Rhodium-catalyzed anti-markovnikov addition of secondary amines to arylacetylenes at room temperature

Article abstract of DOI:10.1021/ol201453h

An efficient method for synthesis of E-enamines by the anti-Markovnikov addition of secondary amines to terminal alkynes is described. The reaction of a variety of aryl- and heteroarylacetylenes proceeded at room temperature using a combination of a 8-quinolinolato rhodium complex and P(p-MeOC₆H ₄)₃ as a catalyst. The products were obtained as enamines by simple bulb-to-bulb distillation.

Full text of DOI:10.1021/ol201453h

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3928–3931
Rhodium-Catalyzed anti-Markovnikov
Addition of Secondary Amines to
Arylacetylenes at Room Temperature
Kazunori Sakai, Takuya Kochi, and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
kakiuchi@chem.keio.ac.jp
Received May 30, 2011
ABSTRACT
An efficient method for synthesis of E-enamines by the anti-Markovnikov addition of secondary amines to terminal alkynes is described. The
reaction of a variety of aryl- and heteroarylacetylenes proceeded at room temperature using a combination of a 8-quinolinolato rhodium complex
and P(p-MeOC6H4)3 as a catalyst. The products were obtained as enamines by simple bulb-to-bulb distillation.
Hydroamination of alkynes provides an efficient way to
construct carbonÀnitrogen bonds and has been extensively
studied over the past decade.1À3 Particularly remarkable
progress has been made for the addition of primary amines
leading to imines with the aid of various transition metal
catalysts. On the other hand, studies concerning catalytic
addition of secondary amines to alkynes are still limited,4À8
though they would offer straightforward and atom-econom-
ical methods to prepare enamines.9 High temperatures were
required for all of the previously reported methods, and
most of these examples exhibited narrow substrate scopes.
Recently, the reaction of substrates with several polar func-
tional groups was reported with catalysts such as a TpRh
catalyst2c and a Au catalyst with a P,N-ligand,7b but the
reactions were performed at no less than 90 °C.
In search of the desired reaction, the hydroamina-
tion was first performed using 8-quinolinolato rhodium
(3) Rhodium- or iridium-catalyzed intramolecular hydroamination
€
€
of alkynes: (a) Muller, T. E. Tetrahedron Lett. 1998, 39, 5961. (b) Muller,
T. E.; Pleier, A.-K. J. Chem. Soc., Dalton Trans. 1999, 583. (c) Burling,
S.; Field, L. D.; Messerle, B. A. Organometallics 2000, 19, 87. (d) Burling,
S.; Field, L. D.; Li, H. L.; Messerle, B. A.; Turner, P. Eur. J. Inorg. Chem.
2003, 3179. (e) Field, L. D.; Messerle, B. A.; Wren, S. L. Organometallics
2003, 22, 4393. (f) Burling, S.; Field, L. D.; Messerle, B. A.; Turner, P.
Organometallics 2004, 23, 1714. (g) Field, L. D.; Messerle, B. A.; Vuong,
K. Q.; Turner, P. Organometallics 2005, 24, 4241. (h) Krogstad, D. A.;
DeBoer, A. J.; Ortmeier, W. J.; Rudolf, J. W.; Halfen, J. A. Inorg. Chem.
Commun. 2005, 8, 1141. (i) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree,
R. H. Org. Lett. 2005, 7, 5437. (j) Field, L. D.; Messerle, B. A.; Vuong,
K. Q.; Turner, P.; Failes, T. Organometallics 2007, 26, 2058. (k) Burling,
S.; Field, L. D.; Messerle, B. A.; Rumble, S. L. Organometallics 2007, 26,
4335. (l) Ebrahimi, D.; Kennedy, D. F.; Messerle, B. A.; Hibbert, D. B.
Analyst 2008, 133, 817. (m) Dabb, S. L.; Ho, J. H. H.; Hodgson, R.;
Messerle, B. A.; Wagler, J. Dalton Trans. 2009, 634. (n) Kennedy, D. F.;
Messerle, B. A.; Rumble, S. L. New J. Chem. 2009, 33, 818. (o) Field,
L. D.; Messerle, B. A.; Vuong, K. Q.; Turner, P. Dalton Trans. 2009,
3599. (p) Clentsmith, G. K. B.; Field, L. D.; Messerle, B. A.; Shasha, A.;
Turner, P. Tetrahedron Lett. 2009, 50, 1469. (q) Kennedy, D. F.; Nova,
A.; Willis, A. C.; Eisenstein, O.; Messerle, B. A. Dalton Trans. 2009,
10296. (r) Beeren, S. R.; Dabb, S. L.; Edwards, G.; Smith, M. K.; Willis,
A. C.; Messerle, B. A. New J. Chem. 2010, 34, 1200. (s) Gainer, M. J.;
Bennett, N. R.; Takahashi, Y.; Looper, R. E. Angew. Chem., Int. Ed.
2011, 50, 684. See also ref 2b.
(1) Reviews on hydroamination of alkynes: (a) Beller, M.; Breindl,
C.; Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O. R.; Tillack, A.;
Trauthwein, H. Synlett 2002, 1579. (b) Pohlki, F.; Doye, S. Chem. Soc.
Rev. 2003, 32, 104. (c) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew.
Chem., Int. Ed. 2004, 43, 3368. (d) Hong, S.; Marks, T. J. Acc. Chem. Res.
2004, 37, 673. (e) Beller, M.; Tillack, A.; Seayad, J. In Transition Metals
for Organic Synthesis, 2nd ed; Wiley-VCH: Weinheim, 2004; p 403. (f)
Odom, A. L. Dalton Trans. 2005, 225. (g) Severin, R.; Doye, S. Chem.
Soc. Rev. 2007, 36, 1407. (h) Aillaud, I.; Collin, J.; Hannedouche, J.;
€
Schulz, E. Dalton Trans. 2007, 5105. (i) Muller, T. E.; Hultzsch, K. C.;
Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. (j)
Fukumoto, Y. J. Synth. Org. Chem. Jpn. 2009, 67, 735.
(2) Rhodium- or iridium-catalyzed intermolecular hydroamination
of alkynes: (a) Hartung, C. G.; Tillack, A.; Trauthwein, H.; Beller, M.
J. Org. Chem. 2001, 66, 6339. (b) Lai, R.-Y.; Surekha, K.; Hayashi, A.;
Ozawa, F.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organometallics 2007, 26,
1062. (c) Fukumoto, N.; Asai, H.; Shimizu, M.; Chatani, N. J. Am.
Chem. Soc. 2007, 129, 13792. (d) Dabb, S. L.; Messerle, B. A. Dalton
Trans. 2008, 6368.
r
10.1021/ol201453h
Published on Web 06/24/2011
2011 American Chemical Society

complexes which we found effective as catalysts for the
addition of alcohols to terminal acetylenes to form enol
ethers.10,11 When the reaction of phenylacetylene (1a) with
3 equiv of piperidine (2a) was carried out with 10 mol % of
dicarbonyl complex 3a or cyclooctadiene (cod) complex 3b
at 80 °C for 24 h, only a small amount of the enamine
product was detected (Table 1, entries 1 and 2). In contrast,
when phosphine complex 3c was used as a catalyst, anti-
Markovnikov addition of 2a to 1a occurred to give enam-
ine 4aa in 7% yield with complete E-selectivity (entry 3).
Use of phosphine with rhodium complexes 3a,b was then
examined (entries 4 and 5), and the reaction using 10 mol %
of 3b with 20 mol % of PPh3 afforded 4aa in 28%
GC yield (entry 5). Replacement of the methyl group on
the quinolinolate ligand to a hydrogen increased the yield to
58% (entry 6). To achieve milder reaction conditions, the
reaction temperature was investigated. Remarkably, the
reaction at room temperature led to only a slight decrease
of the yield to 43% (entry 7). Phosphine additives were then
screened to improve the yield. While less electron-donating
P(p-FC6H4)3 lowered the product yield (entry 8), higher
yields were obtained with more electron-donating phos-
phines (entries 9À11).12 Particularly, the reaction using P(p-
MeOC6H4)3 gave enamine 4aa in 87% GC yield (entry 10).
As a solvent, toluene can also be used, and the reaction
provided 4aa in comparable yield (entry 12). It should be
noted that the reaction was not catalyzed by the phosphine
Table 1. Screening of Catalysts for anti-Markovnikov Addition
of 2a to 1aa
(4) Transition-metal-catalyzed anti-Markovnikov addition of sec-
ondary amines to terminal alkynes: (a) Leitch, D. C.; Payne, P. R.;
Dunbar, C. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 18246. (b)
Leitch, D. C.; Turner, C. S.; Schafer, L. L. Angew. Chem., Int. Ed. 2010,
49, 6382. (c) Cheung, H. W.; So, C. M.; Pun, K. H.; Zhou, Z.; Lau, C. P.
Adv. Synth. Catal. 2011, 353, 411. See also ref 2a and 2c.
(5) Base-catalyzed anti-Markovnikov addition of secondary amines
to phenylacetylene: Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron
Lett. 1999, 40, 6193.
(6) Catalytic Markovnikov addition of secondary amines to terminal
alkynes: (a) Barluenga, J.; Aznar, F.; Liz, R.; Rodes, R. J. Chem. Soc.,
Perkin Trans. 1 1980, 2732. (b) Uchimaru, Y. Chem. Commun. 1999,
1133. (c) Zeng, X.; Frey, G. D.; Kousar, S.; Bertrand, G. Chem.;Eur. J.
2009, 15, 3056.
(7) Catalytic addition of secondary amines to internal alkynes: (a)
Zeng, X.; Frey, G. D.; Kinjo, R.; Donnadieu, B.; Bertrand, G. J. Am.
Chem. Soc. 2009, 131, 8690. (b) Hesp, K. D.; Stradiotto, M. J. Am.
Chem. Soc. 2010, 132, 18026. See also ref 4a.
a Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Rh complex
(0.02 mmol), phosphine (0.04 mmol) in benzene (0.6 mL), 24 h. b GC
yield. c Not detected. d Toluene (0.6 mL) was used as a solvent. e With
0.01 mmol of [RhCl(cod)]2.
itself, and without any rhodium complex, the reaction did
not give any enamine product (entry 13). The use of other
rhodium sources such as [RhCl(cod)]2 in the presence of
P(p-MeOC6H4)3 also significantly decreased the yield (entry
14).
Various secondary amines are applicable for the room
temperature hydroamination, and the products can be
isolated as enamines by bulb-to-bulb distillation13 (Table
2). Enamine 4aa formed by the reaction of 1a with 2a was
isolated in 85% yield (entry 1). The addition of N-methyl-
piperazine (2b) and cis-2,6-dimethylmorpholine (2c) also
provided enamines 4ab and 4ac in 82% and 76% yields,
respectively (entries 2 and 3). Morpholine (2d) and acyclic
amines 2e,f were also added to 1a in good yields when
10 equiv of these amines were used (entries 4À6).14
The anti-Markovnikov hydroamination is applicable to
various terminal alkynes (Table 3). The addition of 2a to
(8) Related transformations: (a) Matsunaga, S. J. Synth. Org. Chem.
Jpn. 2006, 64, 778. (b) Tsuchimoto, T.; Aoki, K.; Wagatsuma, T.;
Suzuki, Y. Eur. J. Org. Chem. 2008, 4035. (c) Zhou, L.; Bohle, D. S.;
Jiang, H.-F.; Li, C.-J. Synlett 2009, 937. (d) Zeng, X.; Kinjo, R.;
Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2010, 49, 942.
(9) Rhodium-catalyzed oxidative hydroamination of olefins to form
enamines: (a) Beller, M.; Eichberger, M.; Trauthwein, H. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2225. (b) Beller, M.; Trauthwein, H.; Eichberger,
€
M.; Breindl, C.; Muller, T. E.; Zapf, A. J. Organomet. Chem. 1998, 566,
€
277. (c) Beller, M.; Trauthwein, H.; Eichberger, M.; Breindl, C.; Muller,
T. E. Eur. J. Inorg. Chem. 1999, 1121. (d) Tillack, A.; Trauthwein, H.;
Hartung, C. G.; Eichberger, M.; Pitter, S.; Jansen, A.; Beller, M.
Monatsh. Chem. 2000, 131, 1327.
(10) Kondo, M.; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc. 2011,
133, 32.
(11) Very recently, an interesting H/D exchange reaction at the β-
position of aromatic R-olefins catalyzed by an 8-quinolinolato rhodium
(13) In the previously reported hydroamination of alkynes with
secondary amines, yields of the enamine products were mostly deter-
mined by 1H NMR or GC analysis or by isolation after reduction to
amines, except for ref 6a.
(14) The hydroamination of 1a under the reaction conditions did not
proceed with less basic secondary nitrogen nucleophiles including
amides such as 2-oxazolidinone, 2-piperidinone, acetamide, and benza-
mide as well as aniline derivatives such as N-methylaniline and 1,2,3,4-
tetrahydroquinoline.
ꢀ
catalyst was reported: Giuseppe, A. D.; Castarlenas, R.; Perez-Torrente,
J. J.; Lahoz, F. J.; Polo, V.; Oro, L. A. Angew. Chem., Int. Ed. 2011, 50,
3938.
(12) Reduction of the catalyst loading under the reaction conditions
was unsuccessful. Use of 5 mol % of 3d with 10 mol % of P(p-
MeOC6H4)3 for the reaction of 1a with 2a resulted in formation of
39% GC yield of 4aa.
Org. Lett., Vol. 13, No. 15, 2011
3929

Table 2. anti-Markovnikov Hydroamination of 1a with Various
Secondary Aminesa
Table 3. anti-Markovnikov Hydroamination of Various
Terminal Alkynes with 2aa
isolated
entry
1
R
4
yield (%)b
1
1b
1c
1d
1e
1f
p-F3CC6H4
o-F3CC6H4
p-NCC6H4
p-MeO2CC6H4
p-AcC6H4
4ba
4ca
4da
4ea
4fa
90%
88%
2
3
49%
4
70%
5
64%
6
1g
1h
1i
p-MeC6H4
4ga
4ha
4ia
82%
7
m-MeC6H4
p-MeOC6H4
o-MeOC6H4
2-naphthyl
2-thienyl
82%
8
68%
9
1j
4ja
55%
10
11
12
13
14
15
1k
1l
4ka
4la
83%
80%
1m
1n
1o
1p
3-thienyl
4ma
4na
4oa
4pa
65%
N-methyl-2-indolyl
3-pyridyl
67%
a Reaction conditions: 1a (0.6 mmol), 2 (1.8 mmol), 3d (0.06 mmol),
P(p-MeOC6H4)3 (0.12 mmol) in benzene (1.8 mL), rt, 24 h. b Enamine
products 4 were isolated by bulb-to-bulb distillation. c Performed with
6.0 mmol of 2.
22% (44%)c
3%d (50%)c,d
1-hexyl
a Reaction conditions: 1 (0.6 mmol), 2a (1.8 mmol), 3d (0.06 mmol),
P(p-MeOC6H4)3 (0.12 mmol) in benzene (1.8 mL), rt, 24 h. b Isolated
yields. c Isolated yields obtained at 80 °C are shown in parentheses.
d Determined by 1H NMR using 1,3-dihydroisobenzofuran as an inter-
nal standard.
arylacetylenes possessing electron-withdrawing groups
such as CF3, CN, CO2Me, and Ac groups proceeded to
afford the corresponding E-enamines (entries 1À5). Parti-
cularly, the reaction of substrates having a CF3 group
(1b,c) gave the product in excellent yields (entries 1 and 2).
Arylacetylenes bearing electron-donating groups, Me and
MeO groups, can also be used for the hydroamination, and
the E-enamines were isolated in 55À82% yields (entries
6À9). 2-Ethynylnaphthalene (1k) was transformedintothe
corresponding enamine 4ka in 83% yield (entry 10).
Heteroarylacetylenes can be used as substrates for the
hydroamination as well (entries 11À14). The reactions
using 2- and 3-ethynylthiophenes (1l,m) afforded β-thie-
nylenamines, which were isolated in 80% and 65% yields,
respectively (entries 11 and 12). Indole derivative 1n also
gave the enamine in 67% yield (entry 13). When the
reaction of 3-ethynylpyridine (1o) was conducted at room
temperature, only 22% yield of the corresponding product
was isolated (entry 14). In this case, heating was necessary
to improve the yield, and the reaction at 80 °C afforded
product 4oa in 44% yield. Alkylacetylene 1p showed poor
reactivity at room temperature, but heating at 80 °C also
increased the yield to 50% by NMR (entry 15).15 Internal
alkynes such as 1-phenyl-1-propyne were not applicable
for this hydroamination, and no conversion of the alkynes
was observed.
rhodium complex possessing two phosphines (5) in 49%
yield. The structure of complex 5 was confirmed by X-ray
crystallographic analysis. When rhodium complex 3d was
mixed with 2 equiv of P(p-MeOC6H4)3 in benzene-d6, the
31P NMR spectrum showed two doublets of doublets at 51.0
and 52.3 ppm, which are nearly identical to the signals
observed for complex 5. In addition, the use of 10 mol % of
5 as a catalyst for the hydroamination of 1a with 2a gave the
corresponding product 4aa in 62% GC yield (Scheme 1).16
These results suggest that the COD ligand of 3d is replaced
by phosphine ligands during the catalytic reaction.
Although the reaction mechanism is yet unclear, based
on the results that addition of amines occurred exclusively
at the terminal carbon of alkynes and internal alkynes were
not hydroaminated in this system, we speculate that the
reaction proceeds via nucleophilic attackof amines at the R
carbon of vinylidene-rhodium intermediates.17
In summary, we developed an efficient method for
synthesis of E-enamines by the anti-Markovnikov addi-
tion of secondary amines to terminal alkynes. The reaction
(16) The yield was lower than that obtained in the reaction using a
mixture of 3d with P(p-MeOC6H4)3 (Table 1, entry 10) probably because
complex 5 could not be completely dissolved in benzene during the
reaction. Once it was crystallized, complex 5 is harder to dissolve in
benzene without heating. Based on this fact, it is advantageous to use 3d
with P(p-MeOC6H4)3 as a catalyst rather than complex 5.
(17) (a) Wiedemann, S. H.; Lee, C. In Metal Vinylidenes and Alleny-
lidenes in Catalysis: From Reactivity to Applications in Synthesis; Bruneau,
C., Dixneuf, P. H., Eds.; WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim,
2008; p 279. (b) Wakatsuki, Y. J. Organomet. Chem. 2004, 699, 4092. See
also ref 2c.
To gain insight into the in situ formed catalyst structure,
a reaction of rhodium complex 3d with 2 equiv of P(p-
MeOC6H4)3 was performed in benzene at rt. Recrystalliza-
tion from benzene with hexane afforded an 8-quinolinolato
(15) β-Alkyl enamine product 4pa could not be isolated by bulb-to-
bulb distillation, while all aryl- and heteroarylenamines were isolable.
3930
Org. Lett., Vol. 13, No. 15, 2011

rhodium complex and P(p-MeOC6H4)3 was found to be
effective as a catalyst for the hydroamination. The
products were obtained as enamines by simple bulb-
to-bulb distillation. Extension of the scope of the
nucleophiles and elucidation of the reaction mechan-
ism are now underway.
Scheme 1. anti-Markovnikov Hydroamination Using Isolated
Rhodium Complex 5a
Acknowledgment. This work was supported, in part, by
a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology
(MEXT), Japan and by The Science Research Promotion
Fund.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data for new compounds, and a
CIF file for complex 5. This material is available free of
charge via the Internet at http://pubs.acs.org.
of a variety of aryl- and heteroarylacetylenes proceeded at
room temperature. A combination of a 8-quinolinolato
Org. Lett., Vol. 13, No. 15, 2011
3931