Stereo- and regioselective gold-catalyzed hydroamination of internal alkynes with dialkylamines

Article abstract of DOI:10.1021/ja109192w

We report the use of a P,N-ligand to support a gold complex as a state-of-the-art precatalyst for the stereoselective hydroamination of internal aryl alkynes with dialkylamines to afford E-enamine products. Substrates featuring a diverse range of functional groups on both the amine (ether, sulfide, N-Boc amine, fluoro, nitrile, nitro, alcohol, N-heterocycles, amide, ester, and carboxylic acid) and alkyne (ether, N-heterocycles, N-phthalimide amines, and silyl ethers) are accommodated with synthetically useful regioselectivity.

Full text of DOI:10.1021/ja109192w

Published on Web 12/06/2010
Stereo- and Regioselective Gold-Catalyzed Hydroamination of Internal
Alkynes with Dialkylamines
Kevin D. Hesp and Mark Stradiotto*
Department of Chemistry, Dalhousie UniVersity, Halifax, Canada B3H 4J3
Received October 13, 2010; E-mail: mark.stradiotto@dal.ca
Abstract: We report the use of a P,N-ligand to support a gold
complex as a state-of-the-art precatalyst for the stereoselective
hydroamination of internal aryl alkynes with dialkylamines to afford
E-enamine products. Substrates featuring a diverse range of
functional groups on both the amine (ether, sulfide, N-Boc amine,
fluoro, nitrile, nitro, alcohol, N-heterocycles, amide, ester, and
carboxylic acid) and alkyne (ether, N-heterocycles, N-phthalimide
amines, and silyl ethers) are accommodated with synthetically
useful regioselectivity.
The intermolecular hydroamination of internal alkynes with basic
dialkylamines represents an appealing method for the synthesis of
functionalized enamine intermediates that are poised for further
synthetic manipulations.1,2 However, the lack of general methods
for promoting these transformations has rendered this strategy
underutilized in synthesis. Although significant contributions
involving group 4 based catalysts have been made for the addition
of primary alkylamines to alkynes,3,4 these catalysts exhibit
characteristically poor performance for dialkylamine and internal
alkyne pairings.4
The most effective catalyst for the addition of dialkylamines to
internal alkynes is a cationic gold complex featuring a CAAC
ancillary ligand (CAAC ) cyclic(alkyl)(amino)carbene).5 However,
this catalyst has only been reported for the addition of a limited
number of dialkylamine and alkyne partners that do not possess
any other functional groups. Moreover, only a single example of
an unsymmetrically substituted alkyne was reported, wherein
negligible regioselectivity was observed. In this regard, the stereo-
selective addition of dialkylamines to a range of internal alkynes
featuring a diverse substrate scope and with controlled regioselec-
Figure 1. Ligand screen for the Au-catalyzed hydroamination of diphe-
nylacetylene with morpholine (conversions determined by GC).
tivity represents an unmet challenge in hydroamination catalysis.
Such challenges must be addressed in order to enable the application
of alkyne hydroamination with dialkylamines in more complex
synthesis.
We report herein on the use of a P,N-ligand (L6, Mor-DalPhos)
to support the gold complex 1 as a highly effective precatalyst for
the stereo- and regioselective hydroamination of internal aryl
alkynes with dialkylamines containing a diverse range of functional
groups. Also presented are the results of preliminary stoichiometric
reactivity studies directed toward providing insight into the nature
of the catalytically active gold species.
conversions, those featuring a bulky, electron-rich di(1-adaman-
tyl)phosphinyl ((1-Ad)2P-) group and an ortho-dialkylamino donor
(L4, L5, or L6) provided the highest yields of the desired enamine
product (68-76%).7 Replacement of the ortho-amine for a benzylic
amine (L7), lowering the basicity of the nitrogen (L8), removing
the pendent nitrogen moiety (L9), or positioning the nitrogen donor
in the para-position (L10) were all deleterious to catalyst activity.
In combination, these results suggest that the ortho-amine fragment
in L4, L5, and L6 may play a direct role in the observed
hydroamination catalysis.8 Alternatively, using the ligand tBu-
JohnPhos (L11), tBu-DavePhos (L12), Ad-JohnPhos (L13), or IPr
(L14) gave comparatively poor results (<40% conv). The test
reaction proved to be highly sensitive to the nature of the chloride-
abstracting metal salt, whereby AgB(C6F5)4 provided superior
conversions versus more commonly used activators in Au-catalysis,
such as triflate and triflimide salts.9 The coordination complex
[(L6)AuCl] (1) was prepared using established methods (eq 1) and
was used as a catalyst precursor for all subsequent hydroamination
reactions.9 Monitoring the initial reaction kinetics for the test
We initiated our studies by evaluating a series of P,N-substituted
phenylene ligands developed in our laboratory,6 as well as other
ligand motifs that have been employed successfully in gold-
mediated hydroamination reactions, for the hydroamination of
diphenylacetylene with morpholine employing
5 mol %
[Au(SMe2)Cl], 5 mol % LiB(C6F5)4•2.5OEt2, and 6 mol % ligand
at 110 °C in 1,4-dioxane for 1 h (Figure 1). Although P,N-ligands
with Ph, Cy, or tBu substituted phosphines provided modest
9
18026 J. AM. CHEM. SOC. 2010, 132, 18026–18029
10.1021/ja109192w  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Gold-Catalyzed Hydroamination of Diphenylacetylene
Table 2. Gold-Catalyzed Hydroamination of Unsymmetrical
with Primary and Secondary Alkylaminesa
Internal Aryl Alkynes with Dialkylaminesa
a Conditions. alkyne/amine/1/AgB(C6F5)4
) 1:1.1:0.025:0.025 (0.8
mmol of alkyne) in 0.8 mL of toluene at 110 °C for 16 h; <5% of the
Z-enamine product was observed prior to reduction (1H NMR and NOE
experiments). b Isolated yield of reduction product. c 5 mol % 1 and 5
mol % AgB(C6F5)4 used. d In THF/1,4-dioxane (3:2) at 90 °C for 16 h.
e GC yield of E-enamine relative to dodecane as an internal standard.
f Reaction time ) 24 h. g In 1,4-dioxane ([alkyne] ) 0.5 mM). h Isolated
as the enamine hydrolysis product.9
a Conditions: alkyne/amine/1/AgB(C6F5)4
) 1:1.1:0.05:0.05 (0.8
mmol of alkyne) in 0.8 mL of toluene at 110 °C for 16 h; major
regioisomer is shown with the ratio of regioisomers in parentheses. In
all cases <5% of the Z-enamine of the major product was observed (1H
NMR and NOE experiments) and the stereochemistry of the minor
regioisomer was not determined. b Isolated yield of combined enamine
reduction products; regiochemistry determined by 1H NMR relative to
reaction using preformed complexes [(L6)AuCl] (1), [(L13)AuCl],
and [(L14)AuCl] in the presence of AgB(C6F5)4 demonstrated that
the discrepancy between the performance of these ligands, under
the test conditions selected, is a consequence of the higher initial
rates of reaction that are achieved when using 1, rather than
differences in the catalyst lifetime (see Figure S4).9
c
1,3,5-trimethoxybenzene prior to reduction. 1H NMR yield of enamine
relative to 1,3,5-trimethoxybenzene. TBS ) tert-butyldimethylsilyl.
Given the ubiquity of 1-arylpiperazines in pharmaceuticals,11
the development of efficient methods for their incorporation into
organic molecules is of significant interest. The hydroamination
of diphenylacetylene with 1-arylpiperazines featuring halide,
ether, nitrile, nitro, hydroxy, and cyclopropylamide functional
groups, as well as a 2,6-pyrimidyl substituted piperazine,
proceeded with excellent isolated yields (entries 13-18).
Notably, dialkylamine substrates containing alcohol or carboxylic
acid groups were readily added to diphenylacetylene without
observable side products arising from hydrophenoxylation or
hydrocarboxylation (entries 17 and 20).12
The scope of the hydroamination of diphenylacetylene with a
diversity of functionalized dialkylamines, as well as primary
alkylamines, using catalytic mixtures of 1 and AgB(C6F4)5 was
explored (Table 1).10 The addition of cyclic secondary alkylamines
containing ether, sulfide, or N-Boc linkages (entries 1-3), as well
as those based on five-, six-, and seven-membered rings (entries
4-6), proceeded stereoselectively in excellent yields. Acyclic
primary and secondary alkylamines, in particular dimethylamine,
were also suitable substrates for the addition to diphenylacetylene
(entries 7-12); however, attempts to use more bulky dialkylamines
such as (iPr)2NH proved unsuccessful.
The hydroamination of unsymmetrically substituted internal
aryl acetylenes with dialkylamines proceeded in good to excellent
yields with moderate to excellent regioselectivity and complete
stereoselectivity (Table 2).10 Using the aryl-benzyl alkyne 4a,
a 4:1 mixture of E-enamine products 5a:6a was isolated as the
corresponding amines in an 86% combined yield. The regio-
chemistry could be improved by substitution of the phenyl ring
with electron-donating groups; for instance, p-OMe substitution
of the aryl ring promoted the exclusive formation of 5b.13 This
trend was further exploited in the hydroamination of aryl-alkyl
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J. AM. CHEM. SOC. VOL. 132, NO. 51, 2010 18027

C O M M U N I C A T I O N S
Scheme 1. Stoichiometric Reactions of 1/AgBC(6F5)4 Mixtures with
Morpholine and 3-Hexyne
represents the only system documented for the stereoselective
addition of a range of functionalized dialkylamines to internal
alkynes. The hydroamination of unsymmetrical internal aryl
acetylenes with dialkylamines has been achieved with synthetically
useful regioselectivities. Studies aimed at further expanding the
scope of the reaction and elucidating the mechanism, in particular
the rate-enhancing role of the P,N-ligand architecture, will be the
subject of future reports.
Acknowledgment. We thank the Natural Sciences and Engi-
neering Research Council of Canada (including a Discovery Grant
for M.S. and a Canada Graduate Scholarship for K.D.H.) and
Dalhousie University for their generous support of this work. We
also thank Dr. Rylan Lundgren for helpful discussions, Pamela
Alsabeh for conducting some key control experiments, and Drs.
Michael Ferguson and Robert McDonald for solving the X-ray
structures of 1 and 8.
alkynes. Using the parent phenyl substrate 4c, E-enamine
products 5c and 6c were observed in a 3:1 ratio; however, p-OMe
substitution resulted in a change in regiochemistry to favor 5d
in a 75% yield with an 18:1 ratio.13 When employing the acyclic
amine 2i in the hydroamination of this alkyne, the enamine
products 5e and 6e were formed with 4:1 regioselectivity. The
use of an electron-deficient pyridyl-substituted alkyne proceeded
with complete regioselectivity affording 6f in 80% yield. Though
it is well-known that 2-alkynylpyridines can be suitable Michael
acceptors, in the absence of catalytic mixtures of 1/AgB(C6F5)4
negligible consumption of the reactants was observed. These
results suggest that the electronic characteristics of the alkyne
significantly guide the regioselectivity of this catalysis. Further-
more, the hydroamination of alkynes possessing a phthalimide-
protected amine or a silyl-protected alcohol with amine substrates
2a or 2o proceeded regioselectively in good yields.
Supporting Information Available: Full experimental details and
characterization data, including crystallographic data in CIF format for
1 and 8. The material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) (a) Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to
Catalysis; University Science Books: Sausalito, CA, 2010; p 700. (b) Mu¨ller,
T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. ReV. 2008,
108, 3795. (c) Severin, R.; Doye, S. Chem. Soc. ReV. 2007, 36, 1407. (d)
Brunet, J. J.; Neibecker, D. In Catalytic Heterofunctionalization: From
Hydroamination to Hydrozirconation; Togni, A., Gru¨tzmacher, H., Eds;
Wiley-VCH: Weinheim, 2001; p 91. (e) Mu¨ller, T. E.; Beller, M. Chem.
ReV. 1998, 98, 675.
(2) For reviews of enamine/imine chemistry, see: (a) Mukherjee, S.; Yang,
L. W.; Hoffman, S.; List, B. Chem. ReV. 2007, 107, 5471. (b) Kobayashi,
S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (c) Kuckla¨nder, U. In The
Chemistry of Enamines; Rappoport, Z., Ed.; Wiley-VCH: New York, 1994;
pp 523-636.
In order to gain insight into the reaction mechanism of the
Au-catalyzed alkyne hydroamination with dialkylamines, some
preliminary stoichiometric experiments were conducted (Scheme
1). The reaction of crystallographically characterized 19 and
AgB(C6F5)4 (1:1) in the presence of 3-hexyne (1 equiv) produced
(3) For lead references, see: (a) Zhang, Z.; Leitch, D. C.; Lu, M.; Patrick,
B. O.; Schafer, L. L. Chem.sEur. J. 2007, 13, 2012. (b) Heutling, A.;
Pohlki, F.; Doye, S. Chem.sEur. J. 2004, 10, 3059. (c) Ackermann, L.
Organometallics 2003, 22, 4367. (d) Tillack, A.; Garcia Castro, I.; Hartung,
C. G.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541. (e) Walsh, P. J.;
Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708.
(4) While the first example of group 4 catalyzed intermolecular additions of
secondary alkylamines to alkynes has recently been reported, only two
examples featuring internal alkynes were reported: Leitch, D. C.; Payne,
P. R.; Dunbar, C. R.; Schafer, L. L. J. Am. Chem. Soc, 2009, 131, 18246.
(5) (a) Lavallo, V.; Frey, G. D.; Kousar, S.; Donnadieu, B.; Bertrand, G. Proc.
Natl. Acad. Sci. U.S.A. 2007, 104, 13569. (b) Zeng, X.; Frey, G. D.; Kousar,
S.; Bertrand, G. Chem.sEur. J. 2009, 15, 3056. (c) Zeng, X.; Frey, G. D.;
Kinjo, R.; Donnadieu, B.; Bertrand, G. J. Am. Chem. Soc. 2009, 131, 8690.
(6) (a) Lundgren, R. J.; Stradiotto, M. Chem.sEur. J. 2008, 14, 10388. (b)
Lundgren, R. J.; Sappong-Kumankumah, A.; Stradiotto, M. Chem.sEur.
J. 2010, 16, 1983. (c) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.;
Stradiotto, M. Angew. Chem., Int. Ed. 2010, 49, 7071. (d) Lundgren, R. J.;
Stradiotto, M. Angew. Chem., Int. Ed. 2010, 49, 8686.
the cationic alkyne complex [(L6)Au(3-hexyne)]+B(C6F5)4
-
(7).14 Upon treatment of 7 with 1 equiv of 2a, the alkyne was
readily displaced to form the isolable and crystallographically
characterized morpholine adduct [(L6)Au(2a)]+B(C6F5)4 (8).9
-
Notably, treatment of 8 with excess alkyne did not regenerate
7, which may suggest the intermediacy of 8 in catalysis (Scheme
1).15 Indeed, using 8 as a precatalyst afforded comparable activity
to that of 1/AgB(C6F5)4 mixtures for the hydroamination of
diphenylacetylene with 2a.
(7) L4 (Me-DalPhos) and L6 (Mor-DalPhos) are commercially available from
Strem Chemicals.
(8) Nishina, N.; Yamamoto, Y. Tetrahedron 2009, 65, 1799.
(9) See Supporting Information.
Collectively, these stoichiometric observations, coupled with the
observed stereo- and regioselectivity, are most consistent with an
alkyne insertion mechanism.14b,16 A plausible inner-sphere mech-
anism might involve associative coordination of the alkyne to 8
concomitant with proton transfer followed by insertion of the alkyne
to generate a vinyl-gold intermediate.17 Subsequent stereoselective
protodeauration would liberate the E-enamine product and, when
in the presence of excess 2a, regenerate 8. In light of the rate-
accelerating effects achieved when employing a P,N-ligand such
as L6, we envision that the pendant nitrogen donor may participate
in catalysis by facilitating one or more mechanistically relevant
proton-transfer steps.18 Given the mechanistic complexities of Au-
mediated transformations,19 further experimentation is needed in
order to elucidate the origin of high catalytic activity when
employing L6 and related ligands.
(10) Attempts to purify enamine products by column chromatography resulted
in significant hydrolysis. To simplify isolation and purification, the enamine
or imine products were isolated as the corresponding amines after in situ
reduction with NaB(OAc)3H/AcOH or LiAlH4, respectively. The regio- and
stereochemistry of the enamine products were determined on the basis of
1H NMR data (including NOE) prior to reduction.
(11) 1-Arylpiperazine derivatives have found successful application in, among
others, antianginal and antidepressant drugs: (a) Caccia, S. Curr. Drug
Metab. 2007, 8, 612. (b) Lo´pez-Rodr´ıguez, M. L.; Morcillo, M. J.;
Ferna´ndez, E.; Rosado, M. L.; Pardo, L.; Schaper, M.-J. J. Med. Chem.
2001, 44, 198.
(12) (a) Kuram, M. R.; Bhanuchandra, M.; Sahoo, A. K. J. Org. Chem. 2010,
75, 2247. (b) Huo, Z.; Patil, N. T.; Jin, T.; Pahadi, N. K.; Yamamoto, Y.
AdV. Synth. Catal. 2007, 349, 680. (c) Rosenfeld, D. C.; Shekhar, S.;
Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org, Lett. 2006, 8, 4179.
(d) Trost, B. M.; Brieden, W.; Baringhaus, K. H. Angew. Chem., Int. Ed.
Engl. 1992, 31, 1335.
(13) Our efforts to extend this chemistry to electron-poor (p-CN-aryl)alkynes
were thwarted either by lack of catalytic turnover or by significant
background Michael addition chemistry.
In summary, we have identified a gold precatalyst (1) featuring
a P,N-ligand (L6) that has significantly extended the substrate scope
and synthetic utility of alkyne hydroamination. This precatalyst
(14) Similar Au-alkyne complexes have been isolated: (a) Akana, J. A.;
Bhattacharyya, K. X.; Mu¨ller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2007,
9
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C O M M U N I C A T I O N S
129, 7736. (b) Lavallo, V.; Frey, G. D.; Donnadieu, B.; Soleilhavoup, M.;
Bertrand, G. Angew. Chem., Int. Ed. 2008, 47, 5224. (c) Reference 5a.
(15) Stoichiometric results similar to these have been observed for the
hydroamination of 3-hexyne with ammonia: see ref 14b.
(16) (a) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349. (b)
Nishina, N.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3314.
(17) Intermediates of this type have recently been isolated and characterized: (a)
Hashmi, A. S. K.; Ramamurthi, T. D.; Rominger, F. AdV. Synth. Catal.
2010, 352, 971. (b) Weber, D.; Tarselli, M. A.; Gagne´, M. R. Angew. Chem.,
Int. Ed. 2009, 48, 5733. (c) Hashmi, A. S. K.; Schuster, A. M.; Rominger,
F. Angew. Chem., Int. Ed. 2009, 48, 8247.
(18) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405.
(19) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232.
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