Enantioselective nickel-catalyzed arylative and alkenylative intramolecular 1,2-allylations of tethered allene-ketones

Article abstract of DOI:10.1039/c9sc05246a

The enantioselective nickel-catalyzed reaction of tethered allene-ketones with (hetero)arylboronic acids or potassium vinyltrifluoroborate is described. Carbonickelation of the allene gives allylnickel species, which undergo cyclization by 1,2-allylation

Full text of DOI:10.1039/c9sc05246a

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Enantioselective nickel-catalyzed arylative and alkenylative
intramolecular 1,2-allylations of tethered allene-ketones†
aaReceived 00th January 20xx,
Accepted 00th January 20xx
Riccardo Di Sanza,‡ab Thi Le Nhon Nguyen,‡ab Naeem Iqbal,ab Stephen P. Argent,§b William Lewis§b
and Hon Wai Lam*ab
DOI: 10.1039/x0xx00000x
The enantioselective nickel-catalyzed reaction of tethered allene–ketones with (hetero)arylboronic acids or potassium
vinyltrifluoroborate is described. Carbonickelation of the allene gives allylnickel species, which undergo cyclization by 1,2-
allylation to produce chiral tertiary-alcohol-containing aza- and carbocycles in high diastereo- and enantioselectivities.
www.rsc.org/
A. Enantioselective Ni-catalyzed arylative intramolecular 1,4-allylations (ref. 8a)
Pyrrolidin-2-ones with a tertiary alcohol at C3 are common
structures in natural products such as pramanicin,1
norsecurinamine A,2 and cytochalasin Z10,3 and also appear in
compounds with herbicidal activity4 (Fig. 1). Therefore, new
methods for the preparation of these chiral structures in
enantiomerically enriched form are valuable. Although
numerous catalytic enantioselective reactions to give the
benzannulated derivatives of these compounds (oxindoles with
a C3 tertiary alcohol) have been described,5,6 it is surprising
that, to our knowledge, methods for the corresponding
pyrrolidin-2-ones are currently limited to palladium-catalyzed
O
O
O
PPh2
N
Ph
(10 mol%)
H
Ar
Ni(OAc)2·4H2O (10 mol%)
•
+
ArB(OH)2
MeCN/dioxane (3:2)
80 °C, 16 h
R
R
X
X
X = NTs, O
B. Ni-catalyzed annulations of activated allenes (ref. 8b)
O
R1
R2
OH
R3
R1
R2
Ni(OAc)2·4H2O (10 mol%)
•
Ar
Ar
+
O
MeCN:1,4-dioxane (3:2)
RT, 24 h
O
B(OH)2
R3
O
O
R2
C. This work
O
H
N
R1
NiLn
O
O
O
O
Ar
R1
HO
O
OH
A
O
R2
N
R2
N
N
Ni (cat.)
R1
•
O
NH
NH
HO
ArB(OH)2
HO
Me
O
R2
N
O
NiLn
N
1
2
OH
Ar
Me
R1
pramanicin
norsecurinamine A
O
Ar
A'
OH Me
F
Scheme 1 Nickel-catalyzed arylative cyclizations of allenes.
O
O
Me
F
HN
HO
OH
HO
Me
O
hydroxylations of cyclic β-ketoesters7a and chromium-catalyzed
cyclizations of enamides onto α-ketoamides.7b
N
OH
H
NH
On the basis of our recent work in nickel-catalyzed arylative
cyclizations involving allenes as substrates (Schemes 1A and
1B),8 it occurred to us that chiral pyrrolidin-2-ones with a C3
tertiary alcohol might be prepared by the nickel-catalyzed
reaction of tethered allene–α-ketoamides 1 with arylboronic
acids (Scheme 1C).9,10 Nickel-catalyzed addition of an
arylboronic acid to the allene would give an intermediate
allylnickel species,8 which could exist as several
interconverting σ- and π-allyl isomers (representative structures
A and A' are shown), which could then engage in enantio- and
diastereoselective nucleophilic allylation11 of the ketone to give
pyrrolidin-2-one 2.12,13,14 While enantioselective metal-
catalyzed nucleophilic allylations of carbonyl compounds are
Me
cytochalasin Z10
Ph
Me
herbicide
Fig. 1 The occurrence of pyrrolidin-2-ones with a C3-tertiary alcohol in
natural products and herbicidal compounds.
a. The GSK Carbon Neutral Laboratories for Sustainable Chemistry, University of
Nottingham, Jubilee Campus, Triumph Road, Nottingham, NG7 2TU, United
Kingdom
b. School of Chemistry, University of Nottingham, University Park, Nottingham, NG7
2RD, United Kingdom
† Electronic Supplementary Information (ESI) available: Experimental procedures,
full spectroscopic data for new compounds, and crystallographic data for 2a, 5a,
and 5d. CCDC 1945864‒1945866. See DOI: 10.1039/x0xx00000x
‡ These authors contributed equally.
§ To whom enquires regarding X-ray crystallography should be addressed.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 2 Enantioselective synthesis of chiral pyrrolidin-2-onesa
well-known,15 the closest approach to that shown in Scheme 1C
is work described by groups of Tsukamoto16a and Lu16b to give
other types of hetero- and carbocycles. However, their work
used palladium catalysis and mainly tethered allene–aldehydes
as the substrates and the single example of arylative cyclization
View Article Online
DOI: 10.1039/C9SC05246A
O
PPh2
N
O
O
R2
N
t-Bu
R1
R2
L3 (5 mol%)
Ni(OAc)2·4H2O (5 mol%)
R1
•
N
HO
of
a
tethered allene–ketone was only modestly
O
TFE, 80 °C, 24 h
1a1f
enantioselective.16a These results are perhaps unsurprising
given that ketones are significantly less reactive than aldehydes,
and the smaller steric differences between the two substituents
flanking the carbonyl group in ketones compared with
aldehydes means that achieving high enantioselectivities in
nucleophilic additions is usually more challenging.
Accordingly, solving this issue through the development of
enantioselective arylative cyclizations of tethered allene–
ketones using cheaper nickel catalysts to give products with
tertiary alcohols is a worthwhile objective.
+
Ar
ArB(OH)2 (1.5 equiv)
2
>19:1 dr
(unless otherwise stated)
Variation of tethered alleneketone
O
O
O
Ph
Me
O
PMP
PMP
PMP
N
N
N
HO
HO
HO
Ph
Ph
Ph
2a 99%, 96% ee
2b 99%, 97% ee
2c 99%, 98% ee
O
O
O
This study was initiated with the reaction of tethered allene–
α-ketoamide 1a, PhB(OH)2 (1.5 equiv), and Ni(OAc)2·4H2O (5
mol%) in MeCN/1,4-dioxane (3:2) at 80 °C for 24 h, which
gave racemic 2a in 32% yield as determined by 1H NMR
analysis, and as one observable diastereomer (Table 1, entry 1).
Repeating this reaction with the addition of 5 mol% of the P,N-
ligand L1 increased the yield of 2a to 77% (entry 2). The chiral
phosphinooxazoline (S)-i-Pr-PHOX (L2) gave 2a in 55% yield
and 90% ee (entry 3).17 Improved results were obtained with
(S)-t-Bu-PHOX (L3) (78% yield and 98% ee, entry 4), while
(R)-Ph-PHOX (L4) gave results similar to L2 (entry 5, compare
with entry 3). With L3 as the ligand, changing the mixed
solvent system to MeCN or 1,4-dioxane alone offered
noimprovement (entries 6 and 7). Finally, we tested TFE (2,2,2-
trifluoroethanol) as the solvent,9b,c which gave 2a in almost
quantitative yield after filtration of the crude reaction mixture
Et
i-Pr
Ph
PMP
PMP
Bn
N
N
N
HO
HO
HO
Ph
Ph
Ph
2d >99%, >99% ee
2e >99%, >99% ee
2f 99%, 87% ee
65%, 99% eeb
Variation of arylboronic acid
O
O
O
Ph
Ph
Ph
PMP
PMP
PMP
N
N
N
HO
HO
HO
R
R
R
2g R = OAc, >99%, 97% ee
2h R = Cl, 99%, 98% ee
2i R = vinyl, 71%, 99% ee
2j R = F, >99%, 98% ee
2k R = CN, 90%, 99% ee
2l R = Me, 69%, 84% ee
2m R = F, 68%, 97% ee
2n R = NH2, 48%, 56% eec
O
O
O
Ph
Ph
Ph
PMP
PMP
PMP
N
N
N
HO
HO
HO
Table 1 Evaluation of reaction conditionsa
O
O
PMP
N
Ph
HO
Me
Cl
ligand (5 mol%)
Ni(OAc)2·4H2O (5 mol%)
PMP
N
O
Ph
•
Br
O
Cl
solvent, 80 °C, 24 h
1a
2o >99%, 98% ee
2p >99%, 98% ee
2q 91%, 7:1 dr, 91% eed
+
Ph
2a >19:1 dr
a
PhB(OH)2 (1.5 equiv)
Reactions were conducted using 0.30 mmol of 1. Yields are of isolated
1
products. Diastereomeric ratios were determined by H NMR analysis of the
crude reaction mixtures. Enantiomeric excesses were determined by HPLC
analysis on a chiral stationary phase. b Conducted in MeCN instead of TFE. c
Conducted using the pinacol boronate instead of the boronic acid. The
diastereomeric ratio of the crude reaction mixture was 7:1. Isolated as a 7:1
mixture of inseparable diastereomers.
Ligands
O
O
O
d
PPh2
N
PPh2
N
PPh2 N
N
PPh2
L1
L2
i-Pr
L3
t-Bu
L4
Ph
Entry
Ligand
–
Solvent(s)
Yield (%)b
ee (%)c
–
through plug of a silica gel, with only a slight decrease in
enantioselectivity (entry 8). On the basis of these results, the
conditions of entry 8 were selected for subsequent experiments.
The scope of this process in the enantioselective synthesis
of chiral pyrrolidin-2-ones was then explored (Table 2).
Pleasingly, various tethered allene–α-ketoamides 1a–1f reacted
successfully with a range of (hetero)arylboronic acids to give
pyrrolidin-2-ones 2a–2q as single observable diastereomers
(with only a single exception) in up to >99% ee. Notably, with
TFE as the solvent, the products were in many cases obtained in
essentially quantitative yields after filtration of the crude
reaction mixtures through silica gel, and purification by column
1
2
3
4
5
6
7
8
a
MeCN/1,4-dioxane (3:2) 32
MeCN/1,4-dioxane (3:2) 77
MeCN/1,4-dioxane (3:2) 55
MeCN/1,4-dioxane (3:2) 78
MeCN/1,4-dioxane (3:2) 61
L1
L2
L3
L4
L3
L3
L3
–
90
98
–91d
MeCN
78
98
1,4-dioxane
TFE
59
98
>99
96
b
Reactions were conducted using 0.10 mmol of 1a. Determined by 1H
NMR analysis of the crude reactions using 1,3,5-dimethoxybenzene as an
internal standard. Determined by HPLC analysis on a chiral stationary
phase.
methoxyphenyl.
c
d
The major product was the enantiomer of 2a. PMP = para-
2 | J. Name., 2012, 00, 1-3
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Table 3 Further exploration of substrate scopea
chromatography was often not required. Regarding the ketone
substituent of the substrate, phenyl (2a and 2g–2q), 2-furyl
(2b), simple alkyl (2c and 2d), and branched alkyl (2e) groups
are tolerated. Changing the nitrogen substituent to a benzyl
group was possible, though the product 2f was obtained in a
lower 87% ee. However, replacing TFE with MeCN as the
solvent gave 2f in >99% ee but in a lower yield. As well as
PhB(OH)2 (2a–2f), the reaction is compatible with other
arylboronic acids, as shown by the reaction of 1a with various
para- (2g–2i), meta- (2j, 2k, and 2o), ortho- (2l–2n), and
disubstituted (2o and 2p) phenylboronic acids with acetoxy
(2g), halide (2h, 2j, 2m, 2o, and 2p), vinyl (2i), cyano (2k), or
methyl (2l and 2o) groups. A heteroarylboronic acid also
reacted smoothly to give 2q in 93% yield and 98% ee. This
example was the only instance where the minor diastereomer
View Article Online
DOI: 10.1039/C9SC05246A
O
PPh2
N
t-Bu
L3 (5 mol%)
Ni(OAc)2·4H2O (5 mol%)
O
n
R
X
X
HO
R
•
n
TFE, 80 °C, 24 h
4a4i
+
n = 1, 2
Ph
X = NPG or C(CO2Me)2
5
>19:1 dr
ArB(OH)2 (1.5 equiv)
Ph
HO
Me
Ph
Ts
Ts
PMP
N
N
N
HO
HO
Ph
Ph
Ph
5a 92%, 84% ee
5b 96%, 83% ee
5c 62%, 75% ee
Cl
t-Bu
Me
PMP
1
was detected (7:1 dr as determined by H NMR analysis of the
N
N
HO
HO
crude reaction mixture). 2-Aminophenylboronic acid pinacol
ester also reacted with 1a to give 2n in 48% yield and 56% ee.
The reaction also worked well with substrate 1g, in which
the nitrogen atom is unprotected, to give 2r in 90% yield as a
single observable diastereomer and 99% ee (eqn (1)).
Ph
5d 73%, 99% eeb
Ph
5e 91%, 90% ee
Ph
HO
CO2Me
CO2Me
Ph
HO
CO2Me
CO2Me
Ph
HO
CO2Me
CO2Me
O
PPh2
N
O
O
Cl
TMS
Ph
5f 33%, 90% eed
t-Bu
H
Ph
HO
5g 47%, 93% eed
5h 34%, 89% eed
N
L3 (5 mol%)
Ni(OAc)2·4H2O (5 mol%)
NH
Ph
•
(1)
O
CO2Me
TFE, 80 °C, 24 h
1g
CO2Me
+
Ph
2r 90%, >19:1 dr, 99% ee
Ts
Ts
N
Me
HO
PhB(OH)2 (1.5 equiv)
N
Ph
HO
Me
HO
Notably, the process is not limited to the use of
Ph
Ph
Cl
(hetero)arylboron reagents, as shown by the reaction of 1a with
potassium vinyltrifluoroborate to give 1,3-diene-containing
pyrroldine-2-one 3 in 65% yield and 93% ee (eqn (2)).
5i 50%, 99% eec
5j 67%, 85% eed
5k 76%, 76% eec,d,e
a Yields are of isolated products. Diastereomeric ratios were determined by
1H NMR analysis of the crude reaction mixtures. Enantiomeric excesses were
b
determined by HPLC analysis on a chiral stationary phase.
A 7.7:1
inseparable mixture of 5d and the starting allene 4d was obtained (the yield
of 5d has been adjusted accordingly). c The reaction time was 48 h. Using
MeCN as the solvent in place of TFE. Conducted using 10 mol% each of
Ni(OAc)2·4H2O and L3.
d
O
e
PPh2
N
O
O
PMP
N
Ph
HO
t-Bu
L3 (5 mol%)
Ni(OAc)2·4H2O (5 mol%)
PMP
N
Ph
•
the nitrogen substituent but rationalization of these observations
is difficult at the present time. Regarding the ketone substituent
in the substrate, methyl (5b, 5e, 5j, and 5k), tert-butyl (5d), and
phenyl (5a, 5c, and 5f–5i) groups were tolerated, and increasing
the size of this group had a beneficial effect on the
enantioselectivity.
Substrates that did not undergo arylative cyclization, but
which only returned unreacted starting materials, are shown in
Fig. 2. The failure of 4j to cyclize indicates that an amide,
sulfonamide, aniline, or a malonyl unit at the allylic position of
the tether connecting the allene and the ketone is important for
reactivity. To probe whether these features aid cyclization by
increasing the proportion of reactive conformers by the geminal
disubstituent18 or related19 effects, we examined substrate 4k,
which contains a geminal dimethyl unit. Because 4k also failed
to cyclize, we speculate that the aforementioned nitrogen-
containing groups or a malonyl unit in the tether aid reactivity
not by a geminal disubstituent or related effect, but perhaps by
(2)
O
TFE, 80 °C, 24 h
1a
+
(1.5 equiv)
KF3B
3
65%, >19:1 dr, 93% ee
Pleasingly, this process is also not restricted to the
preparation of chiral pyrrolidin-2-ones; it can be employed in
the synthesis of other types of aza- and carbocycles, which
were obtained in up to 96% yield and in 75–99% ee (Table 3).
In several cases, superior results were obtained using MeCN in
place of TFE as the solvent (5c, 5f–5h, 5j, and 5k). Various
pyrrolidines (5a–5e), cyclopentanes (5f–5h), piperidines (5i and
5j), and a cyclohexane were successfully prepared using this
chemistry. For the azacyclic products, the method is compatible
with tosyl (5a, 5b, 5i, and 5j), 4-methoxyphenyl (5c and 5d),
and 4-chlorophenyl (5e) substituents on the nitrogen atom. A
comparison of the reactions producing 5a and 5c, and of 5b and
5e, shows the enantioselectivity is dependent on the nature of
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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O
O
Me Me
Z-σ-allylnickel species 10b to give the minor enantiomer ent-2a
View Article Online
is likely to be disfavored because of unfDaOvoI:r1a0b.1l0e39n/oCn9-SbCo0n5d24in6gA
interactions between the tert-butyl group of the chiral ligand
and a phenyl group. Although we currently favor the pathway
shown in Scheme 2, nucleophilic allylation through alternative,
five-coordinate nickel complexes cannot be excluded.
Further transformations of a representative product 2a are
shown in Scheme 3. First, removal of the 4-methoxyphenyl
protecting group from the nitrogen atom of a representative
product 2a was readily accomplished in 98% yield using CAN
in MeCN/H2O (1:1) at –10 °C for 30 min to give 2r in 98%
yield. Alternatively, oxidative cleavage of the alkene of 2r
using K2[OsO2(OH)4] and NaIO4 gave 12 in 91% yield.
Ph
•
Ph
•
4j
4k
Fig. 2 Substrates that do not undergo arylative cyclization.
being able to act as a directing group and coordinating to
catalytic nickel species to aid arylnickelation of the allene.
A possible catalytic cycle for these reactions, using 1a and
PhB(OH)2 as representative reaction partners, is shown in
Scheme 2. After formation of the chiral nickel complex 6,
which in principle could have acetate, hydroxide, or 2,2,2-
trifluoroethoxide ligands resulting from the species present in
the reaction, transmetalation with PhB(OH)2 gives phenylnickel
species 7 with the phenyl ligand trans to the π-accepting
phosphorus atom rather than the stronger σ-donating nitrogen
atom. Phenylnickelation of the internal alkene of substrate 1a,
directed by the amide carbonyl group,20 would give σ
allylnickel species 8, which could interconvert with alternative
allylnickel species (E)-9 and (Z)-9 by a series of σ-π-σ
isomerizations. The stereochemical outcome of the reactions is
consistent with intramolecular nucleophilic allylation through a
cyclic six-membered chair-like conformation in the cationic Z-
σ-allylnickel species 10a, which is formed by substitution of
the anionic oxygen ligand of (Z)-9 from the nickel center by
coordination of the ketone.21 After reassociation of an anionic
oxygen ligand, the resulting nickel alkoxide 11 can then
undergo protonolysis to release pyrrolidin-2-one 2a and
regenerate 6. Nucleophilic allylation through the diastereomeric
O
O
Ph
HO
Ph
HO
PMP
N
NH
CAN ( 2.5 equiv)
MeCN/H2O (1:1)
10 °C, 30 min
Ph
2a
Ph
2r 98%
O
NaIO4 (6.0 equiv)
K2[OsO2(OH)4] (10 mol%)
Ph
HO
PMP
N
THF/H2O (5:2)
0
°C to RT, 18 h
O
Ph
12 91%
Scheme 3 Further transformations of 2a.
The results herein demonstrate the utility of allylnickel
species generated by the carbonickelation of allenes to engage
in stereoselective nucleophilic 1,2-additions to ketones to form
a range of tertiary-alcohol-containing aza- and carbocycles in
high diastereo- and enantioselectivities. Compared with related
palladium-catalyzed reactions reported previously, which focused on
Ni(OAc)2·4H2O + L3
O
TFE
Ph
HO
PMP
N
O
tethered allene–
aldehydes as the substrates,16 this nickel-catalyzed
PhB(OH)2
ROB(OH)2
Ph
2a
Ph2P
RO
N
Ni
process demonstrates that less reactive ketones can serve as effective
electrophiles to enable the synthesis of a range of tertiary-alcohol-
containing aza- and carbocycles. Further applications of
enantioselective catalytic nucleophilic allylations of allylnickel
species will be reported in due course.
OR t-Bu
ROH
O
6
O
Ph
Ln(RO)NiO
PMP
N
Ph2P
N
Ni
7
RO
Ph t-Bu
O
PMP
N
Ph
11
R = Ac, H, or CH2CF3
Ph
•
Conflicts of interest
There are no conflicts to declare.
O
O
PMP
N
RO
1a
PMP
Ph
Ph
N
P
N
Ph
Ni
O
O
NiLn
O
t-Bu
OR
Ph
Ph
Ph
8
O
Acknowledgements
--
10a
--
O
PMP
N
O
PMP
N
This work was supported by the EPSRC Centre for Doctoral
Training in Sustainable Chemistry [grant EP/L015633/1]; the
Leverhulme Trust [grant number RPG-2016-341]; the University of
Nottingham; and GlaxoSmithKline.
RO
Ph
Ph
Ph
Ni(OR)Ln
O
O
Ph
(Z)-9
(E)-9
Ni(OR)Ln
steric interaction
of t-Bu and Ph
O
Ph
O
HO
Ph
Ph
P
PMP
Ph
O
Notes and references
N
PMP
N
disfavored
Ph
Ni
t-Bu
N
1
R. E. Schwartz, G. L. Helms, E. A. Bolessa, K. E. Wilson, R. A.
Giacobbe, J. S. Tkacz, G. F. Bills, J. M. Liesch, D. L. Zink, J. E.
Curotto, B. Pramanik and J. C. Onishi, Tetrahedron, 1994, 50, 1675-
1686.
Ph
ent-2a
O
10b
Scheme 2 Possible catalytic cycle
4 | J. Name., 2012, 00, 1-3
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mechanism via
a five-coordinate nickel intermediate, or a
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O
PMP
N
DOI: 10.1039/C9SC05246A
O
O
Ph
HO
(cat.)
PMP
N
Ph
•
PPh2
N
O
Ni (cat.)
t-Bu
+
TFE, 80 °C
(HO)2B
30 examples
F
F
(1.5 equiv)
68%, >19:1 dr, 97% ee
The enantioselective nickel-catalyzed reaction of tethered allene–ketones with (hetero)arylboronic acids or potassium
vinyltrifluoroborate is described. Carbonickelation of the allene gives allylnickel species, which undergo cyclization by 1,2-
allylation to produce chiral tertiary-alcohol-containing aza- and carbocycles in high diastereo- and enantioselectivities.