Reductive Coupling between C-N and C-O Electrophiles

Article abstract of DOI:10.1021/jacs.9b05224

The cross-electrophile reaction is a promising strategy for C-C bond formation. Recent studies have focused mainly on reactions with organic halides. Here we report a coupling reaction between C-N and C-O electrophiles that demonstrates the possibility of constructing a C-C bond via C-N and C-O cleavage. Several reactions between benzyl/aryl ammonium salts and vinyl/aryl C-O electrophiles have been studied. Preliminary mechanistic studies revealed that the benzyl ammoniums were activated through a radical mechanism.

Full text of DOI:10.1021/jacs.9b05224

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Communication
Reductive Coupling between C-N and C-O Electrophiles
Rong-De He, Chun-Ling Li, Qiu-Quan Pan, Peng Guo, Xue-Yuan Liu, and Xing-Zhong Shu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 31 Jul 2019
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Reductive Coupling between C−N and C−O Electrophiles
Rong-De He, Chun-Ling Li, Qiu-Quan Pan, Peng Guo, Xue-Yuan Liu, Xing-Zhong Shu*
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State Key Laboratory of Applied Organic Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, China
Supporting Information Placeholder
Scheme 1. C–C bond formation via cross-coupling
ABSTRACT: The cross-electrophile reaction is a promising
strategy for C–C bond formation. Recent studies have
focused mainly on reactions with organic halides. Here we
report
a coupling reaction between C–N and C–O
electrophiles that demonstrates the possibility of
constructing a C–C bond via C–N and C–O cleavage. Several
reactions between benzyl/aryl ammonium salts and
vinyl/aryl C–O electrophiles have been studied. Preliminary
mechanistic studies revealed that the benzyl ammoniums
were activated through a radical mechanism.
Cross-coupling reactions catalyzed by transition metals have
become among the most powerful and useful synthetic tools
in chemistry.1 In general, these processes rely upon the use of
stoichiometric organometallic reagents (e.g. Li, Mg, Sn, B
derivatives) to react with electrophile partners. Recently, the
cross-electrophile reaction has provided a practical and
powerful alternative that enables construction of C–C bonds
directly from electrophiles, demonstrating high step-
economy, excellent functional group compatibility, and
unique selectivity orthogonal to conventional methods.2
Since the pioneering work of Weix and Gosmini using nickel
and cobalt catalysis, there have been great achievements in
the development of reactions using organic halides (Scheme
1a, path a).3 Despite the formidable advances in this line,
compared with the traditional procedures capable of
coupling diverse electrophiles with diverse nucleophiles,
extension of the scope to other types of coupling fragments is
highly desirable for enhancing the applicability of this
methodology, yet remains largely undeveloped.
successful implementation of this idea, which enables the
coupling reactions of ammoniums salts with vinyl/aryl C–O
electrophiles (Scheme 1b).
We began our investigation by studying the alkylation
reaction of vinyl acetates. Vinyl acetates are easily available
starting materials bearing a small, nonhazardous leaving
group. They are cheap and stable, and easy to handle in the
air. However, due to the reactivity and selectivity problems
inherent in vinyl C−OAc bond activation, the cross-coupling
of these compounds has been rarely investigated. Major
advance was achieved on Csp2−Csp2 coupling reactions of
vinyl acetates.6 There are only a few reports on their
reactions to form Csp3−Csp2 bonds by using Grignard
reagents and iron catalysis.7 We wondered if vinyl acetates
could be alkylated with unreactive benzyl ammoniums8 by
reductive nickel catalysis, which is very challenging because
of the following facts. 1) Construction of the C−C bond via
C−N and C−O cleavage remains unknown; 2) Reaction of
ammonium salts with R−X electrophiles is unknown; 3) The
alkylation of vinyl acetates with mild reactants or catalyst
other than iron remains unknown. Moreover, the high
activation barrier for C−N/C−O cleavage7a and selectivity
challenge in the presence of multiple C−N and C−O bonds
means controlling the selectivity for the desired product
would be particularly difficult.9
C−N and C−O electrophiles (e.g. ammonium salts, acetates,
and ethers) have recently become
a complementary
alternative to organic halides within the cross-coupling
arena.4 Progress in this field has led to numerous useful
transformations, including a few reductive coupling reactions
with organic halides or CO2,5 with a broad spectrum of C−N
and C−O electrophiles proven to be effective (Scheme 1a,
path b). Encouraged by these results, we wondered about the
possibility of a coupling reaction between C−N and C−O
electrophiles (Scheme 1a, path c). If successful, such a
strategy for C−C bond formation through synergistic C−N
and C−O bond cleavage would provide a new platform for
the cross-electrophile reaction, and would offer a hitherto
unrecognized opportunity for new reaction discovery. Herein,
we describe our preliminary results for detailing the
With these considerations in mind, we studied the
reaction of ammonium salt 1a with acetate 2a (see Table S1 in
the SI for details). After systematic screening of the reaction
conditions, we found that performing the reaction with
NiBr2(diglyme) (10 mol %), Bphen (22 mol %), NaOAc (1.2
equiv), and Mn (4.0 equiv) in DMF (0.1 M) at 80 oC gave
product 3a with 89% isolated yield. Under these conditions,
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the reactions of 2a with benzylic chloride10 or bromide gave
Table 2. Scope of the ammonium salt reactionsa
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the desired product with 25% and 34% yields, whereas only a
trace of product was observed when benzylic pyridinium
salt11 or mesylate12 was used (Table S2). The reaction of 2a
with benzylic oxalate,5h,13 an electrophile used in our previous
reductive alkylation reaction, afforded the product with 61%
yield.
Allylic arenes are ubiquitous motifs in various biologically
active compounds and natural products. While the
established allylation reactions5i,14 and benzyl-vinyl coupling
reactions10-12 are powerful methods for the synthesis of these
valuable targets, they are usually inefficient in producing 2-
substituted allylic arenes. We then studied the reactions of 1a
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with
a wide range of 1-substituted vinyl acetates to
investigate the potential of our method for the preparation of
this type of compounds (Table 1). A wide range of styryl
acetates such as unsubstituted (2b), electron-rich (2c),
electron-poor (2d−2f), and -extended compounds (2g)
coupled with 1a efficiently. The reactions of heterocycle
substituted vinyl acetates (2h, 2i) proceeded readily. Alkyl
substituted vinyl acetates were converted into target
products with high yields (2j−2l). The presence of
vinylcyclopropane or conjugated diene was compatible (2m,
2n). The reactions of functionalized aliphatic vinyl acetates
afforded desired products with good yields (2o−2s). The
reaction of 2-substiuted or 1,2-dialkylated substrate gave the
products with moderate yields (2t, 2u). The reaction of fully
Table 1. Scope of the vinyl acetate reactionsa
o
c
aReactions were performed at 60−100 C. b2a was used. 2b
was used. 4-tBu-cyclohexenyl acetate (2ab) was used. 2aa
(0.2 mmol), 4 (0.6 mmol), and NiBr2 (10 mol %) were used.
fKOAc (1 equiv) was used.
d
e
substituted or non-substituted vinyl acetate was presently
inefficient (2v, 2w). Cyclic vinyl acetates ranging from six- to
eight-membered rings coupled with 1a efficiently (2x−2aa).
The reactions proceeded efficiently with a variety of benzyl
ammonium salts (Table 2). The reactions of naphthyl
substrates (1b, 1c) gave vinylated products with good yields.
Substitution around the aromatic ring was tolerated (1d−1f).
The reaction was highly selective for cleavage of the C−N
bond, leaving the ester (1d−1f), trifluoromethyl group (1g),
terminal styrene (1h), and boronic ester (1i) intact. The
presence of heterocycles such as indole and furan proved
compatible with our conditions (1j−1k). The reaction of
MOM-protected substrate 1l with 4-tBu-cyclohexenyl acetate
2ab afforded 3al in 70% yield, which is an important
intermediate for the synthesis of a grisan analogue (Scheme
2b). The methoxyl group at the ortho and para positions of
the aromatic ring was tolerated (1m−1n). When secondary
benzylic ammonium salts were employed, naphthyl
substituents were required to afford the target products with
good yields (1o−1q).
Anilines are readily available chemical feedstocks. The
coupling of aryl ammonium salts generally requires strong
nucleophiles (e.g. Ar−M, M = Mg, Zn, Sn), and research in
this area has mainly progressed in the field of arylation
aReaction of 1a (0.2 mmol) and 2 (0.4 mmol) for 24 h. Yields
are isolated yields. bReaction with 1n at 100 oC. 2t (E/Z = 1.2:1),
3t (E/Z = 100:0). c2u (E/Z = 1:1.9), product 3u (E/Z = 1:1).
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reactions.15 Under slightly modified conditions, a number of
Scheme 3. Mechanistic studies
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aryl ammonium salts coupled efficiently with acetate 2aa to
form vinylation products (Table 2, 4a−4h). The presence of a
substituent at the para or meta position was tolerated.
Substrates bearing electron-withdrawing groups, including
CF3 (4b, 4c), ester (4d, 4e), sulfone (4f), boronic ester (4g),
and fluorine (4h), have shown high reactivity and selectivity.
Unfortunately, the reaction of electron-rich aryl ammoniums
is currently unsuccessful. Presently, the reaction of allyl
ammonium or alkyl ammonium with vinyl acetate 2b has
failed to give the desired product.
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Table 3. Reactions of 1a with aryl C−O electrophiles
b
aReaction of 1a without a coupling partner. NiBr2(diglyme)
(40 mol%) was used, reaction at rt.
Diarylmethanes are important substructures found in a
substantial number of pharmaceuticals, biologically active
compounds, and organic materials.16 Under our conditions,
various aryl C−O electrophiles coupled with benzylic
ammonium 1a to construct these unique structures (Table 3).
While the reactions of aryl mesylate (6a״) and acetate (6a״׳)
were less effective, either aryl triflate (6a) or tosylate (6a׳)
reacted efficiently. The presence of sterically hindered group
at the ortho position was tolerated (6b, 6h). The reactions of
aryl triflates bearing electron-rich (6b−6e) or electron-poor
(6f) substituents performed well.
analogue 11,
a
urotensin-II receptor agonist,18 was
synthesized from 3ad by hydration and cycloaddition
processes (Scheme 2c).
It is well-known that ammonium salts undergo oxidative
addition to Ni(0).8 However, our control experiments
indicate that the activation of ammonium salts under the
current circumstances might involve a radical process.19 (1)
The reaction of optically pure benzyl ammonium salt gave
the coupling product with no enantiomeric excess (Figure
S1).20 (2) Dimer 14 was isolated in 26% yield when 1a was
subjected to the standard conditions (Scheme 3−1a). (3) In
the presence of Hantzsch ester (1 equiv), a hydrogen atom
donor capable of trapping of carbon radicals,21 formation of
dimer 14 was inhibited, whereas a significant increase of
benzyl−H was observed (Scheme 3−1b).22 (4) It is known that
trapping of benzyl radical with O2 can afford benzaldehyde.23
Under the reductive conditions, in the presence of O2 (10
ppm), the reaction of 1a gave aldehyde 13 with 31% yield
along with a trace of dimer 14 (Scheme 3−1c).
The potential synthetic application of this method has
been demonstrated in Scheme 2. Substrate 8 derived from
stanolone reacted with 1n selectively, affording the
benzylated product 9 with good yield (Scheme 2a). The
method has also provided an alternative approach to
biologically active compounds containing structures. Grisan17
analogue 10 was obtained in 2 steps from product 3al with 94%
yield (Scheme 2b). AC−7954
Scheme 2. Application in synthesis
Further evidence for
a
radical mechanism was
demonstrated by radical clock experiments. The reaction of
1a with α-cyclopropylstyrene 15, a well-known radical clock
substrate probe,24 gave ring-expanded product 16 either in
the presence of [Ni(cod)2/Bphen] or under standard
conditions (Scheme 3−2a). Moreover, the reaction of
cyclopropyl ammonium 17 with 2b exclusively produced ring
opening products (Scheme 3−2b).25 These results further
suggest that the ammonium salts were activated by nickel
catalyst via a radical mechanism.
Previous work by Kochi and Baird have shown the reaction
of aryl/alkyl halide with nickel(0) provided carbon radical
and nickel(I).26 Thus it is possible that benzyl radical could
be generated by one electron reduction of benzyl ammonium
salt with nickel(0). This is consistent with our observation
that, in the presence of Ni(COD)2 (0.5 equiv) and without
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Coupling of Alkyl Halides with Other Electrophiles: Concept and
Mn, the reaction of benzyl ammonium 1a with ethyl acrylate
afforded radical trapping products in 42% yield (Figure S7).
Alternatively, it is also possible that the in situ formed Ni(I)
species would undergo electron transformation with benzyl
ammonium to afford benzyl radical.27 Presently, the precise
mechanism of the reaction remains under investigation.28
Mechanistic Considerations. Org. Chem. Front. 2015, 2, 1411. (e) Lucas,
E. L.; Jarvo, E. R. Stereospecific and Stereoconvergent Cross-
couplings between Alkyl Electrophiles. Nat. Rev. Chem. 2017, 1, 0065.
(f) Richmond, E.; Moran, J. Recent Advances in Nickel Catalysis
Enabled by Stoichiometric Metallic Reducing Agents. Synthesis 2018,
50, 499.
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(3) Selected references: (a) Amatore, M.; Gosmini, C. Efficient
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and Its Application in the Synthesis of a Sartan Intermediate. Angew.
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D. J. Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with
Alkyl Halides. J. Am. Chem. Soc. 2010, 132, 920. (c) Xu, H.; Zhao, C.;
Qian, Q.; Deng, W.; Gong, H. Nickel-catalyzed Cross-coupling of
In conclusion, we have demonstrated the first coupling
reaction to our knowledge between C−N and C−O
electrophiles. This work has established a framework for
constructing C−C bonds through C−N and C−O cleavage. It
thus serves as a newly described and complementary bond
disconnection synthetic strategy that is likely to find broad
applications, because of the broad existence of N- and O-
containing compounds in the natural world and the
synthetic realm. Preliminary mechanistic studies revealed
that the ammonium salts are activated by Ni catalysts to be
carbon radicals, which may provide a new dimension to the
functionalization of C−N bonds.29 Studies of the detailed
mechanism of this reaction, expanding the scope of C−N and
C−O electrophiles, and the asymmetric functionalization of
C−N bonds are ongoing in our laboratory.
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ASSOCIATED CONTENT
Supporting Information
Parts of the mechanistic studies, detailed experimental
1
procedures, characterization data, and copies of H and 13C
NMR spectra for new compounds are available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
shuxingzh@lzu.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
for their financial support (21772072, 21502078). We are
grateful to Prof. Wei Yu (Lanzhou University) for helpful
discussion.
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(11) Guan, W.; Liao, J.; Watson, M. P. Vinylation of Benzylic
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(12) Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix,
D. J. Cobalt co-catalysis for cross-electrophile coupling:
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(13) Ye, Y.; Chen, H.; Sessler, J. L.; Gong, H. Zn-Mediated
Fragmentation of Tertiary Alkyl Oxalates Enabling Formation of
Alkylated and Arylated Quaternary Carbon Centers. J. Am. Chem.
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(16) A review for application, see: (a) Mondal, S.; Panda, G.
Synthetic methodologies of achiral diarylmethanols, diaryl and
triarylmethanes (TRAMs) and medicinal properties of diaryl and
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Synthesis of Aryl(di)azinylmethanes and Bis(di)azinylmethanes via
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alcohols to construct diarylmethanes via palladium catalysis. Chem.
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Wangelin, A. Iron-Catalyzed Cross-Coupling of Alkenyl Acetates.
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Alkenyl/Aryl Carboxylates with Grignard Reagent via Fe-Catalyzed
C−O Bond Activation. J. Am. Chem. Soc. 2009, 131, 14656.
(8) Ammonium salts are readily available from amines, and are
stable to long-term storage. For selected reactions using benzyl
ammoniums, see: (a) de la Herrán, G.; Segura, A.; Csák,ÿ A. G.
Benzylic Substitution of Gramines with Boronic Acids and Rhodium
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Catalyzed Cross Couplings of Benzylic Ammonium Salts and Boronic
Acids: Stereospecific Formation of Diarylethanes via C-N Bond
Activation. J. Am. Chem. Soc. 2013, 135, 280. (c) Zhang, H.; Hagihara,
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16796. (d) Hu, J.; Sun, H.; Cai, W.; Pu, X.; Zhang, Y.; Shi, Z. Nickel-
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Benzylammonium Salts with Boronic Acids under Mild Conditions.
Synthesis 2018, 50, 793.
(9) Our initial studies revealed that at least 7 types of products
were observed, which were formed via cleavage of Bn−N, Me−N,
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Nonpeptide Agonist of the GPR14/Urotensin-II Receptor: 3-(4-
Chlorophenyl)-3-(2- (dimethylamino)ethyl)isochrom-an-1-one (AC-
7954). J. Med. Chem. 2002, 45, 4950.
(19) Methods for generating carbon radicals from ammonium salts
are rarely known. Selected references: (a) Dubois, J. E.; Monviznay,
A.; Lacaze, P. C. Elcctrochimica Acta. 1970, 15, 315. (b) Mfuh, A. M.;
Doyle, J. D.; Chhetri, B.; Arman, H. D.; Larionov, O. V. J. Am. Chem.
Soc. 2016, 138, 2985. Also see: ref. 5k.
5313. (f) Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy
for the Visible‐Light‐Mediated Generation of Alkyl Radicals. Angew.
Chem. Int. Ed. 2017, 56, 12336. (g) Wu, J.; He, L.; Noble, A.; Aggarwal
V. K. Photoinduced Deaminative Borylation of Alkylamines. J. Am.
Chem. Soc. 2018, 140, 10700.
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(20) It is also possible that the reversible β-hydride
elimination/reinsertion pathway may lead to the racemization of the
product.
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(21) Huang, W.; Cheng, X. Hantzsch Esters as Multifunctional
Reagents in Visible-Light Photoredox Catalysis. Synlett 2017, 28, 148.
(22) The deuterium experiments have revealed that most of
benzyl−H was produced from HE (Figure S6).
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(23) Goswami, S.; Mahapatra, A. K. Aromatic aldehydes from
benzylbromides via Cobalt(I) mediated benzyl radicals in the
presence of aerial oxygen: a mild oxidation reaction in neutral
condition. Tetrahedron Lett. 1998, 39, 1981.
(24) (a) Liwosz, T. W.; Chemler, S. R. Copper-Catalyzed Oxidative
Heck Reactions between Alkyltrifluoroborates and Vinyl Arenes. Org.
Lett., 2013, 15, 3034. (b) Feng, Z.; Min, Q.-Q.; Zhao, H.-Y.; Gu, J.-W.;
Zhang, X.
A General Synthesis of Fluoroalkylated Alkenes by
Palladium ‐ Catalyzed Heck ‐ Type Reaction of Fluoroalkyl
Bromides. Angew. Chem. Int. Ed. 2015, 54, 1270. (c) Chatalova-
Sazepin, C.; Wang, Q.; Sammis, G. M.; Zhu, J. Copper-Catalyzed
Intermolecular Carboetherification of Unactivated Alkenes by Alkyl
Nitriles and Alcohols. Angew. Chem. Int. Ed. 2015, 54, 5443.
(25) Terminal alkyl radical might combine with Ni(I) to generate
alkyl-Ni(II), which can undergo β-hydride elimination/reinsertion
process to afford allyl-Ni. The coupling of allyl-Ni with vinyl acetate
would afford branched product 18. Please see Figure S5 in the SI for
details. Selected related references, see：(a) Sommer, H.; Juliá-Hern
á ndez, F.; Martin, R.; Marek, I. Walking Metals for Remote
Functionalization. ACS Cent. sci., 2018, 4, 153. (b) Chen, F.; Chen, K.;
Zhang, Y.; He, Y.; Wang, Y.-M.; Zhu, S. Remote Migratory Cross-
Electrophile Coupling and Olefin Hydroarylation Reactions Enabled
by in Situ Generation of NiH. J. Am. Chem. Soc., 2017, 139, 13929.
(26) For an isolated example that demonstrates radical oxidative
addition of benzyl ammonium to Ni(0), see: (a) Tsou, T. T.; Kochi, J.
K. Mechanism of Oxidative Addition. Reaction of Nickel(0)
Complexes with Aromatic Halides. J. Am. Chem. Soc., 1979, 101, 6319.
For related elegant work, see: (b) Kehoe, R.; Mahadevan, M.;
Manzoor, A.; McMurray, G.; Wienefeld, P.; Baird, M. C. Reactions of
the Ni(0) Compound Ni(PPh3)4 with Unactivated Alkyl Halides:
Oxidative Addition Reactions Involving Radical Processes and
Nickel(I) Intermediates. Organometallics, 2018, 37, 2450.
(27) For related elegant work, see: (a) Dudnik, A. S.; Fu, G. C.
Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles,
Including Unactivated Tertiary Halides, To Generate Carbon−Boron
Bonds. J. Am. Chem. Soc., 2012, 134, 10693. (b) Biswas, S.; Weix, D.
Mechanism and Selectivity in Nickel-Catalyzed Cross-Electrophile
Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2013,
135, 16192. (c) Everson, D. A.; Weix, D. J. Cross-Electrophile Coupling:
Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79, 4793.
(28) Some possible pathways for the reaction of benzyl
ammoniums with vinyl acetates have been listed in Figure S9 in the
SI.
(29) Methods for the generation of alkyl radicals are important.
Selected recent reviews: (a) Shaw, M. H.; Twilton, J.; MacMillan, D.
W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016,
81, 6898. (b) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. Radicals:
Reactive Intermediates with Translational Potential. J. Am. Chem.
Soc. 2016, 138, 12692. (c) Kaga, A.; Chiba, S. Engaging Radicals in
Transition Metal-Catalyzed Cross-Coupling with Alkyl Electrophiles:
Recent Advances. ACS Catal. 2017, 7, 4697. (d) Fu, G. C. ACS Cent.
Sci., 2017, 3, 692. The generation of alkyl radicals from alkylamines
via Katritzky pyridinium salts has recently found numerous
applications, see: (e) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson,
M. P. Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed
Cross Couplings via C–N Bond Activation. J. Am. Chem. Soc. 2017, 139,
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