Nickel-catalyzed reductive and borylative cleavage of aromatic carbon-nitrogen bonds in N-aryl amides and carbamates

Article abstract of DOI:10.1021/ja501649a

The nickel-catalyzed reaction of N-aryl amides with hydroborane or diboron reagents resulted in the formation of the corresponding reduction or borylation products, respectively. Mechanistic studies revealed that these reactions proceeded via the activation of the C(aryl)-N bonds of simple, electronically neutral substrates and did not require the presence of an ortho directing group.

Full text of DOI:10.1021/ja501649a

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Reductive and Borylative Cleavage of Aromatic
Carbon−Nitrogen Bonds in N‑Aryl Amides and Carbamates
Mamoru Tobisu,*,†,‡,§ Keisuke Nakamura,† and Naoto Chatani*,†
†Department of Applied Chemistry, Faculty of Engineering and ‡Center for Atomic and Molecular Technologies, Graduate School of
Engineering, Osaka University, Suita, Osaka 565-0871, Japan
§ESICB, Kyoto University, Katsura, Kyoto 615-8510, Japan
S
* Supporting Information
of bond disconnection for amide derivatives (Scheme 1A,
cleavage b) and represent a valuable addition to the normal
C(acyl)−N cleavage methods (Scheme 1A, cleavage a).
ABSTRACT: The nickel-catalyzed reaction of N-aryl
amides with hydroborane or diboron reagents resulted in
the formation of the corresponding reduction or
borylation products, respectively. Mechanistic studies
revealed that these reactions proceeded via the activation
of the C(aryl)−N bonds of simple, electronically neutral
substrates and did not require the presence of an ortho
directing group.
We initiated our study by examining the reaction of amide 1a
with a variety of different coupling partners in the presence of a
wide range of transition metal catalysts. The results of these
preliminary screening experiments revealed that the use of
HSiMe(OMe)2 in conjunction with a Ni(cod)2/PCy3 catalyst
allowed for the successful conversion of 1a to naphthalene (2)
via the reductive cleavage of the C(aryl)−N bond,7 although
the yield for this transformation was very low at 7% (Scheme
2). Unfortunately, further changes to the catalyst, ligand,
ver the course of the past decade, there has been
Osubstantial progress in the development of metal-
catalyzed C(aryl)−N bond forming reactions for the
construction of aryl amine derivatives (Scheme 1A, forward).1
Scheme 2. Nickel-Catalyzed Reductive Cleavage of C(aryl)−
N Bonds: The Effect of the Reductant and Different N-
Substituents
a
Scheme 1. Cleavage of Aromatic Carbon−Nitrogen Bonds
a
Reaction conditions: 1 (0.50 mmol), reductant (1.0 mmol), Ni(cod)2
In contrast, research toward the reverse process involving the
catalytic cleavage of C(aryl)−N bonds has been scarce (Scheme
1A, reverse).2 The cleavage of the C(aryl)−N bonds of aniline
derivatives has traditionally been accomplished using highly
reactive cationic intermediates such as diazonium3 and
ammonium4 salts, wherein the C(aryl)−N bond cleavage
process is facilitated by the elimination of electronically neutral
molecules, i.e., dinitrogen and an amine, respectively.5 Kakiuchi
et al. reported the development of a notable ruthenium-
catalyzed C(aryl)−N bond activation reaction for electronically
neutral aniline derivatives, but the process was limited to
substrates bearing an ortho directing group.6 Herein, we report
the first catalytic C(aryl)−N bond cleavage reactions of
electronically neutral and structurally simple aryl amine
derivatives via the nickel-catalyzed reduction and borylation
of N-aryl amides. These reactions therefore enable a new mode
(0.050 mmol), and PCy3 (0.10 mmol) in toluene (1.5 mL) at 70 °C
for 20 h. Yields were determined by GC analysis versus a calibrated
internal standard because of the volatility of the product.
substituents on the silicon, solvent, and reaction temperature
did not result in any discernible improvement (details in
Supporting Information (SI)). However, the use of HB(pin) as
a reductant led to an increase in the yield of 2 to 61%. Several
other reducing agents were also screened against the reaction,
including BH3·Me2S, KBH4, and DIBALH, but these reagents
led exclusively to the formation of 1-(naphthalen-2-yl)-
pyrrolidine via the reduction of the carbonyl group, with no
Received: February 17, 2014
Published: March 31, 2014
© 2014 American Chemical Society
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Communication
2 being detected. The nature of the C(aryl)−N bond structure
had a profound effect on the outcome of the current C(aryl)−
N bond cleavage reaction. For example, the acyclic amide 1b
did not react under the current conditions, whereas the cyclic
and acyclic carbamates 1c and 1d successfully underwent the
nickel-catalyzed reductive cleavage to give 2 in good yields. It is
noteworthy that the current cleavage process could be readily
applied to the Boc-protected aryl amine 1d, which represents a
common structural motif in synthetic chemistry, despite the
substantial steric bulk of the Boc group. Furthermore, the
presence of an unprotected N−H group on the carbamate, as in
1e, was determined to be detrimental to the catalytic process.
As shown in Table 1, the current nickel-catalyzed reductive
cleavage reaction could be successfully applied to a variety of
We next conducted a series of labeling experiments to
develop a deeper understanding of the reaction mechanism in
terms of the origin of the hydrogen atom incorporated in the
final product.9 The use of DB(pin) afforded the reduction
product 11 with only 50% deuterium incorporation at the 3-
position. This result suggested that the hydrogen atom in the
reduction product was not derived exclusively from hydro-
borane and that some other source of hydrogen must be
present in the system (Scheme 3A). The deuterium labeling of
Scheme 3. Labeling Studies
Table 1. Nickel-Catalyzed Reductive Cleavage of C(aryl)−N
a
Bonds: Evaluation of the Substrate Scope
a
Reaction conditions: Amide or carbamate (0.50 mmol), HB(pin)
(1.0 mmol), Ni(cod)2 (0.050 mmol), and PCy3 (0.10 mmol) in
the methylene groups of the oxazolidinone ring in compound
12 followed by reduction under the standard conditions
delivered the anticipated reduction product, but with no
deuterium incorporation (Scheme 3B). In contrast, 22%
deuterium incorporated was observed at the 3-position when
deuterium labeled toluene was used as the reaction solvent
(Scheme 3C), which indicated that a H/D exchange reaction
was occurring between the HB(pin) and the toluene solvent.
This possibility was confirmed to be true by a simple
experiment, where the exposure of HB(pin) to the nickel-
catalyzed conditions in toluene-d8 led to the formation of
DB(pin) (Scheme 3D).10 When the reaction was run with
DB(pin) in toluene-d8, deuterium incorporation at the 3-
position of the product increased to 74% (Scheme 3E). The
hydrogen incorporation (26%) in this experiment was
attributed to a decrease in the deuterium content of the
DB(pin) reductant resulting from the H/D exchange reaction
of the C−H bonds in the naphthalene rings of the products and
the starting carbamates with the deuterium of the DB(pin).11
Although the rapidity of the hydrogen exchange reactions
between DB(pin) and the aromatic C−H bonds may have
complicated the outcome of the labeling studies, the
toluene (1.5 mL) at 70 °C for 20 h. Isolated yield is shown unless
b
otherwise noted. GC yield because of the volatility of the product.
c
d
Reaction time of 48 h. Reaction conducted at 120 °C using IMes
instead of PCy3. 71% of 10 was recovered.
different aromatic amides and carbamates. Under these
conditions, the C−N bonds of amines remained intact, whereas
those of amides and carbamates were substituted with hydrogen
in a chemoselective manner (i.e., 4).
Sterically demanding substrates bearing a C−N bond at the
1-position of the naphthalene, such as 5 and 6, as well as those
containing an ortho substituent, such as 7, underwent the
reductive cleavage reaction to give the corresponding reduction
products. Several other fused aromatic systems, including
anthracene 8 and phenanthrene 9, also proceeded smoothly
under the optimized condition to give the corresponding
reduction products, whereas benzene derivatives, such as 10,
were found to be much less reactive. The trend in reactivity
observed in the current transformation is similar to that
reported previously for the nickel-catalyzed cleavage of inert
C−O bonds.8
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Communication
a
experimental observations collectively indicate that the C−N
bonds were substituted by the hydride derived from HB(pin).
The potential utility of this C−N bond cleavage reaction is
demonstrated in Scheme 4. Thus, the 1,4-addition of 14 to enal
Table 2. Nickel-Catalyzed Borylation of C(aryl)−N Bonds
Scheme 4. Synthetic Application
15 using MacMillan’s amine catalyst afforded 16, where the
pyrrolidine group was essential both in terms of the reactivity
and regiochemical outcome of the reaction.12 Subsequent
removal of the pyrrolidine group was enabled by the α-
oxidation of the pyrrolidine followed by the cleavage of the
resulting amide 17 using our newly developed nickel-catalyzed
C−N bond cleavage, which gave the corresponding reduced
product 18 in good yield. This C−N bond cleavage process was
accomplished without having any discernible impact on the
stereochemical integrity of the benzylic stereocenter. In this
way, the amino groups on an aromatic ring can now be used as
a removable activating and directing group in electrophilic
aromatic substitutions.
Importantly, we also found that the use of diboron reagents
instead of hydroborane resulted in the formation of the
borylated product via the cleavage of the C−N bond (Table 2).
Following a brief period of optimization, IMes was determined
to be the optimal ligand for this nickel-catalyzed borylation
reaction (details in SI). This borylation process was found to be
amenable to both acyclic and cyclic amides. In the case of
acyclic amide 1b, the deacylated material N-methyl-2-naphthyl-
amine was also formed as a minor product. The application of
the nickel-catalyzed reaction conditions to N-methyl-2-
naphthylamine, however, did not provide 19, which precluded
its involvement as an intermediate in the catalytic borylation of
1b. Fluoride 20 and quinoline 22 were compatible with the
conditions and gave the corresponding borylated products in
good yields. Once again, polyaromatic substrates, including
naphthalenes, quinolines, anthracenes, and phenanthrenes were
shown to exhibit significantly higher levels of reactivity toward
the borylative cleavage of their C−N bonds under these
conditions than the corresponding benzanilides.13 Unlike the
reductive cleavage reaction using HB(pin), the borylation
reaction was found to be relatively sensitive to the steric
environment of the substrate, as indicated by the decreased
yield with 1-substituted amide 5.
a
Reaction conditions: Amide (0.50 mmol), B2(nep)2 (1.0 mmol),
Ni(cod)2 (0.050 mmol), IMes·HCl (0.10 mmol), and NaOtBu (0.10
mmol) in toluene (1.5 mL) at 160 °C for 20 h. Isolated yield. NMR
yield. 61% of 5 was recovered.
b
c
d
investigated the effect of adding mercury to the reaction. When
the nickel-catalyzed reductive cleavage reaction was conducted
with HB(pin) in the presence of an excess of mercury, the
reaction was completely suppressed, whereas the addition of an
excess of mercury to the borylation reaction involving diboron
still proceeded, albeit to a lesser extent.14 Interestingly, the
reductive cleavage reaction with HB(pin) continued to proceed
even after the reaction mixture was filtered following 5 h, and
the filtrate subsequently reheated.15 Although these data do not
provide a definitive understanding as to whether the catalysis is
homogeneous or heterogeneous,16,17 it is likely that the
reactions described in the current study were mediated by
soluble or nanosized (∼10 nm) nickel species,18 rather than
larger-sized nickel aggregates.
Although several experiments have been conducted with the
aim of establishing the mechanism of this novel nickel-mediated
C−N bond cleavage reaction, very little is known about the
precise nature of the catalyst. To address this issue, we
In summary, we have developed a nickel-catalyzed C(aryl)−
N bond cleavage reaction for the cleavage of amides and
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(d) Bai, Y.; Kim, L. M. H.; Liao, H.; Liu, X.-W. J. Org. Chem. 2013, 78,
8821. N-Arylazoles: (e) Liu, J.; Robins, M. J. Org. Lett. 2004, 6, 3421.
(6) (a) Ueno, S.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007,
129, 6098. (b) Koreeda, T.; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc.
2009, 131, 7238. (c) Koreeda, T.; Kochi, T.; Kakiuchi, F.
Organometallics 2013, 32, 682. (d) Koreeda, T.; Kochi, T.; Kakiuchi,
F. J. Organomet. Chem. 2013, 741−742, 148.
carbamates in the absence of an ortho directing group. In the
current transformation, the C−N bonds were converted into
C−H and C−B bonds with hydroborane and diboron reagents,
respectively. Although further studies will be required to
develop a greater understanding of the scope and efficiency of
the these reactions, this work clearly demonstrates that the
current C(aryl)−N bond cleavage reaction represents a viable
disconnection process capable of enabling a nonconventional
synthetic strategy. The application of this strategy to other C−
N bonds as well as computational studies aimed at revealing the
mechanism of the reaction are currently being investigated in
our laboratory.
(7) This catalyst system is effective for the reductive cleavage of C−O
bonds of aryl ethers, esters, and carbamates. (a) Tobisu, M.;
Yamakawa, K.; Shimasaki, T.; Chatani, N. Chem. Commun. 2011, 47,
2946. For reductive cleavage reactions using a similar catalytic system,
́
see: (b) Alvarez-Bercedo, P.; Martin, R. J. Am. Chem. Soc. 2010, 132,
17352. (c) Cornella, J.; Gomez-Bengoa, E.; Martin, R. J. Am. Chem.
́
Soc. 2013, 135, 1997. (d) Sergeev, A. G.; Hartwig, J. F. Science 2011,
332, 439. (e) Sergeev, A. G.; Webb, J. D.; Hartwig, J. F. J. Am. Chem.
Soc. 2012, 134,, 20226. (f) Mesganaw, T.; Fine Nathel, N. F.; Garg, N.
K. Org. Lett. 2012, 14, 2918.
ASSOCIATED CONTENT
■
S
* Supporting Information
(8) Reviews: (a) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010,
43, 1486. (b) Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem.−Eur. J.
2011, 17, 1728. (c) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.;
Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011,
111, 1346. (d) Mesganaw, T.; Garg, N. K. Org. Process Dev. Res. 2012,
17, 29. (e) Tobisu, M.; Chatani, N. Top. Organomet. Chem. 2013, 44,
35.
(9) Kelley, P.; Lin, S.; Edouard, G.; Day, M. W.; Agapie, T. J. Am.
Chem. Soc. 2012, 134, 5480 See also refs 7a−c.
(10) Hydrogen exchange between a nickel-hydride complex and
benzene: Beck, R.; Shoshani, M.; Johnson, S. A. Angew. Chem., Int. Ed.
2012, 51, 11753.
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
tobisu@chem.eng.osaka-u.ac.jp; chatani@chem.eng.osaka-u.ac.
jp
Notes
The authors declare no competing financial interest.
(11) In the reactions shown in Schemes 3A and 3C, 5−10% of
deuterium was also incorporated into the other positions of
naphthalene rings of the products and of the recovered starting
carbamates.
(12) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
7894.
(13) For example, the reaction of 10 with B2(nep)2 under the
conditions shown in Table 2 afforded none of the borylated product.
(14) Martin reported that Ni(cod)2 could react with mercury in
solution. See ref 7c.
(15) DLS measurement of the filtrate revealed that no particles
whose diameters are >20 nm existed.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
of Japan. M.T. was also supported by the “Elements Strategy
Initiative to Form Core Research Center” from MEXT. We
would like to thank Professors Yusuke Yamada and Shunichi
Fukuzumi (Osaka University) for performing the DLS
measurements and for their many helpful discussions regarding
the phase of the catalyst. We would also like to thank the
Instrumental Analysis Center, Faculty of Engineering, Osaka
University, for assistance with the HRMS measurements.
(16) Crabtree, R. H. Chem. Rev. 2012, 112, 1536.
(17) It is also probable that different metal species are present in the
catalytic reaction mixture, and several of them are responsible for the
catalysis: Kashin, A. S.; Ananikov, V. P. J. Org. Chem. 2013, 78, 11117.
(18) A general aspect of nanoparticle-catalyzed cross-coupling
REFERENCES
■
reactions: Per
́
ez-Lorenzo, M. J. Phys. Chem. Lett. 2012, 3, 167.
(1) Reviews: (a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 6338. (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(2) Geng, W.; Zhang, W.-X.; Hao, W.; Xi, Z. J. Am. Chem. Soc. 2012,
134, 20230 and refs therein.
(3) Reviews: (a) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M.
̃
Chem. Rev. 2006, 106, 4622. (b) Mo, F.; Dong, G.; Zhang, Y.; Wang, J.
Org. Biomol. Chem. 2013, 11, 1582.
(4) Selected examples: (a) Wenkert, E.; Han, A.-L.; Jenny, C.-J. J.
Chem. Soc., Chem. Commun. 1988, 975. (b) Blakey, S. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 6046. (c) Reeves, J. T.;
Fandrick, D. R.; Tan, Z.; Song, J. J.; Lee, H.; Yee, N. K.; Senanayake,
C. H. Org. Lett. 2010, 12, 4388. (d) Xie, L.-G.; Wang, Z.-X. Angew.
Chem., Int. Ed. 2011, 50, 4901. (e) Zhang, X.-Q.; Wang, Z.-X. J. Org.
Chem. 2012, 77, 3658. (f) Guo, W.-J.; Wang, Z.-X. Tetrahedron 2013,
69, 9580. (g) Zhang, X.-Q.; Wang, Z.-X. Org. Biomol. Chem. 2014, 12,
1448. A related benzylic ammonium salts: (h) Maity, P.; Shacklady-
McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P. J. Am.
Chem. Soc. 2013, 135, 280.
(5) Catalytic cleavage of C−N bonds of less common aniline
derivatives was also reported. Triazenes: (a) Saeki, T.; Son, E.-C.;
Tamao, K. Org. Lett. 2004, 6, 617. Hydrazines: (b) Zhu, M.-K.; Zhao,
J.-F.; Loh, T.-P. Org. Lett. 2011, 13, 6308. (c) Liu, J.-B.; Yan, H.; Chen,
H.-X.; Luo, Y.; Weng, J.; Lu, G. Chem. Commun. 2013, 49, 5268.
5590
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