Direct conjugate alkylation of α,β-unsaturated carbonyls by TiIII-catalysed reductive umpolung of simple activated alkenes

Article abstract of DOI:10.1039/c5ob02631h

The titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors represents a unique direct conjugate β-alkylation reaction. It allows the cross-selective preparation of 1,6- and 1,4-difunctionalised building blocks without the requirement of stoichiometric organometallic reagents. In this full paper, the development and scope of the titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors is described. Based on the observed selectivities and additional mechanistic experiments a refined mechanistic proposal is presented.

Full text of DOI:10.1039/c5ob02631h

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Direct conjugate alkylation of α,β-unsaturated
carbonyls by TiIII-catalysed reductive umpolung of
simple activated alkenes†
Cite this: DOI: 10.1039/c5ob02631h
Plamen Bichovski, Thomas M. Haas, Manfred Keller and Jan Streuff*
The titanium(III)-catalysed cross-selective reductive umpolung of Michael-acceptors represents a unique
direct conjugate β-alkylation reaction. It allows the cross-selective preparation of 1,6- and 1,4-difunctio-
nalised building blocks without the requirement of stoichiometric organometallic reagents. In this full
paper, the development and scope of the titanium(III)-catalysed cross-selective reductive umpolung of
Michael-acceptors is described. Based on the observed selectivities and additional mechanistic experi-
ments a refined mechanistic proposal is presented.
Received 22nd December 2015,
Accepted 15th January 2016
DOI: 10.1039/c5ob02631h
www.rsc.org/obc
Introduction
The metal-catalysed conjugate addition reaction to enones and
related Michael-acceptors has been a thriving research field
over the past two decades. Nowadays, it is possible to perform
this transformation in high yield and enantioselectivity using
copper-, rhodium-, or palladium-catalysis for example,1 and
even the asymmetric construction of quaternary carbon
centres can be achieved with high selectivity.2 Still, one draw-
back of the classic protocols has been the requirement of
organometallic coupling precursors that need to be prepared
in advance (Scheme 1a). Only a few exceptions, most being Pd-
or Ni-catalysed reductive Heck reactions, have been reported.3
Radical addition reactions to Michael-acceptors are comp-
lementary to traditional conjugate additions. They can be used
to overcome this drawback and to address in particular conju-
gate β-alkylation reactions,4 which have remained challenging
using conventional catalytic conjugate addition approaches.5
Hence, it has been shown that free radical additions using
stoichiometric and catalytic conditions,6 as well as radical
additions after titanium-catalysed reductive epoxide opening,7
can lead to the desired β-alkylated products in a very efficient
manner. The advantage of the titanium-catalysed process was
the superior catalyst control of the reaction selectivity, leading
to high regio-, stereo- and even enantioselectivity.4
Scheme 1 (a) Traditional β-alkylation of enones using premetallated
reagents. (b) Direct titanium(III)-catalysed reductive umpolung enables
the use of simple alkene precursors.
In 2011, we communicated a direct reductive β-alkylation of
enones that enabled the use of readily available activated
alkenes such as acrylonitrile as cross-coupling partners
(Scheme 1b).8 Thus, the requirement of pre-metallated
reagents or free radical conditions was overcome, which
should be kept in mind with regard to more recent contri-
butions in the field of reductive conjugate cross-couplings.5a–c,9
The reaction was a titanium(III)-catalysed overall umpolung
reaction that led to 1,6-ketonitriles and related products.
Related reductive homocoupling reactions were known before
and had been applied even on industrial scale,10 but cross-
selective tail-to-tail coupling of two Michael-acceptors had no
precedence at that time. It should be noted that a redox-
neutral NHC-catalysed cross-selective Michael umpolung was
published shortly afterwards,11,12 which led to α,β-unsaturated
1,6-difunctionalized motifs.
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertsraße 21,
79104 Freiburg, Germany. E-mail: jan.streuff@ocbc.uni-freiburg.de;
Fax: +49 761 203 8715; Tel: +49 761 203 97717
†Electronic supplementary information (ESI) available: Additional screening
tables, experimental and computational details, characterisation data and NMR
spectra of new compounds. CCDC 1440298 and 1440299. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c5ob02631h
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In this full account, we wish to disclose the initial develop- the competing conjugate reduction of the enone, which was
ment of the titanium-catalysed cross-coupling of Michael- reported earlier by others.15 A five-fold excess of acrylonitrile
acceptors and the further advancement towards substrate further suppressed this conjugate reduction as well as the
classes such as quinolones, chromones and coumarins.13 The homo-dimerisation of the enone or its premature silylation.
results lead to valuable implications for the future develop-
The reaction conditions were the result of a careful optimi-
ment of related transformations and the application of such sation process. For example, tetrahydrofuran, which was often
direct β-alkylation reactions.
employed in catalyses involving single-electron-transfer reac-
tions, was the most suitable solvent. Interestingly, a number of
other solvents with a largely different dielectricity constant or
Gutmann-donor number such as hexane, 1,4-dioxane, diethyl
ether or dichloromethane gave reasonable yields as well. Other
very similar solvents (toluene, chloroform, 1,2-dimethoxy-
ethane) gave essentially no conversion to the product
(Table 1). This illustrates that titanium(III)-chemistry is sensi-
tive to a number of effects and reaction outcomes cannot be
estimated easily. In fact, THF, which is only a moderate donor,
was displaced from the TiIII-centre by acrylonitrile forming a
deep-purple complex. Chelating solvents (1,2-DME) and strong
donors such as acetonitrile or DMF, on the other hand, inhi-
bited the catalyst through irreversible coordination.19 Thus we
concluded, the major role of THF was to ensure a balanced sol-
vation of the reaction partners (Et3N·HCl, is only moderately
soluble, for example) and to promote an efficient reduction of
TiIV to TiIII by the metallic reductant.
Results and discussion
Initial reaction optimisation
In a typical experiment, cyclohexenone (1) and 5 equiv. of inex-
pensive acrylonitrile (2) as coupling partner were reacted in the
presence of titanocene dichloride [Cp2TiCl2] (10 mol%), zinc
dust (2 equiv.), triethylamine hydrochloride (1.3 equiv.), and
chlorotrimethylsilane (1.5 equiv.) in THF at 35 °C, to give alkyl-
ated ketone 3 in 87% yield after workup with aqueous HCl
(Scheme 2). Manganese, a stronger reductant that has been fre-
quently applied in catalytic reductive coupling reactions with
titanocene catalysts and other metals,7,14 gave significantly
reduced yields. The reaction outcome was explained by a pre-
liminary mechanistic proposal started with a single-electron-
transfer from the in situ generated titanium(III)-catalyst to the
enone, generating a nucleophilic allylic radical. This radical
would then add to the component with the lowest LUMO (acry-
lonitrile), forming the new carbon–carbon bond. The resulting
electron-poor carbon radical next to the nitrile was then
quickly reduced and protonated under the reaction conditions.
Alternatively, a hydrogen radical abstraction (for example from
THF) could take place, which still remained to be investigated.
The addition of chlorotrimethylsilane was then vital for achiev-
ing turnover through silylation of the titanium(IV)-enolate that
is generated in the process. This resulted in 4 as crude
product. It was found that 1–2 turnovers could be achieved as
well by addition of small amounts of water. The amount of
Et3N·HCl was carefully balanced, since higher amounts led to
The choice of triethylamine hydrochloride as additive
emerged from a screening of various ammonium salts.
Without such an ammonium salt additive only poor conver-
sion to the desired product was observed (Table 2, entry 1).
H2O
Hydrochlorides within a pKa range of pKa
= 10–11 gave the
most satisfying results. Quinuclidinium and diisopropyl-
ethylammonium salts that were within the pKa range of tri-
ethylamine gave slightly lower yields (78% and 64%,
respectively). The more acidic hydrochlorides of 2,4,6-collidine
and pyridine as well as hydrochlorides of secondary amines
had a negative impact on the reaction (entries 3, 4, 8, and 9).
Interestingly, the addition of unprotonated triethylamine was
beneficial too, but also lead to the formation of larger
Table 1 Results of the solvent screening
DNb
Yieldc (%)
a
Entry
Solvent
ερ
1
2
3
4
5
6
7
8
n-Hexane
1,4-Dioxane
CCl4
Toluene
Et2O
CHCl3
1,2-DME
THF
CH2Cl2
1,2-DCE
t-BuOH
MeCN
1.89 (20 °C)
0
14.8
0
0.1
19.2
4
20.0
20.0
1
0
—
14.1
26.6
60
66
2
3
79
1
2.22 (20 °C)
2.24 (20 °C)
2.39 (20 °C)
4.27 (20 °C)
4.81 (25 °C)
7.3 (23.5 °C)
7.52 (22 °C)
9.14 (20 °C)
10.42 (20 °C)
12.5 (20 °C)
36.64 (20 °C)
38.25 (20 °C)
0
90
61
61
0
16
5
9
10
11
12
13
DMF
a Relative permittivity, see ref. 16. b Gutmann donor number, see ref.
17. c Determined by GC-analysis with 1,3-dimethoxybenzene as
internal standard.
Scheme 2 Typical coupling under the previously optimised reactions
conditions und key steps of the originally proposed mechanism. Manga-
nese gave inferior results.
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Table 2 Screening of ammonium salts and TFA as additives
Entry
Additive
pKa (H2O)a
Yieldb (%)
1
2
3
4
5
6
7
8
9
None
TFA
—
10
0
0.23
5.25
7.48
10.75
11.0
ca. 11
11.05
11.22
>20
Pyridine·HCl
Collidine·HCl
Et3N·HCl
Quinuclidine·HCl
iPr2NEt·TFA
iPr2NH·TFA
Piperidine·HCl
Et3N
28
55
90
78
64
0
26
10
48c
a Literature values, see ref. 18. b Determined by GC-analysis with 1,3-
dimethoxybenzene as internal standard. c Significant amounts of the
trimethylsilyl enol ether of cyclohexenone were observed.
Scheme 3 Stabilising effect of added Et3N·HCl on [Cp2TiIIICl].
Table 3 Optimisation of the catalyst loading
Entry
Cp2TiCl2 [mol%]
t [h]
Yielda [%]
1
2
3
4
10
5
3
2
14
14
14
90 (87%)b
70
55
0
Scheme 4 Reductive Coupling of Cyclic Enones with Acrylonitriles.
Yield of isolated material. a Combined yield. b Syringe pump addition of
the dihydrothiopyranone precursor. c Reaction at 0 °C.
—
a Determined by GC-analysis with 1,3-dimethoxybenzene as internal
standard. b Isolated yield in brackets.
which allowed the selective conjugate alkylation of moderately
complex substrates such as (S)-carvone and (S)-verbenone
(13, 14). In addition, a dihydrothiopyranone (4-thiacyclohexe-
none) could be employed as well giving ketonitrile 15 in a
moderate 46% yield. Here, a slow addition of the dihydrothio-
pyranone via a syringe-pump was required to prevent the unde-
sired reductive dimerization of the substrate.
The scope could be further extended towards linear enone
substrates that were transformed into the corresponding 1,6-
ketonitriles 16–18 in reasonable yields (42–53%). Methyl vinyl
ketone, however, led to uncontrolled polymerisation under the
reaction conditions and, thus, only 17% of compound 19 were
isolated. In addition, α,β-unsaturated amides containing
achiral and chiral oxazolidinone units could be employed as
well with moderate success. However, no diastereoselectivity
amounts of the trimethylsilylenol ether of cyclohexenone
(entry 10). The superiority of triethylamine hydrochloride,
however, cannot be explained by its acidity alone and might
stem from the tendency of Et3N·HCl to form a TiIII-Et3N·HCl
adduct 6 (Scheme 3) with the active titanium(III) monomer 5,
which was proposed to stabilize the catalyst.20
Lowering the catalyst amount to 5 mol% or 3 mol% still
gave 70% and 55% yield, respectively (Table 3). However, the
above mentioned competing reactions (silyl enol ether for-
mation of 1 and homo-coupling of 1) became more prominent.
Without the titanocene catalyst, no product was formed.
Scope of the enone
Using the optimised conditions, a series of substrates was
coupled with acrylonitrile in a similar manner to give the was observed, even if precoordination of the substrate by
corresponding 1,6-ketonitriles in moderate to high yields after AlEt2Cl was attempted.
The titanium-catalysed reductive umpolung/β-alkylation
workup with aqueous HCl (Scheme 4). Different enone ring
sizes (7–9) and substitution patterns were tolerated that could be applied to a number of quinones, chromones, and
enabled the construction of quaternaty carbon centres at the coumarines as described in the following.13 A series of substi-
tuted quinolones was treated under the same conditions with
β-position (9, 10). The coupling proceeded in excellent
diastereoselectivity regarding the newly formed C–C bond, acrylonitrile as coupling partner and good yields were obtained
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Table 4 Reductive coupling of 4-quinolones with acrylonitrile
Table 5 Diastereoselective reductive coupling of 3-substituted
4-quinolones
Entry
R1
R2
R3
Product
Yielda [%]
1
2
3
4
5
6
H
H
MeO
Me
Ph
Ph
H
H
H
H
H
H
Me
Bn
Me
Me
Me
Bn
23a
23b
23c
23d
23e
23f
77
78b
56
47
46
21
7
H
Bn
23g
41
Entry
R1
R2
Products
25a, 26a
25b, 26b
25c, 26c
25d, 26d
Workupa
syn/anti
Yieldb [%]
8
H
Bn
23h
48
1a
1b
2a
2b
3a
3b
4a
4b
Me
Me
Ph
Ph
Me
Bn
Me
Bn
HCl
TBAF
HCl
TBAF
HCl
TBAF
HCl
>95 : 5
>95 : 5
>95 : 5
71 : 29
>95 : 5
71 : 29
>95 : 5
70 : 30
86
74
91
69
72
89
85
69
9
Me
Br
Br
Cl
Me
H
H
Me
Me
Bn
Me
23i
23j
23k
23l
48
31
32
29
10
11
12
H
a Yield of isolated product. b 48 h reaction time.
TBAF
a HCl workup: aq. 1 N HCl, 0 °C, 3 h. TBAF workup: TBAF (1 M in
THF), −78 °C, 3 h. b Yield of isolated product.
for N-methylated and N-benzylated substrates having no
further substitution (Table 4). The reaction worked also with
substitution at position 7 and 8, although the yields were
slightly diminished. For example, 7-methoxy, -methyl, -phenyl,
-thiophen-3-yl, and -phenylethynyl groups worked well (entries
3–8). In some cases (e.g. R1 = Ph), however, significant differ-
ences in yield were observed for the N-methylated and
N-benzylated precursors (entries 5 and 6). Double substitution
was tolerated as well (entry 9) and importantly, halogenation of
the aromatic backbone was tolerated to some extend (entries
10–12).21 This underlined the mildness of the title reaction.
The coupling worked significantly better with 3-substituted
quinolones. Here, yields between 69% and 91% were obtained
for 3-methyl and 3-phenyl derivatives (Table 5). Importantly,
aqueous workup under protic conditions gave exclusively the
syn-diastereomer, which was a result of a pseudo-axial orien-
tation of the cyanoethyl chain due to steric repulsion with the
N-alkyl group. Quenching the silyl enol ether under controlled
conditions instead produced significant amounts of the anti-
diastereomer (in a 2.4 : 1 syn/anti ratio), which could be separ-
ated and structurally confirmed by X-ray analysis (Fig. 1).22,23
The workup had to be carried out with care and removal of
the excess in acrylonitrile under reduced pressure was
required. Otherwise, overalkylation in form of a subsequent
Michael-addition of the enolate to acrylonitrile took place
(Scheme 5). For example, if a reaction of 24a (R = Me) or 24b
(R = Bn) with acrylonitrile was quenched by addition with
TBAF at 0 °C, the desired products 25a and 25b were received
in 30% and 42% yield, respectively, together with the corres-
ponding double addition products 27a and 27b (42% and
39%, respectively).
Fig. 1 X-ray structure of 26d. Thermal ellipsoids drawn at 50% prob-
ability level.
Scheme 5 Workup with TBAF at 0 °C in presence of an excess of
acrylonitrile led in part to double cyanoalkylation products.
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estingly, not only alkyl and aryl groups could be installed at
this position, but also halides such as chloride and bromide
(entries 4 and 5).
Table 6 Reductive coupling of chromones with acrylonitrile
The relative configuration was opposite to the quinolin-4-
one products and the anti-diastereomer was isolated as major
component after workup with aqueous HCl.
The workup procedure drastically influenced the product
distribution. The diastereoselectivity could be even switched
from the favoured anti-products to the syn-products in moder-
ate to good diastereoselectivity when workup was carried out
under kinetically controlled conditions (TBAF, −78 °C).
3-Iodochromone 30f, however, was too reactive and suffered
from dehalogenation under the reaction conditions and cross-
coupling product 29a was isolated (Scheme 6).
Entry
R1
R2
R3
Product
Yielda [%]
1
2
3
4
5
6
7
H
H
H
H
H
MeO
H
H
H
H
H
H
H
Me
Ph
29a
29b
29c
29d
29e
29f
50 (36)b
42 (32)b
37
Me
MeO
Br
H
H
H
0c
32
17b
29g
31b
Finally, the cross-coupling with acrylonitrile was applied to
the reductive β-cyanoalkylation of coumarins. Using precursors
with a diverse substitution pattern, moderate yields were
achieved for the cross-coupling reaction (Table 8). Attempts to
further optimize the reaction outcome were unsuccessful.24
The best yield (65%) was obtained with 6-methylcoumarin
(entry 3). A quaternary stereocentre could be installed in 36%
yield (entry 8) and α,β-disubstituted 2-chromanones were
a Yield of isolated product. b Zinc dust was used as reductant.
c Complex product mixture.
In analogy to the quinolone substrates, C3-unsubstituted
chromones were moderately successful substrates for the tita-
nium-catalysed reductive umpolung (Table 6). Manganese
powder as reductant gave slightly better reaction yields than
zinc dust. Electron-donating substituents were tolerated
(37–50%), but no product could be isolated with 6-bromochro-
mone (28d). A 2-methyl substituted chromone gave only 17%
product and flavone itself was transformed into the desired
chromanone in 31% yield, which corresponded to two catalyst
turnovers. As observed before, the yields were significantly
improved when C3-substituents were present (Table 7). Inter-
Scheme 6 The reaction with 3-iodochromone afforded deiodinated
chromanone 29a.
Table 7 Reductive coupling of 3-substituted chromones workup
dependant switchable diastereoselectivity
Table 8 Reductive coupling of coumarins with acrylonitrile
Entry
R1
R2
R3
R4
R5
Product
Yielda [%]
1
2
3
4
5
6
7
8
H
Br
Me
H
H
H
H
H
H
H
H
H
H
H
Me
MeO
Me2N
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
34a
34b
34c
34d
34e
34f
34g
34h
34i
42
36
65
46
Entry
R1
Me
Ph
Ph
Cl
R2
H
Products
31a, 32a
31b, 32b
31c, 32c
31d, 32d
31e, 32e
Workup
syn/anti
Yielda [%]
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
HCl
TBAF
HCl
TBAF
HCl
TBAF
HCl
TBAF
HCl
TBAF
21 : 79
78 : 22
21 : 79
75 : 25
37 : 63
75 : 25
38 : 62
64 : 36
22 : 78
83 : 17
69
78
73
62
45
26b
33
H
36
i-PrO
H
82
9
10
11
Me
Me
Ph
44c
38b,d
24b,d
81
Me2N
Me2N
34j
34k
49b
54b
42b
42b
a Yield of isolated product. b Calculated yield from an inseparable
mixture with the substrate (∼1 : 1 ratio). c Only the syn-isomer was
formed. d A single isomer was formed, which was assigned in analogy
to 34i.
Br
H
a Yield of isolated product. b Isolated as diastereomeric mixture.
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Table 9 Scope of the cross-coupling partner
Entry Product
dr
Yielda [%]
71
1
2
35, R = H
36, R = Me
—
50 : 50 70b
Fig. 2 X-ray structure of 34i. Thermal ellipsoids drawn at 50% prob-
ability level.
3
37
50 : 50 27b
formed in similar quantities by the reductive cyanoethylation
reaction. The diasteroselectivity was again very high and the
syn-diastereomers were isolated as sole products. The relative
syn-configuration was unambiguously confirmed by X-ray ana-
lysis of product 34i (Fig. 2).22
4
5
38, R = Me
39, R = Ts
—
—
0
73c
Scope of the coupling partner
6
7
40, R = H
41, R = Me
57 : 43 36b
58 : 42 90b
Importantly, the reaction was not limited to acrylonitrile as
coupling partner. Substituted acrylonitrile derivatives and a
number of other activated alkenes including acrylamides and
acrylates could be employed as coupling partners as well
(Table 9). With cyclohexenone, we first observed that meth-
acrylonitrile worked almost as well as acrylonitrile itself (entry
1) and even the quaternary carbon could be formed smoothly
(entry 2). The reaction with crotononitrile was hampered (entry
3), probably due to increased sterics leading to a reduction in
yield to 27%. In both cases, a 1 : 1 mixture of diastereomers
was received. The coupling with N,N-dimethylacrylamide was
unsuccessful, since this compound appeared to inhibit the
catalyst (entry 4). This could be successfully addressed by the
installation of a tosyl group at the amide nitrogen, which pre-
vented the amide resonance and lowered the coordination ten-
dency (entry 5). The coupling proceeded smoothly with 73%
yield in the presence of added cinnamonitrile, which increased
the yield by about 20%. Cinnamonitrile itself was an inferior
coupling partner (<5%), but it was empirically found to be ben-
eficial for this reaction. One possible rationale for this effect
could be a coordination and stabilisation of the catalyst.
8
9
42, R = H
43, R = Me
55 : 45 28b
62 : 38 29b
10
44
62 : 38 18
11
12
13
14
15
45, R = Me
46, R = Et
47, R = t-Bu
48, R = Ph
49, R = Mes
—
—
—
—
—
35d
47d
37d
52
81
a Yield of isolated product. b Combined yield. c Cinnamonitrile
(20 mol%) was added to the reaction mixture. d Workup with TBAF
instead of aq. HCl.
In a second series of experiments with N-methyl-4-quino-
lones 22a and 24a, good results were obtained for the coup-
lings with methacrylonitrile as well. 3-Methylquinolone 24a
gave again exclusively the syn-product with respect to the ring
substitution in excellent 90% yield. The product was obtained
as an inseparable ∼1 : 1-mixture of diastereomers with respect
to the additional stereocentre at the nitrile α-carbon (entry 7).
With crotononitrile, the yields were again reduced to ca. 30%
(cf. entry 3) but a moderate diastereoselectivity of 1.6 : 1 dr was
observed by NMR for the reaction with 24a (entry 9). Cinnamo-
nitrile, which was employed for entry 5 as a beneficial additive,
could be coupled in 18% yield to product 44 (entry 10).
With the 3-methylated quinolone 24a as substrate, acrylates
could be employed efficiently in the reductive catalytic umpo-
lung as well (entries 11–15). Here, reasonable results were
obtained with methyl, ethyl, and tert-butyl acrylate. The yield
was slightly improved with the less electron-rich phenyl acry-
late and with the sterically hindered mesityl acrylate,25 the
coupling proceeded smoothly in 81% yield. In all cases, no
cross-coupling was observed in absence of the titanocene
catalyst.
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Fig. 3 Unsuitable cross-coupling partners.
In addition, a number of other electron-deficient alkenes
were tested as potential coupling partners with less success
(Fig. 3). Other common nitrile-based Michael-acceptors such
as 2-chloroacrylonitrile or Knoevenagel products of malono-
nitrile or ethyl cyanoacetate did not undergo the desired reac-
tion. This was also true for 2-nitropropene and β-nitrostyrene
as well as vinyl sulfones. A saccharine-derived acrylamide,
vinyl diethyl phosphonate or a propargylic ester were not suit-
able as well. In several cases, the reduction of the activated
alkene was observed instead of the desired cross-coupling reac-
tion. With N-acryloylsaccharine, for example, formation of the
corresponding propionic amide took place.
Scheme 7 Substrate-dependent divergent regioselectivity. (a) Meso-
meric forms of a TiIII–cyclohexenone complex. (b) Calculated spin
density distribution for TiIII–cyclohexen-one and TiIII–acrylonitrile com-
plexes (iso value = 0.01). (c) Observed 1,2-addition products from steri-
cally hindered enone substrates.
Mechanistic discussion
From the observations that were made during our studies,
several conclusions could be drawn regarding the underlying
reaction mechanism, which allowed us to refine the initially
proposed mechanism.
As shown in Scheme 7, coordination of the in situ formed
titanium(III)-catalyst to the enone substrate could also be inter-
preted as the formation of an allylic ketyl radical anion that
remained coordinated to a titanium(IV)-centre. In fact, the
unpaired electron was in part located at the titanium centre, at
the β-carbon and at the carbonyl carbon as illustrated by the
three resonance structures shown in Scheme 7. This was sup-
ported by the calculated spin density distribution at the
Cp2TiIIICl–cyclohexenone complex. It was majorly located at
the titanium centre and in part located at the carbonyl and
β-carbon.24 A similar situation was found for an acrylonitrile–
titanium(III) complex. This situation explained our experi-
mental results: reductive coupling at the β-position leading to
conjugate addition products (e.g. ketonitrile 3) was the usually
preferred pathway. However, substrates with increased sterical
bulk at the β-carbon led to a change in the regiochemistry and
the corresponding 1,2-addition products were formed.26 For
example, the reductive cross-coupling of the Wieland–
Miescher ketone gave the corresponding cyanoethylated allylic
alcohol 50 in 55% yield and moderate diastereoselectivity. A
similar experiment with progesterone afforded the corres-
ponding product 51 in excellent 91 : 9 dr and 65% yield.
The origin of the hydrogen atom that was transferred to the
nitrile α-carbon in course of the standard coupling between
cyclohexenone and acrylonitrile was probed as well. A reaction
run in THF-d8 did not lead to any deuterium incorporation
Scheme 8 Deuterium experiments point towards a nitrile α-proto-
nation event.
into the product (Scheme 8). If a carbon-centred radical was
present at this position a deuterium radical abstraction from
the solvent would have been likely to occur. On the contrary, a
reaction with triethylamine deuterochloride resulted in about
70% deuteration of the product at this position, which was evi-
dence for a protonation step under the usual reaction con-
ditions. This protonation at the nitrile α-carbon was
unselective due to the absence of stereoelements in its proxi-
mity, which explains the formation of 1 : 1 diastereomeric mix-
tures in the reactions with methacrylonitrile (see Table 9,
entries 2, 6, and 7).
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Conclusions
In conclusion, we have established the titanium(III)-catalysed
reductive umpolung of Michael-acceptors as an efficient cross-
coupling tool for the synthesis of building blocks with func-
tional groups in 1,6-distances. This was demonstrated on 70
examples in total including couplings with acylonitriles, acyla-
mides and acrylates. Precursors with increased sterical hin-
drance could be employed for the selective synthesis of 1,4-
difunctionalised products. A refined mechanistic picture was
proposed based on the observed product distributions, the
regio- and stereoselectivity, as well as the deuterium experi-
ments. In the future, the development of related reductive
cross-couplings will be accelerated due to the selectivity trends
and mechanistic insight gained in this study. The method
itself will be useful for the preparation of synthetic building
blocks with functionalities in unnatural bond distances.
Currently, efforts are undertaken to develop an enantio-
selective variant of this direct reductive β-alkylation reaction.
Experimental section
Standard procedure for the TiIII-catalysed reductive umpolung
Scheme 9 Mechanistic proposal for the reductive umpolung of
Michael-acceptors.
A flame-dried 50 mL-Schlenk tube containing a magnetic
stirbar was charged under argon atmosphere with Cp2TiCl2
(12.4 mg, 0.05 mmol, 10 mol%), Zn (65.0 mg, 1.00 mmol,
2.0 equiv.) und Et3N·HCl (89.5 mg, 0.650 mmol, 1.3 equiv.).
Stirring was started. The vessel was evacuated and backfilled
with argon after a few minutes. Absolute THF (1.25 ml) was
added and after 1 min the mixture had turned from red to
lime-green. The substrate (e.g. 1, 0.5 mmol, 1.0 equiv.) was
added followed by the cross-coupling partner (e.g. 2, 2.5 mmol,
5 equiv.) and TMSCl (95.2 μl, 1.5 equiv.). The reaction vessel
was sealed with a greased glass-stopper and the reaction
stirred for the given time at 35 °C in an oil bath or at the given
temperature after which the reaction was brought back to
room temperature. Unless noted otherwise, workup was
carried out by addition of 1 N aqueous HCl (4 ml) and CH2Cl2
and stirring was continued for 30 minutes at room tempera-
ture (23 °C). The mixture was transferred into a separation
funnel containing H2O (20 ml) and CH2Cl2 (20 ml). The bipha-
sic mixture was shaken, the organic layer separated and the
aqueous layer extracted with additional CH2Cl2 (3 × 10 ml).
The combined organic extracts were dried (Na2SO4), concen-
trated and purified by flash chromatography as described.
Together with the results from our previous study on the
mechanism of the titanium(III)-catalysed cross-acyloin type
coupling,27 these observations led to a refined mechanistic
proposal for the standard reaction (Scheme 9).
The reaction formally begins with the formation of two
equivalents of 5 from [Cp2TiCl2] zinc followed by reaction with
enone 1 and nitrile 2 to form coordination complexes. These
complexes are in equilibrium through ligand-exchange pro-
cesses. It is likely that a cationic resting state 52 is formed by
solvation of the remaining chloride and coordination of a
second acrylonitrile molecule (acrylonitrile was employed in a
50 fold excess with respect to the catalyst). This species could
be the reason for the observed colour change to deep purple
after addition of acrylonitrile and before addition of TMSCl
during the reaction setup. A similar cationic resting state was
previously established for the related ketone–nitrile coupling by
X-ray analysis.27 The C–C bond formation would then take place
in form of a catalyst-controlled radical combination, avoiding
the presence of free radicals and leading to bistitanated keteni-
mine-enolate 53. The metallated ketenimine was quickly proto-
nated by the hydrochloride (which was supported by the
deuterium experiment) forming enolate 54. The titanium
enolate was then cleaved by chlorotrimethylsilane releasing the
crude product in form of silyl enol ether 4 and enabling catalyst
turnover. Zinc then regenerated the titanium(III) catalyst 5. If
desired, the silyl enol ether 4 could be isolated as one regio-
isomer in 87% yield (workup with water and filtration over flori-
sil)8 or quenched with HCl or TBAF to afford the corresponding
ketonitrile as done for the tables in this work.
Workup with TBAF under kinetically controlled conditions
(see Tables 6 and 7)
The reaction was setup as described in the standard pro-
cedure. After the given reaction time, all volatile components
were removed under reduced pressure and heating was discon-
tinued. The residue was treated with CH2Cl2 (5 ml) and cooled
to −78 °C. At that temperature, TBAF (1 M in THF, 2.50 ml, 2.5
equiv.) was added dropwise. The mixture was stirred for
another 3 h at −78 °C and then allowed to warm to room temp-
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Paper
erature (23 °C). The mixture was transferred into a separation
funnel containing H2O (20 ml) and CH2Cl2 (20 ml). The bipha-
sic mixture was shaken, the organic layer separated and the
aqueous layer extracted with additional CH2Cl2 (3 × 10 ml).
The combined organic extracts were dried (Na2SO4), concen-
trated and purified by flash chromatography as described.
For a full list of materials and methods, detailed experi-
mental data, compound characterizations and computational
details, see the ESI.†
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Acknowledgements
4 J. Streuff and A. Gansäuer, Angew. Chem., Int. Ed., 2015, 54,
14232–14242.
The Fonds der Chemischen Industrie (Liebig-Fellowship and
Dozentenpreis to J. S.) and the Deutsche Forschungs-
gemeinschaft DFG (STR 1150/3-1, STR 1150/7-1, and Heisen-
berg-fellowship to J. S.) are gratefully acknowledged for their
support. We thank Sven Tauscher for initial contributions.
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