Catalytic enantioselective nucleophilic addition of ynamides to aldehydes

Article abstract of DOI:10.1039/c4cc00394b

The first catalytic asymmetric addition of ynamides to aliphatic and aromatic aldehydes is described. This reaction provides unprecedented access to a diverse family of N-substituted propargylic alcohols that are obtained in high yield and ee in the presence of 10 mol% of zinc triflate and N-methylephedrine. The use of apolar solvent mixtures is essential to avoid product racemization and to optimize ee's without compromising conversion. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c4cc00394b

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DOI: 10.1039/C4CC00394B
Catalytic Enantioselective Nucleophilic Addition of Ynamides to
Aldehydes
Andrea M. Cook and Christian Wolf*
Department of Chemistry, Georgetown University, Washington, DC 20057, USA. Fax: (+1) 202 687
6209; Tel: (+1) 202 687 3468; E-mail: cw27@georgetown.edu
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The first catalytic asymmetric addition of ynamides to
aliphatic and aromatic aldehydes is described. This reaction
provides unprecedented access to a diverse family of N-
substituted propargylic alcohols that are obtained in high
yield and ee in the presence of 10 mol% of zinc triflate and
N-methylephedrine The use of apolar solvent mixtures is
essential to avoid product racemization and to optimize ee’s
without compromising conversion.
catalytic asymmetric ynamide addition to aliphatic and aromatic
aldehydes that produces N-substituted propargylic alcohols in
high yields and ee’s, Scheme 1.
The unique synthetic versatility of ynamines and ynamides
has attracted increasing attention in recent years. In particular,
substituted ynamides have been applied in a wide array of
carbon-carbon bond forming reactions and several total
syntheses of natural products using these multifaceted building
blocks as key intermediates have been reported.1 At first glance,
ynamines and their analogues appear to be a hybrid structure of
alkynes and enamines. The properties and reactivity of ynamines
and ynamides, however, is quite unique and by no means an
average of these parent functionalities. The presence of the
adjacent electron-donating nitrogen atom generates a strongly
polarized triple bond. This polarization drastically affects the
reactivity and utility of ynamines and it bears huge synthetic
potential. Because ynamines are very sensitive and difficult to
handle, the incorporation of an electron-withdrawing group that
reduces the electron-donating capacity of the amino moiety is
necessary to afford isolable ynamine derivatives and as a means
to maintain reaction control during catalytic transformations,
Figure 1.
Scheme 1 Nucleophilic addition of ynamides to aldehydes.
Because little information on the reactivity, in particular with
regard to acidity, propensity toward formation of transition metal
alkynyl σ-complexes and nucleophilicity, is available for
terminal ynamides, we decided to start investigating the
possibility of a catalytic enantioselective nucleophilic addition to
aldehydes using readily available N-phenyl-N-tosyl ynamide 1
and alkyne addition protocols introduced by Carreira, Trost,
Shibasaki and others.14 We were able to prepare ynesulfonamide
1
by three high-yielding steps on the gram scale from
commercially available N-tosyl aniline following a literature
procedure.3 With this prototype ynamide in hand, we began our
search for a catalytic reaction with 4-bromobenzaldehyde by
screening a variety of metal salts and chiral ligands, including
bisoxazolines, bisoxazolidines, cinchona alkaloids, amino
alcohols and diamines, in several solvents.14 We were very
pleased to find that the nucleophilic addition occurs in the
presence of catalytic amounts of zinc triflate and N-
methylephedrine (NME) in toluene at room temperature,
providing the N-substituted propargylic alcohol 2 in high yield
and 60% ee, see entry 1 in Table 1. Encouraged by this finding,
we prepared other ynamides including novel 3-acylindole-
stabilized vinylogous ynamides via TBAF-promoted desilylation
of TIPS-protected precursors that were obtained as previously
described by Stahl.15 As expected, incorporation of the ynamide
nitrogen atom into a slightly less electron-withdrawing moiety
increases the reactivity while the enantioselectivity of this
reaction is substantially reduced. We obtained excellent yields
with ynamides 3 and 4 but the ee’s dropped below 40%, entries 2
and 3 in Table 1. The introduction of the indole-derived terminal
ynamides 5-8 gave superior results and the ee’s generally
improved to 80%, entries 4-7. The reaction with the 3-
benzoylindolyl derived ynamide 7 gave the corresponding
propargylic alcohol 13 in 87% yield and 77% ee, which seemed
particularly promising, entry 6.
Figure 1 Representative ynamine and ynamide structures.
Witulski,2 Bruckner,3 Saa4 and others introduced various
procedures for the synthesis of terminal ynamides,
ynesulfonamides and ynecarbamates.1 An impressive variety of
reactions with these practical ynamine analogues, including
cycloadditions,5 cycloisomerizations,6 homo- and cross-
couplings,7 ring-closing metathesis,8 radical additions,9 and
titanium-mediated C-C bond formation,10 are known.11 Hsung
reported an elegant boron trifluoride promoted two-carbon
homologation that yields acrylic amides from aldehydes or
ketones upon reaction with terminal ynamides.12 Few examples
of nucleophilic additions of lithium or sodium ynamides to
aldehydes, imines and ketones toward racemic N-substituted
propargylic alcohols have been reported.13 A broadly applicable,
mild variant that avoids the use of butyllithium, sodium amide or
another strong base has not been developed to date. Moreover, a
catalytic enantioselective nucleophilic addition to carbonyl
electrophiles is unprecedented. We now wish to introduce a mild
Further optimization of the catalytic asymmetric addition of 7
to bromobenzaldehyde revealed an unexpected feature that to the
best of our knowledge has not been observed for additions of
ynamines, ynamides or even simple alkynes to aldehydes.
During extensive screening of the effects of catalyst loading,
solvents and base on the yield and enantioselectivity, we
†
Electronic Supplementary Information (ESI) available: Synthetic
procedures, and spectroscopic and cystallographic details. See
http://dx.doi.org/10.1039/b000000x/
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observed that the ee of 13 decreases over time when the
reactions were allowed to proceed to full completion. We
rationalized that this could be a result of product racemization
which one would expect to have an increasing impact at high
conversion and at extended reaction times. Indeed, stirring of
enantioenriched 13 under typical reaction conditions proved that
the C-C bond formation is reversible.16 Comparison of bases
showed that the reaction is sluggish when DBU (1,8-
with high yields and ee’s, entries 1-12 in Table 2. Screening of
several other halogenated benzaldehyde derivatives showed that
the corresponding products 15-18 can be obtained with excellent
results with the exception of 2-fluorobenzaldehyde which was
obtained in high yield but somewhat lower ee, entries 2-5. This
cannot be attributed to steric hindrance because the ynamide
addition to 2-tolyl aldehyde produced 22 in 93% yield and 95%
ee, entry 9. We were able to extend this method to aliphatic
aldehydes. The reaction with cyclohexanecarboxaldehyde and
decanal afforded 26 and 27 in 87-89% yield and 90-95% ee,
respectively, entries 13 and 14. Finally, we were successful with
growing single crystals of 13 and 20 prepared as described in
Table 2 using (1R,2S)-(-)-N-methylephedrine as chiral ligand by
slow evaporation of a chloroform solution. Crystallographic
analysis of 13 revealed S-configuration, Figure 2 and ESI.
diazabicyclo[5.4.0]undec-7-ene)
and
DMAP
(4-
dimethylaminopyridine) are used while the best results were
obtained with sterically hindered amines and 2,6-lutidine. The
presence of the latter, however, was found to strongly promote
the racemization reaction which was most evident in THF and
diethyl ether. The ee of 13 dropped from 93% to only 23% when
the reaction was performed in the presence of one equivalent of
2,6-lutidine in THF for 20 hours. We then discovered that the
undesirable effect of the concomitant racemization on the ee of
the ynamide addition products can be substantially reduced or
eliminated when the reaction is carried out in apolar solvents.
Because 13 precipitates in toluene and most of its derivatives are
barely soluble in hexane/toluene mixtures, racemization can
easily be avoided with these solvent choices even when
relatively long reaction times are required to achieve high yields.
Under optimized conditions, we were able to produce 13 in 97%
yield and 93% ee and we decided to not further optimize the
reaction with the other ynamides, entry 1 in Table 2.
Table 2 Scope of the zinc catalyzed enantioselective ynamide addition.[a]
Time Yielda Ee
Entry
1b
Aldehyde
Product
(h)
(%)
(%)
O
H
18
97
93
Br
Table 1 Results of the screening of various ynamide nucleophiles.a
2
3
16
18
92
85
95
93
Time Yielda Ee
(h) (%) (%)
OH
Entry
1
Ynamide
Product
4
18.5
87
88
NR2R3
17
F
2.5
87
91
60
38
5
13
18
92
92
71
96
2
3
3
5
6b
100 27
7
8
17
18
15
20
92
87
93
80
90
84
95
88
4
5
6
18
18
24
68
58
87
80
78
77
9
10
11
26
92
87
12
13b
14
21
15
13
81
89
87
87
90
95
7
27
60
81
aBased on NMR analysis
Having optimized the catalytic reaction between
bromobenzaldehyde and toward 3-(4-bromophenyl)-3-
hydroxy-1-(3-benzoylindolyl)propyne, 13, we finally employed
a variety of aldehydes in our method to determine the substrate
scope. The reaction with aromatic substrates generally proceeded
Standard conditions: ynamide (0.20 mmol), aldehyde (0.30 mmol),
Zn(OTf)2 (10 mol%), (-)-NME (11 mol%) in 0.5 mL of toluene/hexane
(1:1). [a] Isolated yields. [b] Toluene. The absolute configuration of 13
was determined by crystallographic analysis, see ESI. All other
assignments are by analogy.
7
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Figueroa, R.; Hsung, R. P. Heterocycles 2007, 74, 553. (c) Li, H.;
Hsung, R. P. Org. Lett. 2009, 11, 4462. (d) Zhang, X.; Li, H.; You,
L.; Tang, Y.; Hsung, R. P. Adv. Synth. Catal. 2006, 348, 2437. (e)
Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun. 2007, 2420. (f)
Kim, J. Y.; Kim, S. H.; Chang, S. Tetrahedron Lett. 2008, 49, 1745.
(g) Zhang, X.; Hsung, R. P.; Li, H.; Zhang, Y.; Johnson, W. L.;
Figueroa, R. Org. Lett. 2008, 10, 3477. [4+2] Cycloadditions: (h)
Martinez-Esperon, M. F.; Rodriguez, D.; Castedo, L.; Saa, C. Org.
Lett. 2005, 7, 2213. [2+2+1] Cycloadditions: (i) Witulski, B.;
Goessmann, M. Synlett 2000, 1793. [2+2+2] Cycloadditions: (j)
Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. 1999, 38, 2426. (k)
Witulski, B.; Stengel, T.; Fernandez-Hernandez, J. Chem. Commun.
2000, 1965. (l) Witulski, B.; Alayrac, C. Angew. Chem. Int. Ed.
2002, 41, 3281. (m) Dateer, R. B.; Shaibu, B. S.; Liu, R.-S. Angew.
Chem. Int. Ed. 2012, 51, 113.
(a) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.;
Malacria, M. Org. Lett. 2004, 6, 1509. (b) Marion, F.; Coulomb, J.;
Servais, A.; Courillon, C.; Fensterbank, L.; Malacria, M.
Tetrahedron 2006, 62, 3856. (c) Hashmi, A. S.; Rudolph, M.; Bats,
J.; Frey, W.; Rominger, F.; Oeser, T. Chem. Eur. J. 2008, 14, 6672.
(d) Couty, S.; Meyer, C.; Cossy, J. Tetrahedron 2009, 65, 1809.
Homocoupling reactions: (a) Rodriguez, D.; Castedo, L.; Saa, C.
Synlett 2004, 377. Negishi cross-couplings: (b) Rodriguez, D.;
Castedo, L.; Saa, C. Synlett 2004, 783. (c) Martinez-Esperon, M. F.;
Rodriguez, D.; Castedo, L.; Saa, C. Tetrahedron 2006, 62, 3843.
Sonogashira couplings: (d) Tracey, M. R.; Zhang, Y.; Frederick, M.
O.; Mulder, J. A.; Hsung, R. P. Org. Lett. 2004, 6, 2209. (e)
Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009, 11,
221. Heck reactions: (f) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J.
Org. Lett. 2004, 6, 2511. (g) Couty, S.; Liegault, B.; Meyer, C.;
Cossy, J. Tetrahedron 2006, 62, 3882.
Figure
2 Crystal structures of 13 (left) and 20 (right). Selected
crystallographic separations [Å] for 13: C(sp)-C(sp): 1.191, N-C(sp) 1.358.
20: C(sp)-C(sp): 1.191, N-C(sp) 1.359.
We then investigated if the presence of a chiral center in the
substrate is tolerated. In fact, the Zn(II)-(-)-NME catalyzed
reaction between (R)-citronellal and ynamide 7, gave 28 in 88%
yield and 98% de within 3 hours, Scheme 2. The same aldehyde
reacted more slowly and with lower diastereoselectivtiy when
(+)-NME was used as chiral ligand under otherwise identical
conditions. As a result, we isolated 29 in only 56% yield and
73% ee. The reduced yield is mostly a result of slow conversion
and 25% of the unreacted ynamide were recovered after 3 hours.
These results show that the sense of asymmetric induction is
overwhelmingly controlled by the chiral catalyst while the
chirality in the substrate may still have a distinctive effect on the
reaction outcome. The Zn(II)-(-)-NME catalyzed reaction with
the (R)-enantiomer of citronellal represents a matched pair
whereas the reduced reaction rate and the lower asymmetric
induction observed with Zn(II)-(+)-NME is in accordance with a
mismatched pair.17
6
7
8
9
Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803.
Banerjee, B.; Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle, S. L.
Org. Lett. 2010, 12, 2650.
10 (a) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67.
(b) Tanaka, R.; Yuza, A,; Watai, Y.; Suzuki, D.; Takayama, Y.;
Sato, F.; Urabe, M. J. Am. Chem. Soc. 2005, 127, 7774. (c) Tanaka,
D.; Sato, Y.; Mori, M. J. Am. Chem. Soc. 2007, 129, 7730.
11 Other examples of important reactions of terminal ynamides:
Hydroboration: (a) Witulski, B.; Buschmann, N.; Bergstraesser, U.
Tetrahedron 2000, 56, 8473. Oxoarylations and cyclizations: (b)
Bhunia, S.; Chang, C.-J.; Liu, R.-S. Org. Lett. 2012, 14, 5522. (c)
Yang, L.-Q.; Wang, K.-B.; Li, C.-Y. Eur. J. Org. Chem. 2013, 2775.
(d) Couty, S.; Meyer, C.; Cossy, J. Synlett 2007, 2819. (e) Al-
Rashid, Z. F.; Hsung, R. P. Org. Lett. 2008, 10, 661. Nucleophilic
alkylations with lithiated ynamides: (f) Frederick, M. O.; Mulder, J.
A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen,
L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368.
Scheme 2 Diastereoselective ynamide addition to citronellal.
In summary, we have developed the first catalytic asymmetric
addition of ynamides to aldehydes. The zinc catalyzed method is
operationally simple, applicable to aliphatic and aromatic
aldehydes, proceeds under mild conditions at room temperature,
and provides practical access to a variety of N-substituted
propargylic alcohols that are obtained in high yields and ee’s.
The use of apolar solvent mixtures proved essential to avoid
product racemization and to achieve high ee’s without
compromising conversion. The unique reactivity and diversity of
the polar ynamide functionality bear remarkable potential for
asymmetric synthesis. The introduction of terminal ynamides to
catalytic enantioselective additions described herein is expected
to provide unprecedented entries to complex chiral building
blocks.
12 You, L.; Al-Rashid, Z. F.; Figueroa, R.; Ghosh, S. K.; Ti, G.; Lu, T.;
Hsung, R. P. Synlett 2007, 1656.
13 (a) Joshi, R.V.; Xu, Z.-Q.; Ksebati, M. B.; Kessel, D.; Corbett, T.
H.; Drach, J. C.; Zemlicka, J. J. Chem. Soc. Perkin Trans. 1 1994,
10, 1089. (b) Rodriguez, D.; Castedo, L.; Saa, C. Synlett 2007, 1963.
(c) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008,
10, 1867. (d) Wang, X.-N.; Winston-McPherson, G. N.; Walton, M.
C.; Zhang, Y.; Hsung, R. P.; DeKorver, K. A. J. Org. Chem. 2013,
78, 6233. (e) Wang, X.-N.; Hsung, R. P.; Rui, Q.; Fox, S. K.; Lv,
M.-C. Org. Lett. 2013, 15, 2514.
14 We generally prefer using 4-bromobenzaldehyde over benzaldehyde
during initial screening due to its superior shelf life. The reaction did
not occur in the absence of a transition metal or under conditions
typically used for nucleophilic additions with enamides or
enecarbamates. For stereoselective C-C bond formations with
enamides and enecarbamates see (a) M. Ryosuke, S. Kobayashi Acc.
Chem. Res. 2008, 41, 292. For examples of catalytic asymmetric
addition reactions with terminal alkynes: (b) Anand, N. K; Carreira,
E. M. J. Am. Chem. Soc. 2001, 123, 9687. (c) Li, X.; Lu, G.; Kwok,
W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124, 12636. (d)
Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 13760. (e) Trost, B. M.; Weiss, A. H.; von
Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8. (f) Gao, G.; Wang,
Q.; Yu, X.-Q.; Xie, R.-G.; Pu, L. Angew. Chem. Int. Ed. 2006, 45,
122. (g) Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006, 128, 10996.
15 Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833.
16 The decrease of the ee of 13 was found to coincide with the
formation of the starting materials.
We gratefully acknowledge financial support from the
National Institutes of Health (GM106260).
Notes and references
1
For excellent reviews, see: (a) Zificsak, C. A.; Mulder, J. A.; Hsung,
R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575. (b)
Evano, G.; Coste, A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49,
2840. (c) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. (d) Wang, X.-
N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.;
Hsung, R. P. Acc. Chem. Res. 2013, DOI: 10.1021/ar400193g.
Witulski, B.; Goessmann, M. Chem. Commun. 1999, 1879.
Bruckner, D. Tetrahedron 2006, 62, 3809.
2
3
4
5
Rodriguez, D.; Castedo, L.; Saa, C. Synlett 2007, 1963.
[3+2] Cycloadditions: (a) IJsselstijn, M.; Cintrat, J.-C. Tetrahedron
2006, 62, 3837. (b) Li, H.; You, L.; Zhang, X.; Johnson, W. L.;
17 Wolf, C. (ed.) Dynamic Stereochemistry of Chiral Compounds, RSC
Publishing, Cambridge, UK, 2008, 194.
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Graphical abstract:
Catalytic enantioselective addition of ynamides to aldehydes has been achieved with high yields and ee’s.
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