Nickel-catalyzed hydroimination of alkynes

Article abstract of DOI:10.1021/jacs.5b02272

A modular and atom-efficient synthesis of 2-aza-1,3-butadiene derivatives has been developed via nickel-catalyzed intermolecular coupling between internal alkynes and aromatic N-H ketimines. This novel alkyne hydroimination process is promoted by a catalyst system of a Ni(0) precursor ([Ni(cod)₂]), N-heterocyclic carbene (NHC) ligand (IPr), and Cs₂CO₃ additive. The exclusive formation of (Z)-enamine stereoisomers is consistent with a proposed anti-iminometalation of alkyne by π-complexation with Ni(0) and subsequent attack by the N-H ketimine nucleophile. An NHC-ligated Ni(0) π-imine complex, [(IPr)Ni(η¹-HN=CPh₂)(η²-HN=CPh₂)], was independently synthesized and displayed improved reactivity as the catalyst precursor.

Full text of DOI:10.1021/jacs.5b02272

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Nickel-Catalyzed Hydroimination of Alkynes
Rajith S Manan, Praveen Kilaru, and Pinjing Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b02272 • Publication Date (Web): 29 Apr 2015
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Nickel‐Catalyzed Hydroimination of Alkynes
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Rajith S. Manan, Praveen Kilaru and Pinjing Zhao*
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Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58102, United States
Supporting Information Placeholder
Satoh and coworkers in 2009,6a several transition metal cata‐
lysts have been developed to promote oxidative [4+2] and
redox‐neutral [3+2] N‐H ketimine/alkyne annulations to
ABSTRACT: A modular and atom‐efficient synthesis of 2‐
aza‐1,3‐butadiene derivatives has been developed via nickel‐
form isoquinoline and indenamine products respectively.2a,6,7
catalyzed intermolecular coupling between internal alkynes
and aromatic N‐H ketimines. This novel alkyne hydroimina‐
In comparison, the current catalyst system promotes alkyne
hydroimination via a formal anti alkyne addition by the im‐
tion process is promoted by a catalyst system of Ni(0) pre‐
cursor ([Ni(cod)2]), N‐heterocyclic carbene (NHC) ligand
ine N‐H bond, leading to the formation of (3Z)‐2‐aza‐1,3‐
(IPr), and Cs2CO3 additive. The exclusive formation of (Z)‐
butadiene products in high chemo‐ and stereoselectivity
enamine stereoisomers is consistent with a proposed anti‐
(Scheme 1b). 2‐Aza‐1,3‐dienes are important building blocks
iminometalation of alkyne by ‐complexation with Ni(0) and
in amine and N‐heterocycle synthesis due to their versatile
subsequent attack by the N‐H ketimine nucleophile. A NHC‐
reactivity towards a broad range of addition and cycloaddi‐
ligated Ni(0) ‐imine complex, [(IPr)Ni(1‐HN=CPh2)(2‐
HN=CPh2)], was independently synthesized and displayed
improved reactivity as the catalyst precursor.
tion reactions including the aza‐Diels‐Alder reaction.13 Exist‐
ing procedures for 2‐aza‐1,3‐diene synthesis typically require
multiple steps and often involve highly reactive interme‐
diates such as phosphazenes and 2H‐azirines.13a Thus, this
work expands the scope of N‐nucleophiles for catalytic hy‐
droamination and provides rapid assembly of valuable 2‐aza‐
1,3‐diene structures from readily available starting materials.
It also paves the way for further development of earth‐
abundant Ni‐based catalysts as a versatile and low‐cost alter‐
native to precious metal catalysts for hydroamination.14,15
Nitrogen‐substituted imines are ubiquitous substrates in
transition metal‐catalyzed transformations.1‐2 By contrast,
catalytic transformations of N‐unsubstituted imines (N‐H
imines) are much less established.3‐8 This is in part because
of concerns over their low stability, difficulty for synthesis,
and potential complications by E/Z isomerism and imine‐
enamine tautomerization. These issues are less pronounced
with aromatic N‐H ketimines, which are readily accessible
via organometallic addition to benzonitriles, usually exist
and react as single isomers, and are relatively stable com‐
pared to N‐H aldimines and aliphatic N‐H ketimines. Thus,
aromatic N‐H ketimines have been successfully explored in a
number of catalytic processes such as the Buchwald‐Hartwig
amination,3 enantioselective imine hydrogenation,4 and im‐
ine‐directed aromatic C‐H functionalization.5‐8 However,
aromatic N‐H ketimines are not known to undergo catalytic
hydroamination, the formal addition of a NH bond across
an unactivated CC ‐bond.9,10 Such “hydroimination” of
alkene or alkyne substrates would provide convenient and
atom‐economical synthesis of imine derivatives with N‐alkyl
or N‐alkenyl substituents.
Scheme 1. Transition metal‐catalyzed couplings be‐
tween aromatic N‐H ketimines and alkynes.
We began our catalyst development with the model reac‐
tion between benzophenone imine (1a in Table 1) and diphe‐
nylacetylene (2a). Results from an initial screening of various
transition metal complexes led us to focus on Ni(0) complex‐
es as catalyst precursors, which selectively promoted the
formation of hydroimination product 3a over byproducts
from [3+2] or [4+2] annulations (Scheme 1).6,7 Thus, we used
[Ni(cod)2] (4) as a commercially available Ni(0) precursor to
evaluate other reaction parameters such as the ligand, salt
additive, and solvent (Table 1). In general, 3a was formed in
We report herein the development of a nickel‐based cata‐
lyst system for intermolecular hydroimination of internal
alkynes with aromatic N‐H ketimines.11 To our best know‐
ledge, this is the first example of catalytic hydroimination
with unactivated alkynes.10 Prior studies on catalytic coupling
between these two classes of substrates have focused on an‐
nulation processes involving cyclometalated imine complex‐
es via imine‐directed C‐H bond activation (Scheme 1a).12
Since the first report of such annulation strategy by Miura,
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Page 2 of 5
higher yields with N‐heterocyclic carbene (NHC) ligands
of 36 h to reach 60‐79% yields (3j, 3k). Di(2‐thiphenyl)‐
1
2
3
4
5
6
7
8
such as IPr (5a) (entries 1‐4), stoichiometric amount of inor‐
ganic base additives (entries 5‐12),16 and nonpolar aromatic
solvents (entries 13‐19). Under the optimized conditions of
120 °C and using m‐xylene solvent, reaction between 1a and
2a (1.2 equiv) was promoted by 10 mol% 4, 22 mol% 5a and 1
equiv Cs2CO3 to selectively form 3a in 91% yield over 24
hours (entry 1). 3a was detected as a single isomer of (3Z)‐2‐
aza‐1,3‐butadiene derivative by NMR spectroscopy and single
crystal X‐ray diffraction, suggesting a formal anti alkyne ad‐
dition by the imine N‐H bond. Traces of byproducts (<5 %)
from alkyne oligomerization11d,17 were also formed under
these conditions, while none of the [3+2] and [4+2] annula‐
tion byproducts (Scheme 1a) was detected by GC analysis.
acetylene also reacted with 1a to give product 3l in 58% yield.
Symmetrical dialkylacetylenes were significantly less reactive
than diarylacetylenes under standard reaction conditions.
Thus, 2 equiv of 1a was required to promote complete con‐
version with dialkylacetylenes as the limiting reagents and
gave products 3m‐o in 49‐62% yields. Notably, aryl alkyl
alkynes such as 1‐phenyl‐1‐propyne failed to give the desired
hydroimination product (e.g. 3p) but instead formed a mix‐
ture of alkyne oligomers.11d,17,19 Scope of the ketimine sub‐
strates was studied by reactions with diphenylacetylene (2a),
and high reactivity was observed for electron‐poor diaryl N‐
H ketimines with para F or meta CF3 groups (3q, 3r). By con‐
trast, the electron‐rich di(p‐anisyl) N‐H ketimine failed to
react with 2a to give the desired product 3s. Interestingly,
the electron‐rich and sterically hindered di(o‐tolyl) N‐H ke‐
timine did react with 2a to give azadiene 3t in 71% yield. Al‐
kyl‐substituted (hetero)aromatic N‐H imines with phenyl,
electron‐poor aryl, or 4‐pyridyl groups showed slightly lower
reactivity and required 1.5 equiv of 2a to give products 3u‐z
in 73‐91% yields. As demonstrated with the solid‐state struc‐
tures of 3n and 3x by X‐ray crystallography, the regio‐ and
stereochemistry of the (3Z)‐2‐aza‐1,3‐diene structure from
formal anti N‐H addition was maintained for products with
alkyl substituents at 1‐, 3‐ or 4‐positions. Thus, it appeared
that no E/Z isomerization or imine‐enamine tautomerization
occurred under current reaction conditions.
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Table 1. Development of the catalytic reaction.a,b
Scheme 2. Substrate scope of N‐H ketimines and in‐
ternal alkynes for Ni‐catalyzed hydroimination.a
3a
With the standard reaction conditions established, various
aromatic N‐H ketimines (1) and internal alkynes18 (2) were
studied for Ni(0)‐catalyzed hydroimination (Scheme 2). In
general, 2‐aza‐1,3‐butadienes (3) were formed in high chemo‐
selectivity, with small amounts of byproducts from alkyne
oligomerization. All of the azadiene products were detected
and isolated as a single isomer of (Z)‐enamine structures
(vide infra). Scope of the alkyne substrates was studied with
benzophenone imine (1a) as the reaction partner. For sym‐
metrical diarylacetylenes, high product yields of 88‐94%
were achieved with those having electron‐donating substitu‐
ents at para or meta positions (3b‐e, 3h). In comparison,
diarylacetylenes with para F/CF3 or meta F groups led to
slightly lower yields of 68‐78% (3f, 3g, 3i). Diarylacetylenes
with ortho OMe or F groups required a longer reaction time
3ne
3xe
The reaction mechanism for Ni(0)‐catalyzed alkyne hy‐
droimination was investigated by several deuterium‐labeling
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experiments and stoichiometric observations (Scheme 3).
Under standard catalytic conditions, N‐deuterated benzo‐
Scheme 3. Results from reaction mechanism studies.
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4
5
6
7
8
(a) Deuterium-labeling experiments
10 mol% [Ni(cod)2] (4)
phenone imine (d1‐1a) reacted with diphenylacetylene (2a) to
give 2‐aza‐1,3‐diene product 3a in 87% yield and with only
trace of deuterium incorporation (< 2%) at the 4‐position. In
comparison, reaction between non‐deuterated 1a and 2a in
the presence of 5 equiv D2O additive led to 42% deuterium
incorporation at the 4‐position of the product (d1‐3a, 89%
yield). These results suggested that the catalytic hydroimina‐
tion pathway likely involved intermolecular proton transfer
processes, which led to rapid H/D exchange between reactive
intermediates and the reaction media. Based on the deute‐
rium‐labeling and stereochemistry results, we proposed that
Ni(0)‐catalyzed alkyne hydroimination was initiated by for‐
mation of a Ni(0)‐alkyne ‐complex (A in Scheme 3b), fol‐
lowed by stereospecific anti‐attack by the N‐H imine nucleo‐
phile (1) to form a zwitterionic alkenylnickel iminium inter‐
mediate B. Subsequent proton dissociation from iminium
and protonation of the Ni‐alkenyl linkage released the hy‐
droimination product (3) and formed a coordinatively unsa‐
turated Ni(0) intermediate, which was stabilized by ‐
complexation with an alkyne substrate (2) and regenerated
intermediate A. The beneficial effects of added inorganic
bases or water on catalytic reactivity (Table 1) suggested that
the proposed proton transfer processes with intermediate B
were possibly assisted by external Brønsted acids or bases,
which also led to the observed H/D exchange during deute‐
rium labeling studies. This proposed nucleophilic attack on a
coordinate alkyne was based on the well‐established “alkyne
activation” pathway for catalytic hydroamination,9,20 and the
observed stereochemistry was consistent with an outer‐
sphere, anti‐aminometalation process rather than an inner‐
sphere nucleophilic attack.21
Ph
Ph
Ph
N
Ph
H
22 mol% IPr (5a)
+
Ph
Ph
Ph
ND
1 equiv Cs2CO3
m-xylene (0.28 M)
120 oC, 24 h
< 2% D
42% D
Ph
3a (87%)
d1-1a
1.0 equiv
2a
1.2 equiv
Ph
Ph
Ph
N
Ph
added D2O (5.0 equiv)
+
Ph
Ph
Ph
NH
otherwise standard
reaction conditions
Ph
D
1a
2a
9
d1-3a (89%)
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(b) Proposed catalytic cycle
R1
Ar
HN
1
R1
R2
LnNi
R
2
A
R2
R1
R2
LnNi(0)
LnNi
Ar
R
H
R1
HN
LnNi
R2
R1
Ar
R
R2
N
3
anti-aminometalation
N
H
proton
Ar transfer
R
B
(c) Synthesis and the X-ray structure of a Ni(0)-imine complex (7)
[Ni(cod)2] (4)
1) 2.0 equiv IPr (5a),
benzene, 80 oC, 2 h
1a
2) 2.1 equiv Ph2C=NH (
)
room temperature, 30 min
Ph
HN
(IPr)
Ph
Ph
Ni
HN
ORTEP diagram at 40% probability level
(aromatic H and iPr groups emitted for clarity)
7
Ph
(d) Evaluation of catalytic activity for Ni(0)-imine complex (7)
[(IPr)Ni(Ph2C=NH)2]
Ph
Ph
Ph
To gain further mechanistic insights, we sought to isolate
or independently synthesize the proposed Ni(0)‐‐alkyne
intermediate (A) with attached IPr ligand and evaluate its
catalytic activity. Unfortunately, our efforts were hindered by
instability of the target Ni‐alkyne complexes and formation
of alkyne oligomers during attempted synthesis (see Sup‐
porting Information for details).11d,17 Thus, we switched our
synthetic target to IPr‐ligated Ni(0)‐imine complexes as a
potential catalyst precursor (Scheme 3c). A 1:2 mixture of
[Ni(cod)2] and IPr in benzene was stirred at 80 C for 2 h
before reacting with 2.1 equiv of benzophenone imine (1a) at
room temperature to generate a dark violet‐colored complex,
[(IPr)Ni(Ph2C=NH)2] (7). The solid‐state structure of com‐
plex 7 was studied by single crystal X‐ray diffraction to reveal
a ‐imine as well as a ‐imine ligand.22 Using complex 7 as a
catalyst precursor to replace [Ni(cod)2] and without added
IPr ligand, a reaction between 1a and 2a was effectively pro‐
moted at a reduced catalyst loading of 3 mol% to give 3a in
87% yield (Scheme 3d). Thus, IPr‐ligated Ni(0)‐imine com‐
plexes were likely involved in the alkyne hydroimination
process as activated catalyst precursors. With a relatively
weak ‐imine ligand, these Ni‐imine intermediates appeared
to favor a single ‐imine replacement by an alkyne substrate
to form the proposed ‐alkyne intermediate A while keeping
the ‐imine ligand intact.23 In consequence, the desired al‐
kyne hydroimination was selectively promoted over alkyne
oligomerization, which probably required two ‐alkynes on a
Ni(0) center for C‐C bond formation via oxidative cycliza‐
tion.17
(7, 3.0 mol%)
N
Ph
H
Ph
Ph
+
Ph
NH
1 equiv Cs2CO3
m-xylene (0.28 M)
120 oC, 24 h
1a
2a
1.2 equiv
Ph
3a (87%)
1.0 equiv
To demonstrate the potential of current method for prac‐
tical synthesis, we carried out a preliminary study on gram‐
scale alkyne hydroimination with benzophenone imine (1a)
(Scheme 4). With a reduced catalyst loading of 3 mol%
[Ni(cod)2] and 6.6 mol% IPr, reactions with diphenylacety‐
lene (2a) and 4‐octyne (2b) could be scaled up 15‐ to 20‐fold
to produce isolated products 3a and 3n in gram quantities,
although the yield percentages were lower than those ac‐
quired under the standard catalytic conditions (Scheme 2).
Scheme 4. Gram‐scale hydroimination reactions.
In summary, we have developed a Ni(0)/NHC‐based cata‐
lyst system for the first example of alkyne hydroimination
with aromatic NH ketimines. Stereochemistry and prelimi‐
nary mechanistic results supported a proposed mechanism of
alkyne activation via ‐complexation with Ni(0) and subse‐
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Ingendoh, A. Chem. Ber. 1979, 112, 1297. (b) Wessjohann, L.;
McGaffin, G.; De Meijere, A. Synthesis 1989, 359. (c) Lykke, L.;
quent nucleophilic attack by the N‐H ketimine. Future stu‐
dies will focus on mechanism‐guided catalyst improvement
for expanded substrate scopes and synthetic applications of
the 2‐aza‐1,3‐diene products.
1
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Monge, D.; Nielsen, M.; Jorgensen, K. A. Chem. Eur. J. 2010, 16, 13330.
11. Nickel‐based catalysts for alkyne hydroamination are rare and
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Organomet. Chem. 1996, 523, 205. (b) Müller, T. E. Tetrahedron Lett.
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M.; Dagousset, G. Chem. Soc. Rev. 2013, 42, 902.
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of alkynes, see ref 9 and representative studies below: (a) Shimada,
T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12670. (b) Mizushima,
E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349. (b) Brunet, J.‐J.;
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Shi, X. J. Am. Chem. Soc. 2009, 131, 12100.
15. For early transition metal or rare earth metal‐catalyzed
intermolecular alkyne hydroamination, see ref 9 and the following:
(a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc.,
1992, 114, 1708. (b) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770.
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20, 3967. (e) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer,
L. L. Chem. Commun. 2003, 2462. (f) Kim, H.; Livinghouse, T.; Shim,
J. H.; Lee, S. G.; Lee, P. H. Adv. Synth. Catal. 2006, 348, 701.
16. Adding H2O led to slightly improved yield for 3a compared to
reactions without any additives (entries 11, 12) and generated only
trace amount of benzophenone (<5%) by GC analysis. However,
imine hydrolysis with added H2O became much more significant
with less stable N‐H ketimines. Thus, our catalyst development
efforts focused on using base additives rather than added H2O.
17. (a) Alphonse, P.; Moyen, F.; Mazerolles, P. J. Organomet. Chem.
1988, 345, 209. (b) Eisch, J. J.; Ma, X.; Han, K. I.; Gitua, J. N.; Krueger,
C. Eur. J. Inorg. Chem. 2001, 77. (c) Ogata, K.; Murayama, H.;
Sugasawa, J.; Suzuki, N.; Fukuzawa, S.‐I. J. Am. Chem. Soc. 2009, 131,
3176. (d) Horie, H.; Kurahashi, T.; Matsubara, S. Chem. Commun.
2010, 46, 7229.
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures, spectral data, and CIF file
for reported single crystals. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
pinjing.zhao@ndsu.edu.
ACKNOWLEDGMENT
Financial support for this work was provided by NSF (CHE‐
1301409). We thank NSF‐CRIF (CHE‐0946990) for funding
the purchase of departmental X‐ray diffractometer and Dr.
Angel Ugrinov for solving the single‐crystal XRD structures.
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Weisel, M.; O'Shea, P. D.; Chen, C.‐y.; Davies, I. W.; Zhang, X. J. Am.
Chem. Soc. 2009, 131, 9882. (b) Hou, G.; Tao, R.; Sun, Y.; Zhang, X.;
Gosselin, F. J. Am. Chem. Soc. 2010, 132, 2124.
5. Katagiri, T.; Mukai, T.; Satoh, T.; Hirano, K.; Miura, M. Chem.
Lett. 2009, 38, 118.
6. (a) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M.
Chem. Commun. 2009, 5141. (b) He, R.; Huang, Z.‐T.; Zheng, Q.‐Y.;
Wang, C. Angew. Chem. Int. Ed. 2014, 53, 4950.
18. Terminal alkynes such as phenylacetylene led to alkyne oligo‐
merization instead of desired hydroimination; see refs 17c and 17d.
19. It is not clear to us why aryl alky alkyne substrates display such
high chemoselectivity towards oligomerization (e.g. cyclotrimeriza‐
tion) over desired hydroimination. Alkyne reactivity for catalytic
cyclotrimerization and hydroamination is known to depend on both
steric and electronic factors and can be difficult to predict. See ref 11d
for an example of chemoselective alkyne hydroamination vs. cyclo‐
trimerization using Ni(II) vs. Ni(0) catalyst precursors.
20. Müller, T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.‐K.; Walter,
E.; Yan, Y.‐K. Organometallics 2000, 1, 170.
21. Formation of the (Z)‐enamine product could also be explained
by E/Z isomerization of an initial (E)‐enamine product from syn‐
hydroamination pathways. Such a scenario cannot be ruled out at
this point, but the lack of observation for any syn‐addition products
suggested that it was unlikely to be the major reaction pathway.
22. Hoberg, H.; Goetz, V.; Krueger, C.; Tsay, Y. H. J. Organomet.
Chem. 1979, 169, 209.
23. The lack of reactivity for electron‐rich diaryl N‐H ketimines
was probably due to strong Ni‐imine complexation that prevented
imine replacement by alkyne substrates. Such catalyst deactivation
by strongly nucleophilic amines are known for catalytic alkyne
hydroamination. See ref 9c and the following example: Karshtedt, D.;
Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2005, 127, 12640.
7. (a) Sun, Z.‐M.; Chen, S.‐P.; Zhao, P. Chem. Eur. J. 2010, 16, 2619.
(b) Tran, D. N.; Cramer, N. Angew. Chem. Int. Ed. 2011, 50, 11098. (c)
Zhang, J.; Ugrinov, A.; Zhao, P. Angew. Chem., Int. Ed. 2013, 52, 6681.
8. Tran, D. N.; Cramer, N. Angew. Chem. Int. Ed. 2010, 49, 8181.
9. Representative recent reviews on transition metal‐catalyzed
hydroamination: (a) Yim, J. C.‐H.; Schafer, L. L. Eur. J. Org. Chem.
2014, 2014, 6825. (b) Hesp, K. D.; Stradiotto, M. ChemCatChem 2010,
2, 1192. (c) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada,
M. Chem. Rev. 2008, 108, 3795. (d) Widenhoefer, R. A.; Han, X. Eur. J.
Org. Chem. 2006, 20, 4555.
10. Aza‐Michael additions by benzophenone imine to electron‐
deficient alkenes and alkynes have been reported: (a) Boehme, H.;
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Journal of the American Chemical Society
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10 mol% [Ni(cod)2]
22 mol% IPr ligand
R'
Ar
Ar
N
R'
R'
+
H
R
NH
1 equiv Cs2CO3
m-xylene (0.28 M)
120 oC, 24 h
R
R'
R, R' = aryl or alkyl groups
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24 examples; 49-93% isolated yield
atom-efficient synthesis of 2-aza-1,3-dienes
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HN
Ni
Ph
(IPr)
Ph
stereoselective formation of (Z)-enamine structures
via proposed anti-iminometalation
Ph
Ph
HN
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isolated Ni(0)-( -imine)( -imine) complex (7) as a
reactive catalyst precursor
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