Catalytic intermolecular β-C-H alkenylation of α-enamino-ketones with simple alkynes

Article abstract of DOI:10.1039/c3cc47556e

A unique strategy to synthesize β-alkenylated α-enamino-ketones via catalytic C-H/alkyne coupling is described. The slow addition of alkyne substrates and the use of NaI as an additive play key roles in controlling the alkyne insertion. Replacement of the pyridyl group with carbamates was also developed. This method allows for rapid synthesis of highly functionalized vinyl-substituted enamino-ketones. the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc47556e

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Catalytic intermolecular b-C–H alkenylation of
a-enamino-ketones with simple alkynes†
Zhiqian Wang,‡ab Brandon J. Reinus‡a and Guangbin Dong*a
Cite this: Chem. Commun., 2014,
50, 5230
Received 2nd October 2013,
Accepted 4th November 2013
DOI: 10.1039/c3cc47556e
www.rsc.org/chemcomm
A unique strategy to synthesize b-alkenylated a-enamino-ketones
via catalytic C–H/alkyne coupling is described. The slow addition of
alkyne substrates and the use of NaI as an additive play key roles in
controlling the alkyne insertion. Replacement of the pyridyl group
with carbamates was also developed. This method allows for rapid
synthesis of highly functionalized vinyl-substituted enamino-ketones.
The functional group-directed addition of aromatic C–H bonds
across alkynes, pioneered by Murai,1 provided a site-selective and
atom-economical2 method for preparing alkenyl substituted com-
pounds.3 This process generally involves oxidative addition of
Scheme 1 Enamine-directed vinyl C–H/olefin and alkyne couplings.
transition metals into aryl C–H bonds, followed by migratory enamine hydrolysis, the 2-aminopyridyl group can be effectively
insertion of the resulting metal hydrides into alkynes and subse- converted to the more synthetically useful carbamates (Scheme 1).
quent reductive elimination to provide the alkenylation products.4
Enamino-ketones are a class of organic compounds often
In contrast, the related addition of vinyl C–H bonds across alkynes employed as key intermediates or building blocks for the synthesis
is more challenging, likely due to the more sensitive nature of of nitrogen-containing molecules.11 In addition, this structural
olefins, thus remaining underdeveloped. Coupling of alkynes with motif has also been found in a number of biological active molecules
acrylates/acylamides was first reported by Mitsudo–Watanabe,5 and food chemicals.12,13 Direct alkenylation of a-enamino-ketones
and improvements were recently achieved by Nishimura–Uemura6 via C–H functionalization would provide an efficient approach to
and Plietker,7 all employing Ru complexes as the catalysts.8 These access highly functionalized 2-amino-2,4-diene-1-one compounds,
seminal efforts suggest that the vinyl C–H/alkyne couplings could which permits further derivatizations; however, this transformation
be a highly attractive method for preparing 1,3-diene compounds; remains elusive.14 Only recently Glorius reported an elegant C–H
however, the scope of the vinyl compounds that can undergo this oxidative Heck-type reaction to achieve vinylation of a-enamide-
transformation so far has been mainly limited to linear esters and esters, albeit requiring over two equivalents of copper salts as an
amides using carbonyl as the directing group.9 Recently, we oxidant.15 Hence, direct addition of vinyl C–H bonds across alkynes
discovered that the vinyl C–H bonds of 2-aminopyridine-derived would provide a complementary and redox-neutral approach to
enamino-ketones can be efficiently activated and coupled with a generate the desired alkenylated enaminoketones. Based on our
variety of terminal olefins.10 In this communication, we describe previous efforts towards C–H/olefin coupling,10 2-aminopyridine-
our development of an intermolecular Rh-catalyzed enamine- derived cyclic enamino-ketones are expected to be suitable sub-
directed vinyl C–H/alkyne coupling to prepare olefin-substituted strates to couple with simple alkynes (Scheme 1). However, the
cyclic a-enamino-ketones, and also demonstrate that, instead of challenge is two-fold: (1) compared to olefin insertion, the insertion
of alkynes is more difficult to control due to the high affinity and
a Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA
b Department of Organic Chemistry, Beijing University of Chemical Technology,
100029 Beijing, People’s Republic of China
reactivity of alkynes with transition metals, which often leads to
self-dimerization16 and/or multiple insertions;17 (2) it is nontrivial
to remove the robust pyridyl group in the presence of many reactive
functional groups, such as ketones, enamines and 1,3-dienes.
To address these challenges, our initial study employed cyclic
enamino-ketone 1a as the model substrate and phenylacetylene as
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data. CCDC 966192–966194. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cc47556e
‡ Z.W. and B.J.R. contributed equally.
5230 | Chem. Commun., 2014, 50, 5230--5232
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Alkenylation of cyclic enamino-ketones with simple alkynesa
the alkyne coupling partner (eqn (1)). As expected, the optimal condi-
tions discovered for olefin insertion (Rh(PPh3)3Cl or [Rh(coe)2Cl]2 in
dioxane) only resulted in low conversion of 1a and complicated
reaction mixtures caused by side reactions of phenylacetylene.
A number of monodentate and bidentate phosphine ligands were
examined, but none was found to enhance the reactivity and selec-
tivity. Halide additives were previously reported to be effective for
acrylate–alkyne coupling reactions.6 Indeed, the use of 1 equiv. of NaI
significantly promotes the conversion of enamino-ketone 1a, likely
due to its role of inhibiting metal vinylidene formation; however, the
major products were found to have multiple alkyne insertions
(confirmed by LC-MS). To solve this problem, we hypothesized that
given the high binding affinity of alkynes with Rh if we could keep the
alkyne substrate in a low concentration, the mono-insertion product
would be favoured. Indeed, when we diluted the reaction mixture and
slowly added phenylacetylene through a syringe-pump, the desired
mono-alkyne-insertion product 1b was isolated in a 75% yield
(Scheme 2). The factor of concentration was found to be more crucial,
as in the absence of NaI; 1b was still isolated in a 71% yield.
Entry
Enamino-ketone
Alkyne
Yield (E : Z)b
1
2
n = 1, R = Me
n = 1, R = Me
1b, 75c,d (3.5 : 1)
2b, 99 (>20 : 1)
3
4
n = 1, R = Me
n = 1, R = Me
3b, 99c (>20 : 1)
3b, 78 (>20 : 1)
5
6
n = 1, R = Me
n = 1, R = Me
4b, 76c,d (>20 : 1)
5b, 94b,c (5.6 : 1)
7
n = 1, R = Me
6b, 74b,c (5.6 : 1)
8
9
n = 1, R = Me
n = 1, R = Me
7b, 99c (2.0 : 1)
8b, 67c (2.5 : 1)
With the optimized conditions in hand, the scope of cyclic
enamino-ketones and alkynes was explored (Table 1). A variety
of terminal alkynes reacted and gave good to excellent yields
(entries 1–6). The alkenylation proceeded with complete regioselec-
tivity, and only anti-Markovnikov addition products were observed.
It is interesting to note that both aryl and alkyl-substituted, as well as
sterically hindered and less hindered alkynes reacted smoothly. In
addition, internal alkynes were also found to be suitable substrates
(entries 8–10). Due to the decreased reactivity and lower binding
affinity of internal alkynes, slow addition of these substrates was not
necessary. For a similar reason, reactions with bulky alkyne substrates,
such as 3,3-dimethylbutyne, also proceed well without slow addition
(entries 2–4). Furthermore, the six-membered a-enamino-ketones
underwent the C–H/alkyne coupling to provide the desired alkenyl-
ation products (entries 11–14). Notably, sterically hindered terminal
alkynes gave excellent selectivity for the E-alkene products; however, a
significant amount of Z-alkene products were formed with disubsti-
tuted alkynes. It is therefore likely that, for the disubstituted-alkyne
insertions, the initially formed E-alkene products (kinetic product)
slowly isomerise to the more thermodynamically stable Z products.18
Given that the a-enamino-ketones were prepared via condensa-
tion between 2-aminopyridine and 1,2-diketones,10 a tandem three-
component coupling was explored next (Table 2). Not surprisingly,
10
11
12
n = 1, R = Me
n = 2, R = Me
n = 2, R = Me
9b, 60c (1.3 : 1)
10b, 99 (>20 : 1)
11b, 92c (>20 : 1)
13
14
n = 2, R = H
n = 2, R = H
12b, 87 (>20 : 1)
13b, 92c (>20 : 1)
a
Conditions: enaminoketone (0.2 mmol), alkyne (0.2–0.4 mmol),
b
Rh(PPh3)3Cl (2.5 mol%), 1,4-dioxane, 130 1C, 20 h. Isolated yields.
E/Z ratio was determined by H-NMR. c Nal (25 mol%) was used. Alkyne
1
d
was diluted with 1,4-dioxane and added slowly in 8 h via a syringe pump.
Table 2 Three-component coupling to give b-alkenyl-a-enamino-ketonesa
Entry
Alkyne
Yieldb (E : Z)
1
2
3
4
1b, tracec,d
2b, 41% (>20 : 1)
2b, traced,e
7b, 64% (1 : 2.5)
5
6
a
7b, 76% (1 : 3.6)d
8b, 51% (1 : 2.5)
Conditions: 1a (0.2 mmol), 2-aminopyridine (0.2 mmol),
alkyne (0.4 mmol), Rh(PPh3)3Cl (5 mol%), 1,4-dioxane, 130 1C, 20 h.
b
c
Isolated yields. E/Z ratio was determined by 1H-NMR. Alkyne was
diluted with 1,4-dioxane and added slowly in 8 h via a syringe pump.
d
e
Nal (25 mol%) was used. The reaction stopped after the condensation
of the diketone and 2-aminopyridine.
the use of phenylacetylene only gave a very low conversion
(entry 1), because the enamine formation prefers high reaction
Scheme 2 Coupling between 1a and phenylacetylene.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 5230--5232 | 5231

View Article Online
ChemComm
Communication
Table 3 Replacement of the pyridyl group with carbamatesa
coupling method provides a complementary approach to access
the branched products.
(2)
We thank UT Austin, CPRIT, the Welch Foundation (F-1781),
the Frasch Foundation and NSF career award (CHE-1254935).
G. D. is a Searle Scholar. Dr Lynch is acknowledged for the X-ray
crystallography work. We thank Johnson Matthey for donation
of Rh.
Notes and references
1 F. Kakiuchi, Y. Yamamoto, N. Chatani and S. Murai, Chem. Lett.,
1995, 681.
a
b
Isolated yields over two steps. The first step provided a 45% yield of
the Boc protection product; however, no de-pyridyl product was found
during the second step.
2 B. Trost, Science, 1991, 254, 1471.
3 For leading Reviews: (a) V. Ritleng, C. Sirlin and M. Pfeffer, Chem.
Rev., 2002, 102, 1731; (b) F. Kakiuchi and S. Murai, Acc. Chem. Res.,
2002, 35, 826; (c) D. Colby, R. Bergman and J. Ellman, Chem. Rev.,
2012, 110, 624; (d) C.-H. Jun, C. W. Moon and D.-Y. Lee, Chem.–Eur. J.,
2002, 8, 2422.
4 A unique dinuclear Pd complex-catalysed arene-alkyne coupling
reaction is reported: N. Tsukada, T. Mitsuboshi, H. Setoguchi and
Y. Inoue, J. Am. Chem. Soc., 2003, 125, 12102.
5 T. Mitsudo, S. Zhang, M. Nagao and Y. Watanabe, J. Chem. Soc.,
Chem. Commun., 1991, 598.
6 T. Nishimura, Y. Washitake and S. Uemura, Adv. Synth. Catal., 2007,
349, 2563.
7 (a) N. Matthias Neisius and B. Plietker, Angew. Chem., Int. Ed., 2009,
48, 5752; (b) T. Schabel and B. Plietker, Chem.–Eur. J., 2013, 19, 6938.
8 For a report of using solid-support Ru catalysts, see: H. Miura,
S. Shimura, S. Hosokawa, S. Yamazoe, K. Wada and M. Inoue, Adv.
Synth. Catal., 2011, 353, 2837.
9 Only a single ketone substrate was reported previously (ref. 7a).
10 Z. Wang, B. Reinus and G. Dong, J. Am. Chem. Soc., 2012, 134, 13954.
11 For a recent review on enamino-ketones see: (a) G. Negri, C. Kascheres
and A. Kascheres, J. Heterocycl. Chem., 2004, 41, 461; for recent synthetic
applications, see: (b) A. Dounay, L. Overman and A. Wrobleski, J. Am.
Chem. Soc., 2005, 127, 10186; (c) R. Figueroa, R. Froese, Y. He, J. Kosin
and C. Theriault, Organometallics, 2011, 30, 1695; (d) S. D. Kuduk, et al.,
Bioorg. Med. Chem. Lett., 2010, 20, 2538; (e) J. Cossy, C. Poitevin, L. Salle
and D. Pardo, Tetrahedron Lett., 1996, 37, 6709; ( f ) T. Taniguchi,
G. Tanabe, O. Muraoka and H. Ishibashi, Org. Lett., 2008, 10, 197.
12 (a) A. Martelli, et al., J. Med. Chem., 2013, 56, 4718; (b) V. Cecchetti,
et al., J. Med. Chem., 2003, 46, 3670; (c) C. Emanuele, et al., Bioorg.
Med. Chem., 2005, 13, 5581.
concentration whereas the C–H coupling with phenylacetylene
requires a low concentration (vide supra). However, the steri-
cally hindered terminal alkynes and disubstituted alkynes
proceeded well in the three-component couplings. It is inter-
esting to note that the use of NaI with 3,3-dimethylbutyne
significantly inhibited the reaction, yielding only a trace
amount of products; however, in the absence of NaI, the
desired adduct was isolated in a 41% yield (entries 2 and 3).
In contrast, for the diphenylacetylene insertion, a slightly
increased yield with adding NaI was observed (entries 4 and 5).
The exact role of NaI in these reactions will be explored system-
atically in the future. Under these reaction conditions, the
thermodynamic products (Z alkene) were isolated as the major
isomer (entries 4–5).
We next explored the feasibility to replace the pyridyl group
with the more user-friendly carbamates. Although there are
several examples previously reported for removing pyridyl groups
from amines,19 to the best of our knowledge, none involves
substrates with rich functional groups, such as enamines,
ketones, and 1,3-dienes. Stimulated by this chemoselective
challenge, we examined a number of reaction conditions, and
ultimately a two-pot (three-step) procedure was found to be most
effective (Table 3). Under these modified conditions, the amine
13 R. Tressl, B. Helak, H. Koppler and D. Rewicki, J. Agric. Food Chem.,
1985, 33, 1132.
(in the aminopyridine) was first protected by dicarbonates, 14 For examples of the alkenylation of b-enamino-ketones, see:
(a) Y. Chun, Y. Ko, H. Shin and S. Lee, Org. Lett., 2009, 11, 3414;
(b) T. Fujimoto, K. Endo, H. Tsuji, M. Nakamura and E. Nakamura,
J. Am. Chem. Soc., 2008, 130, 4492; (c) Y. Yu, M. Niphakis and
followed by methylation of the pyridine nitrogen and then
methanolysis under basic conditions, providing the desired
carbamates. One key step is to control the equivalents of the
methylating agents; for example, the use of excess methyl triflate
led to significantly lower yields of the desired product (or even
G. Georg, Org. Lett., 2011, 13, 5932.
15 (a) T. Besset, N. Kuhl, F. W. Patureau and F. Glorius, Chem.–Eur. J.,
2011, 17, 7167; (b) J. Du, B. Zhou, Y. Yang and Y. Li, Chem.–Asian J.,
2013, 8, 1386.
no product). Note that the more sterically hindered substrates 16 (a) B. Claudio and P. Maurizio, Chemtracts: Inorg. Chem., 1993,
5, 225; (b) M. Puerta and P. Valerga, Coord. Chem. Rev., 1999, 977.
17 (a) H. Horie, I. Koyama, T. Kurahashi and S. Matsubara, Chem.
Commun., 2011, 47, 2658; (b) J.-R. Kong and M. J. Krische, J. Am.
Chem. Soc., 2006, 128, 16040.
18 After sitting at room temperature for one week, compound 7b fully
isomerised to its Z isomer.
19 (a) N. Dastbaravardeh, M. Schmu¨rch and M. D. Mihovilovic, Org.
Lett., 2012, 14, 1930; (b) S. Pan, K. Endo and T. Shibata, Org. Lett.,
2011, 13, 4692; (c) V. Smout, et al., J. Org. Chem., 2013, 78, 9803;
(d) K. J. Jana, S. Grimme and A. Studer, Chem.–Eur. J., 2009, 15, 9078.
20 Replacement of methanolysis with NaBH4 reduction was attempted
but did not improve the yields for the low yielding substrates.
provided much higher yields in the pyridyl-carbamate swap
reaction than the less hindered ones (no product except decom-
position was observed for the phenyl substituted substrate);20
however, the exact reaction is still unclear.
Finally, our preliminary study indicated that the alkenyl
substituent can be chemoselectively reduced in an excellent yield
via catalytic hydrogenation (eqn (2)). Given that the previous
alkene insertion with a-enamino-ketones was limited to terminal
olefins that only gives linear substitutions,10 this C–H/alkyne
5232 | Chem. Commun., 2014, 50, 5230--5232
This journal is ©The Royal Society of Chemistry 2014