Enantioselective nickel-catalyzedanti-arylmetallative cyclizations onto acyclic electron-deficient alkenes

Article abstract of DOI:10.1039/d1cc01166a

Enantioselective nickel-catalyzed reactions of (hetero)arylboronic acids or alkenylboronic acids with substrates containing an alkyne tethered to various acyclic electron-deficient alkenes are described.

Full text of DOI:10.1039/d1cc01166a

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Enantioselective nickel-catalyzed
anti-arylmetallative cyclizations onto acyclic
electron-deficient alkenes†
Cite this: Chem. Commun., 2021,
57, 4436
Received 3rd March 2021,
Accepted 23rd March 2021
Simone M. Gillbard,ab Harley Green,ab Stephen P. Argent ‡b and
ab
Hon Wai Lam
*
DOI: 10.1039/d1cc01166a
rsc.li/chemcomm
Enantioselective nickel-catalyzed reactions of (hetero)arylboronic
This study began with the reactions of PhB(OH)2 with
acids or alkenylboronic acids with substrates containing an alkyne substrates 1a–1p (Table 1). An evaluation of conditions8 led to
tethered to various acyclic electron-deficient alkenes are described. the finding that heating the substrate 1, PhB(OH)2 (1.2 equiv.),
and 5 mol% each of Ni(OAc)2ꢀ4H2O and (S)-t-Bu-NeoPHOX
The metal-catalyzed addition of an arylboron reagent to an alkyne, (L1)2b,9 in TFE at 100 1C for 16–19 h gave the desired products
followed by enantioselective intramolecular nucleophilic addition 2 in generally good yields and high enantioselectivities.10 In
of the resulting alkenylmetal species onto a tethered electrophile, some cases (2j, 2o, and 2p), using 2.0 equivalents of PhB(OH)2
is a versatile domino reaction sequence for the synthesis of and increasing the catalyst loading were required for acceptable
diverse chiral carbo- and heterocycles.1 We2 and others3 have yields. Aromatic ketones with halide (2a and 2b), nitro (2c and
recently described nickel-catalyzed variants of these reactions in 2e), or trifluoromethyl (2d) substituents at various positions of
which reversible E/Z isomerization of the intermediate alkenyl- the benzene are tolerated, as are 2-furyl (2f), 2-thienyl (2g), and
nickel species enables enantioselective arylative cyclizations to methyl ketones (2h and 2k–2n). Notably, an a,b-unsaturated
proceed that would otherwise be impossible because of geometric aldehyde underwent arylative cyclization to give 2i in 58% yield
constraints. Variants of these reactions that give achiral products,4 and 499% ee. An a-chloroketone, containing a potentially
and several related processes,5–7 have also been described.
labile carbon–chlorine bond, is also tolerated (2j). The alkynyl
We have previously described enantioselective desymmetrizing group can be changed from phenyl (2a–2j) to 4-chlorophenyl
nickel-catalyzed arylative cyclizations onto cyclohexa-2,5-dienones, (2k), 3-methylphenyl (2l), 2-thienyl (2m), and vinyl (2n),
which give fused bicyclic products with high diastereo- and although 2m was formed in lower yield and enantioselectivity.
enantioselectivities (Scheme 1A).2a However, the use of a broader Aryl- and alkenyl-substituted alkynes are usually required for
range of acyclic electron-deficient, conjugated alkenes in cycliza- high regioselectivities in the initial arylnickelation step, presumably
tions would be valuable in providing less complex, non-fused because the resulting alkenylnickel intermediates are better stabi-
products, and would substantially increase the synthetic utility of lized by an adjacent sp2-hybridized group. Therefore, it was of
this methodology. Herein, we demonstrate that acyclic enones, interest to evaluate the reaction of methyl-substituted alkyne 1o,
nitroalkenes, a,b-unsaturated esters, and a,b-unsaturated nitriles
can be used as electrophiles in the enantioselective preparation of
various non-fused chiral carbo- and heterocycles (Scheme 1B).
Collectively, these results represent a substantial increase in the
scope of nickel-catalyzed anti-carbometallative cyclizations.
a The GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry,
University of Nottingham, Jubilee Campus, Triumph Road, Nottingham, NG7 2TU,
UK. E-mail: hon.lam@nottingham.ac.uk
b School of Chemistry, University of Nottingham, University Park, Nottingham,
NG7 2RD, UK
† Electronic supplementary information (ESI) available: Experimental proce-
dures, full spectroscopic data for new compounds, and crystallographic data
for 2a, 2r, 2s, and 2y. CCDC 2040010–2040013. For ESI and crystallographic data
Scheme 1 Enantioselective nickel-catalyzed arylative cyclizations onto
in CIF or other electronic format see DOI: 10.1039/d1cc01166a
electron-deficient alkenes.
‡ To whom enquires regarding X-ray crystallography should be addressed.
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Table 1 Scope of alkynes tethered to electron-deficient alkenesa
Further investigations into the scope of these reactions revealed
some interesting findings. For example, the reaction of 2-
fluorophenylboronic acid with substrate (E)-1q, which contains an
a,b-unsaturated t-butyl ketone, gave the arylative cyclization product
2y in only 25% yield but in 499% ee (eqn (1)). This reaction also
gave the alkyne hydroarylation products 3 in 30% yield, which were
isolated as a 0.7 : 1 mixture of inseparable E- and Z-isomers,
respectively. Evidently, the steric hindrance imparted by the t-butyl
group had a negative effect on the efficiency of arylative cyclization.
Interestingly, however, the analogous reaction with the stereoiso-
meric substrate (Z)-1q gave 2y in 90% yield and 499% ee (eqn (2)).
The markedly different propensity of (E)-1q and (Z)-1q to undergo
the desired reaction is reminiscent of our prior work in enantio-
selective nickel-catalyzed intramolecular allylic alkenylations, where
Z-allylic phosphates gave arylative cyclization products but the
corresponding E-isomers did not.2b The reasons for the differing
results obtained from (E)-1q and (Z)-1q are not clear, but perhaps the
lower thermodynamic stability of (Z)-1q is manifested in greater
reactivity toward nucleophilic attack, and/or the steric requirements
of the reaction are better accommodated by (Z)-1q. Moreover, the
major enantiomer of 2y is identical for both reactions (see the ESI†
for tentative stereochemical models). These results contrast with
several other examples of enantioselective 1,4-additions of carbon
nucleophiles to electron-deficient alkenes where E- and Z-isomers
of the substrates give opposite enantiomers of the products.11
However, reactions where E- and Z-isomers give the same major
enantiomers of 1,4-addition products are also known.1j,11b
a
Reactions were conducted using 0.30 mmol of 1 in TFE (3 mL). Yields
are of isolated products. Enantiomeric excesses were determined by
b
HPLC analysis on a chiral stationary phase. Using 2.0 equivalents of
c
d
PhB(OH)2. Using 20 mol% each of Ni(OAc)2ꢀ4H2O and L1. Using
10 mol% each of Ni(OAc)2ꢀ4H2O and L1.
which gave 2o in 31% yield and 92% ee. This reaction also gave a
mixture of other unidentified products, presumably because of low
regioselectivity in the initial arylnickelation. A nitroalkene can also
be used as the electrophile (2p).
The results of evaluating different boronic acids in reactions
with substrates 1g or 1p are shown in Table 2. Substituted
phenylboronic acids with various groups at the para (2t), meta
(2q), or ortho (2r) positions successfully underwent the reaction
to give products with reasonable to high yields and high
enantioselectivities, as did 3,4-dichlorophenylboronic acid
(2u) and 3-thienylboronic acid (2s). Various alkenylboronic
acids also reacted with 1p to give products 2v–2x in 499% ee
but in low yields because of competitive protodeboronation.
Table 2 Scope of boronic acidsa
(1)
(2)
Thus far, only enones or nitroalkenes had been used as
electrophiles. Interestingly, use of an a,b-unsatured ester gave
other types of products (eqn (3)). Substrate 1r reacted with
PhB(OH)2 (2.0 equiv.) in the presence of 10 mol% each of
Ni(OAc)2ꢀ4H2O and (S)-t-Bu-NeoPHOX (L1) to give the arylative
cyclization product 2z (14%, 499% ee), conjugated dienes 5
(23% yield) and 6 (15% yield) resulting from Heck-type
cyclizations,12,13 and what appeared to be the reductive cyclization
product 4, which could not be isolated cleanly. These results can be
a
b
See footnote a of Table 1. Using 2.0 equivalents of boronic acid and
10 mol% each of Ni(OAc)2ꢀ4H2O and L1.
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explained by considering the mechanism of nickel-catalyzed anti- (Z)-11 from (E)-1s and (Z)-1s, respectively, see the ESI.†
carbometallative cyclizations that we have proposed previously
(Scheme 2).2,4c Reaction of 1r and PhB(OH)2 would, after arylnick-
elation and reversible E/Z isomerization,2,4c lead to alkenylnickel
species 7. A syn-stereospecific migratory insertion of the alkene2b
would then give the C-bound nickel enolate 8. Protodenickelation of
8 by TFE gives the arylative cyclization product 2z. However, the low
yield of 2z suggests that this step is slow compared with substrates
containing ketones or nitro groups (Tables 1 and 2).14 In competition
with protodenickelation of 8, bond rotation to give 80 and stereo-
specific syn-b-hydride elimination gives diene 5 and a nickel hydride
species 9. The nickel hydride 9 can then enter analogous reaction
pathways with substrate 1r but via alkyne hydronickelation to give 10
and eventually, the reductive cyclization product 4 and diene 6.
(4)
(5)
Next, the formation of six-membered rings was attempted.
However, reaction of 13 (a higher homologue of substrate 1h
that successfully gave product 2h (see Table 1)) with PhB(OH)2
(2.0 equiv.) in the presence of 10 mol% each of Ni(OAc)2ꢀ4H2O
and (S)-t-Bu-NeoPHOX (L1) failed to provide the desired six-
membered arylative cyclization product. Instead, a 2.3 : 1
mixture of inseparable stereoisomeric alkyne hydroarylation
products (E)-14 and (Z)-14, respectively, was obtained in 57%
yield (Scheme 3). Replacing (S)-t-Bu-NeoPHOX (L1) with other
chiral phosphine–oxazoline ligands did not lead to any
improvement.8 However, use of the achiral ligand pyphos (L2)
gave racemic 15 in 47% yield (Scheme 3).15
The reaction of PhB(OH)2 with substrate 16a, which contains
a para-toluenesulfonamide group, gave only a complex mixture
of unidentified products (Scheme 4). As with 13, improved
results were not obtained with other chiral phosphine–oxazo-
line ligands8 but use of pyphos (L2) gave the racemic arylative
cyclization product 17 in 52% yield.
Given the results shown in Schemes 3 and 4, it was not surprising
that substrate 16b (see eqn (6)), which contains an a,b-unsaturated
ester rather than an a,b-unsaturated ketone, did not provide the
desired arylative cyclization product when it was reacted with
PhB(OH)2 using L1 as the chiral ligand. However, unlike for substrates
13 and 16a, it was interesting to observe that (S)-t-Bu-PHOX (L3) was
an effective chiral ligand in the arylative cyclization of 16b, which
reacted smoothly with PhB(OH)2 (2.0 equiv.) in the presence of
10 mol% each of Ni(OAc)2ꢀ4H2O and L3 to give tetrahydropyridine
(3)
Conjugate dienes were also obtained from substrates containing
an a,b-unsaturated nitrile (eqn (4) and (5)). The reaction of PhB(OH)2
with (E)-1s gave an inseparable 13 : 1 mixture of dienes (E)-11 (18%
yield) and 12 (1.4% yield), and the remainder of the material was a
mixture of unidentified products (eqn (4)). None of the desired
product 2aa was detected. In contrast, the stereoisomeric substrate
(Z)-1s gave 2aa in 60% yield and 99% ee, along with diene (Z)-11 in
25% yield (eqn (5)). The observation that the Z-isomer of the
substrate is more effective in providing the product 2aa is similar
to the results shown in eqn (1) and (2). For a mechanistic rationale
of the production of different stereoisomers of dienes (E)-11 and
Scheme 2 Mechanistic rationale of the formation of 2z and 4–6.
4438 | Chem. Commun., 2021, 57, 4436–4439
Scheme 3
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Scheme 4
18 in 59% yield and 89% ee (eqn (6)).
(6)
In summary, we have reported enantioselective nickel-
catalyzed anti-carbometallative cyclizations of (hetero)arylboro-
nic acids and alkenylboronic acids with acyclic substrates
containing an alkyne tethered to an enone, nitroalkene,
a,b-unsaturated ester, or a,b-unsaturated nitrile. The products
are various non-fused chiral carbo- and heterocycles, and the
enantioselectivities are excellent in most cases (often Z99%
ee). These results represent a substantial increase in the scope
over our previous work.2 Interesting findings comparing the
efficiencies of E/Z stereoisomers of certain substrates, and the
isolation of products resulting from b-hydride eliminations and
reductive cyclizations have also been described (eqn (1)–(5)).16
This work was supported by the Engineering and Physical
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14 A possible reason is that protodenickelation proceeds faster via the
O-bound, rather than the C-bound nickel enolate, and ketone-derived
enolates are more likely to exist as the O-bound form compared with
ester-derived enolates. Similarly, protodenickelation of nickel nitronates
is likely to be more rapid than ester-derived nickel enolates because of a
higher ratio of O- vs. C-bound forms.
15 Product 15 contained an inseparable impurity and therefore the
yield was calculated by 1H NMR analysis using an internal standard.
16 The research data associated with this publication can be found
at:http://dx.doi.org/10.17639/nott.7109.
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