Alkenyl Exchange of Allylamines via Nickel(0)-Catalyzed C-C Bond Cleavage

Article abstract of DOI:10.1021/jacs.8b13251

A functional group exchange reaction between allylamines and alkenes via nickel-catalyzed C - C bond cleavage and formation was developed. This reaction provides a novel protocol, which does not require the use of unstable imine substrates, for the synthesis of allylamines, which are widely used in the production of fine chemicals, pharmaceuticals, and agrochemicals.

Full text of DOI:10.1021/jacs.8b13251

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Alkenyl Exchange of Allylamines via Nickel(0)-Catalyzed C−C Bond
Cleavage
Chao Fan,† Xin-Yang Lv,† Li-Jun Xiao,*,† Jian-Hua Xie,†,‡ and Qi-Lin Zhou*,†,‡
†State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
undergo imine−enamine tautomerization, decomposition, and
self-condensation during preparation and storage.9 This
ABSTRACT: A functional group exchange reaction
between allylamines and alkenes via nickel-catalyzed
CC bond cleavage and formation was developed. This
reaction provides a novel protocol, which does not require
the use of unstable imine substrates, for the synthesis of
allylamines, which are widely used in the production of
fine chemicals, pharmaceuticals, and agrochemicals.
instability limits their utility for the synthesis of allylamines.
Recently, we developed a protocol for synthesizing allyl-
amines via nickel(0)-catalyzed addition of alkenes to imines,
that is, hydroalkenylation of imines.10 The reaction proceeds
via an aza-nickellacycle intermediate. The reversibility of the
reaction suggested that the alkenyl group of the allylamine can
undergo exchange with another alkene to produce a new
allylamine. In this alkenyl group exchange reaction, the
allylamine substrate, the allylamine product, and two alkenes
(one dissociated from the starting allylamine and one added)
are in equilibrium. If the alkene that dissociates from the
starting allylamine was a volatile gas that could be removed
from the reaction system, the equilibrium would shift to favor
the formation of the new allylamine (Scheme 1b). We herein
report our study of alkenyl exchange reactions between
allylamines and alkenes via nickel(0)-catalyzed CC bond
cleavage, which provides a new route to allylamines that does
not involve the use of imine reagents.
unctional group exchange reactions can be used to install
For remove functional groups and thus prepare molecules
that might be tedious to synthesize by traditional methods.
Research in the field of dynamic covalent chemistry1 has led to
the development of group exchange reactions, such as
transesterification2 and olefin metathesis,3 that have greatly
facilitated the synthesis of functionalized molecules under
equilibrium-controlled conditions and have opened up new
avenues for the synthesis of organic compounds and materials.4
However, group exchange reactions that involve CC bond
cleavage and formation remain a challenge.5
Transition-metal-catalyzed selective cleavage and formation
of CC bonds are fundamental transformations in modern
organic synthesis.6 Great progress has been made in catalytic
transfer functionalization reactions that involve cleavage and
formation of CC bonds.7 These reactions can be regarded as
group exchange reactions, but the two exchanged functional
groups are different from each other.
We began by investigating the alkenyl exchange between
styrene (1a) and allylamine 2a. After careful optimization of
the reaction conditions, we established an efficient protocol
using a nickel catalyst generated in situ from Ni(COD)2 and
PCy3 (see the Supporting Information for details). We then
evaluated the effect of the alkenyl group of the allylamine
substrate (Table 1, 2a−d). These experiments offered two
We envisioned a new strategy for using group exchange
reactions to synthesize allylamines. Allylamines are widely used
versatile building blocks for the synthesis of fine chemicals,
pharmaceuticals, and agrochemicals and are typically synthe-
sized by the addition of alkenes or their equivalents to imines
(Scheme 1a).8 However, imines in general, and aliphatic
imines in particular, are reactive and unstable and tend to
Table 1. Alkenyl Exchange of Allylamines Having Different
Vinyl Group
a
Scheme 1. Synthesis of Allylamines
a
Conditions: 1a (0.25 mmol), 2a (0.30 mmol) in hexane (1.0 mL).
b
NMR yields. 15 mol% TsNH2 was added.
Received: December 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b13251
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Journal of the American Chemical Society
Communication
notable insights. First, allylamine 2a, which has a vinyl group
that could be released as ethylene gas during the reaction, was
an ideal substrate for the reaction with styrene, producing
allylamine 3a in 99% yield. Second, all the other tested
allylamines (2b−d) also gave 3a upon reaction with styrene.
The fact that the reaction of 2d provides the same product 3a
excludes the possibility that the reaction proceeded by an
alkene metathesis mechanism, in which the two CC bonds
of starting allylamine and styrene should be cleaved and
reconstituted.3
Using the optimized conditions, we then explored the
substrate scope of the reaction between styrene and various
allylamines 2 (Table 2). Like our previous work of alkene-
imine coupling, allylamines substituted with an alkyl group (2a,
2e−2h) afforded alkenyl exchange products in excellent yields
(88−98%) regardless of the steric bulk of the alkyl group. It
was delighted to find that this protocol also works well for the
substrates 2i and 2j, giving alkenyl exchange products 3i and
3j, which are difficult to be obtained by the coupling of alkenes
and imines10a because the acetaldehyde imine and trifluoro-
acetaldehyde imine are sensitive to moisture and very
unstable.9c The allylamines bearing a small ring, an ether
bond or a CC bond (2k−2p) were compatible with the
reaction conditions. It is worth mentioning that no any
competitive product from the reaction of additional CC
bond in the substrates 2n−2p was detected. The tolerance of
additional CC bond in the substrates 2n−2p not only
indicates that this reaction is an alkenyl exchange of
allylamines, but also shows advantage of this protocol over
olefin metathesis, which is difficult to selectively react with one
of two CC bonds.3 In addition, the racemic allylamine 2q
gave alkenyl exchange product 3q in a 1:1 mixture of two
diastereoisomers, showing no diastereoselectivity in the
reaction.
Table 2. Alkenyl Exchange of Various Allylamines with
a b
,
Styrene
Next, we examined allylamines with an aryl group and found
that these substrates give low conversion in the alkenyl
exchange reaction under the conditions used for alkyl-
substituted allylamines. Therefore, we explored various
additives to promote the reaction, and we found that TsNH2
gave the best result.11 Using the optimized conditions (30%
TsNH2 in toluene), we then carried out alkenyl exchange
reactions between styrene and aryl-substituted allylamines 2r−
2ab. The electronic properties of the aryl group had little
influence on the yield; products 3r−3x were obtained in
moderate to good yields. Exceptions were p-methoxyphenyl-
substituted compound 2y and 2-naphthyl-substituted com-
pound 2z, which gave lower yields (44% and 36%,
respectively). The effect of the protecting group on the
nitrogen atom of the allylamine was also examined; the
sulfonyl group proved to be necessary, and p-trifluoromethyl-
benzenesulfonyl compound 2aa gave a lower yield than p-tosyl-
and p-methoxybenzenesulfonyl compounds 2r and 2ab,
respectively. However, nitrobenzenesulfonyl allylamine was
not compatible with this protocol and could not give the
desired product.
A variety of alkenes were then investigated in alkenyl
exchange reactions with allylamine 2a (Table 3). Aryl alkenes
bearing substituents with various electronic and steric
properties, as well as heteroaryl alkenes, underwent the
reaction smoothly and afforded the desired products in yields
varying from 60% to 98%. The only low yield was that
obtained with thienyl-substituted alkene 4n (45%). Notably,
TMS and Bpin groups were well tolerated, giving products 4g
and 4h, respectively, which can undergo further functionaliza-
tion. Aliphatic α-alkenes also reacted with 2a but delivered
homoallylic amines as the major products (4o−4q). Only
allyltrimethylsilane substrate 1r afforded an allylamine (4r) as
the major product. Notably, this transformation could be used
for complex molecule derivatization (4t). We also succeeded in
synthesizing BW B70C, a very potent 5-lipoxygenase
inhibitor,12 by using the reaction of methyl-substituted
allylamine 2i with alkene 1u as a key step.
a
Condition A: 1a(0.25 mmol), 2 (0.30 mmol), Ni(COD)2 (10 mol
%), PCy3 (20 mol%) in hexane (1.0 mL) at 100 °C for 12 h.
Condition B: 1a (0.50 mmol), 2 (1.0 mmol), Ni(COD)2 (20 mol%),
PCy3 (40 mol%), TsNH2 (30 mol%) in toluene (1.0 mL) at 100 °C
Previous studies by Ogoshi et al.13 and by our group10
showed that nickel(0) can mediate reactions of imines and
alkenes to form five-membered aza-nickellacycle intermediates.
In this study, we focused on elucidating the individual steps of
aza-nickellacycle formation and CC bond cleavage from
allylamines (Scheme 2). First, we found that carbonylation of
b
c
for 5 h. Isolated yields; NMR yields are given in parentheses. 2.0
equiv of 1d was used; PMP = p-MeOC6H4. No desired product was
detected when p-NO2C6H4 was used.
d
B
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Communication
allylamine 2a with stoichiometric Ni(COD)2/PCy3 under a
CO atmosphere afforded γ-lactam 5 (Scheme 2a). Because CO
is known to insert into the Ni−C bond of nickellacycle
compounds,13,14 this result indicates that nickel(0) forms an
aza-nickellacycle intermediate with allylamine 2a. Next, we
carried out deuterium-labeling experiments using d8-styrene
and d-2a (Scheme 2b). The irregular H/D distribution at the
CC bond of the products and the recovered substrates
suggested: (1) the NH proton of 2a participates in the
formation of NiH intermediate; (2) the formation of NiH
and subsequent insertion/cyclization/β-hydride elimination
are all reversible. To assess the CC bond cleavage step,
we studied the decomposition reaction with allylamine 3r
(Scheme 2c), which gives styrene and benzaldehyde15 derived
from the hydrolysis of benzaldimine. This result revealed that
the allylamine can be cleaved by Ni catalyst to imine and
alkene, which will exchange with another alkene. The exchange
reaction of allylamine 3r with 4-tert-butylstyrene, producing
only allylamine 4v, nothing else including 1-phenyl-2-(4-tert-
butylphenyl)ethene was observed, showed that the reaction
proceeds via reversible alkenyl exchange mechanism, instead of
olefin metathesis mechanism.
Table 3. Alkenyl Exchange of Allylamines with Different
Alkenes and Its Applications
a b
,
On the basis of previous studies10 and the above-described
experimental results, we developed a plausible mechanism for
the alkenyl exchange reaction of allylamines (Scheme 3). First,
Scheme 3. Proposed Mechanism
a
Condition A: 1 (0.25 mmol), 2a (0.30 mmol), Ni(COD)2 (10 mol
b
%), PCy3 (20 mol%) in hexane (1.0 mL) at 100 °C for 12 h. Isolated
yields; NMR yields are given in parentheses. 5.0 equiv of alkene 1
was used. Yield of the mixture of two isomers. A/H = ratio of allylic
amine to homoallylic amine. For detailed conditions, see Supporting
c
d
e
Information.
Scheme 2. Mechanistic Study
oxidative addition of the NH bond of tosylamine to
nickel(0) yields NiH intermediate A. The insertion of the
CC bond of 2 into the NiH bond and subsequent
intramolecular coordination/cyclization of B affords aza-
nickellacycle intermediate C. The intermediate C undergoes
a CC bond cleavage to form intermediate D, a nickel
complex coordinated by an alkene and an imine. Ligand
exchange of intermediate D with alkene substrate 1 produces
intermediate E, which undergoes oxidative cyclization to form
new aza-nickellacycle intermediate F. The NH of the
tosylamine promotes ring-opening of F to form intermediate G
by protonating the N atom and coordinating to the nickel
C
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Journal of the American Chemical Society
Communication
atom of the aza-nickellacycle.16 Finally, β-hydride elimination
of G delivers alkenyl exchange product 3 and regenerates the
NiH intermediate A.
(5) During the preparation of this manuscript, two excellent works
on the Pd-catalyzed group exchange reaction involving CC bond
cleavage and formation and metathesis of aryl chlorides and aryl
iodides were reported: (a) Lee, Y.-H.; Morandi, B. Metathesis-active
ligands enable a catalytic functional group metathesis between aroyl
chlorides and aryl iodides. Nat. Chem. 2018, 10, 1016. (b) De La
Higuera Macias, M.; Arndtsen, B. A. Functional group transposition: a
palladium-catalyzed metathesis of Ar-X σ-bonds and acid chloride
synthesis. J. Am. Chem. Soc. 2018, 140, 10140.
(6) For recent reviews, see: (a) Dong, G.-B. C-C bond activation;
Topics in Current Chemistry 346; Springer: Berlin, 2014. (b) Chen,
F.; Wang, T.; Jiao, N. Recent advances in transition-metal-catalyzed
functionalization of unstrained carbon−carbon bonds. Chem. Rev.
2014, 114, 8613. (c) Liu, H.; Feng, M.-H.; Jiang, X.-F. Unstrained
carbon-carbon bond cleavage. Chem. - Asian J. 2014, 9, 3360.
(d) Souillart, L.; Cramer, N. Catalytic C-C bond activations via
oxidative addition to transition metals. Chem. Rev. 2015, 115, 9410.
(e) Marek, I.; Masarwa, A.; Delaye, P.-O.; Leibeling, M. Selective
carbon-carbon bond cleavage for the stereoselective synthesis of
acyclic systems. Angew. Chem., Int. Ed. 2015, 54, 414. (f) Murakami,
M.; Chatani, N. Cleavage of carbon-carbon single bonds by transition
metals; Wiley-VCH: Weinheim, Germany, 2016. (g) Song, F.-J.; Gou,
T.; Wang, B.-Q.; Shi, Z.-J. Catalytic activation of unstrained C-C bond
involving organometallic intermediates. Chem. Soc. Rev. 2018, 47,
7078.
In summary, we have developed a protocol for an
unprecedented nickel-catalyzed alkenyl exchange reaction
between allylamines and alkenes that proceeds via CC
bond cleavage and formation. This novel alkenylation protocol
provides synthetically useful allylamines without the need for
unstable imine substrates. In this reaction, nickel(0) mediates
the formation of an aza-nickellacycle, which decomposes to
afford an alkene and an imine by means of CC bond
cleavage. This catalytic cycle involving aza-nickellacycle
formation and CC bond cleavage may be applicable to
other dynamic covalent chemistry transformations.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b13251.
Experimental procedures, optimization, and character-
ization (PDF)
(7) For a recent review, see: (a) Bhawal, B. N.; Morandi, B. Catalytic
transfer functionalization through shuttle catalysis. ACS Catal. 2016,
6, 7528. For recent examples, see: (b) Murphy, S. K.; Park, J.-W.;
Cruz, F. A.; Dong, V. M. Rh-catalyzed C-C bond cleavage by transfer
hydroformylation. Science 2015, 347, 56. (c) Fang, X.; Yu, P.;
Morandi, B. Catalytic reversible alkene-nitrile interconversion through
controllable transfer hydrocyanation. Science 2016, 351, 832.
(d) Fang, X.; Yu, P.; Prina Cerai, G.; Morandi, B. Cobalt(III)-
catalyzed functionalization of unstrained carbon-carbon bonds
through β-carbon cleavage of alcohols. Chem. - Eur. J. 2016, 22,
15629.
AUTHOR INFORMATION
Corresponding Authors
*1120140207@mail.nankai.edu.cn (L.-J.X.)
*qlzhou@nankai.edu.cn (Q.-L.Z.)
ORCID
Chao Fan: 0000-0002-6981-7292
Li-Jun Xiao: 0000-0002-3998-3628
Jian-Hua Xie: 0000-0003-3907-2530
Qi-Lin Zhou: 0000-0002-4700-3765
■
(8) (a) Volkmann, R. A. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Schreiber, S. L., Eds.; Pergamon Press: Oxford,
1991; Vol. 1, Chapter 1.12. (b) Skucas, E.; Ngai, M.-Y.; Komanduri,
V.; Krische, M. J. Enantiomerically enriched allylic alcohols and allylic
imines via C-C bond-forming hydrogenation: asymmetric carbonyl
and imine vinylation. Acc. Chem. Res. 2007, 40, 1394. (c) Chen, D.;
Xu, M.-H. Transition metal-catalyzed asymmetric addition of
organoboron reagents to imines. Youji Huaxue 2017, 37, 1589.
(9) (a) Li, Z.-J; Ren, X.-H.; Shi, Y.-H.; Ouyang, P.-K. Practical and
general entry to N-tosyl aryl aldimines promoted by sulfamic acid in
water and alcohol. Synth. Commun. 2007, 37, 713. (b) Morales, S.;
Guijarro, F. G.; Garcia Ruano, J. L.; Cid, M. B. A general
aminocatalytic method for the synthesis of aldimines. J. Am. Chem.
Soc. 2014, 136, 1082. (c) Filler, R., Kobayashi, Y., Yagupolski, L. M.,
Eds. Organofluorine compounds in medicinal chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993.
(10) (a) Xiao, L.-J.; Zhao, C.-Y.; Cheng, L.; Feng, B.-Y.; Feng, W.-
M.; Xie, J.-H.; Xu, X.-F.; Zhou, Q.-L. Nickel(0)-catalyzed hydro-
alkenylation of imines with styrene and its derivatives. Angew. Chem.,
Int. Ed. 2018, 57, 3396. (b) Liu, X.-H.; Feng, X.-M. Dual nickel and
Brønsted acid catalysis for hydroalkenylation. Angew. Chem., Int. Ed.
2018, 57, 16604.
(11) For detailed optimization, see Supporting Information.
(12) Yeadon, M.; Dougan, F. L.; Petrovic, A.; Beesley, A.; Payne, A.
N. Effect of BW B70C, a novel inhibitor of arachidonic acid 5-
lipoxygenase, on allergen-induced bronchoconstriction and late-phase
lung eosinophil accumulation in sensitised guinea-pigs. Agents Actions
1993, 38, 8.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21790332 and 21532003) and the “111” project
(B06005) of the Ministry of Education of China for financial
support.
REFERENCES
■
(1) (a) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K.
M.; Stoddart, J. F. Dynamic covalent chemistry. Angew. Chem., Int. Ed.
2002, 41, 898. (b) Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.;
Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Dynamic combinatorial
chemistry. Chem. Rev. 2006, 106, 3652.
(2) Otera, J. Transesterification. Chem. Rev. 1993, 93, 1449.
(3) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH Verlag
GmbH& Co.: Weinheim, Germany, 2003.
(4) For recent examples on group exchange, see: (a) Basset, J.-M.;
Coperet, C.; Soulivong, D.; Taoufik, M.; Cazat, J. T. Metathesis of
alkanes and related reactions. Acc. Chem. Res. 2010, 43, 323.
(b) Belowich, M. E.; Stoddart, J. F. Dynamic imine chemistry.
Chem. Soc. Rev. 2012, 41, 2003. (c) Baker, E. L.; Yamano, M. M.;
Zhou, Y.; Anthony, S. M.; Garg, N. K. A two-step approach to achieve
secondary amide transamidation enabled by nickel catalysis. Nat.
Commun. 2016, 7, 11554. (d) Lian, Z.; Bhawal, B. N.; Yu, P.;
Morandi, B. Palladium-catalyzed carbon-sulfur or carbon-phosphorus
bond metathesis by reversible arylation. Science 2017, 356, 1059.
(e) Gu, R.-R.; Flidrova, K.; Lehn, J.-M. Dynamic covalent metathesis
in the C=C/C=N exchange between Knoevenagel compounds and
imines. J. Am. Chem. Soc. 2018, 140, 5560.
(13) (a) Hoshimoto, Y.; Ohata, T.; Sasaoka, Y.; Ohashi, M.; Ogoshi,
S. Nickel(0)-catalyzed [2+2+1] carbonylative cycloaddition of imines
and alkynes or norbornene leading to γ-lactams. J. Am. Chem. Soc.
2014, 136, 15877. (b) Hoshimoto, Y.; Ashida, K.; Sasaoka, Y.; Kumar,
R.; Kamikawa, K.; Verdaguer, X.; Riera, A.; Ohashi, M.; Ogoshi, S.
D
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Journal of the American Chemical Society
Communication
Efficient synthesis of polycyclic γ-lactams by catalytic carbonylation of
ene-imines via nickelacycle intermediates. Angew. Chem., Int. Ed.
2017, 56, 8206.
(14) Hoberg, H.; Oster, B. W. Modellkomplex des nickels fu
CC verknupfung von alkinen mit isocyanaten. J. Organomet. Chem.
1982, 234, C35.
̈
r die
̈
(15) Benzaldehyde would further convert to benzoic acid and
decompose to benzene and carbon monoxide. See: Xiao, L.-J.; Fu, X.-
N.; Zhou, M.-J.; Xie, J.-H.; Wang, L.-X.; Xu, X.-F.; Zhou, Q.-L.
Nickel-catalyzed hydroacylation of styrenes with simple aldehydes:
reaction development and mechanism insights. J. Am. Chem. Soc.
2016, 138, 2957.
(16) Our previous study (ref 10) showed that the tosylamine-
promoted ring-opening of an azanickelacycle intermediate is more
favorable than the direct β-hydride elimination of an azanickelacycle.
E
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