Ruthenium-catalyzed hydrovinylation of N-acetylenamines leading to amines with a quaternary carbon center

Article abstract of DOI:10.1021/ol201142v

A catalytic hydrovinylation of N-acetylenamines with ethylene is reported. This new hydrovinylation reaction is catalyzed by a ruthenium hydride complex, RuHCl(CO)(PCy₃)₂, providing a series of N-acetylamines with a quaternary carbon center with up to 99% yield.

Full text of DOI:10.1021/ol201142v

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3388–3391
Ruthenium-Catalyzed Hydrovinylation of
N-Acetylenamines Leading to Amines with
a Quaternary Carbon Center
Qiu-Shi Wang, Jian-Hua Xie, Wei Li, Shou-Fei Zhu, Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China
qlzhou@nankai.edu.cn
Received April 29, 2011
ABSTRACT
A catalytic hydrovinylation of N-acetylenamines with ethylene is reported. This new hydrovinylation reaction is catalyzed by a ruthenium hydride
complex, RuHCl(CO)(PCy3)2, providing a series of N-acetylamines with a quaternary carbon center with up to 99% yield.
Transition-metal-catalyzed carbonÀcarbon bond-forming
reactionshavebecomeanessential tool forthe efficient and
environmentally benign synthesis of organic compounds.1
Among these reactions, catalytic hydrovinylation is attrac-
tive not only because it is one of the few practical processes
that utilize feedstock carbon sources but also because the
reaction products can be easily converted into pharmaco-
logically important compounds such as 2-arylpropionic
acids including ibuprofen and naproxen (which are non-
steroidal antiinflammatory drugs).2
Since its discovery,3 catalytic hydrovinylation has been
of perennial interest to chemists, and substantial progress
has been made in this reaction. Olefin substrates such as
vinylarenes, strained olefins, and 1,3-dienes have been
successfully converted to more useful olefin products by
means of various catalysts.4 The hydrovinylation of func-
tionalized olefins such as vinyl acetate, R-ketalsubstituted
vinylarenes and R,β-unsaturated ketones and esters has
also been reported.5 However, the hydrovinylation of
heteroatom-substituted olefins, which generates amines
with a quaternary carbon center, remains a challenging task.6
Recently, we studied hydrovinylation of R-alkyl and
R-ketal vinylarenes and obtained olefin products with an
all-carbon quaternary center in high yields and high
(1) Beller, M. Transition Metals for Organic Synthesis, 2nd ed.; Bolm,
C., Eds.; Wiley-VCH: Weinheim, 2004.
(2) For recent reviews of hydrovinylation reaction, see: (a) Jolly,
P. W.; Wilke, G. In Applied Homogeneous Catalysis with Organometallic
Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: New York,
1996; Vol. 2, p 1024. (b) RajanBabu, T. V. Chem. Rev. 2003, 103, 2845.
(c) RajanBabu, T. V. Synlett 2009, 6, 853. For synthesis of 2-arylpropionic
acids via hydrovinylation, see: (d) Smith, C. R.; RajanBabu, T. V. J. Org.
Chem. 2009, 74, 3066 and references therein.
(3) (a) Studiengesellschaft Kohle m.b.H. Neth. Appl. 6,409,179,
1963; Chem. Abstr. 1965, 63, 5770h. (b) Alderson, T.; Jenner, E. L.;
ꢀ
Lindsey, R. V., Jr. J. Am. Chem. Soc. 1965, 87, 5638. (c) Bogdanovic, B.;
€
Henc, B.; Losler, A.; Meister, B.; Pauling, H.; Wilke, G. Angew. Chem.,
Int. Ed. Engl. 1973, 12, 954.
(4) For recent papers, see: (a) He, Z.; Yi, C. S.; Donaldson, W. A.
Org. Lett. 2003, 5, 1567. (b) Zhang, A.; RajanBabu, T. V. Org. Lett.
2004, 6, 1515. (c) Grabulosa, A.; Muller, G.; Ordinas, J. I.; Mezzetti, A.;
Maestro, M. A.; Font-Bardia, M.; Solans, X. Organometallics 2005, 24,
4961. (d) Shi, W.-J.; Xie, J.-H.; Zhou, Q.-L. Tetrahedron: Asymmetry
2005, 16, 705. (e) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006,
128, 54. (f) Shi, W.-J.; Zhang, Q.; Xie, J.-H.; Zhu, S.-F.; Hou, G.-H.;
Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 2780. (g) Zhang, A.;
RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 5620. (h) Grutters,
€
M. M. P.; Muller, C.; Vogt, D. J. Am. Chem. Soc. 2006, 128, 7414.
€
ꢁ
€
(i) Diez-Holz, C. J.; Boing, C.; Francio, G.; Holscher, M.; Leitner, W.
Eur. J. Org. Chem. 2007, 2995. (j) Sanchez, R. P., Jr.; Connell, B. T.
Organometallics 2008, 27, 2902. (k) Moreau, B; Wu, J. Y.; Ritter, T. Org.
(5) (a) Muller, G.; Ordinas, J. I. J. Mol. Catal. A: Chem. 1997, 125, 97.
(b) Yi, C. S.; He, Z.; Lee, D. W. Organometallics 2001, 20, 802. (c) He, Z.;
Yi, C. S.; Donaldson, W. A. Synlett 2004, 1312. (d) Zhang, Q.; Zhu,
S.-F.; Qiao, X.-C.; Wang, L.-X.; Zhou, Q.-L. Adv. Synth. Catal. 2008,
350, 1507. (e) Ho, C.-Y.; Ohmiya, H.; Jamison, T. F. Angew. Chem., Int.
Ed. 2008, 47, 1893. (f) Ogoshi, S.; Haba, T.; Ohasi, M. J. Am. Chem. Soc.
2009, 131, 10350.
ꢁ
Lett. 2009, 11, 337. (l) Lassauque, N; Francio, G; Leitner, W. Adv. Synth.
Catal. 2009, 351, 3133. (m) Sharma, R. K.; RajanBabu, T. V. J. Am.
Chem. Soc. 2010, 132, 3295. (n) Gavenonis, J.; Arroyo, R. V.; Snapper,
M. L. Chem. Commun. 2010, 46, 5692. (o) Liu, W.; RajanBabu, T. V.
J. Org. Chem. 2010, 75, 7636.
r
10.1021/ol201142v
Published on Web 06/01/2011
2011 American Chemical Society

chemo- and enantioselectivities.4f,5d These results encour-
aged us to investigate the hydrovinylation of heteroatom-
substituted olefins. In this paper, we report the hydrovi-
nylation of N-acetylenamines catalyzed by a ruthenium
complex, RuHCl(CO)(PCy3)2, yielding amines with a
quaternary carbon center in up to 99% yield (Scheme 1).
Table 1. Catalytic Hydrovinylation. Optimization of the Reac-
tion Conditionsa
entry
additive
NaBArF
solvent temp (°C) convb (%) yieldc (%)
Scheme 1. Catalytic Hydrovinylation of N-Acetylenamines
1
2
3
4
5
6
7
DCE
65
45
85
65
65
65
65
65
65
65
65
65
92
64
79
94
10
8
75 (16)
19 (10)
52 (18)
42 (31)
0 (6)
0 (5)
80
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
DCE
DCE
toluene
DMF
dioxane
˚
NaBArF/4 A MS DCE
˚
92
100
89
52
89
85
In exploring the hydrovinylation of N-acetylenamines,
we first investigated a wide range of catalysts in the reac-
tion of N-acetyl-R-phenylenamine (1a) with ethylene. Ni
and Pd complexes with various phosphorus ligands, which
efficiently catalyze the hydrovinylation of vinylarenes,4aÀc
did not catalyze the hydrovinylation of 1a either at room
temperature or at elevated temperature. However, when
the ruthenium hydride complex RuHCl(CO)(PCy3)2, which
is an efficient catalyst for the hydrovinylation of vinylarenes,
1,3-dienes, and dienoates,4a,n,5c was used to catalyze the
reaction, the desired hydrovinylation product 2a was
obtained in 75% yield. The side reactions were decomposi-
tion (to acetophenone, 16% yield) and dimerization of 1a
(<5% yield).7 We then examined the effect of reaction
temperature and found 65 °C to be the optimal tempera-
ture in terms of substrate conversion and product yield. A
solvent-screening experiment revealed that 1,2-dichloro-
ethane (DCE) was the best reaction medium, and coor-
dinating solvents such as N,N-dimethylformamide (DMF)
8d AgOTf/4 A MS
DCE
DCE
DCE
95
˚
9
AgPF6/4 A MS
81
˚
10 AgBF4/4 A MS
˚
33
11 AgSbF6/4 A MS DCE
˚
86
12e AgOTf/4 A MS
DCE
83
a Reaction conditions: 0.01 mmol of RuHCl(CO)(PCy3)2; 0.01 mmol
of additive; 0.2 mmol of 1a; 1 atm of ethylene; 3 mL of solvent, 20 h.
b Determined by GC. c Isolated yield. The number in parentheses is the
yield of acetophenone. d The reaction was completed in 2 h. e 2 mol % of
catalyst was used.
substrate strongly influenced the reaction rate. Electron-
withdrawing groups gave faster reactions. For example,
the hydrovinylations of 1g and 1l, which have 4-CF3 and
3,5-(CF3)2 groups, respectively, yielded the corresponding
products (2g and 2l) in nearly quantitative yields within 0.5
h (entries 7 and 12), whereas the substrate with a 4-MeO
group (1c) provided the hydrovinylation product (2c) in
87% yield with 94% conversion in 10 h (entry 3). The
reaction was also sensitive to the steric effect of the
substituent, with ortho substitution leading to a slow
reaction. For example, the hydrovinylation of N-[1-(2-
methylphenyl)vinyl]acetamide (1j) afforded 2j in only
40% yield after 20 h (entry 10). β-Methyl-substituted
enamine 1q (mixture of Z and E isomers), as well as cyclic
enamines 1r and 1s, also underwent hydrovinylation and
provided the corresponding products in moderate yields,
although 10 mol % of catalyst was needed (entries 17À19).
The heterocyclic N-acetylenamine, N-[1-(thiophene-2-yl)-
vinyl]acetamide, was also a suitable substrate for this
transformation, providing amine product 2p in 100%
conversion with 68% yield, although higher catalyst load-
ing (10 mol %) and higher ethylene pressure (20 atm) were
required (entry 16).
Inthe expansion of the scope ofsubstrate of the reaction,
we found that the N-acetylenamines containing an R-carbonyl
group can also undergo hydrovinylation reaction to form
a quaternary carbon center connecting three functional
groups. Thus, the enamines methyl 2-acetamidoacrylate
(1t) and N-(3-oxo-3-phenylprop-1-en-2-yl)acetamide (1u)
reacted with ethylene in the presence of 10 mol % catalyst
under 20atm ofethylene pressure, producingR-aminoacid
derivative 2t and R-amino ketone 2u in 67 and 72% yield,
respectively (entries 20 and 21). When enamine substrate
˚
and dioxane afforded no product. Addition of 4 A mole-
cular sieves (MS) prevented the decomposition of 1a and
consequently increased the yield of the hydrovinylation
product. The counteranion of the catalyst was reported to
strongly influenceboth the rateand the yield inthe Ru- and
Ni-catalyzed hydrovinylation reactions.4j,8 We studied the
effect of counteranion of the catalyst by adding different
silver salts to exchange the chloride on the catalyst. The
highest rate and yield were achieved with trifluorometha-
nesulfonic acid anion (OTfÀ) as the counteranion, and the
use of OTfÀ also allowed us to reduce the catalyst load to
2 mol % (Table 1).
Under the optimal reaction conditions, a series of N-acetyl-
R-arylenamines 1aÀs were allowed to react with ethylene,
and the results are summarized in Table 2. The electronic
properties of the substituent on the phenyl ring of the
(6) For ruthenium-catalyzed codimerization and cooligomerization
of N-vinylamides with alkenes or alkynes, see: (a) Tsujita, H.; Ura, Y.;
Matsuki, S.; Wada, K.; Mitsudo, T.-a.; Kondo, T. Angew. Chem., Int.
Ed. 2007, 46, 5160. (b) Ura, Y.; Tsujita, H.; Mitsudo, T.-a.; Kondo, T.
Bull. Korean Chem. Soc. 2007, 28, 2139. (c) Goossen, L. J.; Rodrıguez, N.
Angew. Chem., Int. Ed. 2007, 46, 7544.
(7) Baudequin, C.; Zamfir, A.; Tsogoeva, S. B. Chem. Commun. 2008,
4637.
(8) RajanBabu, T. V.; Nomura, N.; Jin, J.; Nandi, M.; Park, H.; Sun,
X. J. Org. Chem. 2003, 68, 8431.
Org. Lett., Vol. 13, No. 13, 2011
3389

Table 2. Hydrovinylation of N-Acetylenamines Catalyzed by
RuHCl(CO)(PCy3)2
Scheme 2. Catalytic Hydrovinylation of 1v and Enantioselective
Hydrovinylation of 1a
a
The N-acetyl R-arylenamines with an electron-with-
drawing substituent on the phenyl ring exhibited higher
reactionrates. Thisresultiscontrarytothatobservedinthe
hydrovinylationof vinylarenes, inwhich substrates withan
electron-withdrawing group show lower or no reactivity.2b
Figure 1 (left) is a comparison of the reaction rates of
various substrates. Substrate 1f, with a p-bromo group,
showed the highest reaction rate, whereas 1c, with a
p-methoxy group, exhibited the lowest reaction rate. How-
ever, when a mixture of 1a, 1c, and 1f was subjected to
competitive hydrovinylation, the reaction rate of the three
substrates decreased in the order 1c > 1a > 1f (Figure 1,
right); this order contrasted with the order observed in the
respective individual reactions.
a The reaction conditions were the same as those in Table 1, entry 8.
For details of operation and analysis, see the Supporting Information.
b Determined by GC. c Isolated yield. d 10 mol % of RuHCl(CO)(PCy3)2
and 20 atm. e 10 mol % of RuHCl(CO)(PCy3)2.
has a vinyl group at the R-position such as N-(1-cyclo-
hexenylvinyl)acetamide (1v), a conjugate hydrovinylation
reaction occurred, giving product 3in 64% yield (Scheme 2).
However, no desired hydrovinylation product was isolated
when the N-acetylenamine substrate has either a hydrogen
(R1 = H) or an alkyl group (R1 = Me, t-Bu) at the R-posi-
tion. These results disclosed that the N-acetylenamine sub-
strate bearing an aromatic ring or an unsaturated group at
the R-position is necessary to drive the reaction.
We then tried to realize the asymmetric version of the
hydrovinylation of N-acetylenamines by introducing chir-
al phosphine ligands into the ruthenium catalyst. Among
the many tested chiral phosphine ligands including dipho-
sphines and monophosphines the phosphine 4a with a
(À)-menthyl moiety was the only one which afforded a low
level of enantioselectivity. When the complex RuHCl(CO)-
(4a)2 was subjected to catalyze the hydrovinylation of
enamine 1a the desired product 2a was isolated in 17%
yield with 14% ee (for the preparation of catalysts RuHCl-
(CO)(4)2 and the crystal structure of RuHCl(CO)(4b)2,
see the Supporting Information). This result indicated a
potential for achieving asymmetric induction in the
ruthenium-catalyzed hydrovinylation of N-acetylena-
mines; however, a more efficient chiral ligand needs to
be developed.
Figure 1. (Left) hydrovinylation 1a, 1c, and 1f, separately.
(Right) competitive hydrovinylation of 1a, 1c, and 1f in one
reaction.
To explain the electronic effect observed in the hydro-
vinylation of the N-acetylenamines and the substrate
dependency of the reaction, we proposed a mechanism of
hydrovinylation of N-acetylenamines.9 As outlined in
Figure 2, the formation of a benzylic, allylic, or oxa-allylic
(X d O) ruthenium intermediate (C) is the key step to
launch the reaction. Only the N-acetylenamines having an
aryl, alkenyl, or carbonyl group at the R-position can form
such intermediate, and no reaction took place for the
substrate with an R-alkyl substituent or without substituent.
In the reaction of N-acetyl R-arylenamines, the electron-
rich substrates preferentially coordinated to the metal
atom of the catalyst (step A to B), but the hydride transfer
step (B to C), which is the rate-determining step, is faster
for electron-deficient substrates. When the enamines 1a,
(9) For the mechanism of Ru-catalyzed hydrovinylation of styrenes
and 1,3-dienes, see ref 4a,4j.
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Org. Lett., Vol. 13, No. 13, 2011

which are building blocks in the synthesis of various
important compounds, such as R-amino acids and amino
alcohols. As an example, 2cwas oxidizedto R-amino acid 5
in high yield (90%) with NaIO4 in the presence of catalytic
RuCl3. Amino acid 5 is the key intermediate in the synthe-
sis of pharmaceuticals such as selective β3 agonist BMS-
201620 (Scheme 3).10
Scheme 3. Synthesis of R-Amino Acid 5
Figure 2. Proposed mechanism of hydrovinylation of enamines.
In conclusion, a ruthenium-catalyzed hydrovinylation
of N-acetylenamines with ethylene has been developed.
This reaction provides a new method for the synthesis of
amines and R-amino acids with a quaternary carbon
center. Further studies on this reaction, especially on
searching efficient chiral ligands to achieve asymmetric
version of the reaction, are in progress in our laboratory.
1c, and 1f reacted separately, electron-deficient 1f had a
higher ability to accept hydride and reacted faster. How-
ever, in the competitive reaction of 1a, 1c, and 1f, the
electron-rich 1c “occupied” the catalyst by preferentially
coordinating to the metal and consequently showed a
higher reaction rate.
Acknowledgment. We thank the National Natural
Science Foundation of China and the National Basic Re-
searchProgram of China (2010CB833300, 2011CB808600)
for financial support.
This study provides a convenient approach to the synth-
esis of amines containing a quaternary carbon center,
(10) Washburn, W. N.; Sun, C.-Q.; Bisacchi, G.; Wu, G.; Cheng,
P. T.; Sher, P. M.; Ryono, D.; Gavai, A. V.; Poss, K.; Girotra, R. N.;
McCann, P. J.; Mikkilineni, A. B.; Dejneka, T. C.; Wang, T. C.;
Merchant, Z.; Morella, M.; Arbeeny, C. M.; Harper, T. W.; Slusarchyk,
D. A.; Skwish, S.; Russell, A. D.; Allen, G. T.; Tesfamariam, B.;
Frohlich, B. H.; Abboa-Offei, B. E.; Cap, M.; Waldron, T. L.; George,
R. J.; Young, D.; Dickinson, K. E.; Seymour, A. A. Bioorg. Med. Chem.
Lett. 2004, 14, 3525.
Supporting Information Available. Experimental pro-
cedures and characterization of substrates and products.
This material is available free of charge via the Internet at
http://pubs.acs.org
Org. Lett., Vol. 13, No. 13, 2011
3391