New approach to oximes through reduction of nitro compounds enabled by visible light photoredox catalysis

Article abstract of DOI:10.1021/ol4009443

A range of nitro compounds are smoothly reduced to their corresponding oximes under the synergistic effects of visible light irradiation, the Ru(bpy)₃Cl₂ photocatalyst, Hünig's base, Mg(ClO ₄)₂ activation, and MeCN solvent. This remarkably mild and environmentally benign protocol, when orchestrated with classical Beckmann rearrangement, enables such high-value industrial feedstock as caprolactam to be readily accessed from simple precursor nitrocyclohexane.

Full text of DOI:10.1021/ol4009443

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
New Approach to Oximes through
Reduction of Nitro Compounds Enabled
by Visible Light Photoredox Catalysis
Shunyou Cai, Shaolong Zhang, Yaohong Zhao, and David Zhigang Wang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Shenzhen Graduate School of Peking University, Shenzhen, China 518055
dzw@pkusz.edu.cn
Received April 5, 2013
ABSTRACT
A range of nitro compounds are smoothly reduced to their corresponding oximes under the synergistic effects of visible light irradiation, the
€
Ru(bpy)3Cl2 photocatalyst, Hunig’s base, Mg(ClO4)2 activation, and MeCN solvent. This remarkably mild and environmentally benign protocol,
when orchestrated with classical Beckmann rearrangement, enables such high-value industrial feedstock as caprolactam to be readily accessed
from simple precursor nitrocyclohexane.
Photoredox catalysis enabled by green visible light
irradiation and efficient transition-metallic as well as
organic photosensitizers has in recent years emerged as a
powerful synthetic technology, bringing about a wide
range of organic transformations that are either impossible
or impractical with conventional protocols.1
As a highly versatile class of substances, oximes are
known to serve as useful precursors to various compounds
that have found numerous applications in material science,
pharmaceuticals, and agrochemicals,2 and great efforts
have been made to develop efficient protocols enabling
their facile preparations. As shown in Scheme 1, traditionally,
direct condensations of an aldehyde or a ketone with
hydroxylamine are the most frequently employed method.
An alternative is the reduction of primary nitroalkanes, as
well as R,β-unsaturated nitrocompounds, to oximes invol-
ving the use of Se/NaBH4, Bu3SnH, SnCl2/PhSH, or
Au/TiO2/H2.3,4 However, these established methods gen-
erally suffer from one or more limitations such as harsh
reaction conditions, poor selectivity, and employment
of toxic metal salts. Therefore, a strong need remains
for mild, convenient methods for oxime synthesis. In
this context, based on recent remarkable progress on
(3) Classical reductions of nitro compounds to their oximes typically
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V. J.; Sobecki, W. Ber. Dtsch. Chem. Ges. 1911, 44, 2526. (b) Hughes,
C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 4556. Controlled
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Chem. 1950, 62, 558. For other methods, see: (d) Barton, D. H. R.;
Fernandez, I.; Richard, C. S.; Zard, S. Z. Tetrahedron 1987, 43, 551. (e)
Albanese, D.; Landini, D.; Penseo, M. Synthesis 1990, 333. (f) Wang,
K. W.; Qian, X. H.; Cui, J. N. Tetrahedron 2009, 65, 10377. (g) Czekelius,
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r
10.1021/ol4009443
XXXX American Chemical Society

Table 1. Identification of the Optimal Reaction Conditions
Scheme 1. Various Synthetic Approaches to Oximes Formation
and Their Common Transformations
uncovering both new catalysis concepts and robust syn-
theticreactions5ꢀ9 by means ofvisible light-enabled photo-
catalysis, exploring its possible implications in designing
and identifying useful scenarios for alternative oxime
synthesis is appealing.
Motivated by this possibility, we set out to explore a set
of optimal reaction conditions conducive for oxime for-
mation by the readily available visible light photosensitizer
Ru(bpy)3Cl2.1 Eventual success emerged from a range of
screenings (Table 1) which proved that the formation of
oximes in synthetically meaningful efficiency depends
critically on the synergy of several factors, most notably
the amine reductive quencher, Lewis acidic additive, and
a No light was employed. b Yield of isolated product. c Only aza-
Henry product (ref 5a).
solvent. Withnitrocompound 1 asthe model substrateand
a 45 W household bulb as the light source, we initially
serendipitously discovered that the desired oxime 2 was
produced in 46% isolated yield (entry 1, Table 1) when the
reaction was performed in MeCN at rt and with 5% mol of
(5) (a) Cai, S. Y.; Zhao, X. Y.; Wang, X. B.; Liu, Q. S.; Li, Z. G.;
Wang, D. Z. Angew. Chem., Int. Ed. 2012, 51, 8050. (b) Kohls, P.;
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€
Ru-catalyst and 3 equiv of amine iPr2NEt (Hunig’s base).
Under otherwise identical conditions, a simple switch of
the reaction solvent MeCN to DMF was found to drama-
tically inhibit the reactivity (entry 2). Control experiments
conducted without either the Ru-photocatalyst (entry 3) or
visiblelight irradiation (entry 4) confirmed unambiguously
that the reproducible formation of 2 demands both. As
the commercial Ru(bpy)3Cl2 photocatalyst was available
in its hexahydrate form, an additional 3 equiv of water
were added to the reaction system (entry 5) as a neutral
additive, which was found to have negatively influenced
the oxime formation. A significant observation was sub-
sequently noted when two reactions with a basic Cs2CO3
(entry 6) or Lewis acidic LiBF4 (entry 7) additive, respec-
tively, were run in parallel; the comparative results re-
vealed the latter to be a far better reaction promoter than
the former (75% vs 20% yield of 2). Thus a number of
Lewis acidic additives, including Sc(OTf)3, La(OTf)3,
Eu(OTf)3, LiClO4, Mg(ClO4)2,10 were screened next at
various loadings and reaction times (entries 8ꢀ13), from
which the substoichiometric Mg(ClO4)2 (0.50 equiv)
clearly stood out for its remarkable capacity to deliver
the product in high isolated yield (82%, entry 13) and
within 12 h at rt. Interestingly, a doubled loading of
Mg(ClO4)2 was found to be detrimental for the product
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Neufeldt, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 18566. (f)
Rueping, M.; Leonori, D.; Poisson, T. Chem. Commun. 2011, 47, 9615.
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D. W. C. Nature 2011, 480, 224. (i) Rueping, M.; Zhu, S.; Koenigs, R. M.
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Chem. Commun. 2011, 47, 8679. (j) Andrews, R. S.; Becker, J. J.; Gagne,
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(7) (a) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J.
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J. Am. Chem. Soc. 2010, 132, 8572. (c) Andrews, R. S.; Becker, J. J.; M.
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R. Gagne, M. R. Angew. Chem., Int. Ed. 2010, 49, 7274. (d) Shih, H. W.;
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S. W.; Stephenson, C. R. J. Chem. Commun. 2010, 46, 4985. (b) Tucker,
J. W.; Stephenson, C. R. J. Org. Lett. 2011, 13, 5468. (c) Wallentin, C. J.;
Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem. Soc.
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lysis, see: (a) Hirao, T.; Shiori, J.; Okahata, N. Bull. Chem. Soc. Jpn.
2004, 77, 1763. (b) Gazi, S.; Ananthakrishnan, R. Appl. Catal., B 2011,
105, 317. Reductions of azides to amines are also possible; see: (c) Chen,
Y.; Kamlet, A. S.; Steinman, J. B.; Liu, D. R. Nat. Chem. 2011, 3, 146.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Survey of Reaction Scope
Scheme 3. Representative Transformations of Oxime 2
or -donating nature of the substituents on the aryl rings
(4cꢀ4i) seemed to pose a significant influence on the
reactivities. The size variations of aliphatic substituents
(4jꢀ4l) werealsowellaccommodated, and for comparison,
the presence of a bulky, π-character ethoxyfuranone in 4m
appeared to retard the reduction to some extent (51%
yield). The formation of aromatic oxime 4n progressed at
a faster rate (6 h); although the isolated yield was moder-
ate (36%), the product was obtained as exclusively an
E-isomer. Heteroaromatic ring-containing substrates were
also successful, and their corresponding oximes 4oꢀ4q
were produced in 63ꢀ82% yields. Purely aliphatic oxime
4r was prepared in 54% yield. Notable reactivity decreases
were observed for 4sꢀ4t. While the formations of aldox-
imes 4aꢀ4r generally required ∼12 h for completion,
ketoximes 4sꢀ4t required more reaction time (74% of 4s
after 26 h and 35% of 4t after 28 h, respectively). From the
results exemplified in Scheme 2, what merits particular
attention is this new protocol’s broad tolerance of such
synthetically versatile functionalities as cyano (4e), bromo
(4g), phenol (4h), alkynyl (4i), ethoxyfuranone (4m), hetero-
cycles (4oꢀ4q), and hydroxyl (4r), thereby yielding consid-
erable freedom for further needed structural manipulations.
The oximes thus prepared are capable of participating
in several characteristic reactions. For example, as illu-
strated in Scheme 3, oxime 2 upon oxidation activation by
NaClO12 or NCS13 could undergo [3 þ 2] dipolar cycload-
dition with ethyl acrylate or acetylacetone to deliver
functionalized heterocycle 5 or 6, respectively. Further-
more, the CdN bond of 2 could be cleaved via ozonolysis14
to give aldehyde 7, and its oxime moiety could be oxidized
by means of I2/PPh315 to yield the corresponding nitrile 8.
The synthetic utilities of this visible light-enabled photo-
redox catalysis technology could be further enhanced
through intelligent orchestrations with other strategic
transformations, thus enabling such operationally simple
“one-pot” processes to be conveniently practiced. A few
yield (entry 14). Two other amines, Et3N and tetramethyl
ethylenediamine (TMEDA), were employed in place of
€
Hunig’s base, and once again dramatic reactivity inhibi-
tions were observed in both cases (entries 15ꢀ16). Further
manifestations of the critical importance of reaction para-
meters came from the experiments shown in entries 17ꢀ18,
where the use of solvent MeOH or N-methylpyrrolidone
(NMP) under condition otherwise identical to those of
entry 13 led to either a complicated mixture or nearly
complete reactivity inhibition. Finally, anorganic dye-type
photosensitizer Eosin11 (5% mol) was examined while the
Ru-catalyst was absent (entry 19); the result suggested
that, at least in this specific context, Eosin is practically
ineffective inpromoting the desiredreactivity. Collectively,
these screenings established that an efficient visible light
photoredox reduction of nitro compound 1 to its oxime 2
at ambient temperature depends on the synergy of 5% mol
€
of Ru(bpy)3Cl2 photocatalyst, 5.00 equiv of Hunig’s base,
0.50 equiv of Mg(ClO4)2 additive, and MeCN as the
solvent.
With the above optimal reaction conditions in hand, a
range of structurally variable aliphatic or aromatic nitro
compounds 3 were subjected to this visible light-promoted
photocatalytic reduction protocol to examine its general
applicability. As compiled in Scheme 2, in each case the
reaction proceeded smoothly to furnish the desired oxime
product 4 in various isolated yields (35ꢀ86%) and geome-
trical isomers (E/Z ratios ranging from 1.0 to 4.1). Neither
the aryl ring sizes (4a and 4b) nor the electron-withdrawing
(12) Rosini, G.; Borzatta, V.; Paolucci, C.; Righi, P. Green Chem.
2008, 10, 1146.
(13) Sperry, J.; Harris, E. J.; Brimble, M. A. Org. Lett. 2010, 12, 420.
(14) Alonso, B.; Reyes, E.; Carrillo, L.; Vicario, J. L.; Badia, D.
Chem.;Eur. J. 2011, 17, 6048.
(15) Narsaiah, A. V.; Sreenu, D.; Nagaiah, K. Synth. Commun. 2006,
36, 137.
(16) This appears to be the first example of visible light-promoted
CꢀN bond cleavage.
(17) (a) Yang, D.; Yan, Y. L.; Law, K. L.; Zhu, N. Y. Tetrahedron
2003, 59, 10465. (b) Hasegawa, E.; Takizawa, S.; Seida, T.; Yamaguchi,
A.; Yamaguchi, N.; Chiba, N.; Takahashi, T.; Ikeda, H.; Akiyama, K.
Tetrahedron 2006, 62, 6581.
€
(11) Hari, D. P.; Konig, B. Org. Lett. 2011, 13, 3852.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. One-Pot Transformations of Some Typical Nitro
Compounds
Scheme 6. A Plausible Mechanistic Proposal
demonstrations were shown in Scheme 4. A one-pot
combination of nitro reductionꢀoxime elimination di-
rectly converted 1 to nitrile 8 in 62% isolated yield. A
merging of oxime formationꢀ[3 þ 2] dipolar cycloaddition
events on 3i constructed the tricyclic 8H-indeno[2,1-c]-
isoxazole core of 9 in 65% yield. Perhaps of most signifi-
cance, by teaming up oxime formation with subsequent
H2SO4-trigger Beckmann rearrangement, the abundantly
available nitrocyclohexane3s could be readily convertedto
caprolactam(43% yield), theindustrialprecursortoNylon
6, an extremely widely used synthetic polymer.
Finally, it is of interest to note that some relevant new
reactivities were uncovered during the course of our in-
vestigationsonthe fatesofnitrocyclopropane 11and nitro-
ketone 13in thisphotoredox catalysis protocol (Scheme 5).
Interestingly, the former was found to fragment efficiently
via CꢀC bond cleavage5h to yield ring-opening product 12
(86%), and the latter was reduced to saturated ketone 14
by formal CꢀN bond cleavage16 (35%). In both cases, no
evidence of oxime formation was obtained. These reactiv-
ities, although rather unexpected, could be economically
rationalized through the radical intermediates17 in situ
generated by hydrogen additions (vide infra) to Lewis acid
activated carbonyls in 11 and 13, respectively.
(in red), and nitro substrate reduction (in blue). Under
visible light stimulation, the initially formed amine radical
cation E should release a hydrogen radical to produce
iminium ion F which could subsequently eject a proton to
return to a neutral state G. Accordingly, the stepwise
hydrogen proton capture by the substrate 3’s resonance
form H should give rise to a reduced cationic species I.18
The electron deficiency of I empowered by its cationic
nature could thus grant its oxidation capacity that ab-
stracts an electron from the Ru(I) intermediate, thereby
fulfilling a critical step while an externally added oxidant
(such as oxygen) was absent. The concomitantly generated
species J next undergoes Lewis acid promoted dehydration
to lead to the final oxime product 4.
In summary, the established visible light-enabled photo-
catalytic reductionsof nitro compounds totheir oximes are
generally applicable and compatible with several syntheti-
cally significant functionalities. The protocol meanwhile
offers a new reaction development platform on which its
synergy with other strategic transformations could be
conceived and executed in operationally simple “one-
pot” fashions. The direct conversion of nitrocyclohexane
to industrial feedstock caprolactam serves as an interesting
lesson and should invite consideration of other exciting
possibilities.
A mechanistic proposal is outlined in Scheme 6, and we
believed that these unusual photocatalytic reduction reac-
tivities originate from dynamic interplays of at least three
intimately coupled pathways, i.e., a Ru(I)/Ru(II)-photo-
redox cycle (in green), amine dehydrogenative oxidation
Acknowledgment. We thank the NSFC (Grants
20872004, 20972008, and 21290180 to D.Z.W.), the national
“973 Project” of the State Ministry of Science and Technol-
ogy (Grant 2013CB911500 to D.Z.W.), the Shenzhen
Bureau of Science and Technology, and the Shenzhen
Shuang Bai Project for financial support.
Scheme 5. Visible Light-Promoted CꢀC/CꢀN Bond Cleavages
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX