A nickel-catalyzed: Anti -carbometallative cyclization of alkyne-azides with organoboronic acids: Synthesis of 2,3-diarylquinolines

Article abstract of DOI:10.1039/c7cc08408k

An anti-carbonickelative cyclization via reversible alkenylnickel E/Z isomerization of 2-azido phenyl propargyl alcohols with aryl boronic acids is achieved using Ni(acac)₂ as the catalyst to access 2,3-diaryl quinolines. It represents a rare example of trapping the vinyl metal intermediate with a nitrogen center, a non-carbon center electrophile.

Full text of DOI:10.1039/c7cc08408k

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A Nickel-Catalyzed anti-Carbometallative Cyclization of
Alkyne-Azides With Organoboronic Acids: Synthesis of
2,3-Diarylquinolines
Received 00th January 20xx,
Accepted 00th January 20xx
Gadi Ranjith Kumar,a,b,‡ Ravi Kumar,a,b,‡ Manda Rajesha and Maddi Sridhar Reddy*,a,b,c
DOI: 10.1039/x0xx00000x
www.rsc.org/
An anti-carbonickelative cyclization via reversible alkenylnickel alkynes,7 we here in present a formal nucleophilic cyclization of
E/Z isomerization of 2-azido phenyl propargyl alcohols with aryl azidophenyl propargyl alcohols8 which deliver medicinally highly
boronic acids is achieved using Ni(acac)2 as the catalyst to access potential quinoline nucleus9 with 2,3-diaryl substitution via
2,3-diaryl quinolines. It represents a rare example of trapping the carbonickelation followed by cyclization to a nitrogen center
vinyl metal intermediate with a nitrogen center, a non-carbon electrophile (Figure 1C).
center electrophile.
Electrophile Triggered Cyclization
E
Carbometalation of alkynes1-4 has opened
a highly reliable
M
M
E
platform for the construction of wide variety of olefin bearing
scaffolds with excellent selectivities (both regioselectivity and
stereoselectivity). The resultant carbometalated species, which
usually gets hydrodemetallated,2 is a gold mine for its carbophilicity
which can be utilized in tandem in variety of coupling and addition
reactions. Most of these carbometalated species are utilized in
tandem for tethering to a carbon centre of the coupling partner
(electrophile) viz. halides, carbonyls, β-carbon of conjugated
carbonyls, γ-carbon of allylic center, cyano, imines etc.3-4 These
tandem reactions can be both intermolecular3 and intramolecular.
M
E
(A)
R
R
R
Nu
Nu
Nu
Nucleophile Triggered Cyclization
(anti-Nucleometallative Cyclization)
Nu
Nu
M
Nu
R
R
R
E
M
E
E
general
: capture of C-M by carbon centere electrophile
(B)
Intramolecular
versions,
formally
nucleophile
triggered
cyclizations,4 afford the construction of a variety of carbocycles, and
such cyclizations are complimentary to the electrophilic cyclizations
(Figure 1A)5 where an electrophile triggers the cyclizations to form
metallated species which consequently offers the coupling.
Whereas in these nucleophile triggered cyclizations, the addition of
carbometalated species to unsaturated centre initiates the reaction
to generate a nucleophilic C-metal centre which ultimately adds on
to a nearby ready electrophile. A limitation in these cyclizations
reported till now is that the resultant vinylmetal intermediate has
always been captured by a carbon center electrophile (Figure 1B)4,6
which leads only to the carbocycles. Addition to a heteroatom
centre would open a new avenue in this realm to produce
heterocycles. Realizing the same and as part of our ongoing
program of unveiling the novel reactivities of functionalized
E = -C(O)-, -CN, -CH=CH-C(O)-, -CH=NR, -CH=CH-CH2X
this work
: capture of C-M by nitrogen centere electrophile
OH
Ar
OH
ArB(OH)2
Ni(II)
(C)
Ar
R
R
N3
N
N2
N
R
Figure 1. Carbometalation of alkyne.
Carbometal complexes with various metals like Zn, Zr, Ti, Mg, Cu,
Rh, Pd, Ni have been extensively studied and most of them have
unique advantages either during addition or in post-addition
modification reactions.1-4,10 Recently, organoboron is identified as
readily available and highly reliable source to form organometal
complexes through trans- metallation.6,11 This source is effectively
utilized with metal centres based on palladium, rhodium and nickel.
Liu et. al.6a and Lam et. al.6b-c recently reported few carbonickelative
cyclizations through an interesting E/Z isomerisation of the
a.Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, BS-
10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
b.Academy of Scientific and Innovative Research, New Delhi 110001, India.
c. MCB Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
E-mail: msreddy@iict.res.in
†Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
‡ Contributed equally
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resultant vinyl nickel intermediate which imparts it with better With the optimization conditions in hand, we went ahead to test
chances to be captured by an electrophile embedded in the the generality of the reaction. Initially, various boronic acids were
premises. Due to highly carbophilic nature, the intermediate was chosen to test on 1a (Scheme 1). Alkylphenyl boronic acids
shown to be trapped by various carbon-centered eletrophiles like irrespective of the position of alkyl groups evenly produced the
carbonyls, conjugated carbonyls and allylic centers. We herein desired products (3ab-ad) in 81-84% yields whereas electron rich
showed the capture of this intermediate by an azide group, a non- alkoxyphenyl boronic acids gave a slightly lower productivity (3ae-
carbon centre electrophile for the first time to the best of our ag in 68-75% yields). Halogens like fluoro, chloro and bromo groups
knowledge.
could comfortably survive the reaction (3ah-al) without noticeable
erosion in the yield (72-88% yield) of the products. Strong electron
withdrawing groups like NO2, CN, CF3 and acetyl group did not
affect the reaction and gave the corresponding products 3am-ap in
practical yields (71-86%). Similarly, 3-naphthyl quinoline 3aq was
obtained in 80% yield whereas 3-thiophenyl quinoline 3ar was
synthesized in 64% yield from the corresponding boronic acids.
The optimization studies were carried out with 1-(2-azidophenyl)-3-
phenylprop-2-yn-1-ol 1a and phenyl boronic acid 2a as shown in
Table 1. Palladium catalysts, along with PPh3 and Cs2CO3, were
found to be totally ineffective for the target reaction (entries 1-2).
Pleasingly, NiCl2 in similar conditions delivered the desired product
3aa12 in 31% yield. In contrast, when Ni(0) was employed in the
reaction, only the starting material was recovered (entry 4).
Delightedly, Ni(acac)2 cleanly converted 1a to 3aa in 92% yield. Use
of other phosphine ligand xanthphos or non-phosphorous ligand
bpy was found to be either less effective or totally unproductive.
Controlled experiments revealed that the nickel catalyst was
essential for the reaction but Cs2CO3 and PPh3 were not really
necessary for the reaction but their presence slightly increased the
yield. Dioxane was found to be best of many solvents tested
(entries 12-16).
Scheme 1. Substrate scope of boronic acids.a,b
Table 1: Optimization studies.
S.No catalyst
ligand
additive
solvent
yield(%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2 PPh3
Pd(PPh3)4 --
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
N.R
N.R
31
NiCl2
PPh3
PPh3
PPh3
Ni(COD)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
N.R
1,4-dioxane 92
Xanthphos Cs2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
EtOH
75
bpy
--
Cs2CO3
Cs2CO3
--
N.R
82
PPh3
--
78
10 Ni(acac)2
11 --
--
65b
N.R
43
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
12c Ni(acac)2
13 Ni(acac)2
14 Ni(acac)2
15c Ni(acac)2
16c Ni(acac)2
17d Ni(acac)2
18e Ni(acac)2
DMSO
15
DMF
56
THF
68
MeCN
N.R
N.R
50
1,4-dioxane
1,4-dioxane
aReaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Ni(acac)2 (10 mol%), PPh3
(10 mol%), Cs2CO3 (20 mol%) in Dioxane (5 mL) at 90 °C for 4 h under N2.
bIsolated yield.
aReaction conditions: 10 mol % catalyst, 10 mol% ligand, 20 mol%
additive at 90 oC under N2 for 4 h. b20% of 1a recoverd. creaction at
60 oC. dreaction at rt for 12 h. eunder open air.
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Next, the influence of substitution variation at the alkyne terminal Interestingly, substrate 1s devoid of propargylic hydroxyl group
of 1 was verified (Scheme 2). Alkyl-, phenyl- and methoxy-phenyl slowly decomposed in the standard conditions. These experiments
substitution caused no much variation in the yield to produce suggest that an electron rich propargylic oxygen is essential for the
various 2-aryl quinolines 3ba-fa in 75-95% yields whereas reaction. We conducted a reaction in the presence of TEMPO to
halophenyl substitution turned down the yields to 58-79%. rule out any radical mediation in the reaction. An intermolecular
Pleasingly, strong electron withdrawing groups like CN and CF3 did reaction of resultant vinyl nickel intermediate with phenylazide was
not affect the reaction producing the corresponding products 3ka failed (only afforded uncoupled adduct 72a) demonstrating that
and 3la in 72% and 74% yields respectively. Further, 2-napthyl
Scheme 3 Control Experiments.
substituted quinoline 3ma was obtained in excellent yield of 89%.
Interestingly, 2-cyclohexenyl adduct was also formed in 71% yield.
Scheme 2 Extended Substrate Scope.a,b
Ni(acac)2 (10 mol %)
PPh3 (10 mol %)
OH
Ph
Cs2CO3 (20 mol %)
R2
R2
PhB(OH)2 (1.2 equiv)
1,4 dioxane, 90 o C, 4 h
N
N3
1b-p
3ba-3pa
Ph
Ph
Ph
N
N
N
tBu
n-Bu
Me
3ba 84%
3ca 79%
3da 75%
Ph
Ph
N
N
3ea 95%
Ph
Ph
3fa 81%
OMe
Ph
Ph
N
N
N
Cl
F
Ph
3ia 64%
3ga 69%
3ha 79%
Cl
Cl
Ph
OMe
N
N
X = Br, 3ja, 58%
X = CN, 3ka, 72%
X = CF3, 3la, 74%
X
3ma 89%
intramolecular azide must have easily coordinated with the E-vinyl
nickel intermediate which did not require much activation energy
for the subsequent denitrogenative cyclization.
Ph
Ph
O
O
Ph
Ph
N
N
N
From the aforementioned experiments, a plausible mechanism is
described in Scheme 4. LnNi(OR)2 after exchanging the aryl group
with arylboronic acid adds on the propargylic system in a regio- and
stereoselective manner to give the intermediate A. E/Z
isomerization6a-c of A led to B which is immediately stabilized by
azido group facilitating the subsequent denitrogenative cyclization
to form cyclic intermediate C. Protodenickelation of C followed by
dehydrative aromatization yielded the final desired product 3. From
our previous experience2a and based on a recent report by Liu et
al,6a we also cannot rule out the initiation of reaction with Ni(I)-
complex which is expected to be formed through the reduction by a
catalytic amount of arylboronic acid.
3pa 0%
3na 71%
3oa 91%
aReaction conditions: 1 (0.5 mmol), PhB(OH)2 (0.6 mmol), Ni(acac)2 (10
mol%), PPh3 (10 mol%), Cs2CO3 (20 mol%) in Dioxane(5 mL) at 90 °C for 4 h,
under N2. bIsolated yield.
Setting a limitation, alkyl substitution on alkyne terminal of 1
totally blocked the reaction. Further, non aryl azido alkynol 1p
formed no product in the standard conditions. Some control
experiments were conducted as shown in Scheme 3 to understand
the mechanism of the reaction. TBS protected 1q equally
participated in the reaction whereas acetyl protection (1r) led to a
simple intramolecular alkyne-azide cycloaddition product 4.
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Scheme
4 Plausible Mechanism through anti-carbonickelative
cyclization.
In conclusion, azidophenyl propargyl alcohols could be cyclized to
2,3-diaryl quinolines via arylation with aryl boronic acids under
Ni(II)- catalysis. Selective carbonickelation, E/Z isomerization of the
nickel intermediate and capture of the C-M centre by an internal
azide as a rare non-carbon electrophile were highlights of the
redox-free catalytic process. A thorough verification of substrate
scope with respect to both boronic acids and the alkyne-azides was
done to prove the practicality of the method.
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This work was supported by MoES (09-DS/03/2014 PC-IV), New
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8
9
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