sonaga-
shira coupling; see the Supporting Information for details.
[6] For asymmetric allylation reactions of diaryl ketones, see: N. Z.
Burns, B. M. Hackman, P. Y. Ng, I. A. Powelson, J. L. Leighton,
Angew. Chem. 2006, 118, 3895; Angew. Chem. Int. Ed. 2006, 45,
3811.
[7] B. L. Kohn, E. R. Jarvo, Org. Lett. 2011, 13, 4858.
[8] H. M. Wisniewska, E. R. Jarvo, Chem. Sci. 2011, 2, 807.
[9] Alternative propargylation reactions of imines: a) for catalytic
enantioselective reactions, see: E. M. Vieira, F. Haeffner, M. L.
Snapper, A. H. Hoveyda, Angew. Chem. 2012, 124, 6722; Angew.
Chem. Int. Ed. 2012, 51, 6618; b) for diastereoselective addition
to tert-butanesulfinyl imines, see: D. R. Fandrick, C. S. Johnson,
K. R. Fandrick, J. T. Reeves, Z. Tan, H. Lee, J. J. Song, N. K. Yee,
C. H. Senanayake, Org. Lett. 2010, 12, 748; c) for diastereose-
lective addition to oximes, see: H. Miyabe, Y. Yamaoka, T.
Naito, Y. Takemoto, J. Org. Chem. 2004, 69, 1415.
[10] For silver-catalyzed Sakurai-Hosomi allylation of ketones that
proceed by transmetallation from silicon to silver, see: M.
Wadamoto, H. Yamamoto, J. Am. Chem. Soc. 2005, 127, 14556.
[11] For silver-catalyzed asymmetric transformations, see: M. Nao-
dovic, H. Yamamoto, Chem. Rev. 2008, 108, 3132.
[12] a) H. Yamamoto, Comprehensive Organic Synthesis, Vol. 2
(Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991,
pp. 81 – 98; b) H. P. Acharya, K. Miyoshi, Y. Kobayashi, Org.
Lett. 2007, 9, 3535, and references therein.
[13] The cause of the change in product selectivity is not currently
fully understood and is under investigation.
[14] For a review on the effect of halide additives on transition-metal
catalysts, see: K. Fagnou, M. Lautens, Angew. Chem. 2002, 114,
26; Angew. Chem. Int. Ed. 2002, 41, 26.
[15] Additional chiral ligands, such as BINAP, DuPhos, Josiphos, or
Mandyphos, gave < 17% ee.
tuted prochiral benzophenones, undergo smooth reaction to
provide optically enriched diaryl alcohols in good yields and
high enantioselectivities. Experiments designed to elucidate
the mechanism of this reaction are underway.
Received: August 28, 2012
Revised: December 5, 2012
Published online: && &&, &&&&
Keywords: allenylation · asymmetric catalysis · propargylation ·
.
silver · tertiary alcohols
[1] Examples of propargylation and propargylic alcohols used in
total synthesis: a) J. A. Marshall, M. R. Palovich, J. Org. Chem.
1998, 63, 3701; b) H. Lebel, E. N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 9624; c) A. Francais, A. Leyva, G. Etxebarria-Jardi,
S. V. Ley, Org. Lett. 2010, 12, 340.
[2] a) For a recent review on propargylation methods, see: C.-H.
Ding, X.-L. Hou, Chem. Rev. 2011, 111, 1914. For representative
recent examples of enantioselective propargylation reactions
that provide secondary homopropargylic alcohols, see: b) D. R.
Fandrick, J. Saha, K. R. Fandrick, S. Sanyal, J. Ogikubo, H. Lee,
F. Roschangar, J. J. Song, C. H. Senanayake, Org. Lett. 2011, 13,
5616; c) P. Jain, W. Pankaj, H. Wang, K. N. Houk, J. C. Antilla,
Angew. Chem. 2012, 124, 1420; Angew. Chem. Int. Ed. 2012, 51,
1391; d) L. M. Geary, S. K. Woo, J. C. Leung, M. J. Krische,
Angew. Chem. 2012, 124, 3026; Angew. Chem. Int. Ed. 2012, 51,
2972; e) S. K. Woo, L. M. Geary, M. J. Krische, Angew. Chem.
2012, 124, 7950; Angew. Chem. Int. Ed. 2012, 51, 7830.
[16] We acknowledge Charlotte A. Osborne for this data.
[17] Absolute configurations of alcohols 2a, 2e, 2i and 2j were
assigned by comparison to products previously reported in
Refs [5c] and [5e].
[18] For silver-catalyzed aldol-type reactions, see: M. Kawasaki, H.
Yamamoto, Silver in Organic Chemistry (Ed.: M. Harmata),
Wiley, Hoboken, 2010, pp. 259 – 284.
[19] For examples of the asymmetric reduction of prochiral diaryl
ketones, see: a) E. J. Corey, C. J. Helal, Tetrahedron Lett. 1995,
36, 9153; b) E. J. Corey, C. J. Helal, Tetrahedron Lett. 1996, 37,
5675; c) W. C. Shieh, W. R. Cantrell, Jr., J. A. Carlson, Tetrahe-
dron Lett. 1995, 36, 3797; d) H. Ushio, K. Mikami, Tetrahedron
Lett. 2005, 46, 2903; e) T. Ohkuma, M. Koizumi, H. Ikehira, T.
Yokozawa, R. Noyori, Org. Lett. 2000, 2, 659; f) C.-T. Lee, B. H.
Lipshutz, Org. Lett. 2008, 10, 4187; g) N. S. Shaikh, S. Enthaler,
K. Junge, M. Beller, Angew. Chem. 2008, 120, 2531; Angew.
Chem. Int. Ed. 2008, 47, 2497.
[3] Alternative methods to form homopropargylic tertiary alcohols:
a) For the kinetic resolution of terminal epoxides followed by
acetylide ring opening, see Ref. [1a]; b) for phase transfer
catalysis, see: T. Ooi, K. Fukomoto, K. Maruoka, Angew.
Chem. 2006, 118, 3923; Angew. Chem. Int. Ed. 2006, 45, 3839;
c) for diastereoselective synthesis, see: D. R. Li, A. Murgan, J. R.
Falck, J. Am. Chem. Soc. 2008, 130, 46; d) for asymmetric
hydroxylation, see: D. Sano, K. Nagata, T. Ito, Org. Lett. 2008,
10, 1593; e) for asymmetric Corey – Chaykovsky epoxide syn-
thesis followed by acetylide ring opening, see: T. Sone, A.
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[20] An alternative strategy for preparing these compounds involves
the asymmetric arylation of arylketoesters; see: a) H.-F. Duan,
J.-H. Xie, X.-C. Qiao, L.-X. Wang, Q. L. Zhou, Angew. Chem.
2008, 120, 4423; Angew. Chem. Int. Ed. 2008, 47, 4351; b) F. Cai,
X. Pu, X. Qi, V. Lynch, A. Radha, J. M. Ready, J. Am. Chem. Soc.
2011, 133, 18066.
[21] For the auxiliary-directed addition of Grignard reagents to diaryl
ketones, see: M. Albert, H. Sturm, A. Berger, P. Kremminger,
Patent US 2011/0009648A1, Jan. 13, 2011.
C.-M. Park, H. Ding, X. Wang, H. Zhang, P. Nimmer, R.
Mendoza, C. Sun, J. Mack, K. Walter, S. Dorwin, E. Gramling, U.
Ladror, S. H. Rosenberg, S. W. Elmore, S. W. Fesik, P. J. Hajduk,
Bioorg. Med. Chem. Lett. 2010, 20, 6587; d) Anti-cancer: J. H.
Van Duzer, R. Mazitsheck, W. Ogier, J. E. Bradner, G. Huang, C.
Xie, N. Yu, Patent WO 2011/091213A2, July 28, 2011.
[23] J. N. N. Eildal, J. Andersen, A. S. Kristensen, A. M. Jørgensen, B.
Bang-Andersen, M. Jørgensen, K. Strømgaard, J. Med. Chem.
2008, 51, 3045.
[22] a) PKB inhibitors: S. J. Woodhead, R. Downham, C. Hamlett, S.
Howard, H. F. Sore, M. L. Verdonk, D. W. Walker, R. W. A.
Luke, Patent WO 2006/136830A1, Dec. 28, 2006; b) Renin
inhibitor: J. J. Baldwin, D. A. Claremon, C. M. Tice, S. Cacatian,
L. W. Dillar, A. V. Ishchenko, J. Yuan, Z. Xu, G. McGee-Han, W.
Zhao, R. D. Simpson, S. B. Singh, Patent WO 2007/117559A2,
Oct. 18, 2007; c) Anti-cancer: A. M. Petros, J. R. Huth, T. Oost,
[24] Propargylation of naphthyl phenyl ketone provides 33% yield,
a 36:1 ratio of propargyl/allenyl product, and 10% ee.
[25] For recent lead references on escitalopram, see: a) R. N. Rao,
A. N. Raju, J. Pharm. Biomed. Anal. 2007, 43, 311; b) P. Zhang,
G. Cyriac, T. Kopajtic, Y. Zhao, J. A. Javitch, J. L. Katz, A. H.
Newman, J. Med. Chem. 2010, 53, 6112.
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Asymmetric Catalysis
B. L. Kohn, N. Ichiishi,
E. R. Jarvo*
&&&& — &&&&
More than a silver lining: Certain silver
complexes are capable of selective catal-
ysis of either allenylation or asymmetric
propargylation reactions of ketones.
Ligand-free conditions lead to allenyl
alcohols as the major product, whereas
ligation with Walphos-8 gives enantioen-
Silver-Catalyzed Allenylation and
Enantioselective Propargylation
Reactions of Ketones
riched homopropargyl alcohols. This
method can be applied to reactions of
prochiral diarylketones to provide opti-
cally enriched tertiary diaryl alcohols.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!