Rhodium(iii)-catalyzed oxidative mono- and di-olefination of isonicotinamides

Article abstract of DOI:10.1039/c2ob25773d

[RhCp*Cl₂]₂ can catalyze the oxidative coupling of secondary isonicotinamides with activated olefins using Cu(OAc)₂ as an oxidant. The selectivity can be controlled by the solvent. In MeCN, the mono-olefination and two-fol

Full text of DOI:10.1039/c2ob25773d

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Rhodium(III)-catalyzed oxidative mono- and di-olefination of
isonicotinamides†
Xiaohong Wei,a,b Feng Wang,a Guoyong Song,a Zhengyin Dub and Xingwei Li*a
Received 23rd April 2012, Accepted 8th June 2012
DOI: 10.1039/c2ob25773d
[RhCp*Cl2]2 can catalyze the oxidative coupling of second-
ary isonicotinamides with activated olefins using Cu(OAc)2
as an oxidant. The selectivity can be controlled by the
solvent. In MeCN, the mono-olefination and two-fold oxi-
dation reaction is the major pathway, while in THF this reac-
tion gave mostly diolefination products. In both cases, the
coupled products contain an exocyclic CvC bond.
The oxidative olefination of arenes, pioneered by Fujiwara and
Moritani,1 has been increasingly explored because this reaction
allows direct functionalization of a C–H bond with an olefin,
leading to the construction of a C–C bond and molecular com-
plexity under simple conditions.2 This protocol is advantageous
in that no prior functionalization of the C–H bond is necessary,
thus representing a step-economic and waste-reducing process.
While palladium complexes have been well-known for decades
in catalyzing oxidative olefination of arenes, rhodium(III)-
catalyzed reactions have been increasingly explored, which has
allowed the olefination of simple arenes3 as well as arenes
bearing various directing groups such as amide,4 pyridyl,5 carba-
mate,6 sulfonamide,7 imine,8 ketone and aldehydes,9 ester,9b,10
Scheme 1 Rhodium-catalyzed olefination–cyclization of amides.
and carboxylic groups.11 In addition, inexpensive ruthenium
catalysts have also been recently used for related oxidative coup-
ling sequences, which could offer complementary reactivity and
efficiency.12
now report the olefination of isonicotinamides to give isoindolin-
1-one rings, which represents a key structural motif in various
natural and synthetic products that exhibit a wide range of bio-
logical activities as immunostimulants and anticancer agents.13
We embarked on our studies with the screening of the con-
ditions for the coupling of isonicotinamide 1a with tert-butyl
acrylate. Using [RhCp*Cl2]2 (2 mol%) as a catalyst and
Cu(OAc)2 as an oxidant (110 °C, sealed tube), both the mono-
(2aa) and di-olefination products (3aa) were generated in all the
solvents examined. These two products were characterized by
NMR spectroscopy and mass spectrometry. Moreover, the (E)
configuration of the exocyclic double bond in 2aa was
confirmed by NOESY, and this observed geometry is in line with
that in the oxidative coupling of benzoic acids with acrylates.11a
When acetone was used as a solvent, 2aa and 3aa were isolated
in comparably low yields (Table 1, entry 3). Switching to DMF
as a solvent gave no improvement of the coupling efficiency and
selectivity (entry 4). Gratifyingly, the selectivity of mono-olefi-
nation was significantly improved when MeCN was used as a
solvent, under which conditions (Conditions A) 2aa was isolated
We have recently studied Rh(III)-catalyzed oxidative coupling
of N-aryl benzamides with activated olefins,4a in which process
the olefination product is followed by aza-Michael cyclization to
give γ-lactams (Scheme 1). To expand the synthetic utility of
rhodium(III)-catalyzed oxidative coupling reactions, it is necess-
ary to explore other electronically complementary carboxamide
substrates. Isonicotinamides are interesting substrates, and we
reasoned that the inclusion of the pyridine ring should signifi-
cantly change the properties such that different reactivity and
selectivity can be attained.4f In fact, achieving complementary
reaction selectivity should be an important task in synthesis. We
aDalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, P.R. China
bCollege of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou 730070, P.R. China. E-mail: xwli@dicp.ac.cn
†Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and analytical data. See DOI: 10.1039/c2ob25773d
This journal is © The Royal Society of Chemistry 2012
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Table 1 Screening of reaction conditionsa
Yieldb (%)
Entry
Oxidant
x
Solvent
2aa
3aa
4aa
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
2
2
2
2
2
2
4
4
THF
THF
12
8
40
72
26
15
6
9
<3
<3
<3
<3
<3
<3
<3
<3
12
23
2c
3
Acetone
DMF
CH3CN
CH3CN
CH3CN
CH3CN
30
17
69
61
78
<3
4
5
6d
7
Scheme 2 Mono-olefination of 1a using activated olefins.a,b
8
a Conditions: 1a (0.5 mmol), tert-butyl acrylate (1.5 equiv), oxidant (4.2
equiv for Cu(OAc)2 and 2.1 equiv for Ag2CO3), [RhCp*Cl2]2 (2 or
4 mol%), solvent (5 mL), 12 h, sealed tube under N2. b Isolated yield.
c 1a (0.5 mmol), tert-butyl acrylate (2.5 equiv), Cu(OAc)2 (4.2 equiv),
[RhCp*Cl2]2 (2 mol%), solvent (5 mL), 12 h, sealed tube under N2. d 1a
(0.3 mmol), tert-butyl acrylate (1.1 equiv), Cu(OAc)2 (4.2 equiv),
[RhCp*Cl2]2 (2 mol%), solvent (3 mL), 12 h, sealed tube under N2.
The scope of the isonicotinamide substrate was defined in the
coupling with tert-butyl acrylate under the mono-olefination
conditions (Scheme 3). While isonicotinamides bearing both
in 69% yield and 3aa in only 6% yield. However, we failed to
further suppress the di-olefination product by lowering the molar
ratio of tert-butyl acrylate to isonicotinamide (entry 7). Further-
more, by increasing the loading of the catalyst to 4 mol%, while
the efficiency of the synthesis of 2aa was expectedly improved
(78%), the yield of the minor product 4aa was also increased
(entry 6). In contrast, by following the conditions of choice in
the oxidative olefination of N-aryl benzamides (Scheme 1a),4b
the expected lactam 4aa was isolated in only 23% (entry 8), indi-
cating that replacing the phenyl group with a pyridine ring has
caused significant changes in selectivity and reactivity.4f Interest-
ingly, when THF was used as a solvent, the diolefination product
3aa was isolated as the major product (40%). Further optimiz-
ation by providing an excess of the olefin (2.5 equiv, Conditions
B) afforded 3aa in 72% yield. It is noteworthy that Glorius and
coworkers have recently reported an example of Rh(III)-catalyzed
two-fold oxidative olefination of a primary benzamide leading to
exocyclized NH γ-lactams.9a However, the exocyclic CvC bond
in those products are exclusively (Z)-configured (Scheme 1b).
We also noted that the related benzene ring analogues of
γ-lactam 2aa with an exocyclic CvC bond have been
synthesized via cyclization of ortho-alkynylbenzamides when
mediated by a base or silver salts14 and by a stoichiometric amount
of iodine.15 In addition, Yu and coworkers have achieved a Pd(0)-
catalyzed arylation of related nicotinamides and isonicotinamides.16
With the mono-olefination conditions in hand, we next
explored the coupling of 1a with a series of activated olefins
(Scheme 2). Acrylates readily coupled with 1a in comparably high
yields. The activated alkene substrate is not limited to acrylates;
acrylamide and acrylonitrile also coupled with 1a (2ac and 2ae)
although lower efficiency was observed for acrylonitrile.
Scheme 3 Coupling of isonicotinamides with tert-butyl acrylate.a,b
5522 | Org. Biomol. Chem., 2012, 10, 5521–5524
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electron-rich and -poor N-aryl groups reacted to afford the
desired product (35–80%), those with an electron-rich N-aryl
ring tend to react slowly (2ba and 2ca). In most cases, only a
small amount of the diolefination product was isolated (3–8%),
which corresponds to a typical selectivity of 10 : 1 in favor of
mono-olefination. para-Halogen substitution in the N-aryl group
is tolerated to some extent. While para-fluoro and -chloro substi-
tuted substrates reacted smoothly (2ka and 2la), a mixture of
both halogen-retentive and hydrodehalogenative coupled pro-
ducts (2ia and 2ja) was isolated for para-Br and para-I substi-
tuted isonicotinamides. We further demonstrated that this
coupling reaction is applicable to substrates bearing different
substituents in the pyridine ring. Introduction of a fluoro group
ortho to the amide functionality lowered the efficacy of this reac-
tion (2ea, 26%). However, the yield was improvable to 41%
when the loading of [RhCp*Cl2]2 was increased to 4 mol%.
When a 2-methylisonicotinamide was used as a substrate,
product 2da was generated as the single isomeric product, indi-
cating that olefination occurred selectively at the less hindered
position. In addition, by fusing a benzene ring to the pyridine
unit, selective olefination of this quinoline-functionalized amide
occurred at the ortho position (2fa), instead of at the possible
peri position.4b The N-substituents are not limited to aryl groups;
N-Me, -allyl, and -benzyl substrates all coupled with tert-butyl
acrylate albeit in somewhat lower yield. Mono-olefination of
N-methyl isonicotinamide suffered from lower selectivity; in
addition to the mono-olefination product 2ha (52%), the di-
olefination product was isolated as a minor product (21%).
For comparison purposes, N-phenylnicotinamide was allowed
to react with tert-butyl acrylate under the mono-olefination con-
ditions (eqn (1)), and the 4-position olefination product 5aa was
isolated as the major product (51% yield) in addition to an un-
identifiable mixture, while the 2-position olefination product was
not detected.
Scheme 4 Proposed catalytic cycle for mono-olefination.
reductive elimination to give the olefination intermediate E, and
a subsequent rhodium-catalyzed intramolecular aza-Michael
addition furnishes 4aa.
The scope of diolefination of isonicotinamides was next
explored (Conditions B, Scheme 5). Diolefination of N-phenyl
isonicotinamide with acrylates afforded products 3aa–3ad in
good yields.17 However, the efficiency of this reaction dropped
significantly when a para-OMe group was introduced to the
N-phenyl ring (3ba). Moderate to good yields of the diolefina-
tion products were obtained when para-substituents such as Me,
halogens, and CF3 were introduced to the N-aryl ring. In contrast
to the hydrodehalogenative coupling products (2ia and 2ja)
observed in mono-olefination reactions, all halogen substituents
are retained. Extension of the N-substituent to allyl and Me
groups met with some difficulty and the expected products were
isolated in rather low yield. Thus the efficiency of this coupling
reaction is strongly dependent on the N-substituent, and sub-
strates with an N-alkyl or an electron-rich N-aryl tend to give a
sluggish reaction. When mono-olefination product 2aa was
allowed to react with tert-butyl acrylate under the same conditions,
no diolefination product was detected, suggesting that the 2nd olefi-
nation should occur prior to the cyclization step. Thus it is likely
that intermediate C (Scheme 4) undergoes a competitive ortho
C–H activation, leading to a diolefination intermediate, the
CvC bond in which was oxidatively amidated to give product
3aa.
In summary, we have achieved Rh(III)-catalyzed mono- and
di-olefination of secondary isonicotinamides using activated
olefins. Although both mono- and di-olefination products were
generated under conditions examined, mono-olefination occurred
as the major reaction pathway when carried out in MeCN using
Cu(OAc)2 as an oxidant. This reaction likely follows a sequence
of oxidative olefination-oxidative amidation. In contrast, when
conducted in THF as a solvent, the selectivity is shifted such that
the diolefination product becomes the major product. Under
these conditions, the reaction occurred with moderate selectivity
and efficiency. The contrast between the current isonicotinamides
and the previously reported benzamides in olefination reactions
highlighted the differences in reaction selectivity and efficiency
ð1Þ
Several experiments have been carried out to probe the reac-
tion mechanism. Subjection of 4aa to the mono-olefination con-
ditions afforded no 2aa, suggesting that product 4aa is not a
possible intermediate. Similarly, we confirmed that 2aa is not an
intermediate leading to 3aa. Thus a plausible catalytic cycle is
given in Scheme 4. N-Ligation of the isonicotinamide is fol-
lowed by cyclometallation to give a five-membered metallacycle
A. Insertion of an olefin to the Rh–C bond of A generates a
seven-membered metallacycle B, which is proposed to undergo
β-hydride elimination to afford a rhodium amidate C. cis
Amidorhodation of the CvC bond via a four-membered ring
transition affords a rhodium(III) alkyl species D, which further
undergoes β-hydride elimination to release the final product 2aa.
The resulting rhodium hydride species is then converted to the
active rhodium(III) catalyst in the presence of a Cu(II) oxidant. It
should be noted that four equivalents of Cu(OAc)2 oxidant is
necessary in this step. Indeed, a slight excess was provided in
our experiment. Alternatively, intermediate C can undergo
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2 For selected reviews, see: (a) T. Satoh and M. Miura, Chem.–Eur. J.,
2010, 16, 11212–11222; (b) T. Satoh, K. Ueura and M. Miura, Pure Appl.
Chem., 2008, 80, 1127–1134; (c) L. Ackermann, R. Vicente and
A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792–9826; (d) X. Chen,
K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009,
48, 5094–5115; (e) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010,
110, 1147–1169; (f) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius,
Chem. Soc. Rev., 2011, 40, 4740–4761; (g) O. Baudoin, Chem. Soc. Rev.,
2011, 40, 4902–4911; (h) S. Enthaler and A. Company, Chem. Soc. Rev.,
2011, 40, 4912–4924; (i) C. S. Yeung and V. M. Dong, Chem. Rev.,
2011, 111, 1215–1292; ( j) G. Song, F. Wang and X. Li, Chem. Soc. Rev.,
2012, 41, 3651–3678; (k) C. Zhu, R. Wang and J. R Falck, Chem.–Asian
J., 2012, 7, 1502–1514.
3 (a) T. Matsumoto, R. A. Periana, D. J. Taube and H. Yoshida, J. Catal.,
2002, 206, 272–280; (b) F. W. Patureau, C. Nimphius and F. Glorius,
Org. Lett., 2011, 13, 6346–4349.
4 (a) F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 2010, 132, 9982–
9983; (b) F. Wang, G. Song and X. Li, Org. Lett., 2010, 12, 5430–5433;
(c) D. R. Stuart, M. G. Bertrand-Laperle, K. M. N. Burgess and
K. Fagnou, J. Am. Chem. Soc., 2008, 130, 16474–16475; (d) S. Rakshit,
F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 2010, 132, 9585–9587;
(e) T. K. Hyster and T. Rovis, J. Am. Chem. Soc., 2010, 132, 10565–
10569; (f) G. Song, X. Gong and X. Li, J. Org. Chem., 2011, 76, 7583–
7589; (g) S. Mochida, N. Umeda, K. Hirano, T. Satoh and M. Miura,
Chem. Lett., 2010, 39, 744–746; (h) F. Wang, G. Song, Z. Du and X. Li,
J. Org. Chem., 2011, 76, 2926–2932; (i) S. Rakshit, C. Grohmann,
T. Besset and F. Glorius, J. Am. Chem. Soc., 2011, 133, 2350–2353;
( j) N. Guimond, S. I. Gorelsky and K. Fagnou, J. Am. Chem. Soc., 2011,
133, 6449–6457; (k) C. Zhu and J. R. Falck, Chem. Commun., 2012, 48,
1674–1676. For a leading example on palladium-catalyzed olefination–
cyclization, see: (l) M. Wasa, K. M. Engle and J.-Q. Yu, J. Am. Chem.
Soc., 2010, 132, 3680–3681.
5 (a) Z.-H. Guan, Z.-H. Ren, S. M. Spinella, S. Yu, Y.-M. Liang and
X. Zhang, J. Am. Chem. Soc., 2009, 131, 729–733; (b) N. Umeda,
K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2009, 74, 7094–7099;
(c) N. Umeda, H. Tsurugi, T. Satoh and M. Miura, Angew. Chem., Int.
Ed., 2008, 47, 4019–4022.
6 (a) T.-J. Gong, B. Xiao, Z.-J. Liu, J. Wan, J. Xu, D.-F. Luo, Y. Fu and
L. Liu, Org. Lett., 2011, 13, 3235–3237; (b) C. Feng and T.-P. Loh,
Chem. Commun., 2011, 47, 10458–10460.
7 X. Li, X. Gong, M. Zhao, G. Song, J. Deng and X. Li, Org. Lett., 2011,
13, 5808–5811.
8 (a) A. S. Tsai, M. Brasse, R. G. Bergman and J. Ellman, Org. Lett., 2011,
13, 540–542; (b) N. Guimond and K. Fagnou, J. Am. Chem. Soc., 2009,
131, 12050–12051; (c) T. Fukutani, N. Umeda, K. Hirano, T. Satoh and
M. Miura, Chem. Commun., 2009, 5141–5143.
9 (a) F. W. Patureau, T. Besset and F. Glorius, Angew. Chem., Int. Ed.,
2011, 50, 1064–1067; (b) S. H. Park, J. Y. Kim and S. Chang, Org. Lett.,
2011, 13, 2372–2375.
10 T. Besset, N. Kuhl, F. W. Patureau and F. Glorius, Chem.–Eur. J., 2011,
17, 7167–7171.
Scheme 5 Coupling of N-phenylisonicotinamide with tert-butyl acry-
late.a,b
11 (a) K. Ueura, T. Satoh and M. Miura, Org. Lett., 2007, 9, 1407–
1409; (b) S. Mochida, K. Hirano, T. Satoh and M. Miura, J. Org.
Chem., 2009, 74, 6295–6298; (c) T. Ueyama, S. Mochida,
T. Fukutani, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2011, 13,
706–708.
caused by electronic effects. The inclusion of a pyridine ring has
engendered rich and diversified reactivity.
12 L. Ackermann and J. Pospech, Org. Lett., 2011, 13, 4153–4155.
13 (a) Z. L. Chang and D.-Y. Zhu, in The Alkaloids, ed. A. Brossi, Academic
Press, New York, 1987, vol. 31, p. 29; (b) H. S. Lee, D. S. Han and
D. K. Won, Korean J. Pharmacogn., 1990, 21, 52–55.
14 (a) N. G. Kundu and M. W. Khan, Tetrahedron, 2000, 56, 4777–4792;
(b) G. Bianchi, M. Chiarini, F. Marinelli, L. Rossi and A. Arcadi, Adv.
Synth. Catal., 2010, 352, 136–142.
15 (a) T. Yao and R. C. Larock, J. Org. Chem., 2005, 70, 1432–1437;
(b) D. Chen, G. Song, A. Jia and X. Li, J. Org. Chem., 2011, 76,
8488–8494.
Acknowledgements
We thank the Dalian Institute of Chemical Physics, Chinese
Academy of Sciences for financial supports. This work was also
supported by the NSFC (No. 21072188). We thank Dr. Jian Xiao
for the synthesis of 5aa during the revision of this manuscript.
16 M. Wasa, B. T. Worrell and J.-Q. Yu, Angew. Chem., Int. Ed., 2010, 49,
1275–1277.
Notes and references
1 (a) I. Moritani and Y. Fujiwara, Tetrahedron Lett., 1967, 8, 1119–1122;
(b) C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001, 34, 633–639.
17 In most cases, only a small amount of the mono-olefination product was
obtained
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This journal is © The Royal Society of Chemistry 2012