Cobalt-Catalyzed Markovnikov Selective Sequential Hydrogenation/Hydrohydrazidation of Aliphatic Terminal Alkynes

Article abstract of DOI:10.1021/jacs.0c07258

Here, we reported for the first time a mechanistically distinctive cobalt-catalyzed Markovnikov-type sequential semihydrogenation/hydrohydrazidation of aliphatic terminal alkynes in one pot. A cobalt hydride species was employed as two roles for both a unique metal-catalyzed Markovnikov-type insertion of the aliphatic terminal alkynes and then metal-catalyzed hydrogen atom transfer of alkenes. This operationally simple protocol exhibits excellent functional group tolerance and step economy. The hydrazone products could be easily transferred to various valuable amine derivatives.

Full text of DOI:10.1021/jacs.0c07258

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Communication
Cobalt-Catalyzed Markovnikov Selective Sequential
Hydrogenation/Hydrohydrazidation of Aliphatic Terminal Alkynes
Chen jieping, Xuzhong Shen, and Zhan Lu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07258 • Publication Date (Web): 09 Aug 2020
Downloaded from pubs.acs.org on August 9, 2020
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Cobalt-Catalyzed Markovnikov Selective Sequential Hydrogenation/Hy-
drohydrazidation of Aliphatic Terminal Alkynes
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Jieping Chen, Xuzhong Shen, and Zhan Lu*
Department of Chemistry, Zhejiang University, Hangzhou 310058, China
Supporting Information Placeholder
ABSTRACT: Here, we reported for the first time a mechanisti-
Scheme 1. Metal-catalyzed synthesis of aliphatic amines via com-
cally distinctive cobalt-catalyzed Markovnikov-type sequential
bination of hydrogenation and hydroamination of aliphatic alkynes
semi-hydrogenation/hydrohydrazidation of aliphatic terminal al-
in one pot.
kynes in one pot. A cobalt hydride species was employed as two
roles for both a unique metal-catalyzed Markovnikov-type inser-
tion of the aliphatic terminal alkynes and then metal-catalyzed hy-
drogen atom transfer of alkenes. This operationally simple protocol
exhibits excellent functional group tolerance and step economy.
The hydrazone products could be easily transferred to various val-
uable amine derivatives.
Aliphatic amines derivatives are widely represented in biologi-
cally active natural products and medicines.1 The development of
efficient and diverse methods for the selective synthesis of amines
from readily available precursors is an important and long-standing
project. Many useful methods have been discovered and modified
to address this challenge, such as nucleophilic addition to imines,2
metal-catalyzed cross-coupling,3 and nitrene insertion.4 Transition-
metal-catalyzed hydroamination of unsaturated carbon-carbon
bonds represents one of the most straightforward and atom-eco-
nomical approach to prepare valuable amine derivatives.5 Alkynes,
a part of the fundamental synthon for academy and industry, are
alkynes to access amine derivatives.11 According to the proposed
also good candidates for the synthesis of aliphatic amine deriva-
mechanisms, both semi-hydrogenation and hydroamination reac-
tions are initiated by unsaturated carbon-carbon bonds insertion to
copper hydride bond with anti-Markovnikov selectivity, then the
active species undergo protonation or electrophilic amination.
However, due to the steric factors, the insertion of aliphatic alkenes
or alkynes to metal hydride bond will usually direct the metal to the
less hindered carbon atom, which make the generation of Markov-
nikov-type intermediate more challenging. So far, to the best of
knowledge, double Markovnikov selective sequential semi-hydro-
genation/hydroamination of aliphatic alkynes has not been reported.
With our continuing interests on cobalt-catalyzed hydrofunc-
tioinalization of alkenes or alkynes.12 Here, we reported a mecha-
nistically distinctive cobalt-catalyzed Markovnikov-type sequen-
tial semi-hydrogenation/hydrohydrazidation of aliphatic alkynes to
access amine derivatives with high levels of chemo- and regiose-
lectivity in one pot (Scheme 1b).
We performed the study on the sequential reaction of 4-phenyl-
1-butyne 1a as a model substrate and benzyl 2-diazo-2-phe-
nylacetate 2a as a nitrogen source10f,12g,13 (table 1). Optimal condi-
tions were obtained by using catalyst derived from Co(OAc)2 and
N-oxazolinylphenyl 8-aminoquinoline (OPAQ) L1 in the presence
of phenyl silane and H2O as hydrogen donor in a solution of THF
at room temperature, generating 3a in 83% yield (entry 1). Control
tives via the merge of hydroamination and hydrogenation (Scheme
1a).6 The first example of catalytic sequential intermolecular reduc-
tive hydroamination of alkynes with anilines and hydrosilane using
a titanium complex as the catalyst was reported in 2005 by Doye
and co-workers.7 Subsequently, various inter- and intramolecular
reactions have been reported using Lewis acid catalysis by Liu,
Gong, Che, Beller, Shi, and others.8 However, the aliphatic alkynes
are less explored and the tolerance of functional groups is still lim-
ited.
The sequential semi-hydrogenation/hydroamination of alkynes
provides another ideal and step-economic strategy. Due to weak
electronic and steric effects, the aliphatic alkyne is a challenging
substrate in organic transformation. Although both semi-hydro-
genation of alkynes9 and hydroamination of alkenes5d-5k,10 have
been reported respectively, there are several challenges in a com-
bined system: (1) avoiding the side-reactions in semi-hydrogena-
tion, including alkene isomerization, over reduction, and alkyne hy-
droamination; (2) controlling the regioselectivity to make the trans-
formation synthetically useful, particularly the regioselectivity of
semi-hydrogenation of terminal alkynes is not well explored; (3)
achieving the compatibility of two transformations in one pot.
Since 2015, Buchwald and co-workers reported an elegant sequen-
tial semi-hydrogenation/hydroamination reaction of aliphatic
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experiments indicated that ligand L1, PhSiH3 or Co(OAc)2 were
Terminal alkynes containing bioactive molecules such as amino
acid, menthol, cholesterol, naproxen and citronellol could be
employed to deliver products (3ab-3af) in 61-76% yield, which
also demonstrated that this transformation would be suitable for
late-stage functionalization of complicated molecules.
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essential (entries 2-4). Using CoCl2 instead of Co(OAc)2, no prod-
uct was observed (entry 5). When the reaction was exposed to air
rather than under N2, poor yield of semi-hydrogenation product was
observed (entry 6). Later, some C2- or C1-symmetrical NNN pincer
ligands were investigated. The symmetrical bisaminoquinoline L2
(entry 7) or bis2-oxazolinylaniline L3 (entry 8) showed no or poor
catalytic activity. The unsymmetrical tridentate ligands L4 with 2-
oxazolinyl aniline scaffold could promote the reactions smoothly
to deliver 3a in 63% yield (entry 9). Additionally, neither PDI nor
PyBox, could promote this transformation (entries 10 and 11).
Table 2. Reaction Scope.a
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Table 1. Effect of Sequential Reaction Parameters.a
entry
1
variation from “standard conditions”
none
yield (%)b
83%
2
3
no PhSiH3
no L1
-
-
-
-
4
no Co(OAc)2
5
CoCl2 instead of Co(OAc)2
Under air, rather than under N2
L2 instead of L1
L3 instead of L1
L4 instead of L1
L5 instead of L1
L6 instead of L1
c
6
-
7
-
9%d
63%
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8
a 1 (0.72 mmol), 2 (0.60 mmol), Co(OAc)2 (5 mol%), L1 (6 mol%), PhSiH3 (2.5
equiv.) and water (3 equiv.) in THF (2.4 mL) under N2 at rt for 24 h, isolated
yield of 3. b Stirred for 36 h. c Without water.
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The reaction could be carried out on gram scale at room temper-
ature to afford 3a in 60% yield (eq. 1). To showcase the utility of
the functionalized amines, further transformations of the semi-hy-
drogenation/hydrohydrazidation products were investigated. Re-
flux under hydrogen chloride gases atmosphere, 3h could be con-
verted into hydrazine hydrochloride 5 (eq. 2). Hydrazones could
also be converted into pyrazole 6 (eq. 3) and 1,3-disubstituted in-
dazole 7 (eq. 4) which are key skeletons for valuable drugs.14 In
addition, the protected primary amines 8a-8b and an antihistamine
drug promethazine 9a could be obtained by the simple three-step
operation. The nitrogen-nitrogen bond cleavage of hydrazone 3a
could be also carried out smoothly in the presence of SmI2 as a re-
ducing reagent (eq. 6).
a The reaction was conducted using 1a (0.72 mmol), 2a (0.6 mmol), Co(OAc)2
(5 mol %), ligand (6 mol%), PhSiH3 (2.5 equiv.) and water (3 equiv.) and THF
(2.4 mL) under N2 at rt for 24 h. b Determined by 1H NMR using TMSPh as an
internal standard. C13% terminal alkene was detected. d45% terminal alkene was
detected.
With the optimized reaction conditions in hand, we set out to
explore the substrate scope of this transformation (table 2). Simple
terminal alkynes (1a-k) were also amenable to this transformation.
A variety of functional groups, such as ether, ester, oxalate, amide,
acetal, nitrile, halide, free alcohol, free amine, and so on, could be
well tolerated to afford the corresponding products in moderate to
good yields. 2-(Prop-2-yn-1-yl)aniline 1w, which would undergo
intramolecular cyclization in the presence of Lewis catalysts, was
transferred to the corresponding product 3w in 54% yield. The
alkynes containing heterocycles, such as indole (1x), carbazole (1y),
and thiophene (1z) could also be delivered to corresponding
products in 74-86% yield. For phenylacetylene 1aa, the
corresponding hydrazone 3aa can be obtained with 96% yield.
To elucidate the possible reaction pathway, several control
experiments were conducted. The semi-hydrogenation of
biphenylacetylene has been carried out (see the Supporting
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Markovnikov selectivity of hydrometallation which is mechanisti-
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Scheme 2. Gram-scale reaction and synthetic applications.
cally different from Lalic’s results9j with anti-Markovnikov selec-
tivity. Compared to Liu’s proposal9b of a combination of the vinyl-
idene-type and alkynyl-type mechanisms on cobalt-catalyzed semi-
hydrogenation of terminal alkynes using PNP and NNP pincer lig-
and, to the best of knowledge, it is the first time for cobalt catalysis
to achieve such unique Markovnikov-type hydrometallation as a
major selectivity which would encourage to explore and improve
other Markovnikov-type hydrofunctionalization of alkynes. Radi-
cal clock experiments illustrated that alkene hydrohydrazidation-
was a HAT process (eq. 9).16 The primary study on asymmetric re-
action which has been carried out with 41% yield and 78 : 22 er
(see the Supporting Information).
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Based on the experimental studies and previously reported
literatures,9b,9j,12g a possible mechanism is shown in Scheme 4. The
cobalt hydride species A obtained from the reaction of Co(OAc)2
with ligand and hydrosilane. The alkyne coordination with species
A followed by alkyne insertion to the cobalt hydrogen bond
delivers cobalt vinyl species C. Species C undergoes hydrolysis
with H2O to form species D and alkene. Species D goes through σ-
bond metathesis with hydrosilane to regenerate species A.
Followed by alkyne semi-hydrogenation, species A undergo a
metal hydride HAT process to deliver the carbon radical
intermediate and cobalt species E. The cobalt species E may
coordinate with diazo compound which would reduce the rate of
alkyne semi-hydrogenation. The carbon radical intermediate was
trapped by species E to afford the cobalt–carbon species F, which
could undergo alkyl group migration from cobalt to nitrogen atom
to generate cobalt enolate species G.13a The SH2 pathway could be
not exclusively ruled out.17 The possibility that carbon radical
directly attacked the cobalt coordinated diazo compound could not
be ruled out. The cobalt species G could react with hydrosilane to
regenerate the cobalt hydride species A and afford the vinyl silyl
ether intermediate, which could undergo hydrolysis and
isomerization to give the product.
Information) which illustrated that the reaction initially underwent
stereospecific alkynes insertion to cobalt hydride bond without
HAT process15 and then alkene isomerization could occur smoothly.
The semi-hydrogenation of aliphatic alkyne could proceed slowly
under anhydrous conditions (see the Supporting Information), how-
ever, the reaction was dramatically accelerated by the addition of
three equivalents of water whose TOF (turnover frequency) was
upto 1020 h-1(eq. 7). The time course studies showed that the pres-
ence of diazo compounds would reduce the rate of alkyne semi-
hydrogenation as well as over-hydrogenation and isomerization
(see the Supporting Information), which could make the reaction
conduct smoothly. For the terminal alkynes, the semi-hydrogena-
tion of deuterium labelling dodec-1-yne 12 with PhSiH3 and deu-
terated water was performed in one minute to give the deuterated
alkene in 50 % NMR yield with 85% D at 2-position9h,9j (eq. 8),
E/Z-isomerization might lead to lose the amount of D-atom at a
1(E)-position and increase the amount of D-atom at a 1(Z)-position.
This result demonstrated that this semi-hydrogenation of aliphatic
terminal alkynes should mainly undergo with a
Scheme 4. Proposed Mechanism.
Scheme 3. Deuterium labelling and radical clock experiments.
In summary, we reported a mechanistically distinctive cobalt-
catalyzed double Markovnikov selective, sequential semi-hydro-
genation/hydrohydrazidation of aliphatic terminal alkynes with hy-
drosilanes and diazo compounds to access amine derivatives with
excellent functional group tolerance and regioselectivity in one pot.
The OPAQ cobalt hydride complex plays two roles for both semi-
hydrogenation of aliphatic terminal alkynes via a unique cobalt-
catalyzed Markovnikov-type hydrometallation and hydrohydra-
zidation of alkenes via cobalt-catalyzed HAT process. The water
could dramatically accelerate alkyne semi-hydrogenation whose
TOF was upto 1020 h-1. The hydrazone compounds could easily be
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Metal (Iron, Cobalt, Copper and Zinc) Catalysis:AMechanistic Overview
Adv. Synth. Catal. 2020, 362, 1550–1563.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Experimental procedures, characterization
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AUTHOR INFORMATION
Corresponding Author
*E-mail: luzhan@zju.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by NSFC (21922107 and
21772171), Zhejiang Provincial Natural Science Foundation of
China (LR19B020001), ZJU-NHU United Research & Develop-
ment Centre, and the Fundamental Research Funds for the Central
Universities (2019QNA3008).
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