A robust, efficient, and highly enantioselective method for synthesis of homopropargyl amines

Article abstract of DOI:10.1002/anie.201202694

Fast, robust, selective: Copper-catalyzed enantioselective additions of homopropargyl groups to a wide range of aldimines proceed readily and with high enantioselectivity. The catalytic method is scalable and practical, the allenylboron reagent is commerc

Full text of DOI:10.1002/anie.201202694

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Angewandte
Communications
DOI: 10.1002/anie.201202694
Enantioselective Catalysis
A Robust, Efficient, and Highly Enantioselective Method for Synthesis
of Homopropargyl Amines**
Erika M. Vieira, Fredrik Haeffner, Marc L. Snapper, and Amir H. Hoveyda*
Catalytic protocols that generate a-branched amines effi-
ciently and enantioselectively facilitate the preparation of
many important biologically active molecules.[1] Among such
entities are homopropargyl amines, used in the total synthesis
of a number of natural products.[2] Several investigations have
adopted the chiral auxiliary strategy; the desired products are
obtained in high diastereoselectivity as trimethylsilyl-substi-
tuted alkynes.[3] In contrast, the corresponding catalytic
protocols are scarce. The first relevant report included three
examples of reactions of allenyl stannanes with a glyoxylate-
derived tosylimine,[4] affording homopropargyl sulfonamides
salt and CuCl or the more robust CuCl2·2H2O, both of which
are commercially available. Aryl-, heteroaryl-, alkenyl-, as
well as alkyl-substituted N-phosphinoyl imines can serve as
substrates. Additions proceed to completion in seven hours or
less, delivering homopropargyl amides in 65% to more than
98% yield and 92:8 to more than 98:2 e.r. The Cu-catalyzed
process is amenable to gram-scale operations, and can be
performed in a common fume hood without the need for
strictly anhydrous and/or oxygen-free conditions.
We began by probing the capacity of chiral C1-symmetric
imidazolinium salt[9] 3a (Scheme 2), effective for reactions of
in 34–96% yield and 55:45–93:7 enantiomeric ratio (e.r.).[5]
A
notable recent advance entails enantioselective additions of
a readily available allenylboron to tosylimines catalyzed by
a Ag-phosphine catalyst to furnish a wider range of products
and higher enantioselectivity (87:13 to more than 98:2 e.r.).
Nonetheless, reactions of substrates that do not bear an aryl
substituent proved to be less efficient, those of enolizable
alkyl-substituted tosylimines were not reported and, as with
the aforementioned initial development, removal of the tosyl
unit requires strong reducing conditions.[6–8]
Herein, we present a broadly applicable and efficient
catalytic method for enantioselective synthesis of homopro-
pargyl amides (Scheme 1); acid hydrolysis generates the
parent amines. Transformations are performed with 0.25–2.0
mol% of a chiral N-heterocyclic carbene (NHC) complex of
copper, derived from a readily available chiral imidazolinium
Scheme 2. NHC–Cu-catalyzed propargyl addition can be performed
with CuCl or the air-stable CuCl2·2H2O with exceptional efficiency and
high enantioselectivity. Mes=2,4,6-(Me)3C6H2.
allylborons with N-phosphinoyl imines,[10] in serving as the
catalyst precursor. In the presence of the NHC–Cu complex
prepared in situ with CuCl and NaOtBu, more than 98%
conversion is achieved within six hours, and the desired amine
4a is formed in 98% yield and 98:2 e.r (Scheme 2, top). None
of the allene addition product is formed (less than 2%, as
Scheme 1. A practical and broadly applicable, efficient, and highly
enantioselective method for synthesis of homopropargyl amines.
[*] E. M. Vieira, Dr. F. Haeffner, Prof. M. L. Snapper,
Prof. A. H. Hoveyda
1
judged by 400 MHz H NMR analysis). When CuCl2·2H2O,
Department of Chemistry, Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
more stable to air and moisture than CuCl, is utilized, the
reaction is complete in 30 min and similarly enantioselective
(Scheme 2). The practicality of the catalytic process is under-
lined by the gram-scale transformation shown in Scheme 3.
The reaction is performed with 0.25 mol% of the catalyst in
a standard fume hood; treatment of the product mixture with
aqueous HCl affords the homopropargyl amine (5) in 86%
overall yield and 96:4 e.r. The desired product is isolated in
analytically pure form after routine aqueous wash without the
need for costly silica gel chromatography and the associated
[**] Financial support was provided by the NIH (GM-57212). We are
grateful to Dr. B. Li for securing X-ray structures and to Frontier
Scientific, Inc. for gifts of the allenylboron reagent. We thank Boston
College Research Services for providing access to computational
facilities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202694.
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Scheme 3. Gram-scale NHC–Cu-catalyzed homopropargyl amine syn-
thesis performed in a standard fume hood.
solvents. The amide can be obtained through simple tritu-
ration; such ease of isolation is due to the strong tendency of
N-phosphinoyl amides to be crystalline.[11,12]
Enantioselective homopropargyl amine synthesis can be
performed with a range of aryl-substituted imines; trans-
formations proceed to completion with 1.0 mol% of the chiral
catalyst (Table 1). Regardless of whether the substrate carries
an electron-withdrawing (entries 2, 5 and 6), electron-donat-
Table 1: NHC–Cu-catalyzed enantioselective propargyl additions to aryl-
Scheme 4. NHC–Cu-catalyzed enantioselective synthesis of heteroaryl-,
substituted aldimines.[a]
alkenyl-, and alkyl-substituted homopropargyl amines. (Conditions as
in Table 1 with 3a and CuCl2·2H2O, except 3c used for 13. See the
Supporting Information for details.)
Heterocycle-, alkenyl-, and alkyl-substituted N-phosphi-
noyl imines serve as substrates (Scheme 4). Enantioselective
additions proceed readily with O-, as well as S- or N-
substituted heterocyclic aldimines without detectable catalyst
inhibition (6–8, Scheme 4); homopropargyl amides are iso-
lated in 94% to more than 98% yield and 94:6–97:3 e.r.
Allylamide 9 and the more sterically hindered 10 (Scheme 4)
are obtained in similarly high yields and enantiomeric purities
(81% and 98% yield, and 96:4 and 96.5:3.5 e.r., respectively).
The catalytic protocol can be readily extended to substrates
that bear a linear, b- or a-branched alkyl group (11–13,
Scheme 4); products are isolated in 65–80% yield and in
92:8–97:3 e.r. Optimal results for synthesis of 13 are obtained
with the catalyst derived from imidazolinium salt 3c; 90.5:9.5
and 90:10 e.r. and 76% and 83% yield are obtained,
respectively, with 3a and 3b. In all transformations shown
in Scheme 3, conditions involve the more robust CuII salt (1.0
mol% loading, 1.0 h). As with aryl-substituted imines
(Scheme 2 and Table 1), the additions proceed with similar
efficiency and slightly higher enantioselectivity when CuCl is
used; for example, thienyl 7 and pyridyl 8 are generated in
91% yield and 95% yield and in more than 98:2 and 97:3 e.r.,
respectively (with 3a as catalyst precursor; more than 98%
conversion and less than 2% allene addition).[13]
The NHC–Cu-catalyzed processes likely involve allenyl–
copper species, such as A (Scheme 5).[14] Complex A origi-
nates from the corresponding Cu–alkoxide, either by s-bond
metathesis with the allenylboron 1, or through ligand
exchange via allenylboronate derived from addition of
a metal alkoxide to 1.[15] Computational studies[16] point out
that the Cu–allene is energetically favored as opposed to the
alternative, and probably more nucleophilic, Cu–propargyl
(A is 9.9 kcalmolꢀ1 lower in energy compared to B;
Scheme 5); the alkynyl complex would produce the unob-
served allenyl amides. Examination of the geometry-opti-
mized structures of C and D indicates that the mode of
Entry Substrate (Ar)
3
With CuCl
With CuCl2·2H2O
yield [%][b] e.r.[c]
yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
2b (2-naphthyl) 3b
2c (o-FC6H4)
2d (o-MeC6H4)
2e (o-MeOC6H4) 3a
2 f (m-BrC6H4)
2g (p-ClC6H4)
2h (p-MeOC6H4) 3a
97
96
93
97
97
92
98
98:2
97.5:2.5
97.5:2.5
97:3
96:4
97:3
95
96
92
98
93
88
92
94:6
95:5
94:6
94:6
93:7
96:4
96:4
3a
3a
3a
3a
97:3
[a] Reactions were performed in an N2 atmosphere. Addition reactions
with CuCl: 3.0 mol% NaOtBu at ꢀ508C for 6.0 h; addition reactions with
CuCl2·2H2O: 5.0 mol% NaOtBu at ꢀ78!ꢀ158C for 1.0 h; 1.4 equiv of
1 in all cases. Less than 2% allene addition in all cases. [b] Yields of
isolated purified products (ꢁ5%). [c] Determined by HPLC analysis
(ꢁ2%). See the Supporting Information for all experimental details and
analytical data.
ing (entries 4 and 7), or a sterically demanding aryl group
(entries 1 and 3), products are isolated in 88–98% yield and
93:7–98:2 e.r. Reaction times span from one to six hours;
either CuCl or the more robust CuCl2·2H2O can be used.
Homopropargyl amides are obtained in high yield regardless
of the metal salt employed.
The occasional use of structurally modified imidazolinium
salts, such as 3b (Table 1, entry 1), is not because the catalyst
derived from 3a is ineffective. Rather, in some cases, slightly
higher efficiency and/or enantioselectivity can be attained
with modified NHC–Cu complexes 3b and 3c. For example,
with 3a, formation of 4b proceeds to more than 98%
conversion, affording 4b in 96% yield and 95:5 e.r. (vs.
97% yield and 98:2 e.r. with 3b).
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Scheme 5. Theoretical studies point to a strong energetic preference
for the NHC–Cu–allenyl A versus the derived propargyl complex B and
a model that accounts for the observed stereochemical outcomes.
reaction C, with the substrate coordinating from the most
accessible quadrant of the chiral complex is preferred (vs.
D);[16] such a scenario accounts for the identity of the
observed major enantiomers.[17]
Scheme 6. Representative examples demonstrate the utility of the
NHC–Cu-catalyzed method for enantioselective synthesis of homopro-
pargyl amines; o-NBSH=o-nitrobenzenesulfonylhydrazide.
The strong preference for the intermediacy of allenyl–
copper A (vs. the propargyl derivative B) might be the reason
that the processes presented here are operationally more
robust than the corresponding allyl additions.[10] Although the
CuII salt can be used in either case, unless stringently
controlled conditions are adopted, there is significant dimin-
ution in e.r. when allylcopper intermediates are involved. For
example, when the reaction with (pinacolato)allylboron and
2a is carried out under the conditions shown in Scheme 2
(bottom reaction), the desired homoallyl amide is generated
in 84:16 e.r. (vs. 97:3 e.r. under strictly inert (glove box)
conditions). Such disparity may originate from the higher
other members of the same family through a formerly
reported strategy based on catalytic cross-coupling.[24]
In summary, we introduce the first practical, general, and
efficient method for catalytic enantioselective preparation of
homopropargyl amines. The protocol requires a catalyst
composed of an inexpensive metal salt, a chiral ligand that
can be prepared in four or five steps, and the allenylboron
reagent, which can be purchased; product isolation is
straightforward and inexpensive. Design and development
of additional chiral catalysts for efficient and enantioselective
ꢀ
sensitivity of the more nucleophilic allylmetals (Cu Csp3 vs.
ꢀ
Cu Csp2 in allenylmetals; see Scheme 6). Moreover, when
ꢀ
CuCl2·2H2O is used, transformations are likely catalyzed by
an NHC–CuI complex,[18] a scenario supported by the close
similarity of the stereochemical outcomes compared to
processes involving CuCl. The in situ reduction of the
transition metal thus occurs under the reaction conditions.[19]
The two instances depicted in Scheme 6 demonstrate
utility. As illustrated by the formation of 14, the homopro-
pargyl amides can be transformed to the derived carboxylic
acids through an efficient and mild Ru-catalyzed transforma-
tion.[20] The corresponding b-amino acids, building blocks in
the preparation of biologically active molecules,[21] can be
accessed by removal of the phosphinoyl group (see
Scheme 3).
C C bond forming processes with readily accessible organo-
boron reagents is in progress.
Received: April 7, 2012
Published online: May 23, 2012
Keywords: copper · enantioselective catalysis ·
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homopropargyl amines · N-heterocyclic carbenes ·
propargyl additions
[1] a) T. C. Nugent, M. El-Shazly, Adv. Synth. Catal. 2010, 352, 753 –
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The second application is connected to the preparation of
the amine segment of the anticancer agent aza-epothilone A
(Scheme 6).[22] Catalytic enantioselective addition to hetero-
cyclic aldimine 15 proceeds in 98% yield and more than 98:2
e.r. Homopropargyl amide 16 is then converted to the derived
iodoalkyne and subsequently reduced[23] with complete Z se-
lectivity to deliver 17 in 76% overall yield and exceptional
enantiomeric purity. The Z-vinyl iodide (17) can be utilized in
enantioselective synthesis of the biologically active target or
[2] For example, see: indolizidine alkaloid family: a) Y. Song, S.
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2010, 12, 748 – 751; c) M. Cyklinsky, C. Botuha, F. Chemla, F.
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[16] See the Supporting Information for details.
[4] For a review on catalytic enantioselective propargyl additions,
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[5] H. Kagoshima, T. Uzawa, T. Akiyama, Chem. Lett. 2002, 298 –
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ꢀ
ꢀ
[17] Since protonation of the intermediate NHC Cu allene by
MeOH does not constitute a major pathway, it is likely that N-
phosphinoylimines are associated to the Lewis acidic transition
ꢀ
metal when an NHC Cu species is generated, leading to an
[6] H. M. Wisniewska, E. R. Jarvo, Chem. Sci. 2011, 2, 807 – 810.
[7] A single case has been reported involving an acylhydrazone as
the substrate and the relatively moisture-sensitive trichlorosilyl-
allene as the reagent; the phenyl-substituted homopropargyl
amine was obtained in 53% yield and 89:11 e.r. See: a) J. Chen,
B. Captain, N. Takenaka, Org. Lett. 2011, 13, 1654 – 1657.
Furthermore, in a recent study, homopropargyl amines were
obtained as minor byproducts; see: b) Y.-Y. Huang, A. Chakra-
barti, N. Morita, U. Schneider, S. Kobayashi, Angew. Chem. 2011,
123, 11317 – 11320; Angew. Chem. Int. Ed. 2011, 50, 11121 –
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intramolecular allyl transfer. Such considerations, together with
the high levels of enantioselectivity, suggest that open transition
structures are likely not involved. For a related discussion, see:
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Roubineau, K. Bentayeb, J. Marrot, P. Mangeney, J. Am. Chem.
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[18] For catalytic processes that involve the use of CuII salts and
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Korean Chem. Soc. 2010, 31, 551 – 552; b) A. Guzman-Martinez,
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[19] A possible route for reduction of CuII involves reaction of NHC–
[8] For an example of catalytic enantioselective synthesis of
propargyl glycine derivatives through the use of chiral-phase
transfer catalysts, see: S. L. Castle, G. S. C. Srikanth, Org. Lett.
2003, 5, 3611 – 3614.
CuIICl(OtBu) with 1 to generate (pin)B-OtBu and NHC–
II
ꢀ
Cu Cl(allene). Subsequent homolytic Cu C bond cleavage
[9] For the use of C1-symmetric NHC–Cu complexes in enantiose-
affords NHC–CuICl and the product from allene dimerization.
[20] D. Yang, F. Chen, Z.-M. Dong, D.-W. Zhang, J. Org. Chem. 2004,
69, 2221 – 2223.
ꢀ
ꢀ
ꢀ
lective synthesis of C C, C Si, and C B bond formation,
respectively, see: a) K.-s. Lee, A. H. Hoveyda, J. Org. Chem.
2009, 74, 4455 – 4462; b) K.-s. Lee, A. H. Hoveyda, J. Am. Chem.
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[10] E. M. Vieira, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc.
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[21] For a review on the significance of b-amino acids, see: D.
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[22] For synthesis and biological activity of aza-epothilones, see: D.
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mann, ChemBioChem 2000, 1, 67 – 70.
[23] For examples of Z-selective reduction of iodoalkynes with o-
nitrobenzenesulfonylhydrazide (o-NBSH), see: a) J. Rouden, T.
Seitz, L. Lemoucheux, M.-C. Lasne, J. Org. Chem. 2004, 69,
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Soc. 2010, 132, 9175 – 9187.
[11] The addition can be performed on gram-scale with the catalyst
derived from CuCl (0.25 mol% loading, 10 h, under otherwise
the same conditions as shown in Scheme 2), affording 4a in 81%
yield and more than 98:2 e.r (without chromatography).
[12] For an overview regarding the utility of N-phosphinoylimines in
chemical synthesis, see: S. M. Weinreb, R. K. Orr, Synthesis
2005, 1205 – 1227.
[13] Additionally, 6 is obtained in more than 98% yield and 96.5:3.5
e.r., 9 is isolated in 88% yield and 98:2 e.r., and 12 is formed in
75% yield and 98:2 e.r. (> 98% conv. and < 2% allene addition
in all cases). See the Supporting Information for additional
details.
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[14] For the role of MeOH in the catalytic cycle, see Ref. [10].
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