Enantioselective synthesis of propargylamines through Zr-catalyzed addition of mixed alkynylzinc reagents to arylimines

Article abstract of DOI:10.1021/ol035138b

(Matrix presented) Addition of mixed alkynylzinc reagents to various arylimines is catalyzed by chiral amino acid-based ligand 1 and Zr(Oi-Pr) ₄·HOi-Pr to afford chiral propargylamines in up to 90% ee. Oxidative removal of the o-anisidyl group

Full text of DOI:10.1021/ol035138b

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3273-3275
Enantioselective Synthesis of
Propargylamines through Zr-Catalyzed
Addition of Mixed Alkynylzinc Reagents
to Arylimines
John F. Traverse, Amir H. Hoveyda,* and Marc L. Snapper*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
amir.hoVeyda@bc.edu; marc.snapper@bc.edu
Received June 19, 2003
ABSTRACT
Addition of mixed alkynylzinc reagents to various arylimines is catalyzed by chiral amino acid-based ligand 1 and Zr(Oi-Pr)4‚HOi-Pr to afford
chiral propargylamines in up to 90% ee. Oxidative removal of the o-anisidyl group affords the free amine, which can then be acylated.
Recent efforts in these laboratories have focused on the
development of a general class of readily available and easily
modifiable amino acid-based chiral ligands that can be used
to effect a variety of synthetically important C-C bond-
forming reactions enantioselectively.1 One objective of this
program is to design protocols for the asymmetric synthesis
of nonracemic chiral aryl-2 and alkylamines. In this context,
we have reported methods that allow access to aryl-3 and
alkylamines4 efficiently and with high optical purity through
three-component syntheses. These Zr-catalyzed transforma-
tions5 involve enantioselective addition of alkylzinc reagents
to different imines promoted by peptidic chiral ligands (e.g.,
1 shown in eq 1). After the above studies, we set out to
develop methods for the asymmetric synthesis of alkynyl-
amines.6 In principle, such a task may involve two different
types of C-C bond-forming reactions (Scheme 1): catalytic
(1) For representative examples, see: (a) Cole, B. M.; Shimizu, K. D.;
Krueger, C. A.; Harrity, J. P.; Snapper, M. L.; Hoveyda, A. H. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1668-1671. (b) Krueger, C. A.; Kuntz, K.
W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284-4285. (c) Degrado, S.
J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755-756.
(d) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2001, 40, 1456-1460. (e) Deng, H.; Isler, M. P.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2002, 41, 1009-
1012. (f) Luchaco-Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 8192-8193. (g) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2003, 125, 4018-4019. (h) Murphy, K. E.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 4690-4691.
(3) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 984-985. For related studies involving catalytic
asymmetric alkylations of imines, see: (b) Denmark, S. E.; Stiff, C. M. J.
Org. Chem. 2000, 65, 5875-5878 and references therein. (c) Fujihara, H.;
Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055-12056. (d)
Zhang, X.-M.; Zhang, H.-L.; Lin, W.-Q.; Gong, L.-Z.; Mi, A.-Q.; Cui, X.;
Jiang, Y.-Z.; Yu, K.-B. J. Org. Chem. 2003, 68, 4322-4330. (e) Dahmen,
S.; Brase, S. J. Am. Chem. Soc. 2002, 124, 5940-5941. (f) Boezio, A. A.;
Charrette, A. B. J. Am. Chem. Soc. 2003, 125, 1692-1693.
(4) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 10409-10410.
(5) For a review of Zr-catalyzed asymmetric transformations, see:
Hoveyda, A. H. In Titanium and Zirconium in Organic Synthesis; Marek,
I., Ed.; VCH-Wiley: Weinheim, 2002; pp 180-229.
(6) For a review of asymmetric syntheses of propargylamines, see:
Blanchet, J.; Bonin, M.; Micouin, L. Org. Prep. Proced. Int. 2002, 34, 459.
(2) For reviews on catalytic asymmetric additions to imines, see: (a)
Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946.
(b) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094.
10.1021/ol035138b CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/12/2003

occurred under a variety of conditions. To address this
reactivity problem,9 we investigated reactions in the presence
of mixed organozinc reagents formed upon addition of bis-
[(trimethylsilyl)methyl]zinc 5.10 Such a modification led to
significant improvement in reaction efficiency: in certain
cases, >98% conversion to 3a was observed after 48 h at
22 °C.11,12 These studies illustrated that dipeptide amine 1
and Zr(Oi-Pr)4‚HOi-Pr, a system that had proven to be
optimal in previous studies, again is the combination of
choice. Subsequent optimization led us to establish that, as
illustrated in eq 1, addition of only 0.6 equiv of 4 to 2a
affords alkynylamine 3a in 90% ee and 83% isolated yield
in a 2 mmol scale process. It should be noted that there is
only 5-10% conversion in the absence of 1. Moreover, when
the Zr-catalyzed reaction is carried out at elevated temper-
atures, lower enantioselectivity as well as reduced yields are
obtained. The lower yields are due in part to competing side
reactions at higher temperatures, for example at 55 °C, only
25% of 3a is obtained after 24 h. Lower catalyst loadings
may be used to promote enantioselective additions. With 5
mol % 1 and 10 mol % of the metal alkoxide, 3a is isolated
in 88% ee and 86% isolated yield; identical conditions,
except with 2.5 mol % 1, delivers the desired unsaturated
amine in 86% ee and 90% yield after purification (48 h in
both cases). Any further reduction in the loading of the chiral
ligand significantly diminishes reaction efficiency and the
level of asymmetric induction. Use of 1 mol % 1 and 10
mol % Zr(Oi-Pr)4‚HOi-Pr leads to the formation of 3a in
63% ee and 61% yield (after 48 h).
Scheme 1. Two C-C Bond-Forming Routes toward
Alkynylamines.
asymmetric addition of alkynylmetals to an imine (pathway
A) or the addition of an alkylmetal to an alkynylimine
(pathway B).7 Two catalytic enantioselective approaches for
the synthesis of propargylamines have been reported that
proceed along pathway A.8 One disclosure by Li8a involves
additions to various arylimines in the presence of 10 mol %
Cu-pybox; reactions proceed in high enantioselectivity but
are limited to phenylacetylene (78-96% ee), and protocols
for conversion of the N-arylamines to the corresponding free
amines were not outlined. The other procedure, also Cu-
catalyzed (Quinap as a chiral ligand), is by Knochel;8b,c this
method delivers aliphatic alkynylamines, bearing N-allyl or
N-Bn groups, through asymmetric addition of alkynes to
enamine substrates (54-90% ee).
In this report, we outline catalytic enantioselective addi-
tions of alkynylzinc reagents to a variety of o-anisidyl imines
(pathway A). Transformations are promoted by chiral ligand
1 in the presence of Zr(Oi-Pr)4‚HOi-Pr to afford the derived
alkynylamines in up to 90% ee and g69% isolated yield.
Products bearing a variety of alkyne substituents can be
readily accessed by the present protocol. Moreover, the
o-anisidyl group may be removed efficiently to afford the
corresponding amines or other related derivatives.
As the data summarized in Table 1 indicate, a variety of
aryl imines with different steric and electronic attributes can
be converted to nonracemic alkynylamines. Electron-poor
2b (entry 1, Table 1) as well as electron-rich 2c (entry 2,
Table 1) are alkylated to afford the corresponding unsaturated
amines in 81 and 86% ee, respectively. The presence of an
ortho substituent in 2d (entry 3, Table 1) can cause a
(8) (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638-5639. (b)
Koradin, C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem. Eur. J.
2003, 9, 2797-2811. (c) Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2002, 41, 2535-2538. For enantioselective synthesis of
propargylamines through the use of chiral controllers and auxiliaries, see:
(d) Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J.
Org. Chem. 1995, 60, 1590-1594. (e) Kolb, M.; Barth, A. Angew. Chem.,
Int. Ed. Engl. 1980, 19, 725-726. (f) Hattori, K.; Miyata, M.; Yamamoto,
H. J. Am. Chem. Soc. 1993, 115, 1151-1152. (g) Enders, D.; Schankat, J.
HelV. Chim. Acta 1995, 78, 970-992. (h) Blanchet, J.; Bonin, M.; Chiaroni,
A.; Micouin, L.; Riche, C.; Husson, H.-P. Tetrahedron Lett. 1999, 40, 2935-
2938. (i) Fassler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew.
Chem., Int. Ed. 2002, 41, 3054-3056. (j) Blanchet, J.; Bonin, M.; Micouin,
L.; Husson, H.-P. J. Org. Chem. 2000, 65, 6423-6426. For an example
regarding synthesis of optically pure propargylamines through enzymatic
resolution, see: (k) Messina, F.; Botta, M.; Corelli, F.; Schneider, M. P.;
Fazio, F. J. Org. Chem. 1999, 64, 3767-3769.
(9) It is likely that such a lack of reactivity is partly due to the low
solubility of dialkynylzinc reagents in toluene. Initial studies indicated that
catalytic alkylations in THF, a solvent that more effectively dissolves
alkynylzincs, lead to significantly lower enantioselectivity.
(10) (a) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.;
Kishan Reddy, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 1496-1498. (b)
Bertz, S. H.; Eriksson, M.; Snyder, J. P. J. Am. Chem. Soc. 1996, 118,
10906-10907.
Our investigations began with screening for optimal amino
acid-based ligands and metal salts to effect the enantio-
selective addition of dialkynylzinc reagent 4 to imine 2a (eq
1). In all cases, only 5-10% conversion to the desired 3a
(11) See Supporting Information for details.
(12) Reactions involving terminal alkynes and Me2Zn or those in the
presence of dialkynylzincs and Me2Zn resulted in the formation of amines
derived from predominant or exclusive addition of a Me group. See: Li,
Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis
1999, 1453-1458.
(7) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2003, 42, in press.
3274
Org. Lett., Vol. 5, No. 18, 2003

reactions.13 Alkynylzinc reagents bearing aliphatic substit-
uents may also be used in the Zr-catalyzed reactions, albeit
with some reduction in enantioselectivity.14 As an example,
amine 6 can be prepared by the protocol outlined above in
79% ee and 81% isolated yield. The diminution in asym-
metric induction is higher when aryl-substituted alkynylzincs
are utilized; synthesis of unsaturated amine 7 in 68% ee and
81% yield is illustrative.
Table 1. Zr-Catalyzed Enantioselective Addition of
Alkynylzincs to Imines
entry
R
yield (%)b
ee (%)c
1
2
3
4
5
6
p-ClC6H4
p-OMeC6H4
o-BrC6H4
1-naph
2-naph
2-furyl
b
c
d
e
f
90
69
84
77
85
72
81
86
69d
86d
81
g
82d
a Conditions: 10 mol % 1, 11 mol % Zr(Oi-Pr)4, 0.6 equiv of 4, 2 equiv
of 5, toluene, 22 °C, 72 h (entries 1, 2, and 4), 48 h (entries 3 and 5), 24
h (entry 6). b Isolated yield after silica gel chromatography. c Determined
by HPLC (chiralcel OD). d Determined through analysis of the derived
desilylated product (HPLC; chiralcel OD).
Optically enriched secondary alkynylamines can be pre-
pared through oxidative removal of the o-anisidyl activating
group;4 the example shown in Scheme 2, which proceeds in
71% overall yield, via the corresponding unprotected amine,
is illustrative.
In summary, we report a Zr-catalyzed method for the
enantioselective addition of a range of mixed alkynylzinc
reagents to various arylimines to afford optically enriched
secondary propargylamines in up to 90% ee. The present
protocol demonstrates the utility of Si-containing mixed
alkynylzincs. In addition, this study extends the utility of
amino acid-based ligands such as 1, which is prepared from
inexpensive and commercially available amino acids and
5-methoxysalicylaldehyde, to include the asymmetric prepa-
ration of another class of biologically important organic
building blocks.15
significant reduction in asymmetric induction (69% ee).
Sterically hindered naphthylimines 2e and 2f (entries 4 and
5, Table 1) are converted to propargylamines in 86 and 81%
ee, respectively. As the example in entry 6 of Table 1
illustrates (2g f 3g), products bearing heterocyclic aromatic
substituents can be obtained by the present method (entry 6,
Table 1).
The decision to focus our studies on the utility of
silylalkyne reagent 4 was largely based on the principle that
removal of the SiMe3 unit (e.g., 3a f 8 in Scheme 2) can
Acknowledgment. This research was supported by the
NIH (GM-57212). J.F.T. is grateful for a graduate fellowship
from Schering-Plough. We thank Dr. James R. Porter and
Laura C. Akullian for helpful discussions.
Scheme 2. Optically Enriched Alkynylamines through
Oxidative Removal of the o-Anisidyl Group.
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for all substrates
and reaction products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL035138B
(13) For representative examples, see: (a) Ritleng, V.; Sirlin, C.; Pfeffer,
M. Chem. ReV. 2002, 102, 1731-1769. (b) Negishi, E.; Anastasia, L. Chem.
ReV. 2003, 103, 1979-2017.
(14) Alkynylzincs 1-2 equiv vs 0.6 equiv) derived from 1-hexyne and
phenylacetylene are required for efficient Zr-catalyzed alkynylations (see
Supporting Information for details). For example, with 0.6 equiv of the
alkynylzinc reagent, 6 is obtained in 50-58% yield (vs 81%).
(15) For example, see: (a) Shirota, F. N.; DeMaster, E. G.; Nagasawa,
H. T. J. Med. Chem. 1979, 22, 463-464. (b) Yu, P. H.; Davis, B. A.;
Boulton, A. A. J. Med. Chem. 1992, 35, 3705-3713.
be easily effected and the resulting terminal alkyne can be
converted to a wide range of other nonracemic acetylenic
amines through a number of alkylation or cross coupling
Org. Lett., Vol. 5, No. 18, 2003
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