Highly regioselective Au(I)-Catalyzed hydroamination of ynamides and propiolic acid derivatives with anilines

Article abstract of DOI:10.1021/ol901565p

A highly regioselective hydroamination of unsymmetrical electron-poor and electron-rich alkynes with anilines catalyzed by Au(I) under mild conditions Is reported. In addition, applications toward indole syntheses are presented including an example of a one-pot synthesis from a nonfunctlonallzed aniline

Full text of DOI:10.1021/ol901565p

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4208-4211
Highly Regioselective Au(I)-Catalyzed
Hydroamination of Ynamides and
Propiolic Acid Derivatives with Anilines
Søren Kramer,† Karin Dooleweerdt,† Anders Thyboe Lindhardt,†
Mario Rottla¨nder,‡ and Troels Skrydstrup*,†
Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the
Interdisciplinary Nanoscience Center, Aarhus UniVersity, Langelandsgade 140,
8000 Aarhus C, Denmark, and DiVision of Medicinal Chemistry, H. Lundbeck A/S,
OttiliaVej 9, 2500 Valby, Denmark
ts@chem.au.dk
Received July 9, 2009
ABSTRACT
A highly regioselective hydroamination of unsymmetrical electron-poor and electron-rich alkynes with anilines catalyzed by Au(I) under mild
conditions is reported. In addition, applications toward indole syntheses are presented including an example of a one-pot synthesis from a
nonfunctionalized aniline.
Intermolecular hydroaminations and hydrations of alkynes
have received much attention in the recent literature,
representing an efficient means of accessing substituted
amines and imines or ketones. A common feature in these
reactions is the use of transition-metal catalysts (e.g., Ti, Ta,
Pd, Au),1,2 although in these cases usually elevated temper-
atures and long reaction times are required. Problems with
regioselectivity are often avoided using symmetrical or
terminal alkynes, with the latter predominantly giving rise
to the Markovnikov product. On the other hand, the attempts
with unsymmetrical internal alkynes have been restricted to
alkyl arylacetylenes, which again lead to the product of
Markovnikov addition. Whereas this predominantly gives the
desired regioisomer, the substrate scope is quite narrow.
† Aarhus University.
‡ H. Lundbeck A/S.
(1) Hydroaminations. Gold: (a) Mizushima, E.; Hayashi, T.; Tanaka,
M. Org. Lett. 2003, 5, 3349. (b) Bertrand, G.; Donnadieu, B.; Kinjo, R.;
Frey, G. D.; Zeng, X. J. Am. Chem. Soc. 2009, 131, 8690. (c) Zeng, X.;
Frey, G. D.; Kousar, S.; Bertrand, G. Chem.sEur. J. 2009, 15, 3056. (d)
Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555. (e) Liu, X.-
Y.; Ding, P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645. Titanium:
(f) Synthesis 2005, 7, 1200. (g) Ackermann, L. Organometallics 2003, 22,
4367. (h) Schafer, L. L.; Zhang, Z. Org. Lett. 2003, 5, 4733. (i) Bytschkov,
I.; Siebeneicher, H.; Doye, S. Eur. J. Org. Chem. 2003, 2888. (j) Cao, C.;
Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853. (k) Ackermann, L.; Born,
R. Tetrahedron Lett. 2004, 9541. (l) Cao, C.; Ciszewski, J. T.; Odom, A. L.
Organometallics 2001, 20, 5011. Palladium: (m) Shimada, T.; Yamamoto,
Y. J. Am. Chem. Soc. 2002, 124, 12670. (n) Shi, Z.; Zhang, C.; Li, S.; Pan,
D.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572.
Cobalt: (o) Liu, C.-C.; Korivi, R. P.; Cheng, C.-H. Chem.sEur. J. 2008,
14, 9503. Silver: (p) Lingaiah, N.; Babu, N. S.; Reddy, K. M.; Prasad,
P. S. S.; Suryanarayana, I. Chem. Commun. 2007, 278. (q) Luo, Y.; Li, Z.;
Li, C.-J. Org. Lett. 2005, 7, 2675. Tantalum: (r) Bergman, R. G.; Arnold,
J.; Anderson, L. L. Org. Lett. 2004, 6, 2519. Review: (s) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 6, 3079.
Herein, we report a fully regioselective and high-yielding
protocol for the hydroamination of unsymmetrical internal
alkynes represented by ynamides and propiolates/propiola-
mides with anilines under mild reaction conditions with the
(2) Gold-catalyzed hydrations: (a) Corma, A.; Leyva, A. J. Org. Chem.
2009, 74, 2067. (b) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M.
Angew. Chem., Int. Ed. 2002, 41, 4563
.
10.1021/ol901565p CCC: $40.75
Published on Web 08/21/2009
 2009 American Chemical Society

Gagosz catalyst ((PPh3)AuNTf2).3 Furthermore, it was found
that the electronics of the alkyne can be used to ensure full
regioselectivity overruling sterical effects. Finally, applica-
tions of the resulting products for the preparation of 2,3-
disubstituted indoles will be presented.
Ynamides have become an increasingly popular reagent
in numerous synthetic transformations.4-6 Their high interest
can undoubtedly be linked to the development of more
efficient protocols for their access, notably from the groups
of Hsung, Danheiser, and others.7 In connection with our
work on the application of ynamides for the synthesis of
2-amidoindoles,5a we examined the possibility of exploiting
gold catalysis8 for the hydroamination of terminally substi-
tuted ynamides to prepare precursors for 3-substituted
2-amidoindoles.
The preliminary results from the hydroamination of
iodoaniline with the model ynamide 1 using (PPh3)AuNTf2
as the catalyst revealed fast conversion to a single regioi-
somer in dichloromethane even at low catalyst loading (Table
1, entry 2). Of the solvents tried, only DMF was incompatible
Figure 1. X-ray crystal structure of 2a.
rich alkynes led to exclusively one regioisomer of the
hydroamination products, and full conversion was achieved
Table 1. Solvent Screening
Scheme 1.
Hydroamination with Ynamidesa
entry
solvent
conversiona (%)
1
2
3
4
5
6
DCE
89
88
84
CH2Cl2
MeCN
toluene
dioxane
DMF
78
>95b
13b
a Conversion was determined by 1H NMR of the crude reaction mixture.
b 2 mol %, 4 h.
(entry 6), while the reaction in dioxane required higher
catalyst loading and longer reaction time (entry 5). Support
for the regioselectivity was obtained from the X-ray structure
of the resulting imidoyl 2a (Figure 1).
The scope of this hydroamination with various anilines
and ynamides is illustrated in Scheme 1. These electron-
(3) Me´zailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
(4) For a special issue dedicated ynamides, see: (a) Tetrahedron-
Symposium-In-Print: “Chemistry of Electron-Deficient Ynamines and
Ynamides.” Tetrahedron 2006, 62, Issue No. 16. For reviews on ynamides,
see: (b) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.;
Wei, L. L. Tetrahedron 2001, 57, 7575. (c) Zhang, Y.; Hsung, R. P.
ChemTracts 2004, 17, 442. (d) Katritzky, A. R.; Jiang, R.; Singh, S. K.
Heterocycles 2004, 63, 1455
.
(5) For some recent examples, see: (a) Dooleweerdt, K.; Ruhland, T.;
Skrydstrup, T. Org. Lett. 2009, 11, 221. (b) Gourdet, B.; Lam, H. W. J. Am.
Chem. Soc. 2009, 131, 3802. (c) Saito, N.; Katayama, T.; Sato, Y. Org.
Lett. 2008, 10, 3829. (d) Istrate, F. M.; Buzas, A. K.; Jurberg, I. D.;
Odabachian, Y.; Gagosz, F. Org. Lett. 2008, 10, 925. (e) Hashmi, S. K.;
Rudolph, M.; Bats, J. W.; Frey, W.; Rominger, F.; Oeser, T. Chem.sEur.
J. 2008, 14, 6672. (f) Couty, S.; Meyer, C.; Cossy, J. Synlett 2007, 2819.
(g) Tanaka, K.; Takeishi, K. Synlett 2007, 2920. (h) Kohnen, A. L.; Mak,
X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser, R. L. Tetrahedron 2006, 62,
3815. (i) Couty, S.; Meyer, C.; Cossy, J. Angew. Chem., Int. Ed. 2006, 45,
6726. (j) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006,
a Isolated yields after column chromatography. b 3.7 mmol scale. On
the standard scale, 91% was isolated after 2 h. c 2 mol %. d 3 mol %.
at room temperature within a few hours.9,10 It was noted
though, that electron-withdrawing groups on the aniline led
to longer reaction times for completion. In one attempt, we
128, 4586
.
Org. Lett., Vol. 11, No. 18, 2009
4209

scaled up the hydroamination of 1 with 2-iodoaniline to 3.75
mmol. In this case, it was possible to lower the catalyst
loading to 0.5 mol %, although a longer reaction time (7 h)
was required for completion.
Unfortunately, when iodopyridinamines were used no
conversion to the desired product was observed. Instead, a
heavy precipitation was seen in the reaction mixtures possibly
due to strong coordination of these pyridinamines to Au(I).
Electron-poor alkynes were also examined and generally
displayed a lower reactivity (Scheme 2). Longer reaction
this was ruled out by control experiments at 60 °C for 24 h
without the catalyst showing no conversion.
Interestingly, when comparing the electron-rich and the
electron-poor alkynes, a complete switch in selectivity was
observed. These observations show how the electronics of
the internal alkyne strongly influence the regioselectivity in
the intermolecular Au(I)-catalyzed hydroaminations. The
difference in regioselectivity between 2a and 3d demonstrates
this effect by reversing the order of the nitrogen and the
carbonyl on the sp carbon leading to opposite regioisomers.
Also, products 2e and 3f examplify the strong electronic
effect by only yielding the product resulting from attack on
the more sterically hindered carbon.
Scheme 2.
Hydroamination with Electron-Poor Alkynesa
Next, the application toward indole syntheses was at-
tempted. To our delight, this proved possible in high yields
using a Pd(0)-catalyzed ring closing (Scheme 3). Optimiza-
Scheme 3.
Pd(0)-Catalyzed Indole Synthesisa
a Isolated yields after column chromatography. b 1 mol %. c 1:1 mixture
of imine/enamine.
times were thus required for these substrates, but in all cases
tested, high yields of the products were obtained. Only the
Z-enamines were observed as products.11 In principle, these
products could also arise from a Michael addition. However,
a Isolated yields after column chromatography. b 2 equiv of K3PO4. c 100 °C.
(6) Recent applications of ynamides from the group of R. P. Hsung: (a)
Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.; Huang, J.; Hsung,
R. P. Org. Lett. 2009, 11, 899. (b) Oppenheimer, J.; Johnson, W. L.;
Figueroa, R.; Hayashi, R.; Hsung, R. P. Tetrahedron 2009, 65, 5001. (c)
Yao, P.-Y.; Zhang, Y.; Hsung, R. P.; Zhao, K. Org. Lett. 2008, 10, 4275.
(d) Al-Rashid, Z. F.; Johnson, W. L.; Hsung, R. P.; Wei, Y.; Yao, P.-Y.;
Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780. (e) Zhang, X.; Hsung,
R. P.; Li, H.; Zhang, Y.; Johnson, W. L.; Figueroa, R. Org. Lett. 2008, 10,
3477. (f) Al-Rashid, Z. F.; Hsung, R. P. Org. Lett. 2008, 10, 661. (g) Li,
H.; You, L.; Zhang, X.; Johnson, W. L.; Figueroa, R.; Hsung, R. P.
Heterocycles 2007, 74, 553. (h) You, L.; Al-Rashid, Z. F.; Figueroa, R.;
Ghosh, S. K.; Li, G.; Lu, T.; Hsung, R. P. Synlett 2007, 1656. (i)
Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung, R. P.; Yao, P.-Y.;
Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361. (j) Song, Z.; Lu, T.; Hsung,
R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46,
4069. (k) Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun. 2007, 23, 2420.
(7) (a) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. Org. Chem. 2009, 74,
4630. (b) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem.,
Int. Ed. 2009, 48, 4381. (c) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem.
Soc. 2008, 130, 833. (d) Dooleweerdt, K.; Birkedal, H.; Ruhland, T.;
Skrydstrup, T. J. Org. Chem. 2008, 73, 9447. (e) Riddell, N.; Villeneuve,
K.; Tam, W. Org. Lett. 2005, 7, 3681. (f) Sagamanova, I. K.; Kurtz,
K. C. M.; Hsung, R. P. Org. Synth. 2007, 84, 359. (g) Zhang, X.; Zhang,
Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen,
M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006,
71, 4170. (h) Kohnen, A. L.; Dunetz, J. R.; Danheiser, R. L. Org. Synth.
2007, 84, 88. (i) For reviews on the synthesis of ynamides, see: Mulder,
J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379.
tion studies on the iodide 2a showed that the catalytic system
consisting of Pd(dba)2, X-Phos, and K3PO4 in dioxane at 80
°C with a reaction time of 23 h gave the indoles in good to
excellent yields.12
Surprisingly, we also found that by exploiting the Larock
indole synthesis,13 with the ynamide 1, we could access the
opposite regioisomer, the 3-amidoindole 5, as the major
product (Scheme 4).
Recently, Yu et al. revealed how N-arylenamines can be
cyclized to indoles under oxidizing conditions with PhI-
(8) Selected reviews on Au catalysis: (a) Gorin, D. J.; Toste, D. Nature
2007, 446, 395. (b) Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108,
3239. (c) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (d) Fu¨rstner, A.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (e) Arcadi, A. Chem.
ReV. 2008, 108, 3266.
(9) As the imine functionality of 2a was found to be the E-isomer
(Figure 1) and only one isomer was observed in all the reactions, the
products 2b-k reported were tentatively assigned this configuration.
(10) Due to the ynamides utilized being either sulfonamides or cyclic
carbamates no conversion to the oxazolone products as reported by Gagosz
et al. were observed (ref 5d).
4210
Org. Lett., Vol. 11, No. 18, 2009

In conclusion, we have shown a promising method for
expanding the often narrow substrate scope of intermolecular
hydroaminations on internal alkynes with ynamides and
propiolic acid derivatives, leading to only one of the two
possible regioisomers. The simplicity, mild reaction condi-
tions, and for the most cases short reaction times makes this
an appealing strategy for accessing N-arylimines and enam-
ines. Furthermore, some examples of the application toward
indoles have been presented.
Scheme 4
.
One-Pot Indole Synthesis Utilizing the Larock Indole
Synthesisa
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foun-
dation, H. Lundbeck A/S, the OChem graduate school, and
Aarhus University. Furthermore, we thank Dr. Jacob Over-
gaard at Aarhus University for X-ray structure analysis.
a
1
Isolated yield. Ratio determined by H NMR.
(OAc)2.14 Utilizing their protocol in an unoptimized manner,
a one-pot approach to indoles from a simple aniline was
shown (Scheme 5). Interestingly, the hydroamination, yield-
Supporting Information Available: Experimental pro-
cedures and characterizataion data for all the prepared
compounds as well as X-ray structural data (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 5
.
One-Pot Indole Synthesis Starting from a Simple
Aniline
OL901565P
(11) Stereochemistry was assigned according to the hydrogen bond
visible in 1H NMR and by comparison with the known compound. Lo´pez-
Alberca, M. P.; Manchen˜o, M. J.; Ferna´ndez, I.; Go´mez-Gallengo, M.;
Sierra, M. A.; Torres, R. Org. Lett. 2007, 9, 1757. The regioselectivity of
3e was confirmed by acid hydrolysis.
(12) Several attempts to develop a one-pot protocol for the hydroami-
nation and ensuing Pd(0)-catalyzed cyclization were unsuccesful. In these
cases, it was necessary to purify the intermediates in order to secure good
cyclization yields.
ing 3b, which took up to 24 h using 2 mol % catalyst at
room temperature, could be led to full conversion in 4 h at
60 °C with lower catalyst loading and no loss of regiose-
lectivity.
(13) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(14) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417.
Org. Lett., Vol. 11, No. 18, 2009
4211