The cross-selective titanium(III)-catalysed acyloin reaction

Article abstract of DOI:10.1039/c3cc46894a

A titanium(iii)-catalysed intermolecular reductive coupling of ketones or imines with nitriles is described, which gives direct access to α-hydroxylated and α-aminated ketones. This coupling reaction is cross-selective and a catalytic version of the classical acyloin condensation. A reaction mechanism that is supported by first DFT calculations is discussed. the Partner Organisations 2014.

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The cross-selective titanium(III)-catalysed acyloin reaction
Markus Feurer,a Georg Frey,a Hieu-Trinh Luu,a Daniel Kratzertb and Jan Streuff*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
(EtCp)2TiCl2 (4a, 10 mol%)
Zn (2.0 equiv)
5
A titanium(III)-catalysed intermolecular reductive coupling
of ketones or imines with nitriles is described, which gives
direct access to α-hydroxylated and α-aminated ketones. This
coupling reaction is cross-selective and a catalytic version of
the classical acyloin condensation. A reaction mechanism that
O
N
O
HO
+
R
Et3N•HCl (2 equiv)
TMSCl (1.5 equiv)
THF, 35 ºC
Ph
Me
O
R
Ph Me
1a
2a–h
3a–h
X
O
O
10 is supported by first DFT calculations is discussed.
HO
Ph
HO
HO
Ph
The acyloin condensation reaction allows the formation of α-
hydroxyketones (acyloins) by C-C coupling of two esters in
the presence of sodium metal in liquid ammonia.1 It is a so-
called reductive "umpolung" reaction,2 a process that enables
15 the connection of similarly polarised coupling partners by
single-electron transfer. In the past, the use of other
stoichiometric reducing agents and electrochemical setups
enabled the development of related intramolecular acyloin
reactions,3,4 but an intermolecular reductive cross-coupling
20 was achieved only in a few cases.5 Despite the usefulness of
this reaction to access valuable building blocks, no
corresponding catalysis has been developed with the
exception of intramolecular cyclisations by our group.6
Ph Me
Ph Me
3b, X = OMe: 85%
Ph Me
Ph
3a
81%a
3e
80%b
3c, X = Cl:
3d, X = F:
79%
79%
O
O
O
HO
HO
HO
Ph
n-Pr
Ph Me
3f
Ph Me
Ph Me
3g
3h
46%
66%
67%
Scheme 2 Ti-catalysed cross-coupling of acetophenone with various
nitriles. Conditions: 1a (0.5 mmol), 2 (5 equiv), 4a (10 mol%), zinc (2
equiv), TMSCl (1.5 equiv), Et3N•HCl (2.0 equiv), abs. THF (c = 1.0 M),
35 ºC, 48 h; TBAF (1 M in THF) then H2O. Isolated yields. a 24 h
reaction time. b The reaction was quenched with TBAF (1 M in THF)
followed by aq. 1 N HCl.
45
We herein report a catalytic intermolecular acyloin-type
25 cross-coupling in the presence of a low-valent titanium
catalyst (Scheme 1),7 which connects various ketones or
imines with nitriles for the direct construction of
unsymmetrical α-hydroxy- and α-aminoketones. The reaction
is highly cross-selective and the competing pinacol-type homo
30 dimerisation of the ketone or imine is suppressed.2b In
addition, this titanium catalysis installs tetrasubstituted α-
carbons, which was particularly challenging in the synthesis
of α-oxygenated or α-aminated carbonyls using alternative
protocols such as organocatalysed benzoin-type couplings, for
35 instance.8 We propose that the mechanism proceeds via a
single electron transfer to the carbonyl or imine, followed by a
C-C bond forming radical coupling to the nitrile.
We explored the coupling of acetophenone (1a) with an
excess of benzyl cyanide (2a, 5 equiv) as standard substrates,
50 chlorotrimethylsilane
(1.5
equiv)
and
triethylamine
hydrochloride (2 equiv) as additives and zinc (2 equiv) as
terminal reductant (Scheme 2). In first optimisation studies
bis(ethylcyclopentadienyl)titanium(IV) chloride (4a) was
identified as the most efficient catalyst.9 Workup after 24 h
55 led to the isolation of the desired product 3a in 81% yield and
its structure was unambiguously verified by X-ray analysis.
Importantly, with a reduced excess of nitrile 2a (1.5 equiv)
still a high yield of 70% was maintained. The group of Hirao
attempted this intermolecular coupling in an earlier study with
60 titanocene dichloride (4b) as catalyst and imidazole as
additive but no formation of 3a was observed.10 In our hands,
these conditions were unsuccessful too and the addition of
imidazole appeared to suppress the reaction.
Ti-catalyst
reductant
O
X
N
+
HX
R1 R2
R3
R1
R2
aq. workup
R3
X = O, NBn
reductive umpolung
We further investigated different nitriles in the reductive
65 coupling with acetophenone (1a) as substrate (Table 2).
Compared to benzyl cyanide the 4-methoxy substituted benzyl
cyanide was superior (85% yield, 3b). Chlorine or fluorine
substitution resulted both in 79% yield for products 3c and 3d.
The reaction worked equally well with the bulkier
70
TiIII
N
TiIV
TiIV
X
N
TiIV
X
R1
R3
R2
R1
R2
R3
Scheme 1 Concept of a titanium-catalysed intermolecular acyloin
reaction.
40
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DOI: 10.1039/C3CC46894A
O
4a (10 mol%)
Zn (2.0 equiv)
sequence A
sequence B
N
O
R1
X
+
R3
+
Et3N•HCl
(2 equiv)
[Cp2TiCl]
Et3N•HCl (2 equiv)
TMSCl (1.5 equiv)
THF, 35 ºC
R2
R1
R2
Ph
Me
R3
2a,f,g
Ph
CN
X
7
(1 equiv)
1a
2a
1b–j: X = O
5a,b: X = NBn
3i–q: X = OH
6a–d: X = NHBn
(5 equiv)
B1: 20 s
B2: 5 minutes
A: 20 s
X
O
O
O
O
Ph
Me
Ph
Ph
Ph
O
Ph
Cp2Ti
Cl
8 (blue)
N
Cp2Ti
Cl
O
HO Et
3i
HO Me
3j, X = OMe: 74%
HO Me
3o
62%
Ph
9 (dark green)
74%
3k, X = Me: 61%
58%a
3l, X = Cl:
O
O
Me OH
Ph
2a
(5 equiv)
CN
3m, X = Br:
68%
74%
O
Ph
Ph
Ph
+
3n, X = OAc:
Ph
Ph
Me
1a
O
O
HO Me
HO Me
H
N
Ph
Ph
Ph
Ph
3a
10
S
O
Bn
Bn
A:
B1: 58% (12.8 : 1.0)
B2: 25%
53% (14.4 : 1.0)
4%
5%
HO Me
3p
61%
HO Me
Me Ph
6a
77%a,b
3q
68%
(1.0 : 1.4) 34%
Scheme 4 Stoichiometric reactions with precoordination of acetophenone
or benzyl cyanide. Product ratios were determined by crude NMR.
O
O
O
H
N
H
N
H
N
40
Bn
Ph
Bn
the order of addition on the product distribution was probed
by mixing in situ generated 7 with benzyl cyanide (5 equiv,
sequence A) or acetophenone (sequence B),12 followed by
addition of the second reaction partner. The coordination of
Me Ph
6b
Me Ph
6c
Ph
6d
61%a,b
66%a,b
47%a,b
Scheme 3 Ti-catalysed acyloin reaction employing various ketones and
imines. Conditions: 1 or 5 (0.5 mmol), 2 (5 equiv), 4a (10 mol%), zinc (2
equiv), TMSCl (1.5 equiv), Et3N•HCl (2.0 equiv), abs. THF (c = 1.0 M),
35 ºC, 48 h; TBAF (1 M in THF) then H2O. Isolated yields. a With 3
equiv TMSCl. b With 0.5 equiv Et3N•HCl and catalyst 4b (10 mol%).
45 benzyl cyanide resulted in formation of a blue complex, which
matched the reported colour for titanium(III)-nitrile complex-
es such as 8.13 Subsequent addition of acetophenone (1 equiv)
gave product 3a together with a small amount of diol
diastereomers 10 in a ratio of 14.4:1. The pre-coordination of
5
diphenylacetonitrile and delivered the corresponding product
3e in 80% yield. With benzonitrile the reaction was slower
leading to 46% of α-hydroxyketone 3f. Aliphatic nitriles
10 could be employed as well (3g, 66%) and even cyclopropyl
carbonitrile was successfully transformed into the desired
product 3h in 67% yield. Here, only traces of the
corresponding ring-opening product 3g (<5%) were
observed.11 We then examined the cross-coupling of various
15 ketones with benzyl cyanide (Scheme 3). With propiophenone
instead of acetophenone 74% of the desired product 3i was
50 acetophenone gave
a dark-green solution indicating the
formation of 9, but the product ratio after subsequent addition
of the nitrile was nearly the same (12.8:1) (sequence B1). Pre-
stirring acetophenone with 7 for 5 minutes (sequence B2),
changed this ratio in favor of 10, indicating a competing
55 pinacol coupling reaction of acetophenone.14 An excess of the
nitrile, suppressed this side-reaction. These results indicate an
equilibrium reaction between 8 and 9, in which ketone and
nitrile compete for the coordination to the titanium.
isolated. In
a
similar manner, acetophenones further
A plausible catalytic cycle is shown in Scheme 5 with the
60 cross-coupling of acetone with acetonitrile and 4b as catalyst
as a model system. First DFT calculations of the reaction
energies on the PBE0/def2-TZVPP//BP86/def2-SV(P)-level
(Gaussian 09) support this mechanistic scenario.15–19 The
SMD model was applied for the calculation of solvation
65 energies on the BP86/def2-SV(P)-optimised structures.20 The
cycle starts with the formation of the low-valent titanium
species A from Cp2TiCl2 (G) and zinc (Figure 3). This
titanium(III)-complex coordinates the nitrile, forming an
adduct B, which is in equilibrium with the corresponding
70 ketone-complex C. Both titanium(III)-complexes (B and C)
are converted in the C-C bond formation via a probably
transition-state free radical combination (D) to complex E.21
The two Ti-O bonds are subsequently cleaved by the
hydrochloride and TMSCl resulting in formation of H as
75 primary product. Together with the negative free energy for
the reduction of two equivalents G to A the overall Gibbs free
energy of this cycle was found to be negative at room
temperature. This catalytic cycle is in agreement with our
earlier observations6 and the conclusions of others for related
substituted at the aromatic moiety gave good results ranging
from electron rich (3j,k,o) to electron poor derivatives (3l–n).
20 In case of 3l, the addition of 3 equiv of TMSCl provided the
highest yield. Heterocyclic ketones bearing a thiophenyl or
furyl unit were smoothly converted to the corresponding
products 3p and 3q (61% and 68% yield). Furthermore, we
probed the direct synthesis of α-aminoketones by substitution
25 of the ketone precursor with an imine. To our delight, the
coupling proceeded in a similar fashion and aminoketones 6a–
c with a fully substituted α-carbon were isolated in 47–77%
yield. Here, it was observed that a reduction of the amount of
Et3N•HCl to 0.5 equiv was beneficial for the reaction outcome
30 and that titanocene dichloride (4b) as catalyst provided the
best results.9 The reaction also worked well with an aldimine
(6d), which demonstrates that the reaction is not limited to
ketimine precursors. In all cases no product formation was
observed in absence of the catalyst.
35 To gain first information about the underlying reaction
mechanism, experiments with stoichiometric amounts of
[Cp2TiCl] (7) were carried out (Scheme 4). The influence of
2
|
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DOI: 10.1039/C3CC46894A
1
3
(a) E. J. Corey and S. G. Pyne, Tetrahedron Lett., 1983, 24, 2821; (b)
G. A. Molander and C. Kenny, J. Org. Chem., 1998, 63, 9031; (c) Y.
Yamamoto, D. Matsumi and K. Itoh, Chem. Commun., 1998, 875.
For example, see: T. Shono and N. Kise, Tetrahedron Lett., 1990, 31,
1303.
/
2 ZnCl2•2THF
NH
MeCN
TMSO
Ph
1
/
2 Zn, THF
Me
[Cp2TiCl]
45
50
55
60
65
70
75
4
5
6
–14.90 A +3.62
–5.34
Me
H
Cl
Cp2TiCl2
+3.75
Cp2Ti
G
N. Kise, S. Agui, S. Morimoto and N. Ueda, J. Org. Chem., 2005, 70,
9407.
TMSCl
NC Me
–4.86
–7.78
B
(a) J. Streuff, M. Feurer, P. Bichovski, G. Frey and U. Gellrich,
Angew. Chem. Int. Ed., 2012, 51, 8661; (b) G. Frey, H.-T. Luu, P.
Bichovski, M. Feurer and J. Streuff, Angew. Chem. Int. Ed., 2013, 52,
7131.
Cl
+OCMe2
Cp2Ti
O
NH
+6.51
+8.09
–MeCN
–33.88 kcal/mol
–2.47 kcal/mol
ΣꢀG =
Me
Cl
7
For selected reviews, see: (a) J. M. Cuerva, J. Justicia, Oller-López
and J. E. Oltra, Top. Curr. Chem., 2006, 264, 63; (b) A. Gansäuer, J.
Justicia, C.-A. Fan, D. Worgull and F. Piestert, Top. Curr. Chem.,
2007, 279, 25; (c) U. Jahn, Top. Curr. Chem., 2012, 320, 121; (d) B.
Rossi, S. Prosperini, N. Pastori, A. Clerici and C. Punta, Molecules,
2012, 17, 14700. For selected references, see: (e) T. V. RajanBabu
and W. A. Nugent, J. Am. Chem. Soc., 1994, 116, 986; (f) A.
Gansäuer, H. Bluhm and M. Pierobon, J. Am. Chem. Soc., 1998, 120,
12849; (g) J. Justicia, J. L. Oller-López, A. G. Campaña, J. E. Oltra,
J. M. Cuerva, E. Buñuel and D. J. Cárdenas, J. Am. Chem. Soc.,
2005, 127, 14911; (h) A. Gansäuer, M. Behlendorf, D. v. Laufenberg,
A. Fleckhaus, C. Kube, D. V. Sadasivam and R. A. Flowers, II,
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G. M. Brändle and J. Friedrich, Angew. Chem. Int. Ed., 2012, 51,
8891; (j) X. Zheng, X.-J. Dai, H.-Q. Yuan, C.-X. Ye, J. Ma and P.-Q.
Huang, Angew. Chem. Int. Ed., 2013, 52, 3494.
Me Me
F
Cp2Ti
Me
Me
Et3N
Cp2TiCl2 (G)
–12.44
–7.60
O
C
Cl
TiCp2
Et3NH
Cl
Cl
B
–0.53
+8.00
Cp2Ti
N
Me
Me
O
O
Me
via:
Cp2Ti
Cl
Me Me
Me
N
TiCp2
Cl
E
D (barrier free)
Scheme 5 Proposed mechanism and calculated energies ꢀG (kcal/mol) in
the gas-phase (italics) and in solution.
pinacol coupling reactions,22 as well as for titanium catalysed
radical addition reactions to carbonyls and nitriles, for which
the coordination of a second TiIII-species was discussed.3c,23
The structure of Zn-reduced titanocenes 4 in solution depends
in part on its bulkiness and can involve equilibria between
monomeric, dimeric, and ZnCl2-bridged TiIII-species.2b,7,24 In
5
8
For selected reviews, see: (a) D. Enders, O. Niemeier and A.
Henseler, Chem. Rev., 2007, 107, 5606; (b) J. Streuff, Synlett, 2013,
24, 276. For key publications, see: (c) D. Enders, K. Breuer and J. H.
Teles, Helv. Chim. Acta, 1996, 79, 1217; (d) D. A. DiRocco and T.
Rovis, Angew. Chem. Int. Ed., 2012, 51, 5904. For an exception, see:
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Commun., 2010, 46, 6282.
10 an elegant study by Daasbjerg, Grimme, Gansäuer and co-
workers on the titanium(III)-catalysed opening of epoxides, a
half-opened catalyst dimer was proposed in the case of 4b to
be the most reactive reducing complex.25 In addition, the
hydrochloride additive was assumed to prevent catalyst
15 deactivation by coordination to the catalyst.7h Hence, the
mechanism of the catalytic acyloin reaction herein could be
more complex.
9
See supporting information for further details.
10 L. Zhou and T. Hirao, Tetrahedron, 2001, 57, 6927.
11 Here, peroxides in the solvent were found to lead to this ring-opening
product.
80 12 We also observed formation of the desired product when the excess
zinc was removed by filtration before the substrate addition.
13 E. J. M. d. Boer and J. H. Teuben, J. Organomet. Chem., 1977, 140,
41.
14 M. Paradas, A. G. Campaña, R. E. Estévez, L. A. d. Cienfuegos, T.
In conclusion, we have developed a versatile intermolecular
acyloin-type cross-coupling that proceeds in the presence of a
20 low-valent titanium catalyst and zinc as stoichiometric
reductant. This methodology gives fast access to important α-
hydroxyketone and α-aminoketone building blocks with a
fully substituted α-carbon, which are difficult to synthesise by
other ways. A plausible mechanistic scenario was presented
25 that was supported by first DFT calculations.
85
Jiménez, R. Robles, J. M. Cuerva and J. E. Oltra, J. Org. Chem.,
2009, 74, 3616.
15 M. J. Frisch et al. Gaussian 09, Revision B.01 (Gaussian Inc., 2010).
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Chem. Phys., 1993, 98, 5648.
18 A. Schäfer, H. Horn and R. Ahlrichs, J. Chem. Phys., 1992, 97, 2571.
19 For IMOMO benchmark calculations, see the supporting information.
20 A. V. Marenich, C. J. Cramer and D. G. Truhlar, J. Phys. Chem. B.,
This work was supported by the Fonds der Chemischen
Industrie and the Deutsche Forschungsgemeinschaft (DFG).
95
2009, 113, 6378.
21 For a discussion, see: J. F. LeBlanc and P. D. Pacey, J. Chem. Phys.,
1985, 83, 4511.
Notes and references
22 (a) A. Gansäuer, Synlett, 1997, 363; (b) A. Gansäuer, Chem.
Commun., 1997, 457.
a Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg,
30 Albertstraße 21, 79104 Freiburg, Germany. Fax: +49 761 203 8715;
Tel: +49 761 203 97717; E-mail: jan.streuff@ocbc.uni-freiburg.de
b Institut für Anorganische und Analytische Chemie, Albert-Ludwigs-
Universität Freiburg, Albertstraße 21, 79104 Freiburg, Germany
† Electronic Supplementary Information (ESI) available: Experimental
35 procedures, characterisation data, and NMR spectra for all new
compounds and computational details. Crystallographic data in CIF or
other electronic format for CCDC 948380. See DOI: 10.1039/b000000x/
100 23 For example, see: (a) A. Fernández-Mateos, P. H. Teijón, L. M.
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9973; (b) R. E. Estévez, J. Justicia, B. Bazdi, N. Fuentes, M. Paradas,
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J. M. Cuerva and J. E. Oltra, Chem. Eur. J., 2009, 15, 2774.
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