Combining NHC-Cu and Bronsted base catalysis: Enantioselective allylic substitution/conjugate additions with alkynylaluminum reagents and stereospecific isomerization of the products to trisubstituted allenes

Article abstract of DOI:10.1002/anie.201303501

All-catalytic route to trisubstituted allenes: The first examples of catalytic enantioselective allylic substitution reactions that involve alkyne-based nucleophiles and lead to products having tertiary stereogenic centers are followed by an exceptionally

Full text of DOI:10.1002/anie.201303501

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DOI: 10.1002/anie.201303501
Enantioselective Catalysis
Combining NHC–Cu and Brønsted Base Catalysis: Enantioselective
Allylic Substitution/Conjugate Additions with Alkynylaluminum
Reagents and Stereospecific Isomerization of the Products to
Trisubstituted Allenes**
Jennifer A. Dabrowski, Fredrik Haeffner, and Amir H. Hoveyda*
Among different types of unsaturated carbon–carbon bonds,
allenes carry significant but relatively unexplored potential in
chemical synthesis.[1] Research in more recent years has been
focused on the development of catalytic enantioselective
protocols that generate allenes[1] or on providing access to
molecules that contain them.[2] Various procedures have been
introduced for site-, chemo-, and/or stereoselective allene
functionalization.[3] Nonetheless, methods of preparation
have been largely centered on disubstituted variants;[1]
protocols that furnish the trisubstituted allenes, especially
those that are catalytic, are less common and typically involve
nucleophilic SN2’ additions to enantiomerically enriched
alkynyl entities.[4] Among alternative approaches, strategies
that deliver trisubstituted allenes through catalytic isomer-
ization of alkyne-containing substrates[5] pose an attractive
Scheme 1. Strategy for synthesis of enantiomerically enriched trisubsti-
tuted allenes by stereospecific transformation of an appropriate alkynyl
substrate accessed through catalytic EAS with alkynylaluminum
reagents as nucleophiles. LG=Leaving group.
but somewhat uncharted pathway.[6] We thus envisioned the
plan outlined in Scheme 1, involving the feasibility of catalytic
and stereospecific isomerization of an enantiomerically
enriched alkyne.[7] Bringing such a goal to fruition, however,
required a stereoselective catalytic process to effect the
desired 1,3-proton shift as well as an efficient, site- and
enantioselective method for synthesis of the requisite sub-
strates. Indeed, catalytic enantioselective allylic substitution
(EAS) reactions[8] with alkynyl nucleophiles are rare;[9]
related catalytic enantioselective processes that generate
tertiary stereogenic carbon centers are unknown.[10] Herein,
we describe the realization of the plan illustrated in Scheme 1
to address the above-mentioned shortcomings.
which a relatively limited number of examples exist.[11]
3) Catalytic EAS with alkenes possessing the suggested
substitution pattern have been less widely investigated[12]
and provide a challenge in reaction efficiency and/or enan-
tioselectivity (vs. variants that afford quaternary carbons or
disubstituted olefins[9]). 4) Carboxylic esters and derivatives
would allow for exploration of the influence of electronic
effects and a chelating Lewis basic group on the catalytic EAS
and the subsequent alkyne-to-allene interconversion.
We selected trisubstituted allylic phosphates containing
a C2 carboxylic ester as substrates (Scheme 1) for several
reasons: 1) Preliminary studies indicated that a number of the
products from EAS with disubstituted alkenes can be
unstable. 2) The presence of a carboxylic ester renders the
We began by probing transformations that involve the
alkynylaluminum reagent generated in situ by reaction of
phenylacetylene, diisobutylaluminum hydride (dibal-H), and
5.0 mol% Et3N.[13] Trisubstituted allylic phosphates (2a–j,
Table 1) undergo reaction to afford the desired enynes (3a–j)
in 58–98% yield and 90:10–98.5:1.5 e.r.; > 98% SN2’ selec-
tivity is observed except for cyclohexyl-substituted 3j (95:5
SN2’/SN2, entry 10, Table 1). The bidentate Cu complex
derived from 1a serves as the optimal catalyst.[14] Different
aryl-substituted alkenes, including those with a sterically
demanding ortho group (cf. entries 2–4, Table 1) can be used.
Alkyl-substituted allylic phosphates react with high site- and
enantioselectivity (entries 9 and 10, Table 1). Reactions in
Table 1 proceed at a slower rate than the previously reported
EAS with regioisomeric trisubstituted alkenes (24–48 h at
ꢀ158C vs. 6.0 h at ꢀ308C),[9] although the latter set generates
quaternary carbon stereogenic centers; this highlights the
aforementioned challenges associated with the present set of
substrates.[15]
ꢀ
C C bond-forming processes equivalent to a catalytic enan-
tioselective conjugate addition of an acetylenic group, of
[*] J. A. Dabrowski, Dr. F. Haeffner, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
[**] Financial support was provided by the NIH (GM-47480); J.A.D. is
grateful for a LaMattina Graduate Fellowship. We thank Boston
College Research Services for providing access to computational
facilities and G. Talavera and S. M. Couvertier for experimental
assistance. NHC=N-heterocyclic carbene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303501.
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Table 1: NHC–Cu-catalyzed EAS with phenylacetylene-derived reagent.[a]
efficiency and selectivity. The X-ray structure of enyne 4
offers support for the stereochemical identity of the major
isomers (Scheme 2). Transformations with alkyl-substituted
alkynylaluminum species, represented by 10 and 11
(Scheme 2), proceed to ꢁ 95% conversion and deliver
products in 84–85% yield, > 98:2 SN2’/SN2, and 93:7–98:2 e.r.
Additions to substrates that contain a larger carboxylic
ester unit (vs. CO2Me) proceed with exceptional enantiose-
lectivity (ꢁ 99:1 e.r.; Scheme 3), in spite of relatively elevated
Entry
G
t [h];
Conv. [%][b] [%][c]
Yield SN2’/SN2[b] e.r.[d]
1
2
3
4
5
6
7
8
9
10
C6H5; 2a
36; 98
30; 92
90
91
58
78
90
98
98
93
80
96
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
95:5
95:5
92:8
97:3
96:4
94:6
90:10
92:8
94:6
98.5:1.5
96:4
1-naphthyl; 2b[e]
o-MeOC6H4; 2c[f] 48; 69
o-FC6H4; 2d
2-naphthyl; 2e
m-BrC6H4; 2 f
p-BrC6H4; 2g
p-F3CC6H4; 2h
Ph(CH2)2; 2i
Cy; 2j
36; 95
24; 98
36; >98
24; >98
36; >98
24; >98
24; >98
[a] Reactions were performed under N2 atmosphere. [b] Determined
through analysis of 400 MHz 1H NMR spectra of unpurified mixtures
(ꢂ2%). [c] Yield of isolated and purified products. [d] Determined by
HPLC analysis (ꢂ2%); see the Supporting Information for details.
[e] Reaction performed at 48C. [f] 5.0 mol% 1a and 10 mol% Cu salt
used. Mes=2,4,6-Me3C6H2, Cy=cyclohexyl.
Catalytic EAS with a range of alkynylaluminums bearing
an aryl unit, whether they contain an electron-donating (cf. 4,
Scheme 2), an electron-withdrawing (cf. 6 and 8), a heteroaryl
(cf. 7), or an alkenyl (cf. 9) group proceed with similarly high
Scheme 3. Additional products of high enantiomeric purity obtained
through EAS with alkynylaluminum reagents and the catalyst precursor
used to generate them. Reactions were performed under conditions
shown in Table 1.
temperatures (4 vs. ꢀ158C), when NHC–AgI complex 1b is
used (vs. 1a).[16] The crystal structure for 12 provides addi-
tional stereochemical support, and synthesis of silanes 13 and
14 underscore the wide scope of the Cu-catalyzed protocol.
Cu-catalyzed EAS can be performed on reasonable scale
with 0.05–0.25 mol% of the NHC–Cu complex, derived from
commercially available and air-stable CuCl2·2H2O. For
instance, 3a (0.4 g 2a, 0.1 mol% 1a), 7 (0.2 g, 0.5 mol%
1a), and 11 (0.2 g, 0.5 mol% 1a) were obtained in 93%,
> 98%, and 84% yield and 93:7, 90:10, and 98:2 e.r.,
respectively (> 98% conv. in 36 h at ꢀ158C; > 98% SN2’).
The stability of the electrophilic a,b-unsaturated ester
products underlines the mildness of the conditions. There is
little or no residual dibal-H from the in situ preparation of
alkynylaluminums when the catalytic EAS is commenced;
there is no 1,2- or conjugate addition to the a,b-unsaturated
ester moiety. This is in contrast to the more recently reported
diastereoselective Cu-catalyzed transformations involving
enantiomerically enriched Z-allylic phosphates where stoi-
chiometric amounts of a strong base are present through-
out.[10]
We then turned to the possibility of catalytic stereoselec-
tive formation of trisubstituted allenes. We screened the
ability of some readily available Brønsted bases to effect the
desired isomerization (Table 2). Treatment of 3a (93:7 e.r.)
with 15 mol% LiOtBu, NaOtBu, or KOtBu at 228C results in
Scheme 2. A range of products can be accessed in high efficiency and
site- and enantioselectivity through catalytic EAS. Reactions were
performed under the conditions shown in Table 1 (1a as catalyst
precursor); 0.5 mol% 1a and 1.0 mol% Cu salt used for EAS affording
7 and 11.
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Table 2: Catalytic isomerization to allene: screening of bases.[a]
Entry Base
Conv. 15/16 e.r.[c]
e.s.
[%][b]
[%][d]
1
2
3
4
5
6
7
LiOtBu
NaOtBu
KOtBu
dbu
97
>98
95
67
38
72:28 58.5:41.5 63
75:25 86:14
51:49 60:40
86:14 92:8
92
64
>98
>98
NA
NA
tetramethylguanidine
tetramethylethylenediamine <2
(iPr)2NEt <2
97:3
NA
92:8
NA
Scheme 4. Alkyne-to-allene isomerization proceeds to completion
within 30 min; labeling experiment indicates a significant primary
kinetic isotope effect. Yields correspond to mixtures of isomers; see
the Supporting Information for details.
NA
NA
[a] Reactions were performed under N2 atmosphere. [b] Determined
through analysis of 400 MHz 1H NMR spectra of unpurified mixtures
(ꢂ2%). [c] Determined by HPLC analysis (ꢂ2%); see the Supporting
Information for details. [d] e.s. (enantiospecificity)=product e.r./sub-
strate e.r. ꢀ100. dbu=1,8-diazabicycloundec-7-ene; NA=not applica-
ble.
ꢁ 95% conversion in less than two hours at 228C. Formation
of allene 22 is exceptionally stereoselective (97% e.s.), but
requires an equivalent of dbu (vs. 15 mol%) to reach the 67%
conversion mark (48% yield) in 48 h (vs. 2.0 h); such a rate
ꢁ 95% consumption of the starting material in five minutes
(entries 1–3, Table 2). Moderate selectivity in
favor of allene 15 is observed with the Li and Na
salts (72:28–75:25 15/16), whereas reaction with
KOtBu delivers nearly an equal mixture of
isomers (entry 3). Moreover, reactions with
LiOtBu and KOtBu lead to substantial loss of
stereoisomeric purity [63–64% enantiospecific-
ity (e.s.)][17] whereas the derived Na salt promotes
isomerization with 92% e.s. Among a number of
amines examined (entries 4–7, Table 2),[18] it is
the more basic 1,8-diazabicycloundec-7-ene
(dbu) and tetramethylguianidine[19] that deliver
15 with > 98% e.s. and with higher site selectivity
than the metal alkoxides, albeit less efficiently
(67% and 38% vs. ꢁ 95% conv.; 86:14 and 97:3
vs. up to 75:25 15/16). There is no detectable
reaction with other amines (entries 6 and 7,
Table 2).[18]
Subsequent optimization studies led us to
establish that, as illustrated in Scheme 4, with
15 mol% dbu and when the reaction time is
extended to 30 min (vs. 5.0 min.), there is > 98%
conversion of 3a to an 83:17 mixture of 15/16 in
86% yield and > 98% e.s. When [D1]-3a is used,
complete transfer of deuterium is observed (kH/
kD = 3.1) and [D1]-15 is formed with > 98% e.s.
Various skipped enynes, obtained by NHC–
Cu-catalyzed EAS, can be converted to trisub-
stituted allenes in 63% to 98% site selectivity,
48–98% yield, and 94% to > 98% e.s.
(Scheme 5). Stereoselective isomerizations pro-
moted by 15 mol% dbu can be carried out with
an ethyl ester (cf. 17, Scheme 5), an alkyne
substrate bearing an electron-donating (cf. 18),
electron-withdrawing (cf. 19), a heteraoryl sub-
Scheme 5. Trisubstituted allenes can be accessed efficiently in high enantiomeric
purity through dbu-catalyzed isomerization; the X-ray structure of a derivative of 23
stituent (cf. 20), or a sterically demanding
naphthyl group (cf. 21); reactions proceed to supports the syn mode of proton transfer. Yields correspond to mixtures of isomers.
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difference (vs. aryl-substituted variants) is likely because of
the lower acidity of the propargylic proton of the correspond-
ing alkyne substrate. Reaction of the allylic alcohol derivative
is facile and highly site- and stereoselective, as exemplified by
the synthesis of 23, formed after three hours in 70% yield
(> 98% conv.), 98:2 allene/alkene, and 98% e.s. The X-ray
structure of the p-bromobenzoate derived from 23 confirms
that the dbu-catalyzed isomerization occurs with retention of
stereochemistry (i.e., proton deposited on the same face of
allene as the propargyl H). Reaction of the derived silyl ether
affords 24 with similarly high site selectivity (98% allene) and
with slightly improved stereochemical control (> 98% vs.
98% e.s. for alcohol 23), but is less efficient, presumably due
to steric factors (> 98% conv. in 12 vs. 3.0 h for 23). The
transformation involving cyclohexyl-containing allene 25
proceeds to 97% conversion and in 98% e.s. in 16 h with
1.0 equivalent of dbu with moderate site selectivity (63%
allene).
nature (vs. NaOtBu; see entries 1–3, Table 2). The Na
counterion is likely of the appropriate Lewis acidity and
size to establish a bridge between the carboxylic ester group
and the tBuOH generated by deprotonation, causing a facile
protonation prior to loss of stereochemistry;[20] on the other
hand, the less Lewis acidic K ion or the relatively diminutive
Li ion are less capable of serving the same function, thereby
allowing tBuOH to separate from the anionic intermediate to
result in racemization before a proton can be deposited to
form an allene. In support of the above proposal, when the
tert-butyldimethylsilyl ether derived from 3a is subjected to
conditions involving NaOtBu (15 mol%, 5.0 min, 228C),
allene 24 is formed in 60:40 e.r. (65% e.s.; > 98% conv.,
90:10 allene/alkene, 64% yield vs. 86:14 e.r. and 92% e.s. with
carboxylic ester 3a). Nonetheless, the precise origin of site-
selective protonation leading to preferential generation of the
trisubstituted allenes is unclear; it is plausible that the lower
degree of electron density that resides at the site more
proximal to a carboxylic ester or its reduced variants (i.e., C3’
in Scheme 1) is less capable of capturing a proton; however,
such a possibility is inconsistent with the higher site selectivity
in reactions that generate allenes containing a more electron-
deficient aryl unit (e.g., compare 18 and 19 in Scheme 5).
Development of additional catalysts for EAS reactions,
study of other unexplored modes of functionalization, and
To gain mechanistic insight regarding the isomerization
process, extensive DFT calculations were performed
(Scheme 6). Congruent with the kinetic isotope effect
shown in Scheme 4, the deprotonation emerges as the most
energetically demanding step (3a!I, Scheme 6). The tran-
sition state for protonation to afford the allene (via III to give
15) is lower in energy than that leading to the thermodynami-
cally
favored
tetrasubstituted
alkene (16 via IV). A similar profile
is calculated for reactions with
NaOtBu.[20] The above considera-
tions suggest that the lower e.s. with
the latter alkali metal base as well as
the corresponding Li and K salts
might be partly the result of erosion
of kinetic selectivity by facile equi-
libration (i.e., deprotonation/repro-
tonation of allenyl H). Control
experiments support the validity of
the latter scenario; for example,
treatment of a sample of an enan-
tiomerically enriched allene 15
(87:13 e.r.) with 15 mol% NaOtBu
leads to substantial loss of enantio-
meric purity within 30 min (61:39
e.r.); the same experiment but with
15 mol% dbu does not lead to any
detectable change in e.r.[21] It
appears that dbu can bring suffi-
cient basicity[19] (vs. other N-con-
taining bases) to promote effective
removal of the propargylic proton,
generating a conjugate acid that
protonates the resulting anion at
a sufficiently rapid rate to avoid loss
of stereochemical integrity, which
can occur through bond rotation.
Theoretical investigations fur-
ther suggest that the lower selectiv-
ity observed with LiOtBu and
Scheme 6. DFT calculations indicate that, with dbu as base, the deprotonation step might be rate
limiting and generation of the allene product is kinetically preferred although the tetrasubstituted
KOtBu might be partly kinetic in alkene is thermodynamically favored. See the Supporting Information for details.
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Boissarie, M. Burns, A. P. Pulis, V. K. Aggarwal, Angew. Chem.
2012, 124, 11965; Angew. Chem. Int. Ed. 2012, 51, 11795.
[7] For an early report regarding isomerization of an alkyne-
containing substrate to an allene under basic conditions, see: G.
Eglinton, E. R. H. Jones, G. H. Mansfield, M. C. Whiting, J.
Chem. Soc. 1954, 3197.
applications of such protocols to the synthesis of biologically
active molecules are in progress.
Received: April 24, 2013
Published online: June 18, 2013
[8] For reviews on catalytic EAS, see: a) A. H. Hoveyda, A. W.
Hird, M. A. Kacprzynski, Chem. Commun. 2004, 1779; b) H.
Yorimitsu, K. Oshima, Angew. Chem. 2005, 117, 4509; Angew.
Chem. Int. Ed. 2005, 44, 4435; c) A. Alexakis, J. E. Bꢂckvall, N.
Krause, O. Pꢆmies, M. Diꢃguez, Chem. Rev. 2008, 108, 2796.
[9] For Cu-catalyzed EAS with alkynylaluminum reagents that
generate quaternary carbon stereogenic centers, see: J. A.
Dabrowski, F. Gao, A. H. Hoveyda, J. Am. Chem. Soc. 2011,
133, 4778.
Keywords: alkynylaluminum reagents · allenes ·
Brønsted bases · copper · N-heterocyclic carbenes
.
[1] For recent reviews regarding the utility of allenes in chemical
synthesis, see: a) Modern Allene Chemistry (Eds.: N. Krause,
A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004; b) K. M. Brum-
mond, J. E. DeForrest, Synthesis 2007, 795; c) F. Lꢀpez, J. L.
MascareÇas, Chem. Eur. J. 2011, 17, 418; d) S. Yu, S. Ma, Angew.
Chem. 2012, 124, 3128; Angew. Chem. Int. Ed. 2012, 51, 3074.
[2] For examples of catalytic enantioselective additions of allenes to
aldehydes, see: a) C.-M. Yu, S.-K. Yoon, K. Baek, J.-Y. Lee,
Angew. Chem. 1998, 110, 2504; Angew. Chem. Int. Ed. 1998, 37,
2392; b) M. Inoue, M. Nakada, Angew. Chem. 2006, 118, 258;
Angew. Chem. Int. Ed. 2006, 45, 252; c) G. Xia, H. Yamamoto, J.
Am. Chem. Soc. 2007, 129, 496; d) V. Coeffard, M. Aylward, P. J.
Guiry, Angew. Chem. 2009, 121, 9316; Angew. Chem. Int. Ed.
2009, 48, 9152; e) M. Durꢁn-Galvꢁn, S. A. Worlikar, B. T.
Connell, Tetrahedron 2010, 66, 7707; f) L. R. Reddy, Chem.
Commun. 2012, 48, 9189; g) L. R. Reddy, Chem. Commun. 2012,
48, 9189. For catalytic EAS with an allene-based nucleophile,
see: h) B. Jung, A. H. Hoveyda, J. Am. Chem. Soc. 2012, 134,
1490. For catalytic enantioselective allene additions to isatins,
see: i) D. L. Silverio, S. Torker, T. Pilyugina, E. M. Vieira, M. L.
Snapper, F. Haeffner, A. H. Hoveyda, Nature 2013, 494, 216.
[3] For selected examples, see: a) K. Nꢂrhi, J. Franzꢃn, J.-E.
Bꢂckvall, J. Org. Chem. 2006, 71, 2914; b) F. Grillet, K. M.
Brummond, J. Org. Chem. 2013, 78, 3737; c) T. Suzuki, Y.
Miyajima, K. Suzuki, K. Iwakiri, M. Koshimizu, G. Hirai, M.
Sodeoka, S. Kobayashi, Org. Lett. 2013, 15, 1748; d) N. Cox,
M. R. Uehling, K. T. Haelsig, G. Lalic, Angew. Chem. 2013, 125,
4978; Angew. Chem. Int. Ed. 2013, 52, 4878.
[4] For examples involving trisubstituted allenes, see: a) S.-C. Hung,
Y.-F. Wen, J.-W. Chang, C.-C. Liao, B.-J. Uang, J. Org. Chem.
2002, 67, 1308; b) G. A. Molander, E. M. Sommers, S. R. Baker,
J. Org. Chem. 2006, 71, 1563; c) R. K. Dieter, N. Chen, V. K.
Gore, J. Org. Chem. 2006, 71, 8755; d) Z. Liu, A. S. Wasmuth,
S. G. Nelson, J. Am. Chem. Soc. 2006, 128, 10352; e) K.
Kobayashi, H. Naka, A. E. H. Wheatley, Y. Kondo, Org. Lett.
2008, 10, 3375; f) P. Cꢃrat, P. J. Gritsch, S. R. Goudreau, A. B.
Charette, Org. Lett. 2010, 12, 564; g) H. Ohmiya, U. Yokobori, Y.
Makida, M. Sawamura, Org. Lett. 2011, 13, 6312; h) M. Yang, N.
Yokokawa, H. Ohmiya, M. Sawamura, Org. Lett. 2012, 14, 816.
[5] For catalytic enantioselective synthesis of trisubstituted allenes,
see: a) C.-Y. Li, X.-B. Wang, X.-L. Sun, Y. Tang, J.-C. Zheng, Z.-
H. Xu, Y.-G. Zhou, L.-X. Dai, J. Am. Chem. Soc. 2007, 129, 1494.
For catalytic enantioselective synthesis of disubstituted allenes
through base-catalyzed isomerization reactions, see: b) M. Oku,
S. Arai, K. Katayama, T. Shioiri, Synlett 2000, 493; c) H. Liu, D.
Leow, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2009, 131,
7212; d) H. Li, D. Mꢄller, L. Guꢃnꢃe, A. Alexakis, Org. Lett.
2012, 14, 5880.
[10] For Cu-catalyzed diastereoselective addition of alkynyl groups
to enantiomerically enriched secondary Z allylic phosphates,
see: Y. Makida, Y. Takayama, H. Ohmiya, M. Sawamura, Angew.
Chem. 2013, 125, 5458; Angew. Chem. Int. Ed. 2013, 52, 5350.
[11] For catalytic enantioselective additions of alkynes to unsatu-
rated carbonyls, see: with Ni-based catalysts: a) Y.-S. Kwak, E. J.
Corey, Org. Lett. 2004, 6, 3385; b) O. V. Larionov, E. J. Corey,
Org. Lett. 2010, 12, 300. With binol-based catalysts: c) T. R. Wu,
J. M. Chong, J. Am. Chem. Soc. 2005, 127, 3244. With Cu-based
catalysts: d) T. F. Knçpfel, P. Zarotti, T. Ichikawa, E. M.
Carreira, J. Am. Chem. Soc. 2005, 127, 9682; e) R. Yazaki, N.
Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 10275.
With Rh-based catalysts: f) T. Nishimura, T. Sawano, T. Hayashi,
Angew. Chem. 2009, 121, 8201; Angew. Chem. Int. Ed. 2009, 48,
8057; g) E. Fillion, A. K. Zorzitto, J. Am. Chem. Soc. 2009, 131,
14608; h) T. Nishimura, S. Tokuji, T. Sawano, T. Hayashi, Org.
Lett. 2009, 11, 3222. For related Rh-catalyzed additions involving
nitroalkenes, see: i) T. Nishimura, T. Sawano, S. Tokuji, T.
Hayashi, Chem. Commun. 2010, 46, 6837. For enantioselective
synthesis of b-alkynyl carbonyls by Rh-catalyzed rearrangement
of alkynyl alkenyl carbinols, see: j) T. Nishimura, T. Katoh, K.
Takatsu, R. Shintani, T. Hayashi, J. Am. Chem. Soc. 2007, 129,
14158.
[12] a) C. A. Falciola, K. Tissot-Croset, A. Alexakis, Angew. Chem.
2006, 118, 6141; Angew. Chem. Int. Ed. 2006, 45, 5995; b) D. G.
Gillingham, A. H. Hoveyda, Angew. Chem. 2007, 119, 3934;
Angew. Chem. Int. Ed. 2007, 46, 3860; c) Y. Lee, K. Akiyama,
D. G. Gillingham, M. K. Brown, A. H. Hoveyda, J. Am. Chem.
Soc. 2008, 130, 446.
[13] C. Feuvrie, J. Blanchet, M. Bonin, L. Micouin, Org. Lett. 2004, 6,
2333.
[14] See the Supporting Information for screening of different
complexes.
[15] The precise reason for the observed rate differences has not been
determined, but might but might be because reductive elimi-
nation of the (alkyne)(alkyl)-CuIII intermediate with the more
congested system (release of steric strain) is faster.
[16] For example, with 1a, reaction to generate 12 proceeds to 73%
conversion at ꢀ158C within 24 h to afford the desired product in
96:4 e.r. (vs. > 99:1 e.r. at + 48C with 1b). The modification in
catalyst structure points to a somewhat sensitive nature of
catalyst–substrate interactions. Enhanced reactivity and selec-
tivity is likely due to the availability of sufficient space for the
relatively more congested substrates provided by the 3,5-
disubstituted NAr unit of the chiral Cu complex in the vicinity
of the transition metal center (vs. 2,4,6-trisubstituted moiety of
1a).
[17] S. E. Denmark, T. Vogel, Chem. Eur. J. 2009, 15, 11737.
[18] See the Supporting Information for the complete list of Brønsted
base amines investigated.
[19] A pKa value of 18.0 has been measured for dbu in thf (vs. 17.0 for
tetramethylguanidine and 13.4 for tetramethylethylenedia-
[6] For use of Clasien rearrangements to synthesize allenes, see: D.
Tejedor, G. Mꢃndez-Abt, L. Cotos, F. Garcꢅa-Tellado, Chem.
Soc. Rev. 2013, 42, 458. For conversion of alkynyl carbamates to
4-hydroxyallenyl compounds by (noncatalytic) enantioselective
deprotonation with (ꢀ)-sparteine as the source of base, see: C.
Schultz-Fademrecht, B. Wibbeling, R. Frçhlich, D. Hoppe, Org.
Lett. 2001, 3, 1221. For a related study involving protonation of
the anionic intermediate, see: B. M. Partridge, L. Chausset-
7698 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 7694 –7699

Angewandte
Chemie
mine); see: I. Kaljurand, T. Rodima, A. Pihl, V. Mꢂemets, I.
Leito, I. A. Koppel, M. Mishima, J. Org. Chem. 2003, 68, 9988.
[20] See the Supporting Information for energetics of isomerization
with NaOtBu.
[21] When lower substrate acidity demands the use of stoichiometric
amounts of dbu, adventitious isomerization to the trisubstituted
alkene occurs. For example, treatment of 25 with 1.0 equiv dbu
leads to significant isomerization (78% in 12 h at 228C in thf).
Angew. Chem. Int. Ed. 2013, 52, 7694 –7699
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 7699