A single Cu(II) catalyst for the three-component coupling of diverse nitrogen sources with aldehydes and alkynes

Article abstract of DOI:10.1021/ol2029492

A single Cu(II) catalyst without the addition of ligand or base couples a diverse range of nitrogen sources with alkynes and aldehydes bearing alkyl, halogenated, silyl, aryl, and heteroaryl groups. The first example of a copper-catalyzed alkynylation involving p-toluenesulfonamide provides high yields of N-Ts-protected propargylamines. The superior activity of copper(II) triflate also allows this three-component alkynylation to incorporate a ketone.

Full text of DOI:10.1021/ol2029492

ORGANIC
LETTERS
2012
Vol. 14, No. 4
964–967
A Single Cu(II) Catalyst for the Three-
Component Coupling of Diverse Nitrogen
Sources with Aldehydes and Alkynes
Courtney E. Meyet, Conor J. Pierce, and Catharine H. Larsen*
Department of Chemistry, University of California, Riverside, California 92521,
United States
catharine.larsen@ucr.edu
Received November 3, 2011
ABSTRACT
A single Cu(II) catalyst without the addition of ligand or base couples a diverse range of nitrogen sources with alkynes and aldehydes bearing
alkyl, halogenated, silyl, aryl, and heteroaryl groups. The first example of a copper-catalyzed alkynylation involving p-toluenesulfonamide
provides high yields of N-Ts-protected propargylamines. The superior activity of copper(II) triflate also allows this three-component alkynylation
to incorporate a ketone.
From chiral HIV reverse transcriptase inhibitors to
achiral antihypertensives, propargylamines display a
wide range of therapeutic activity.1,2 Methods for the
catalytic alkynylation of imines (as opposed to stoichio-
metric metal acetylides3) are limited, as most reports
use only anilines4 or piperidines5 as the nitrogen source.
The scope is further restricted by the predominance of
benzaldehyde-derived imines attacked by phenylacety-
lenes.2À5 Knochel and co-workers utilized the broadest
scope of alkynes with alkyl aldehydes, but only secondary
amines are tolerated (e.g., N,N-dibenzyl).6 A recent re-
port for the alkynylation of p-toluenesulfonyl (Ts) imines
required 6 equiv of Me2Zn and 20 mol % of binol ligand,
but the N-sulfonylated propargylamines were depro-
tected in high yield leaving the alkyne intact.7
(1) (a) Boulton, A. A. J. Med. Chem. 1992, 35, 3705. (b) Yu, P. H.;
Davis, B. A.; Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski,
E. J. J. J. Org. Chem. 1995, 60, 1590. (c) Jiang, B.; Si, Y.-G. Angew.
Chem., Int. Ed. 2004, 43, 216. (d) Kihara, K.; Aoki, T.; Moriguchi, A.;
Yamamoto, H.; Maeda, M.; Tojo, N.; Yamanaka, T.; Ohkubo, M.;
Matsuoka, N.; Seki, J.; Mutoh, S. Drug Dev. Res 2004, 61, 233.
(2) (a) Yamada, K.; Tomoika, K. Chem. Rev. 2008, 108, 2874. (b)
Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963. (c) Blay, G.;
To our knowledge, no catalyst has alkynylated imines
from these readily deprotected sulfonamides.2À7 As the
reported procedures allowed for neither (1) the catalytic
production of the electron-poor N-Ts-propargylamines
required for our synthetic studies8 nor (2) a single
ꢀ
Monleon, A.; Pedro, J. R. Curr. Org. Chem. 2009, 13, 1498.
(3) (a) Zani, L.; Bolm, C. Chem. Commun. 2006, 4263. (b) Zani, L.;
Alesi, S.; Cozzi, P. G.; Bolm, C. J. Org. Chem. 2006, 71, 1558. (c) Zani,
L.; Eichhorn, T.; Bolm, C. Chem.;Eur. J. 2007, 13, 2587.
(6) (a) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2002, 41, 2535. (b) Three-component coupling: Koradin, C.; Polborn, K.;
Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763. (c) Koradin, C.;
Gommerman, N.; Polborn, K.; Knochel, P. Chem.;Eur. J. 2003, 9,
(4) Selected references with aniline as nitrogen source (dozens more
in ref 2c): (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (b)
Wei, C. M.; Mague, J. T.; Li, C. J. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5749. (c) Ji, J.-X.; Wu, J.; Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.
A. 2005, 102, 11196. (d) Rueping, M.; Antonchick, A. P.; Brinkmann, C.
Angew. Chem., Int. Ed. 2007, 46, 6903. (e) Lu, Y.; Johnstone, T. C.;
Arndtsen, B. A. J. Am. Chem. Soc. 2009, 131, 11284. (f) de Armas, P.;
Tejedor, D.; Garcia-Tellado, F. Angew. Chem., Int. Ed. 2010, 49, 1013.
(5) Piperidine examples after ref 2c: (a) Zhou, L.; Bohle, D. S.; Jiang,
H.-F.; Li, C.-J. Synlett 2009, 937. (b) Li, P.; Zhang, Y.; Wang, L.
Chem.;Eur. J. 2009, 15, 2045. (c) Chen, W.-W.; Nguyen, R. V.; Li, C.-J.
Tetrahedron Lett. 2009, 50, 2895. (d) Zeng, T.; Chen, W.-W.; Cirtiu,
C. M.; Moores, A.; Song, G.; Li, C.-J. Green Chem. 2010, 12, 570.
€
2797. (d) As an application of pinap ligand: Knopfel, T. F.; Aschwanden,
P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed.
2004, 43, 5971. (e) Reviewed in: Gommerman, N.; Knochel, P.
Chem.;Eur. J. 2006, 12, 4380.
(7) N-Ts-propargylamine formed with 6 equiv of Me2Zn and depro-
tected with SmI2 leaving alkyne intact: Blay, G.; Cardona, L.; Climent,
E.; Pedro, J. R. Angew. Chem., Int. Ed. 2008, 47, 5593.
(8) Cu-catalyzed N-vinylation needs sulfonamide/amide: (a) Shen,
R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333. (b) Jiang, L.; Job, G. E.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667. (c) Pan, X.; Cai,
Q.; Ma, D. Org. Lett. 2004, 6, 1809. (d) Lu, H.; Li, C. Org. Lett. 2006, 8,
5365. (e) Lu, H.; Yuan, X.; Sun, C.; Li, C. J. Org. Chem. 2008, 73, 8665.
r
10.1021/ol2029492
Published on Web 01/19/2012
2012 American Chemical Society

protocol that could tolerate a wide variety of functional
groups on amine, aldehyde, and alkyne, we began by
exploring the copper-catalyzed alkynylation of alkyl-N-
Ts-imines with alkylalkynes (Scheme 1). Ideally, this
catalyst should also prove operable for anilines, alkylamines,
N-heterocycles, amides, and benzylamines. Herein we report
that copper(II) trifluoromethanesulfonate, Cu(OTf)2, is
unique in its ability to catalyze the three-component coupling
of the aforementioned nitrogen sources with alkyl, aryl, and
heteroaryl aldehydes and even ketones.
situ formed imine (Scheme 3) suggests that rate-determin-
ing alkynylation could occur on the protonated iminium
of 2 rather than copper-bound imine 2.6c
Scheme 3. Three-Component Coupling Proceeds More Rapidly
and with a Higher Yield than from Preformed Imine
Scheme 1. Could Cu(II) Catalyze the Direct Synthesis of Pro-
pargylamines with Electron-Poor Protecting Groups Like Ts?
Cu(I) sources11 were uniformly inactive with or without
added base or ligand. Propargyl alcohols from direct alky-
nylation of aldehyde were not observed.12 The sole bypro-
duct of this one-pot process is 1 equiv of water; the addition
of water (1À5 equiv) to the reaction has a negligible effect.
Table 1 shows the variety of functional groups avail-
able on the terminal alkyne. Both straight chain and
branched alkyl alkynes reacted efficiently, and tert-butyl
acetylene provided 3c in 88% yield. Propargylsulfon-
amides 3d and 3f from sensitive alkynes bearing phenyl
groups required an equivalent of sodium sulfate (Na2-
SO4) to proceed cleanly to 76% and 80% yield, respec-
tively. Similarly, higher yields of acid-sensitive silyl
alkynes 3e and 3h (78% and 80%) were produced with
10 mol % of Cs2CO3 added.
To identify a catalyst capable of generating a range of
propargylamines, we postulated that the increased Lewis
acidity of Cu(II) catalysts could activate Ts-imine 2
toward the addition of 1-octyne via its copper acetylide
(Scheme 2).9 The sole catalyst found to produce 3a was
Cu(OTf)2. The key to the first catalytic alkynylation to
form sulfonylated propargylamines3,7 was the specific
combination of Cu(II) with the triflate counteranion.
Scheme 2. Copper(II) Triflate Is Uniquely Capable As the
Catalyst
Table 1. Alkyne Variation in Forming N-Ts-propargylaminesa
As comparison to internal standard confirmed that 3a
did not decompose under reaction conditions, incomplete
conversion after two days was attributed to the hydrolysis
of N-Ts-imine 2 to sulfonamide observed by gas chroma-
tography. Buffering with 10 mol % of base (Cs2CO3,
K2CO3, KO-t-Bu) slowed the reaction rate, while 20 mol %
of base halted the reaction completely.
To circumvent imine hydrolysis (and the two-step,
three-day synthesis of N-Ts-imine),10 the three-component
coupling of cyclohexane carboxaldehyde, sulfonamide 4,
and 1-octyne was attempted (Scheme 3). Mixing the
coupling partners with 10 mol % Cu(OTf)2 in toluene at
100 °C was sufficient to provide 79% yield of desired
product 3a in 2 h, a rate 20 times faster than with
preformed imine. The dramatic rate increase between
the alkynylation of isolated imine (Scheme 2) versus in
a Isolated yields with (a) 1.0 equiv of Na2SO4 and (b) 10 mol %
of Cs2CO3.
While 10 mol % of Cu(OTf)2 at elevated temperatures
was routinely employed in this investigation, couplings
with sulfonamides did proceed at room temperature, but
(11) CuI, CuBr, CuBr Me2S, CuCl, Cu(OAc), Cu(OTf), [(PPh3)2Cu]-
3
NO3, [(CH3CN)4Cu]PF6, and [(CH3CN)4Cu]OTf.
(12) (a) Yamamoto, K.; Hirusawa, Y.; Yoshimura, M. Bull. Chem.
Soc. Jpn. 1954, 27, 386. (b) Reppe, W. Liebigs Ann. Chem. 1955, 596, 25.
(c) Asano, Y.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2007, 9, 3901.
(d) Asano, Y.; Ito, H.; Hara, K.; Sawamura, M. Organometallics 2008,
27, 5984.
(9) Homocoupling of terminal alkynes via highly reactive Cu(II)-
acetylides not observed under these optimized conditions: Siemsen, P.;
Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2633.
(10) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
Org. Lett., Vol. 14, No. 4, 2012
965

reaction time increased from hours to a week. Catalyst
loadings could be lowered to 2 mol % in some cases if the
temperature was decreased to avoid decomposition while
awaiting reaction of the remaining starting materials.
A limitation to the scope of the aldehyde appeared with
sulfonamide 4, which when treated with a benzaldehyde
and Cu(OTf)2 formed imines that subsequently did not
react. As all other nitrogen sources that form imine under
Cu(II) triflate catalysis underwent alkynylation, this could
be attributed to the expanded conjugation extending from
the aryl imine through the p-toluenesulfonyl group.
The reactions in Figure 1 were carried out with the
amino source (5) as the limiting reagent and a slight excess
of aldehyde (6, 1.1 equiv) and alkyne (1.5 equiv). For
coupling partners whose label states “air sensitive” or
recommends desiccator or cold storage, the addition
of Na2SO4 improved conversion to product whereas
˚
MgSO4 or pulverized 4 or 5 A molecular sieves did not.
Benzylamine provided propargylamines with 2-fluoro-
phenyl (7a) and isopropyl groups (7b)13 in 88% and 94%
yield (Figure 1). Dibenzyl propargylamine 7c bears a
furan. Not surprisingly, 3-fluorobenzaldehyde combines
efficiently with piperidine5 to afford 7d in 90% yield.
While one of the highlights of this protocol is that it
applies to nonaniline nitrogen sources, even hindered
N-methylaniline reacts efficiently (7e). HeterocycleÀ
heteroaryl propargylamines 7f and 7i connect morpholine
via one carbon to benzothiophene or pyridine. The nearly
quantitative reaction of morpholine forms 4-CF3-phenyl-
substituted 7g in 97% yield.
The last row depicts propargylamines bearing protect-
ing groups: p-methoxybenzyl (PMB, 7m), Ts (7n), and
tert-butoxycarbonyl (Boc, 7o). While phenylacetylene-
derived 7o is a rare example of alkynylation providing
an R-substituted N-Boc-propargylamine,14 7o is unstable
to base-treated silica or alumina.15 Therefore, it is not
useful when compared to the ease of handling and
deprotecting N-Ts-propargylamines.3,7,16 Figure 1 show-
cases how this single catalyst can couple a variety of
aldehyde-derived pharmacophores (R3) with a wide range
of amino sources: anilines, alkylamines, benzylamines,
N-heterocycles (piperidine, morpholine, and pyrrolidine),
p-methoxybenzylamine, and sulfonamide.
Figure 1. Diverse range of nitrogen sources with single Cu(OTf)2
catalyst: amines, amides, anilines, and N-heterocycles. Isolated
yieldsandtimeswith(a) 1 or 2 equivofNa2SO4 and/or (b) 100 °C.
for further derivatization at multiple positions: free posi-
tion at nitrogen, electron-rich p-methoxybenzyl group,
aryl fluoride, alkyne, and alkyl chloride.
Scheme 4. One Step to Products with Multiple Functional
Groups
Commercially available starting materials can provide
over 70% yield of o-, m-, or p-fluorobenzylpropargyla-
mines 8a, 8b, or 8c (Scheme 4). The molecular complexity
developed in this single reaction is extensive and allows
(13) Alkynylation of the benzylamineÀisobutyraldehyde imine was
one of the few cases where 10 mol % of CuBr Me2S was a more effective
3
catalyst than 10 mol % of Cu(OTf)2: 99% versus 90% conversion to 7b
in 2 days. In contrast, formation of 7a from its benzylimine proceeded to
74% with Cu(OTf)2 but only 42% with CuBr Me2S in the same period.
(14) Repeated trials with benzyl carbamate (Cbz-NH2) under our
conditions or then as in Dou, X.-Y.; Shuai, Q.; He, L.-N.; Li, C.-J. Adv.
Synth. Catal. 2010, 352, 2437 never gave more than 20À30% conversion.
(15) Compare commercially available, stable unsubstituted N-Boc
propargylamine versus a sole report of 16% yield of R-substituted
compound: Hatano, M.; Asai, T.; Ishihara, K. Tetrahedron Lett. 2008,
49, 379.
3
Formation of benzyl-protected propargylamine 9
in 80% yield from cyclohexanone represents a rare
catalytic three-component alkynylation involving a ketone
(Scheme 5).2À7 Despite the lower general reactivity of
ketones compared to aldehydes, no additional reagents
are required besides catalytic Cu(II) triflate for convers-
ion of cyclohexanone to product.17
(16) Utility of deprotected propargylamines: Klauber, E. G.; De,
C. K.; Shah, T. K.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 13624.
966
Org. Lett., Vol. 14, No. 4, 2012

Scheme 5. Three-Component Alkynylation with a Ketone
As imine alkynylation generally proceeds with Cu(I),2À7
the possibility of disproportionation of Cu(II) as a source
of an active Cu(I) species was addressed with a mixed
catalyst study (Figure 2). Gas chromatography analysis of
aliquots provided the concentration of propargylamine
(product 3a) formed by correcting to a known amount of
dodedcane internal standard. Treating N-Ts-imine 2 with
10 mol % of Cu(OTf)2 and 1-octyne in dichloroethane
(a solvent that provides nearly identical results to toluene)
at a lower temperature of 40 °C to slow the rate of reaction
allowed tracking of the initial rate of formation of product
3a (Figure 2, purple). An additional 10 mol % of Cu(OTf)2
doubled the initial rate (blue, 20 mol % of catalyst).
Adding an additional 10 mol % of either CuBr or CuI
(red or green) resulted in a rate nearly identical to only
10 mol % of Cu(OTf)2 rather than 20 mol % of catalyst.
In summary, we have found that Cu(OTf)2 is uniquely
capable of alkynylating sulfonamide-derived imines, and
the three-component coupling of aldehydes, amines, and
alkynes proceeds at a faster rate and higher yield than
from preformed imine. Whether electron-rich or -poor,
nitrogen sources that form imine/iminium are alkyny-
lated with this catalyst, and the sole byproduct is water.
While not tolerant of aerobic conditions, these reactions
proceed in the presence of up to 5 equivalents of water.
The dense functionality of these propargylic products,
all from commercially available starting materials, marks
them as malleable synthetic building blocks. As alkyl,
aryl, heteroaryl, and fluoroaryl aldehydes react effi-
ciently, compounds for structureÀactivity studies can
be delivered rapidly. With a three-component alkynyla-
tion incorporating ketones, fully substituted nitrogen-
bearing carbon centers can be attained in one step. The
factors underlying the need for the precise combination of
triflate counterion with Cu(II) remain to be determined.
Further studies to explore the complete range of operable
coupling partners are underway.
Figure 2. Rate dependent on Cu(OTf)2, not CuBr or CuI.
Acknowledgment. Financial support was provided by
the University of California (UC), a UC Regents Faculty
Fellowship, and a Cancer Research Coordinating Com-
mittee Grant. We thank Alan Pearce (UCR) for his
assistance.
Note Added after ASAP Publication. In the version
published ASAP on January 19, 2012, in the Abstract,
line 3, and on p C, under Scheme 4, the claim “...first
catalytic three-component alkynylation involving a ke-
tone...” was incorrect. The following references discuss
catalytic three-component alkynylations with a ketone
ꢀ
and should have been included: (1) Aliaga, M. J.; Ramon,
D. J.; Yus, M. Org. Biomol. Chem. 2010, 8, 43. (2)
Pereshivko, O. P.; Peshkov, V. A.; Van der Eycken, E.
V. Org. Lett. 2010, 12, 2638. (3) Cheng, M.; Zhang, Q.;
Hu, X.-Y.; Li, B.-G.; Ji, J.-X.; Chan, A. S. C. Adv. Synth.
Catal. 2011, 353, 1274. The corrected statement now
asserts the rarity of these examples. We apologize to these
authors. The corrected version was posted ASAP on
February 7, 2012.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) [IrCl(COD)]2 and MgI2 for alkynylation of N-benzylcyclohex-
ylketimine: Fischer, C.; Carreira, E. M. Synthesis 2004, 1497.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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