Rh(III)-Catalyzed Aryl and Alkenyl C-H Bond Addition to Diverse Nitroalkenes

Article abstract of DOI:10.1021/acscatal.6b03217

The transition-metal-catalyzed C-H bond addition to nitroalkenes has been developed. Very broad nitroalkene scope was observed for this Rh(III)-catalyzed method, including for aliphatic, aromatic, and β,β-disubstituted derivatives. Additionally, various directing groups and both aromatic and alkenyl C-H bonds were effective in this transformation. Representative nitroalkane products were converted to dihydroisoquinolones and dihydropyridones in a single step and in high yield by iron-mediated reduction and in situ cyclization. Moreover, preliminary success in enantioselective Rh(III)-catalyzed C-H bond addition to nitroalkenes was achieved as was X-ray structural characterization of a nitronate intermediate.

Full text of DOI:10.1021/acscatal.6b03217

Letter
pubs.acs.org/acscatalysis
Rh(III)-Catalyzed Aryl and Alkenyl C−H Bond Addition to Diverse
Nitroalkenes
Tyler J. Potter, David N. Kamber, Brandon Q. Mercado, and Jonathan A. Ellman*
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: The transition-metal-catalyzed C−H bond addition to nitro-
alkenes has been developed. Very broad nitroalkene scope was observed
for this Rh(III)-catalyzed method, including for aliphatic, aromatic, and
β,β-disubstituted derivatives. Additionally, various directing groups and both
aromatic and alkenyl C−H bonds were effective in this transformation.
Representative nitroalkane products were converted to dihydroisoquino-
lones and dihydropyridones in a single step and in high yield by iron-
mediated reduction and in situ cyclization. Moreover, preliminary success in
enantioselective Rh(III)-catalyzed C−H bond addition to nitroalkenes was
achieved as was X-ray structural characterization of a nitronate intermediate.
KEYWORDS: C−H functionalization, Rh(III) catalysis, nitroalkene, enantioselective catalysis, dihydroisoquinolone
itroalkenes are valued and extensively employed electro-
philes for the addition of a broad range of different
nucleophiles to give nitroalkanes, which are versatile inter-
mediates to amines, carbonyl compounds, and other useful
chemotypes (Scheme 1A).1 Many heteroatom and carbon
in a single step and in high yield to dihydroisoquinolones
N
and dihydropyridones that cannot be accessed by alternative
Rh(III)-catalyzed methods. Finally, promising initial results for
enantioselective catalytic C−H bond addition to nitroalkenes
was accomplished.
After evaluating a number of reaction parameters for cou-
pling pyrrolidine benzamide 1a and nitroalkene 2a, optimal
conditions were identified to be [Cp*RhCl2]2 as the pre-
catalyst, AgSbF6 as the chloride abstractor, dichloroethane
as the solvent, and an 80 °C reaction temperature (entry 1,
Table 1). Importantly, product 3a was obtained in high yield
without the formation of any bis-addition byproduct.7 Both
[Cp*RhCl2]2 and AgSbF6 are essential as is apparent by the
complete absence of product obtained when either is excluded
(entries 2 and 3). Replacing AgSbF6 with the less-coordinating
AgB(C6F5)4 did not improve the yield of the reaction
(entry 4).8 The addition of 20 mol % of AgOAc, an additive
that has been reported to be successful for other Rh(III)-catalyzed
transformations,9 decreased the yield to 65% for this reaction
(entry 5). However, this additive was found to be beneficial
for other C−H functionalization substrates (vide infra). The
reaction proceeded equally well in 1,4-dioxane as solvent
(entry 6), but a significantly lower yield was observed in AcOH
despite its previous use as solvent in other Rh(III)-catalyzed
additions to Michael acceptors.10,11 When the reaction was
performed at room temperature, a slightly diminished yield
was observed (entry 8). Because 80 °C proved to be the opti-
mal temperature for more challenging C−H functionalization
substrate/nitroalkene pairs, this reaction temperature was
chosen for evaluating substrate scope. Use of the bench-stable
Scheme 1. Nitroalkenes as Versatile Electrophiles
nucleophiles have been added to nitroalkenes, including
additions catalyzed by Lewis acids and organocatalysts.
Nitroalkenes have also been used as Michael acceptors in
Rh- and Pd-catalyzed additions of stable organometallic
reagents such as aryl boronic acids.2 However, despite dramatic
recent advances in C−H bond functionalization, to our knowl-
edge,3−5 transition-metal-catalyzed C−H bond additions to
nitroalkenes have not been reported.
Herein, we report on the Rh(III)-catalyzed addition of aryl
and alkenyl C(sp2)-H bonds to nitroalkenes (Scheme 1B).
A broad range of C−H functionalization substrates with dif-
ferent directing groups as well as branched and unbranched
aliphatic and aromatic nitroalkenes are effective inputs. More-
over, β,β-disubstituted nitroalkenes also coupled efficiently and
represent the first examples of Rh(III)-catalyzed intermolecular
C−H bond additions to trisubstituted alkenes.6 The utility of
representative products was demonstrated by their conversion
Received: November 14, 2016
Revised: November 26, 2016
© XXXX American Chemical Society
150
DOI: 10.1021/acscatal.6b03217
ACS Catal. 2017, 7, 150−153

ACS Catalysis
Letter
a,b
Table 1. Control Reactions
Table 2. Nitroalkene Scope
a
b
entry
variation from the standard conditions
yield 3a (%)
1
2
3
4
5
6
7
8
9
none
84
0
no [Cp*RhCl2]2
no AgSbF6
0
AgB(C6F5)4 instead of AgSbF6
with 20 mol % AgOAc
71
65
82
14
66
80
78
53
62
0
in 1,4-dioxane
in AcOH
room temperature instead of 80 °C
Cp*Rh(CH3CN)3(SbF6)2 instead of [Cp*RhCl2]2
Cp*Rh(CH3CN)3(SbF6)2 instead of [Cp*RhCl2]2
[Cp*IrCl2]2 instead of [Cp*RhCl2]2
[RuCl2(p-cymene)]2 instead of [Cp*RhCl2]2
[Cp*CoCl2]2 instead of [Cp*RhCl2]2
c
10
11
12
13
a
Standard conditions: 0.15 mmol of 1a, 0.10 mmol of 2a with
b
[Cp*RhCl2]2, AgSbF6 in dichloroethane at 80 °C for 20 h. Yields
determined by H NMR spectroscopic analysis relative to SiMe3Ph as
an external standard. Reaction conducted on the benchtop.
1
a
c
Conditions: 0.30 mmol of 1a, 0.20 mmol of 2a with [Cp*RhCl2]2,
b
AgSbF6 in dichloroethane at 80 °C for 20 h. Isolated yields after silica
gel chromatography. Reaction conducted on the benchtop using
c
preformed catalyst Cp*Rh(CH3CN)3(SbF6)2 resulted in a
comparable yield of 80% (entry 9), and when the reaction was
performed on the benchtop with the preformed catalyst, a
78% yield was observed (entry 10). While not as effective as
[Cp*RhCl2]2, [Cp*IrCl2]2 and [RuCl2(p-cymene)]2 precata-
lysts did afford product 3a in 53% and 62% yield, respectively
(entries 11 and 12). No conversion was observed for the cobalt
precatalyst [Cp*CoCl2]2 under these conditions (entry 13).
Very broad scope for the nitroalkene coupling partner
was observed (Table 2). Product 3a was isolated by silica gel
chromatography in 85% yield, and when the reaction was
conducted on the benchtop with the preformed catalyst
Cp*Rh(CH3CN)3(SbF6)2, 3a was isolated in 75% yield. This
result highlights the tolerance of this reaction to air and
ambient conditions. Additional branched and unbranched
aliphatic nitroalkenes afforded products 3b, 3c, and 3d in
high yields. A broad range of aromatic β-nitrostyrenes were also
effective coupling partners (3e−3h), including electron-rich (3f),
electron-poor (3g), and ortho-substituted (3h) derivatives. Nitro-
alkenes containing indole (3i) and furan (3j) heterocycles also
coupled in acceptable yields.
10 mol % of Cp*Rh(CH3CN)3(SbF6)2.
meta-position, high regioselectivity was observed for the least
hindered site (3q−3s). Heteroaromatic C−H bond activation
substrates such as thiophene (3t), furan (3u), and indoles
(3v and 3w) afforded the addition products in good to
excellent yields. In addition to aryl substrates, alkenyl amides
were also effective C−H bond substrates with products 3x, 3y,
and 3z obtained in good yields. We also expanded the scope of
the directing group beyond amides. The electron rich urea
directing group afforded product 3aa in a high yield. Addi-
tionally, N-heterocyclic directing groups such as pyrazole (3ab),
triazole (3ac), and tetrazole (3ad) provided the addition
products in good yields. Surprisingly, 2-phenylpyridine resulted
in <5% of the desired addition product 3ae, instead giving
multiple unassigned decomposition products. The poor results
obtained for the archetypal 2-pyridyl directing group, which is
more basic than all of the other directing groups used, perhaps
clarify why C−H bond additions to nitroalkenes had not pre-
viously been reported.
The weakly coordinating acetophenone C−H functionaliza-
tion substrate was also evaluated, and it required more forcing
conditions similar to those reported for the Rh(III)-catalyzed
synthesis of indenes from acetophenones and enones.9 Under
these conditions, addition and cyclization with concomitant loss
of water afforded nitroindene 4 (eq 1).
We next explored β,β-disubstituted nitroalkenes. Although
acyclic 2-methyl-1-nitroprop-1-ene and trans-α-methyl-β-nitro-
styrene did not couple under these reaction conditions, we
were pleased to find modest to good yields of the coupled
products when employing azetidine (3k and 3l) and cyclo-
butane (3m) nitroalkenes. Significantly, these products represent
the first examples of a Rh(III)-catalyzed intermolecular C−H
bond addition to trisubstituted alkenes.6
After establishing broad nitroalkene scope, we next explored
the scope of the C−H functionalization substrate (Table 3).
In addition to pyrrolidine benzamide, other amide direct-
ing groups such as N,N-diisopropylbenzamide (3n) and
N-methylbenzamide (3o) were also successful in this reaction.
Electron-rich (3p and q) and electron-poor (3s) substituents
on the C−H bond functionalization substrate were well
tolerated, and when the substituents were placed at the
To demonstrate the utility of the nitroalkene addition
products 3, representative derivatives were subjected to a
single-step iron-mediated nitro group reduction/cyclization
151
DOI: 10.1021/acscatal.6b03217
ACS Catal. 2017, 7, 150−153

ACS Catalysis
Letter
a,b
isomers and they represent structural types that have not
previously been prepared by Rh(III)-catalyzed alkene annula-
tion approaches and would likely be very difficult to access.
A plausible mechanism for the Rh(III)-catalyzed C−H bond
addition to nitroalkenes is shown in Scheme 2. Concerted
Table 3. C−H Functionalization Substrate Scope
Scheme 2. Proposed Mechanism for the Transformation
metalation/deprotonation of 2 generates the well-documented
rhodacycle 6.14 Coordination of the nitroalkene 1 provides
complex 7, which upon insertion to the nitroalkene provides
the Rh(III) nitronate 8. Coordination of 2 followed by con-
certed metalation/deprotonation then concomitantly releases
product 3 and regenerates rhodacycle 6.
To investigate the mechanism of this transformation,
we sought to characterize the proposed Rh(III) nitronate
intermediate by X-ray crystallography (Scheme 3). Subjecting
a
Conditions: 0.30 mmol of 1a, 0.20 mmol of 2a with [Cp*RhCl2]2,
b
AgSbF6 in dichloroethane at 80 °C for 20 h. Isolated yields after silica
gel chromatography. 20 mol % of AgOAc was added.
c
Scheme 3. Preparation of a Rh(III) Nitronate
sequence (Table 4). Dihydroisoquinolones have previously
been synthesized by Rh(III)-catalyzed annulations of O-pivaloyl
or O-Boc benzhydroxamic acids and alkenes, but controlling
selectivity is often a challenge, and a mixture of isomers is
typically observed.12 Dihydroisoquinolone 5a was obtained in
high yield with the structure confirmed by X-ray crystallo-
graphic analysis. This is a different isomer than that obtained by
the Rh(III)-catalyzed annulation of O-Boc benzhydroxamic acid
and styrene.13 Moreover, both dihydroisoquinolone 5b and
dihydropyridone 5c were also obtained in good yields as single
a,b
Table 4. Product Reduction and Cyclization
the preformed rhodacycle 9 to stoichiometric AgSbF6 followed
by excess β-nitrostyrene gave the Rh(III) nitronate 10 in 72%
yield after trituration. The structure of 10 was rigorously
characterized by X-ray crystallographic analysis as a C-bound
nitronate dimer and to our knowledge represents the first
X-ray structure of a rhodium nitronate.15 While 10 exists as the
η1-C-bound rhodacycle nitronate dimer in crystal form, it is
possible that an η3-bound monomer exists in solution.16
Finally, in preliminary results using the Rh-diiodo dimer 11
employing Cramer’s elegantly designed chiral ligand,17 we
observed promising selectivities in the catalytic enantioselective
synthesis of various alkyl (3a) and aromatic (3e, 3f, 3g)
nitroalkene addition products (eq 2). Notably, electron-poor,
a
Conditions: 3 (1 equiv), Fe (6 equiv) in 1:1 EtOH/AcOH (0.2 M) at
b
80 °C for 3−6 h. Isolated yields after aqueous workup.
152
DOI: 10.1021/acscatal.6b03217
ACS Catal. 2017, 7, 150−153

ACS Catalysis
Letter
(3) For recent reviews on C−H functionalization, see: (a) Yamaguchi,
J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960−
9009. (b) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y.
Org. Chem. Front. 2015, 2, 1107−1295. (c) Yang, L.; Huang, H. Chem.
Rev. 2015, 115, 3468−3517. (d) Gensch, T.; Hopkinson, M. N.;
Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev. 2016, 45, 2900−2936.
(4) For reviews on Rh(III)-catalyzed C−H functionalization, see:
(a) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212−11222.
(b) Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta
2012, 45, 31−41. (c) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012,
41, 3651−3678.
(5) For the Pd-catalyzed synthesis of C1-benzoyl isoquinolines from
isoquinoline N-oxides and β-nitrostyrenes via oxidative alkene
cleavage, see: Li, J.-L.; Li, W.-Z.; Wang, Y.-C.; Ren, Q.; Wang, H.-S.;
Pan, Y.-M. Chem. Commun. 2016, 52, 10028−10031.
(6) For examples of intramolecular Rh(III)-catalyzed C−H bond
additions to trisubstituted alkenes, see: (a) Davis, T. A.; Hyster, T. K.;
Rovis, T. Angew. Chem., Int. Ed. 2013, 52, 14181−14185. (b) Davis, T.
A.; Wang, C.; Rovis, T. Synlett 2015, 26, 1520−1524. For examples of
intramolecular Rh(III)-catalyzed C−H bond additions to disubstituted
alkenes, see: (c) Shi, Z.; Boultadakis-Arapinis, M.; Koester, D. C.;
Glorius, F. Chem. Commun. 2014, 50, 2650−2652. (d) Chabaud, L.;
Raynal, Q.; Barre, E.; Guillou, C. Adv. Synth. Catal. 2015, 357, 3880−
3884.
-neutral, and -rich aromatic nitroalkenes all coupled with
≥90:10 er. These results suggests a new general strategy for
catalytic asymmetric additions to nitroalkenes.1b
In conclusion, we have developed the first transition-metal-
catalyzed C−H bond addition to nitroalkenes. Broad substrate
scope was realized for both the C−H bond and nitroalkene
coupling partners. Representative addition products were con-
verted to dihydroisoquinolone and dihydropyridone heterocycles
in a single step and in high yield by iron-mediated reduction/
cyclization. Additionally, preliminary success with the catalytic
enantioselective addition of C−H bonds to nitroalkenes was
achieved as was X-ray structural characterization of a Rh(III)
nitronate intermediate.
(7) For early examples of Rh-catalyzed transformations employing
pyrrolidine amides as directing groups, see: (a) Shibata, Y.; Otake, Y.;
Hirano, M.; Tanaka, K. Org. Lett. 2009, 11, 689−692. (b) Park, J.;
Park, E.; Kim, A.; Lee, Y.; Chi, K.-W.; Kwak, J. H.; Jung, Y. H.; Kim, I.
S. Org. Lett. 2011, 13, 4390−4393. (c) Hesp, K. D.; Bergman, R. G.;
Ellman, J. A. Org. Lett. 2012, 14, 2304−2307. (d) Wang, F.; Qi, Z.;
Sun, J.; Zhang, X.; Li, X. Org. Lett. 2013, 15, 6290−6293.
(8) For select examples where AgB(C6F5)4 was more effective than
AgSbF6 in Rh(III)-catalyzed reactions, see: (a) ref 7c. (b) Otley, K.
D.; Ellman, J. A. Org. Lett. 2015, 17, 1332−1335.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b03217.
■
S
Procedures and spectral data (PDF)
Crystal data for 5a (CIF)
Crystal data for 10 (CIF)
(9) Shi, X. Y.; Li, C. J. Org. Lett. 2013, 15, 1476−1479.
(10) Yang, L.; Qian, B.; Huang, H. Chem. - Eur. J. 2012, 18, 9511−
9515.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
ORCID
Jonathan A. Ellman: 0000-0001-9320-5512
Notes
The authors declare no competing financial interest.
(11) Boerth, J. A.; Ellman, J. A. Chem. Sci. 2016, 7, 1474−1479.
(12) (a) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2011, 133, 6449−6457. (b) Rakshit, S.; Grohmann, C.; Besset, T.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350−2353. (c) Wodrich, M.
D.; Ye, B.; Gonthier, J. F.; Corminboeuf, C.; Cramer, N. Chem. - Eur. J.
2014, 20, 15409−15418. (d) Hyster, T. K.; Dalton, D. M.; Rovis, T.
Chem. Sci. 2015, 6, 254−258.
(13) Although compound 5a was reported to be the product of
Rh(III)-catalyzed annulation using styrene,12c our spectral data for 5a,
whose structure was rigorously confirmed by X-ray crystallographic
analysis, is very different than the reported data. We conclude that the
previously reported compound was incorrectly assigned.
(14) For select relevant mechanistic studies for Rh(III)-catalysis, see:
(a) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008,
130, 12414−12419. (b) Brasse, M.; Campora, J.; Ellman, J. A.;
Bergman, R. G. J. Am. Chem. Soc. 2013, 135, 6427−6430. (c) Walsh, A.
P.; Jones, W. D. Organometallics 2015, 34, 3400−3407.
■
ACKNOWLEDGMENTS
■
This work was supported by the NIH (GM069559). We
gratefully acknowledge Dr. James Phelan (Yale) for important
discussions contributing to the inception of this project,
Dr. Michael Witten (Yale) for assistance with the acquisition
of high-resolution mass spectrometric data, and Vlad Bacauanu
(Yale) for providing an initial batch of chiral catalysts.
(15) For examples of Co(III) and Ir(III) nitronates, see: (a) C-
bound Ir: Murata, K.; Konishi, H.; Ito, M.; Ikariya, T. Organometallics
2002, 21, 253−255. (b) C-bound Co: Beckmann, U.; Ewing, J. D.;
Brooker, S. Chem. Commun. 2003, 1690−1691. (c) O- and C-bound
Ir: Zhang, X.; Emge, T. J.; Ghosh, R.; Krogh-Jespersen, K.; Goldman,
A. S. Organometallics 2006, 25, 1303−1309.
REFERENCES
■
(1) For select reviews on nitroalkenes and their use as Michael
acceptors, see: (a) Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986,
86, 751−762. (b) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 2002, 1877−1894. (c) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713−5743.
(16) A related η3-bound Cp*Rh(III) enolate was recently
characterized by X-ray crystallography, see ref 11.
(2) For select examples of Rh- and Pd-catalyzed additions of aryl
boronic acids to nitroalkenes, see: (a) Hayashi, T.; Senda, T.;
Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716−10717. (b) Lu, X.;
Lin, S. J. Org. Chem. 2005, 70, 9651−9653. (c) Wang, Z.-Q.; Feng, C.-
G.; Zhang, S.-S.; Xu, M.-H.; Lin, G.-Q. Angew. Chem., Int. Ed. 2010, 49,
5780−5783. (d) Xue, F.; Wang, D.; Li, X.; Wan, B. J. Org. Chem. 2012,
77, 3071−3081. (e) He, Q.; Xie, F.; Fu, G.; Quan, M.; Shen, C.; Yang,
G.; Gridnev, I. D.; Zhang, W. Org. Lett. 2015, 17, 2250−2253.
(17) For an outstanding recent Perspective on the application of
Cramer’s chiral ligands, see: Newton, C. G.; Kossler, D.; Cramer, N. J.
Am. Chem. Soc. 2016, 138, 3935−3941.
153
DOI: 10.1021/acscatal.6b03217
ACS Catal. 2017, 7, 150−153