A mild, ferrocene-catalyzed C-H imidation of (hetero)arenes

Article abstract of DOI:10.1021/ja501879c

A simple method for direct C-H imidation is reported using a new perester-based self-immolating reagent and a base-metal catalyst. The succinimide products obtained can be easily deprotected in situ (if desired) to reveal the corresponding anilines directly. The scope of the reaction is broad, the conditions are extremely mild, and the reaction is tolerant of oxidizable and acid-labile functionality, multiple heteroatoms, and aryl iodides. Mechanistic studies indicate that ferrocene (Cp₂Fe) plays the role of an electron shuttle in the decomposition of the perester reagent, delivering a succinimidyl radical ready to add to an aromatic system.

Full text of DOI:10.1021/ja501879c

Communication
pubs.acs.org/JACS
A Mild, Ferrocene-Catalyzed C−H Imidation of (Hetero)Arenes
Klement Foo,† Eran Sella,† Isabelle Thome,† Martin D. Eastgate,‡ and Phil S. Baran*,†
́
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
‡Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States
S
* Supporting Information
ABSTRACT: A simple method for direct C−H imidation
is reported using a new perester-based self-immolating
reagent and a base-metal catalyst. The succinimide
products obtained can be easily deprotected in situ (if
desired) to reveal the corresponding anilines directly. The
scope of the reaction is broad, the conditions are extremely
mild, and the reaction is tolerant of oxidizable and acid-
labile functionality, multiple heteroatoms, and aryl iodides.
Mechanistic studies indicate that ferrocene (Cp2Fe) plays
the role of an electron shuttle in the decomposition of the
perester reagent, delivering a succinimidyl radical ready to
add to an aromatic system.
irect, intermolecular C−H amination of arenes is a highly
D
sought-after transformation in organic chemistry. The
ubiquity of amines in medicine, agrochemicals, and materials
demands efficiency in their synthesis.1 Great strides have been
made toward these goals using both guided and innate C−H
functionalization logic.2 Guided approaches (Figure 1A) can be
extremely useful if common functional groups can serve the
dual role of directing groups, as has been expertly demonstrated
by the groups of Yu, Nakamura, Daugulis, Sanford, and
others.2b−j The area of innate arene amination is just beginning
to blossom. In 2011, Cho and Chang described a metal-free
oxidative C−H phthalimidation of benzene using PhI(OAc)2 as
oxidant (Figure 1A).2k Although the reaction was conducted at
140 °C with solvent quantities of substrate, it was an important
proof of principle. Hartwig discovered that adding a Pd catalyst
to the Cho−Chang system enables a lower operating
temperature and higher selectivity.2m In the same year, Zhang
and co-workers reported a guided imidation of arenes using
Pd(OAc)2 and NFSI as the amine source.2e Ritter demon-
strated that the directing group was not needed in the Zhang
system by utilizing a novel Pd system.2n The Ritter conditions
also broadened the substrate scope by including pyrroles and
thiophenes. Other significant reports in this area involve the
Cu-catalyzed C−H amination of azoles.2o−q This Communica-
tion describes a fundamentally different approach to C−H
imidation enabled by an imide-radical precursor and an unusual
catalyst system employing ferrocene (Cp2Fe). The reaction is
scalable and mild and, most importantly, functions on both
electron-rich and -poor (hetero)arenes.
Figure 1. (A) Examples of intermolecular oxidative amination of
arenes. (B) Preliminary studies toward a radical-based C−H amination
reagent. (C) Invention of NSP (7).
N-radicals to undergo hydrogen abstraction or to engage in
other degradation pathways.4 These challenges are evident from
prior studies where a large excess (solvent quantities) of simple
Our laboratory has a longstanding interest in radical-based
C−H functionalization of heteroaromatic systems.3 The
present study was aimed at forging C−N bonds via N-centered
radicals (N-radicals). However, intermolecular radical amina-
tion is a notoriously difficult reaction, due to the propensity of
Received: February 26, 2014
Published: March 23, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
arenes was needed in the context of aromatic C−H
imidation.2s−v
Having achieved a proof of concept for the basic reactivity,
we turned our attention to developing a more chemoselective
system. Thus, perester 7 (N-succinimidyl perester, NSP) was
targeted, as we envisaged that homolysis of the weak O−O
bond would lead to the same radical under neutral conditions
(Figure 1C). Perester 7 can be easily synthesized (decagram
scale) in three steps from N-hydroxysuccinimide. This
compound is a white solid, can be stored without degradation
at −20 °C, and is currently in the process of commercialization
(precursor 1g is available through Aldrich: cat. no. ALD00008).
Gratifyingly, even in the absence of catalyst, NSP (7) (3 equiv)
reacted directly with 4a in CH2Cl2 at 50 °C to furnish 5a in 7%
yield (Table 1). Since Cu(I) or Fe(II) salts are commonly used
to promote the decomposition of peresters or peroxides, an
extensive search for the optimal catalyst was undertaken.9
Surprisingly, and after significant exploration (Table 1
summarizes >100 experiments), it was found that Cp2Fe (5
mol%) was ideal (see Supporting Information). It is also
noteworthy that the more redox-active Cp*2Fe10 gave a lower
yield.11a The mechanistic implications of this finding are
discussed below and, to the best of our knowledge, represent an
uncommon use of Cp2Fe in a preparative setting.9e,f,11
Drawing inspiration from Forrester’s work on iminyl
radicals,5 we synthesized a library of over 15 closely related
precursors 1 by modifying the substituents on the nitrogen
atom (Figure 1B). The guiding principle in this design was to
generate N-radicals 2 upon radical decarboxylation/deformyl-
ation. Preliminary studies were performed on 4-methoxypyr-
idine (4a), and gratifyingly one of the reagents, 1f, was met
with success. This result was surprising, considering (1)
Minisci’s prediction that such reactions on pyridines were
bound to fail6 and (2) numerous reports pointing to
succinimidyl radicals as being inherently unstable, undergoing
immediate ring-opening.7 Subsequent succinimide deprotection
was achieved by heating the crude mixture to 100 °C (8 h) to
deliver amine 6a directly, resulting in a one-pot aniline
synthesis. It was also found that radical precursor 1g gave
identical yields, except that the rate of decarboxylation was
faster.8 Unfortunately, attempts to expand the scope of this
reaction by including more electron-rich substrates led only to
decomposition of starting material due to the strongly oxidizing
nature of the reaction media (excess K2S2O8).
This new reagent and catalyst system could be employed on
a variety of electron-rich and -poor (hetero)aromatic systems
(Table 2). The imidation process occurs on a wide variety of
pyridines and phenyl rings with good yields in most cases. The
observed regioselectivity of the imidation is similar to that of
electrophilic aromatic substitution reactions: electron-donating
groups such as alkoxy/alkyl are ortho/para directing (5a−c and
5g−k). This procedure is tolerant of sensitive groups such as
esters, halogens, and silyl protecting groups, which is
particularly important if subsequent functionalization is
required. Interestingly, highly electron-rich heterocycles (such
Table 1. Catalyst Optimization Summary for Reaction
between NSP (7) and 4a
a
b
5−10 mol% of catalyst was used. Yield is based on NMR
comparison.
Table 2. Substrate Scope of Ferrocene-Catalyzed C−H Imidation of (Hetero)Arenes 4
a
b
Cp2Fe (5 mol%), (hetero)arene 4 (0.2 mmol), NSP (7) (3 equiv), CH2Cl2 (0.05 M), 50 °C, 2−7 h; isolated yields reported. NSP (7) (4 equiv)
c
d
e
f
was used. NSP (7) (2.75 equiv) was used. NSP (7) (5 equiv) was used. Cp2Fe (10 mol%) was used. Ipso-substitution observed.
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Journal of the American Chemical Society
Communication
as 5l−r) and electron-poor substrates (such as 5s−w) can be
imidated successfully. Alternate approaches to aromatic amine
synthesis (e.g., nitration/reduction), in many cases, would not
result in a comparable yield. For instance, the nitration of
pyrroles is a classic problem, with little in the way of progress
with respect to the yield. Many of the compounds, which
demonstrate efficient reactivity under these conditions, are
useful to the pharmaceutical industry, where the synthesis of
aromatic amines is a key area of need. Although the reaction
could be conducted under air, an inert atmosphere generally
gave more consistent results. One limitation of the process was
the occasional observation of ipso-substitution in 1,4-
disubstituted benzenes (5i (15:2)) as a side reaction.
completely disappears upon heating to 50 °C (III). Increasing
the signal peak intensity reveals a broad signal (δ 5.14 ppm)
(IV), characteristic of a paramagnetic species. This observation
is consistent with a ferrocenium species, which are known to be
paramagnetic.10 A control experiment with a mixture of Cp2Fe
and 4a was conducted in an identical fashion, and the Cp2Fe
signal remained unchanged. Additional evidence of ferrocenium
ions is the green color (VI) achieved upon heating of the yellow
Cp2Fe mixture with NSP (7) (V). The use of Cp2Fe as an
electron shuttle forms the essence of this interesting catalytic
cycle.
To demonstrate the utility of NSP (7) as a potential direct
amination reagent, a one-pot imidation/deprotection procedure
was developed (Scheme 1A). Upon completion of the
imidation step, the reaction was quenched with MeOH,
concentrated, and heated to reflux in a dilute solution of
H2SO4. This procedure was effective for the one-pot amination
of 4d to give 6d in 60% yield. Iodoarene 4j was directly
aminated using a similar procedure to give amine 6j in 40%
yield (6j has been commercialized by Aldrich using this
method: cat. no. ALD00071). It was found that the hydrolysis
of imide 5j was significantly slower, and more acid was added to
accelerate the deprotection. Finally, the C−H imidation was
successfully carried out on gram scale with 4d, giving the
desired imide 5d in 48% yield. This is comparable to the result
obtained on 0.2 mmol scale as shown in Table 2.
Scheme 1. (A) One-Pot C−H Imidation/Deprotection of 4d
and 4j and (B) Gram-Scale C−H Imidation of 4d
1
Figure 2. (A) Proposed catalytic cycle. (B) Mechanistic probe by H
NMR spectroscopy.
A plausible mechanistic proposal for this reaction is described
in Figure 2. Outer-sphere single-electron transfer from Cp2Fe
to NSP (7) initiates O−O bond cleavage, resulting in concerted
fragmentation, generating the imidyl radical, CO2, acetone, and
ferrocenium tert-butoxide. C−N bond formation between the
imidyl radical and 4 leads to radical 8. One-electron oxidation
of 8, followed by deprotonation, yields 5 and regenerates Cp2Fe
in the process. Although there are a few examples of Cp2Fe
acting either as a Fenton-like reagent9e,f or to mediate aryl
radical formation from diazonium salts,11 Cu(I) salts are
normally employed for perester activation.9a,b Figure 2B depicts
The mild and chemoselective nature of this imidation
reaction (and subsequent deprotection to an amine) bodes well
for its use at both the early and late stages of a synthesis
program. The ability to aminate in the presence of oxidizable
functionality and halogen atoms enables sequential aryl
functionalizations. NSP (7) represents a unique self-immolat-
ing12 reagent that might inspire the design of other synthetically
useful reactive species. Finally, the use of Cp2Fe as a mild
electron shuttle in other reaction types is a topic worthy of
further investigation.
1
a H NMR study that supports the role of Cp2Fe in the
reaction. The spectra overlay shows clearly that the Cp2Fe
signal (I) diminishes as 7 is added to the mixture (II) and then
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Journal of the American Chemical Society
Communication
Katsaros, M. G.; Kocher, W. D.; Scott, A. E.; Skell, P. S. J. Am. Chem.
Soc. 1978, 100, 1950. (v) Lu, F.-L.; Naguib, Y. M. A.; Kitadani, M.;
Chow, Y. L. Can. J. Chem. 1979, 57, 1967. (w) Togo, H.; Hoshina, Y.;
Muraki, T.; Nakayama, H.; Yokoyama, M. J. Org. Chem. 1998, 63,
5193.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(3) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Daa Funder, E.; Dixon, D.
D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.;
́
Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95.
(4) (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603. (b) Danen, W. C.;
Neugebauer, F. A. Angew. Chem., Int. Ed. 1975, 14, 783. (c) Stella, L.
Angew. Chem., Int. Ed. 1983, 22, 337.
AUTHOR INFORMATION
Corresponding Author
pbaran@scripps.edu
■
Notes
The authors declare no competing financial interest.
(5) (a) Forrester, A. R.; Gill, M.; Meyer, C. J.; Sadd, J. S.; Thomson,
R. H. J. Chem. Soc., Chem. Commun. 1975, 291. (b) Boivin, J.; Fouquet,
E.; Zard, S. Z. Tetrahedron 1994, 50, 1769.
(6) Minisci, F. Synthetic and Mechanistic Organic Chemistry, Topics in
Current Chemistry 62; Springer: Berlin/Heidelberg, 1976; p 1.
ACKNOWLEDGMENTS
■
Financial support was provided by Bristol-Myers Squibb, NSS
(PhD) A*STAR (predoctoral fellowship to K.F.), G. E. Hewitt
Foundation (postdoctoral fellowship to E.S.), AvH Foundation
(postdoctoral fellowship to I.T.), and the NIH/NIGMS (GM-
106210). We thank Prof. A. L. Rheingold, Dr. C. E. Moore, and
Dr. J. A. Golen for X-ray crystallographic analysis.
(7) (a) Luning, U.; Seshadri, S.; Skell, P. S. J. Org. Chem. 1986, 51,
̈
2071. (b) Day, J. C.; Lindstrom, M. J.; Skell, P. S. J. Am. Chem. Soc.
1974, 96, 5616. (c) Hedaya, E.; Hinman, R. L.; Schomaker, V.;
Theodoropulos, S.; Kyle, L. M. J. Am. Chem. Soc. 1967, 89, 4875.
(d) O’Reilly, R. J.; Karton, A.; Radom, L. J. Phys. Chem. A 2013, 117,
460.
(8) Hilborn, J. W.; Pincock, J. A. J. Am. Chem. Soc. 1991, 113, 2683.
(9) For Cu(I)-catalyzed O−O cleavage, see: (a) Kharasch, M. S.;
Sosnovsky, G. J. Am. Chem. Soc. 1958, 80, 756. (b) Beckwith, A. L. J.;
Zavitsas, A. A. J. Am. Chem. Soc. 1986, 108, 8230. For Fe(II)-catalyzed
O−O cleavage, see: (c) Fenton, H. J. H. J. Chem. Soc., Trans. 1894, 65,
899. (d) Yang, H.; Yan, H.; Sun, P.; Zhu, Y.; Lu, L.; Liu, D.; Rong, G.;
Mao, J. Green Chem. 2013, 15, 976. (e) Wertz, S.; Leifer, D.; Studer, A.
Org. Lett. 2013, 15, 928. (f) Ohtsuka, Y.; Yamakawa, T. Tetrahedron
2011, 67, 2323.
(10) Yang, E. S.; Chan, M.-S.; Wahl, A. C. J. Phys. Chem. 1980, 84,
3094.
(11) (a) Marciasini, L. D.; Richy, N.; Vaultier, M.; Pucheault, M. Adv.
Synth. Catal. 2013, 355, 1083. (b) Chernyak, N.; Buchwald, S. L. J. Am.
Chem. Soc. 2012, 134, 12466.
REFERENCES
■
(1) For intramolecular (hetero)arene C−H amination, see:
(a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (b) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010,
132, 3676. (c) Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2011, 50, 1478. (d) Jordan-Hore, J. A.; Johansson, C. C.
C.; Gulia, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130,
16184. (e) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am.
Chem. Soc. 2010, 132, 13217. (f) Antonchick, A. P.; Samanta, R.;
Kulikov, K.; Lategahn, J. Angew. Chem., Int. Ed. 2011, 50, 8605.
(g) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.;
Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068. (h) Brasche, G.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. For reviews on
(hetero)arene C−H aminations, see: (i) Hartwig, J. F. Acc. Chem. Res.
2012, 45, 864. (j) Mueller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.
(k) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (l) Davies,
H. M. L.; Long, M. S. Angew. Chem., Int. Ed. 2005, 44, 3518.
(m) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. (n) Cho,
S. H.; Kim, J. Y.; Kwak, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011,
40, 5068.
(12) Sagi, A.; Weinstein, R.; Karton, N.; Shabat, D. J. Am. Chem. Soc.
2008, 130, 5434.
(2) (a) Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
̈
Res. 2012, 45, 826. For guided (hetero)arene C−H amination, see:
(b) Shang, M.; Zeng, S.-H.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. Org. Lett.
2013, 15, 5286. (c) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-
Q. J. Am. Chem. Soc. 2011, 133, 7652. (d) Shang, M.; Sun, S.-Z.; Dai,
H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 3354. (e) Sun, K.; Li, Y.;
Xiong, T.; Zhang, J.; Zhang, Q. J. Am. Chem. Soc. 2011, 133, 1694.
(f) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128,
9048. (g) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc. 2010,
132, 12862. (h) Dick, A. R.; Remy, M. S.; Kampf, J. W.; Sanford, M. S.
Organometallics 2007, 26, 1365. (i) Matsubara, T.; Asako, S.; Ilies, L.;
Nakamura, E. J. Am. Chem. Soc. 2014, 136, 646. (j) Tran, L. D.; Roane,
J.; Daugulis, O. Angew. Chem., Int. Ed. 2013, 52, 6043. For innate
(hetero)arene intermolecular C−H amination, see: (k) Kim, H. J.;
Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2011, 133, 16382.
(l) Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.;
DeBoef, B. J. Am. Chem. Soc. 2011, 133, 19960. (m) Shrestha, R.;
Mukherjee, P.; Tan, Y.; Litman, Z. C.; Hartwig, J. F. J. Am. Chem. Soc.
2013, 135, 8480. (n) Boursalian, G. B.; Ngai, M.-Y.; Hojczyk, K. N.;
Ritter, T. J. Am. Chem. Soc. 2013, 135, 13278. (o) Kawano, T.; Hirano,
K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900. (p) Wang,
Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (q) Monguchi, D.;
Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607.
(r) Citterio, A.; Gentile, A.; Minisci, F.; Navarrini, V.; Serravalle, M.;
Ventura, S. J. Org. Chem. 1984, 49, 4479. (s) Lidgett, R. A.; Lynch, E.
R.; McCall, E. B. J. Chem. Soc. 1965, 3754. (t) Cadogan, J. I. G.;
Rowley, A. G. J. Chem. Soc., Perkin Trans. 1 1975, 1069. (u) Day, J. C.;
5282
dx.doi.org/10.1021/ja501879c | J. Am. Chem. Soc. 2014, 136, 5279−5282