Phosphine gold(I)-catalyzed hydroamination of alkenes under thermal and microwave-assisted conditions

Article abstract of DOI:10.1021/ol060719x

Phosphine gold(I) complexes catalyzed isomerization of terminal alkenes and hydroamination of unactivated alkenes under thermal and microwave-assisted conditions. This is the first example of the use of microwave radiation as a heat source for gold(I)-catalyzed organic reactions.

Full text of DOI:10.1021/ol060719x

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2707-2710
Phosphine Gold(I)-Catalyzed
Hydroamination of Alkenes under
Thermal and Microwave-Assisted
Conditions
Xin-Yuan Liu, Cheng-Hui Li, and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug DiscoVery and Synthesis, The UniVersity of
Hong Kong, Pokfulam Road, Hong Kong, P. R. China
cmche@hku.hk
Received March 24, 2006
ABSTRACT
Phosphine gold(I) complexes catalyzed isomerization of terminal alkenes and hydroamination of unactivated alkenes under thermal and microwave-
assisted conditions. This is the first example of the use of microwave radiation as a heat source for gold(I)-catalyzed organic reactions.
Gold complexes have increasingly been used as catalysts in
a variety of organic transformations.1,2 While the majority
of such transformations draw on the propensity of Au(I) to
activate alkynes toward nucleophilic addition,3 reactions
involving nucleophilic addition to unactivated alkenes cata-
lyzed by Au(I) are sparse.4,5 The catalytic addition of an
organic N-H bond to alkenes or alkynes (hydroamination)
to give nitrogen-containing molecules is of great interest to
both the academic and industrial community.6 In the litera-
ture, most amines are made in multistep syntheses, and as
(1) For reviews of homogeneous gold-catalyzed reactions, see: (a)
Hashmi, A. S. K. Gold Bull. 2004, 37, 51. (b) Arcadi, A.; Di Giuseppe, S.
Curr. Org. Chem. 2004, 8, 795. (c) Hoffman-Ro¨der, A.; Krause, N. Org.
Biomol. Chem. 2005, 3, 387. (d) Hashmi, A. S. K. Angew. Chem., Int. Ed.
2005, 44, 6990.
(2) (a) Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8,
325. (b) Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006,
8, 1529.
(3) (a) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729. (b) Teles,
J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998, 37, 1415. (c)
Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122,
11553. (d) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem.,
Int. Ed. 2002, 41, 4563. (e) Mizushima, E.; Hayashi, T.; Tanaka, M. Org.
Lett. 2003, 5, 3349. (f) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J.
Am. Chem. Soc. 2004, 126, 4526. (g) Staben, S. T.; Kennedy-Smith, J. J.;
Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350. (h) Zhang, L.; Kozmin,
S. A. J. Am. Chem. Soc. 2004, 126, 11806. (i) Sherry, B. D.; Toste, F. D.
J. Am. Chem. Soc. 2004, 126, 15978. (j) Nevado, C.; Echavarren, A. M.
Chem.sEur. J. 2005, 11, 3155. (k) Markham, J. P.; Staben, S. T.; Toste,
F. D. J. Am. Chem. Soc. 2005, 127, 9708. (l) Antoniotti, S.; Genin, E.;
Michelet, V.; Geneˆt, J.-P. J. Am. Chem. Soc. 2005, 127, 9976. (m) Zhang,
L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442. (n) Genin, E.; Toullec,
P. Y.; Antoniotti, S.; Brancour, C.; Geneˆt, J.-P.; Michelet, V. J. Am. Chem.
Soc. 2006, 128, 3112. (o) Ferrer, C.; Echavarren, A. M. Angew. Chem.,
Int. Ed. 2006, 45, 1105. For a specific review on the activation of alkynes
by gold catalysts, see: (p) Hashmi, A. S. K. Gold Bull. 2003, 36, 3.
(4) (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285. (b) Kobayashi, S.; Kakumoto, K.; Sugiura,
M. Org. Lett. 2002, 4, 1319. (c) Yao, X.; Li, C.-J. J. Am. Chem. Soc. 2004,
126, 6884.
(5) (a) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966. (b) Zhang,
J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798. (c) Brouwer,
C.; He, C. Angew. Chem., Int. Ed. 2006, 45, 1744. (d) Han, X.; Widenhoefer,
R. A. Angew. Chem., Int. Ed. 2006, 45, 1747.
10.1021/ol060719x CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/03/2006

such, hydroamination offers an attractive alternative means
to give organic nitrogen compounds. Addition of N-H bond
to unactivated alkenes provides a pathway for N-C bond
formation6 and can be catalyzed under acidic conditions7 or
using Lewis acid metal catalysts that are likely to coordinate
and activate the alkene toward nucleophilic addition.8
However, most of the reported catalysts for hydroamina-
tion show limited scope of substrates, modest selectivity,
and sluggish rates for reactions involving unactivated
substrates, and in the case of palladium catalyst for
hydroamination reaction, â-hydride elimination to afford
unsaturated products is usually encountered as a side
reaction.
Table 1. Intramolecular Hydroamination of Alkenesa
Owing to the ability of Au(I) to activate alkenes,5a we
conceived that Au(I) complexes could be potentially useful
catalysts for intramolecular hydroamination of unactivated
alkenes. During the preparation of this paper, He5b,c and
Widenhoefer5d independently reported the utility of cationic
AuI-phosphine complexes as catalysts for hydroamination
of unactivated alkenes, though the reported alkene substrates
are different from those described in this work. However,
the reported gold(I)-catalyzed hydroamination reactions
require long reaction times that would be disadvantageous
for its future application in high-throughput synthesis. We
conceived that rapid and reliable microwave applications9
could be advantageous for gold(I)-catalyzed intra- and
intermolecular hydroamination of unactivated alkenes. Herein,
we report gold(I)-catalyzed isomerization of terminal alkenes
and highly efficient intra- and intermolecular hydroamination
of unactivated alkenes under conventional thermal conditions
as well as under microwave irradiation.
A study was performed to investigate the activity of
different gold and AgOTf (OTf ) trifluoromethane sulfonate)
catalysts in the intramolecular hydroamination of tosylamide
1a (Table 1, entry 1; see also Table S1 in Supporting
Information). AgOTf, (PPh3)AuCl, and AuCl3/AgOTf all
failed to give the desired product 2a in good yields. While
using a combination of 5 mol % of (PPh3)AuCl and AgOTf
as a catalyst in toluene, the hydroamination product 2a was
formed in nearly quantitative yield. [((PPh3)Au)3O]OTf and
other (PR3)AuOTf catalysts can replace (PPh3)AuOTf as the
catalyst with no significant decrease in product yield. Using
1 mol % of (PCy3)AuOTf or Au2(dcpm)(OTf)2 (dcpm )
(6) For leading reviews, see: (a) Roundhill, D. M. Chem. ReV. 1992,
92, 1. (b) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675. (c) Johannsen,
M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1689. (d) Nobis, M.; Drieâen-
Ho¨lscher, B. Angew. Chem., Int. Ed. 2001, 40, 3983. (e) Brunet, J.-J.;
Neibecker, D. In Catalytic Heterofunctionalization; Togni, A., Gru¨tzmacher,
H., Eds.; Wiley-VCH: New York, 2001; p 91. (f) Seayad, J.; Tillack, A.;
Hartung, C. G.; Beller, M. AdV. Synth. Catal. 2002, 344, 795. (g) Pohlki,
F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104. (h) Bytschkov, I.; Doye, S.
Eur. J. Org. Chem. 2003, 935. (i) Hong, S.; Marks, T. J. Acc. Chem. Res.
2004, 37, 673. (j) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347, 367.
(7) (a) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471. (b)
Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127,
14542.
a In toluene, 5 mol % of (PPh3)AuCl/AgOTf. b After column chroma-
1
tography. c Yield was determined by H NMR.
(8) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.
(b) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14286.
(c) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (d) Qian, H.; Han,
X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536. (e) Oe, Y.;
Ohta, T.; Ito, Y. Chem. Commun. 2004, 1620.
(9) (a) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717. (b) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38, 653.
bis(dicyclohexylphosphino)methane), 2a was exclusively
formed after 36 h at 85 °C. However, [(PPh3)2Au]+ or [Au2-
(dppm)2]2+ (dppm ) bis(diphenylphosphino)methane) did not
show any catalytic activity under the same reaction condi-
2708
Org. Lett., Vol. 8, No. 13, 2006

tions. Different solvents were screened, and toluene was
found to be the best one.
Scheme 1
Due to the therapeutic application of sulfonamide antibiot-
ics,10,11 we prepared a series of ortho-substituted benzene-
sulfonamides12 as precursors for the preparation of cyclic
sulfonamides (Table 1). When N-ethylbenzenesulfonamide
1b was used as the substrate, the corresponding cyclic
product 2b was obtained in essentially quantitative yield at
100 °C for 24 h (entry 2). When N-tert-butylbenzenesulfona-
mide 1c was heated in toluene at 60 °C in the presence of 5
mol % of (PPh3)AuOTf, the tert-butyl group was cleaved
(entry 3). Increasing the reaction temperature to 85 °C
resulted in the formation of a 3:5 mixture of 2c and 3c with
a total 99% yield. Hydroamination product 3c was formed
exclusively when the reaction temperature was increased to
100 °C and the reaction time was extended to 48 h (entry
4). When substrate 1d was subjected to the same reaction
conditions, the tert-butyl group was readily cleaved (entry
5). According to a previous report,12 cleavage of the tert-
butyl group in similar substrates was performed in the
presence of anisole, and neat trifluoroacetic acid was used
as the solvent. Here, the gold(I)-catalyzed cleavage of the
tert-butyl group could be conducted under mild conditions.
We then examined the intramolecular hydroamination of
N-unsubstituted sulfonamides. In the presence of 5 mol %
of (PPh3)AuOTf, a series of unsaturated sulfonamides 2c and
1e-j were found to readily undergo intramolecular hydro-
amination to give the corresponding products 3c and 2e-j
in excellent yields (Table 1). In a number of cases, product
yields were nearly quantitative (entries 6-10). Interestingly,
substrates 1g and 1h bearing a bulky 2-methylpropenyl group
were the most reactive and gave the corresponding products
in 99% yield within 12 h (entries 9 and 10). When
2-vinylbenzenesulfonamide 2d was used as the substrate, no
reaction was observed. The substrate 1i, which could form
an unstable seven-membered ring intermediate or a six-
membered ring through a stabilized cyclohexyl intermediate,
gave a six-membered ring product 3i along with the
isomerized product 2i (see Chart S1 in Supporting Informa-
tion) in excellent yield within 24 h. Prolonged heating was
necessary for the reaction to give 3i as the only product (entry
11). When 1j was used as the substrate, the six-membered
ring product was formed exclusively in good yield (entry
12). The substrate 1k failed to provide the hydroamination
product, and the isomerized product 2k was obtained instead.
This could be due to steric hindrance on the terminal position
of alkene and the instability of the five-membered intermedi-
ate (entry 13). On the basis of these results, migration of
double bonds catalyzed by gold(I) occurred (entries 11-
13). We extended this reaction to other nitrogen-containing
molecules, such as acetamide (4a) and benzamide (4b), and
aniline (4c), as well as free amine (4d); the reactions gave
none or very low yields of the desired products (Scheme 1;
see also Table S2 in Supporting Information).
To elucidate the effect of electronic properties of the
nitrogen and activating group on this reaction, we prepared
benzamides 6a-e as depicted in Table 2. Hashmi reported
Table 2. Intramolecular Hydroamination of Benzamidesa
T
(°C)
time
(h)
yield
(%)b
entry
substrate
R
X
1
6a
6a
6b
6c
6d
6e
Ph
Ph
p-Cl-Ph
PhCO
Ts
C
C
C
C
C
O
100
100
100
100
60
30
30
30
30
24
24
50
89
90
60
40
0e
2c
3c
4d
5d
6
Ts
60
a In toluene, 20 mol % of (PPh3)AuCl/AgOTf. b Isolated yield. c In
toluene, 100 mol % of (PPh3)AuCl/AgOTf. d In toluene, 50 mol % of
(PPh3)AuCl/AgOTf. e p-Toluenesulfonamide was isolated.
conversion of propargylcarboxamides to 2,5-disubstituted
oxazoles under mild reaction conditions via homogeneous
catalysis by AuCl3.13 We found that substrate 6a underwent
conversion to cyclic product 7a in 50% yield in the presence
of 20 mol % of (PPh3)AuOTf. When the reactions were
conducted in the presence of a stoichiometric amount of
(PPh3)AuOTf, γ-lactams 7a and 7b were obtained in
excellent yields (entries 2 and 3). When 6c and 6d were used
as the substrates, the cyclic products were obtained in 60
and 40% yield, respectively, along with benzamide and
p-toluenesulfonamide as byproducts (entries 4 and 5).
According to previous reports,7a,14 these substrates readily
underwent cleavage of the amide bond under similar reaction
conditions. The allyl alcohol-derived carbamate completely
underwent cleavage of the amide bond to give the p-
toluenesulfonamide (entry 6).
To shorten the reaction times, we subjected the reaction
to microwave irradiation, which is known to accelerate
transition metal-catalyzed homogeneous reactions.9 Consid-
erably shorter reaction times of less than 1 h were found for
intramolecular hydroamination of unactivated alkenes cata-
(10) Bowman, W. C.; Rand, M. J. Textbook of Pharmacology, 2nd ed.;
Blackwell: London, 1979; Chapter 34.
(11) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. ComprehensiVe
Heterocyclic Chemistry II; Elsevier: Oxford, 1996; Vols. 3 and 4.
(12) Dauban, P.; Dodd, R. H. Org. Lett. 2000, 2, 2327.
(13) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett.
2004, 6, 4391.
(14) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int.
Ed. 2000, 39, 622.
Org. Lett., Vol. 8, No. 13, 2006
2709

completely transformed, and the corresponding products were
efficiently formed in moderate yields in the presence of 20
mol % of (PCy3)AuOTf within 30 min (Table 3, entries
5-7), while, for the same reactions under conventional
thermal conditions, a stoichiometric amount of catalyst and
a reaction time of 30 h were required (Table 2, entries 2-4).
This result shows that gold(I)-catalyzed intramolecular
hydroamination is efficient under microwave irradiation.
We also examined the intermolecular hydroamination of
unactivated alkenes under microwave irradiation (Table 3,
entries 8-12). Noticeably, the reaction worked smoothly,
and corresponding products could be isolated in excellent
and moderate yields with reaction times of 40-60 min. We
found that carboxylic acid can also be added to alkene to
give ester in excellent yield in a reaction time of 40 min
under similar reaction conditions (Table 3, entry 13).
Table 3. Gold(I)-Catalyzed Intra- and Intermolecular
Hydroamination under Microwave-Assisted Conditionsa
In conclusion, a variety of phosphine gold(I) complexes
have been demonstrated to be efficient catalyst for inter- and
intramolecular hydroamination reactions of alkenes. The use
of microwave radiation as a heat source allows a convenient
access to the temperature needed to allow completion of the
reaction in a much shorter time than that required under
conventional thermal conditions. The microwave-assisted
phosphine gold(I)-catalyzed organic reactions could provide
an entry for further development of gold(I) organic catalysis
in high-throughput synthesis.
Acknowledgment. We are thankful for the financial
support of The University of Hong Kong (University
Development Fund), Hong Kong Research Grants Council
(HKU 7012/05P), and the Areas of Excellence Scheme
established under the University Grants Committee of
the Hong Kong Special Administrative Region, China (AoE/
P-10/01).
a Reactions were conducted with 0.1 mmol of substrate and 5 mol % of
(PPh3)AuCl/AgOTf in 1 mL of ClCH2CH2Cl at 140 °C while being
irradiated with microwave. b Conversion (%) was determined by 1H NMR
spectroscopy. c Isolated yield. d Reactions were conducted with 0.1 mmol
of substrate and 20 mol % of (PCy3)AuCl/AgOTf in 1 mL of ClCH2CH2Cl
at 140 °C while being irradiated with microwave. e Reactions were
conducted with 0.1 mmol of TsNH2, 0.4 mmol of alkenes, and 5 mol % of
(PPh3)AuOTf in 1 mL of ClCH2CH2Cl at 140 °C while being irradiated
with microwave. f See Chart S1 in Supporting Information. g The yield in
parentheses refers to a reaction performed under thermal conditions. h A
1:1 ratio of nucleophile and norbornene was used.
Supporting Information Available: Experimental pro-
cedure, product characterizations, Table S1, Table S2, and
Chart S1. This material is available free of charge via the
Internet at http://pubs.acs.org.
lyzed by gold(I) complexes, affording the corresponding
products in good yields in each case (Table 3, entries 1-4).
Using this procedure, benzamide derivatives (6a-c) were
OL060719X
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Org. Lett., Vol. 8, No. 13, 2006