Enantioselective 1,4-additions of ClMeAl(CHCHR) (R = alkyl, alkenyl, Ph) to cyclohexenones

Article abstract of DOI:10.1039/c3cc48191c

Chloromethylvinyl alanes (E)-ClMeAl(CH=CHR) prepared directly from terminal alkynes undergo 1,4-addition to cyclohexenone and 3-methylcyclohexenone in moderate to good yield (30-70%) and good to excellent stereoselectivity (80-98% ee) using readily availa

Full text of DOI:10.1039/c3cc48191c

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Enantioselective 1,4-additions of
Q
ClMeAl(CH CHR) (R = alkyl, alkenyl, Ph)
Cite this: Chem. Commun., 2014,
50, 1655
to cyclohexenones†
D. Willcox,a S. Woodward*a and A. Alexakisb
Received 25th October 2013,
Accepted 19th November 2013
DOI: 10.1039/c3cc48191c
www.rsc.org/chemcomm
Q
Chloromethylvinyl alanes (E)-ClMeAl(CH CHR) prepared directly
We were attracted to the terminal alkyne hydroalumination
from terminal alkynes undergo 1,4-addition to cyclohexenone and products derived from the appreciably stabilised, easily pre-
3-methylcyclohexenone in moderate to good yield (30–70%) and pared hydride HAlCl2Á(THF)2;6 e.g. Cp*2ZrCl2 (2–5 mol%) (Cp* =
good to excellent stereoselectivity (80–98% ee) using readily avail- Z5-C5Me5) affords (E)-Cl2AlCHQCHC6H13 (1a) quantitatively
able copper(I) sources and chiral ligands.
from HCRCC6H13. Preliminary trials indicated the absence
of background reactions of 1a with cyclohexenone.7 Reaction of 1a
Asymmetric conjugate addition (ACA) has become a mainstay with cyclohexenone is highly accelerated by CuTC/PCy3 (5–10 mol%;
of contemporary chiral synthesis in the last 10 years.1 Sublime TC = 2-thiophenecarboxylate) at À30 1C but this provides an enone
levels of enantioselectivity are realised in 1,4-additions of trimerisation product‡ by a mechanism identical to that we demon-
simple alkyl groups to various Michael acceptors, but the strated earlier for PhCH2ZnBr.8 This trimeric by-product originates
situation for C(sp2) vinyl-based nucleophiles is not so clear from slow transmetalation of the post-ACA Cu-bound enolate by
cut. Rhodium-diphosphine catalysts are normally preferred fresh 1a. Improving the nucleophilicity of 1a is therefore predicted to
for additions of C(sp2) nucleophiles, especially aryls, to mono overcome this. Co-promotion of 1a with AlMe3 and running the
substituted enones2 but these fail to elicit any reaction for reaction at 25 1C led to chemoselective formation of 1,4-addition
b,b-substituted enones – where copper(I)/phosphorus-ligand products. However, under CuI/chiral phosphorus ligand catalysis the
catalysts are required.1,3 The choice of C(sp2) nucleophile also maximum ee value attained was o55% for a library of 17 ligands.
has issues: vinyl boronic acids, and their derivatives, are rather Fortunately, when treated with MeLi (1.0 equiv.) 1a provided an
more susceptible to hydrolytic deboronation compared to their alane (nominally (E)-ClAlMeCHQCHC6H13)§ leading to ee values
aryl cousins – causing lower yields or the need for excess (>80%) with readily available Feringa’s ligand L1. Strangely, use
reagents. Alkenylalanes, used with CuI catalysts, are often of two equivalents of MeLi gave poor processes (o12% yield,
prepared from RCCH and DIBAL-H (either through heating,4 o5% ee) – despite the known efficacy of Me2AlCHQCHR species
or Ni-catalysis5) have issues: (i) deprotonation by-products are in related processes.9 Finally, the addition mode for 1a/MeLi to
common under thermal DIBAL-H procedures except for alkyl cyclohexenone was optimised (Table 1).
substituted cases; (ii) b-aryl Bui2AlCHQCHAr, prepared by
Although higher enantioselectivities were attained (runs
Ni-catalysis, are normally contaminated with B5% of the a-aryl 1 and 5), we optimised on yield of 2a as poor chemical yields
isomer; finally (iii) the bulky Bui substituents can cause problems are often a more challenging problem in copper(I)-catalysed
in the subsequent ACA catalysis leading to low yields and 1,4-additions of alkenyls than enantioselectivity.10 The mass
slow reactions. Alternative hydroalumination-ACA approaches balance of the reactions was enone trimerisation.‡ Taking the
are desirable, particularly if they use simple reagents catalysts best compromise a range of copper(I) catalyst precursors were
and conditions to deliver high ee values for 1,4-additions to screened (Table 2) using the conditions of Table 1 (slow addition
both mono and b,b-disubstituted enones.
of cyclohexenone, run 3).
In all cases the yields of 2a attained with CuI precursors
other than CuTC (run 5) were lower. Although high enantio-
selectivity was attained using Fletcher’s conditions10 only trivial
amounts of product were attained. In this, and all other cases,
running the reactions for longer times (>1 h) did not improve the
situation (product decomposition occurred instead). Having con-
firmed that the CuTC system was optimal for chemoselectivity,
a School of Chemistry, The University of Nottingham, University Park, Nottingham,
UK. E-mail: simon.woodward@nottingham.ac.uk; Fax: +44 (0)115 9513564;
Tel: +44 (0)115 9513541
b Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30,
CH-1211 Geneva 4, Switzerland
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc48191c
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Table 1 Yield and ee effects of addition modesa
Table 3 Ligand structure effectsa
Run
Ligand
Yield 2a (%)
ee (%)
Run
Addition mode
Yield 2a (%)
ee (%)
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
62
65
65
81
63
54
84
36
49
76
88
38
56
50
44
42
10
6
1
2
3
4
5
Normal (enone to 1a + MeLi)
Reverse (1a + MeLi to enone)
Slow addition of enone
Slow addition of 1a + MeLi
Enone (1a + MeLi) slow addition
54
70
66
84
60
76
o5
n.d.b
90
20
a
Active alane from 1a (1.4 mmol) and MeLi (0.65 mmol); cyclohexenone
(0.5 mmol) in toluene/tBuOMe (2.5 mL/0.5 mL). The structure of L1
b
is shown in Scheme 1. Yield and ee determination by GC. Not
determined.
a
Using the conditions of Table 1. Yield and ee determination by GC.
Table 2 Copper pre-catalyst effects on the formation of 2aa
Satisfyingly, the final process shows rather good generality in
1,4-additions to cyclohexenone (leading to 2) and to 3-substituted
cyclohexenones (leading to 3–4) and even easily deprotonated
terminal alkynes (required for 2c, 2d, 2f and 3c) are tolerated.¶
Only very temperamental cyclopropylacetylene derived 3g gave
modest yields. An identical CuTC/L2 catalyst provides practical
levels of enantioselectivity for formation of both 2 (80–96% ee)
and 3 (88–98% ee). Previously mixed success has been attained
in cyclohexanone alkenylation with related Cu-catalysts. For
example, ACA addition of Me2AlCHQCHPh to cyclohexenone
proceeds with rather poor ee (17%).13 However, high selectivities
(B90% ee) are attained in a ACA reactions of a,b-unsaturated
lactams and dehydro-4-piperidones (whether 3-substituted or
not).14 Based on known correlations15 (S,R,R)-L2 provides (+)-(S)-2a
and the other addition products are assumed to proceed with
Run
Copper salt
Yield 2a (%)
ee (%)
1
2
3
4
5
Cu(OTf)2
6
47
34
7
64
78
80
90
76
(CuOTf)2ÁPhMe
Cu(MeCN)4BF4
CuCl + AgNTf2 (15 mol%)
CuTC
66
a
Using the conditions of Table 1. Yield and ee determination by GC.
ease of use and activity, the enantioselectivity as a function of
ligand structure was optimised. On the basis of the known
trend the ligand library of Scheme 1 was selected to compare
against L1. Use of 2-naphthyl units in phosphoramidites L2–L3
is often favourable in enantioselective 1,4-alane addition.11
Similarly, the ‘simplephos’ ligands L4–L9 are often effective.12
The results of this screening are presented in Table 3.
Unusually in this case, the phosphoramidite L2 was optimal
(run 2) compared to the tropos ligand L3 and the simplephos
derivatives (L4–L9). The optimal catalytic system (CuTC/L2) was then
applied to a combination of acceptors and vinylalanes (Scheme 2).
Scheme 2 Scope of the hydroalumination–ACA process; series 2 from
cyclohexenone,
cyclohexenone.
3
from 3-methylcyclohexenone,
4
from 3-ethyl
Scheme 1 Ligands used in this study.
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in Et2O afforded nominal ClAlMe(CHQCHBu) (1.4 equiv.). The alane
solution was added to CuTC (0.05 equiv.) mixed with L2 (0.075 equiv.)
in toluene and cyclohexenone (0.5 equiv.) added slowly. After 1 h at
25 1C the reaction was quenched and worked up in the normal way to
afford 2a (65%, 88% ee).
1 General overviews of ACA reactions: (a) A. Alexakis, N. Krause and
S. Woodward, in Copper Catalysed Asymmetric Synthesis, ed.
A. Alexakis, N. Krause and S. Woodward, Wiley-VCH, Weinheim,
2014, ch. 2, pp. 33–68; (b) D. Mu¨ller and A. Alexakis, Chem. Com-
mun., 2012, 48, 12037; (c) Catalytic Asymmetric Conjugate Reactions,
ed. A. Cordova, Wiley-VCH, Weinheim, 2010; (d) S. R. Harutyunyan,
T. den Hartog, K. Geurts, A. J. Minnaard and B. L. Feringa, Chem.
Scheme 3 Hydroalumination–ACA product yields from acyclic enones
and for MeAlClCHQCHTMS addition.
¨
Rev., 2008, 108, 2824; (e) A. Alexakis, J. E. Backvall, N. Krause,
the same facial selectivity. Preliminary studies indicate that the
scope of the reaction could be partially extended to products 5–7
(in the racemic sense), derived from linear enones (Scheme 3) and
via hydroalumination of problematic Me3SiCCH (leading to 8).
However, the present conditions do not provide synthetically
useful isolable yields – this is under further investigation at
present and will be reported later.
`
´
O. Pamies and M. Dieguez, Chem. Rev., 2008, 108, 2796;
( f ) O. Pamies and M. Dieguez, Top. Organomet. Chem., 2013,
41, 277 and references therein.
´
´
2 Rh-catalysed alkenylation (arylation): (a) T. Hayashi and K. Yamasaki,
Chem. Rev., 2003, 103, 2829 (overview); (b) T. Hayashi, K. Ueyama,
N. Tokunaga and K. J. Yoshida, J. Am. Chem. Soc., 2003, 125, 11508;
(c) T. Hayashi, M. Takahashi, Y. Takaya and M. Ogasawara, J. Am.
Chem. Soc., 2002, 124, 5052; (d) S. Oi, T. Sato and Y. Inoue, Tetra-
hedron Lett., 2004, 45, 5051.
3 Cu-catalysed quaternary centre formation: (a) C. Hawner and
A. Alexakis, Chem. Commun., 2010, 46, 7295 (overview); (b) D. Mu¨ller
and A. Alexakis, Org. Lett., 2013, 15, 1594; (c) M. Sidera, P. M. C. Roth,
R. M. Maksymowicz and S. P. Fletcher, Angew. Chem., Int. Ed., 2013,
52, 7995; (d) D. Mu¨ller, M. Tissot and A. Alexakis, Org. Lett., 2011,
13, 3040; (e) D. Mu¨ller and A. Alexakis, Chem.–Eur. J., 2013, 19, 15226.
4 Thermal alkyne hydroalumination: E. Negishi, T. Takahashi and
S. Baba, Org. Synth., 1988, 66, 60.
In conclusion, simple ambient temperature ACA addition to
cyclohexenones of terminal alkyne derived ClAlMeCHQCHR
gives moderate to good chemical yields in synthetically useful ee
values. The latter are readily available from hydroalumination
with significantly air stabilised HAlCl2Á(THF)2.6
SW and DW gratefully acknowledge the Engineering and
Physical Sciences (EPSRC; EP/G026882/1) Research Council and
the University of Nottingham for funding. SW thanks AA for
many fruitful collaborations over the last 20 years and wishes
him a diverse and productive retirement.
5 Ni-catalysed hydroalumination: K. Akiyama, F. Gao and
A. H. Hoveyda, Angew. Chem., Int. Ed., 2010, 49, 419 based on the
work of J. J. Eisch and M. W. Foxton, J. Org. Chem., 1971, 36, 3520.
6 P. Andrews, C. M. Latham, M. Magre, D. Willcox and S. Woodward,
Chem. Commun., 2013, 49, 1488.
7 With reactive acceptors, e.g. alkylidenemalonates spontaneous additions
are observed.
8 A. J. Blake, J. Shannon, J. C. Stephens and S. Woodward, Chem.–Eur. J.,
2007, 13, 2462.
Notes and references
‡ The structure of the by-product is:
9 D. Mu¨ller and A. Alexakis, Org. Lett., 2012, 14, 1842.
10 Lower 1,4-addition yields from MCHQCHR species attained by
hydrometallation are unfortunately not uncommon, for example:
see Table 2 in ref. 3d (3 runs o 50%); ref. 9 (5 runs o 50%) ref. 14
(30–70%). See also R. Maksymowicz, P. M. C. Roth, A. Thompson
and S. P. Fletcher, Chem. Commun., 2013, 49, 4211.
11 C. Hawner, K. Li, V. Cirriez and A. Alexakis, Angew. Chem., Int. Ed.,
2008, 47, 8211.
12 D. Mu¨ller, C. Hawner, M. Tissot, L. Palais and A. Alexakis, Synlett,
2010, 1694.
§ The formation of the alternative ‘ate’ species Li[Cl2AlMeCHQCHC6H13
]
¨ller, PhD thesis, University of Geneva, No. Sc. 4502, see
was discounted on the basis of the formation of copious LiCl precipitates. 13 D. Mu
¶ Representative procedure for the formation of 2a. 1-Octyne was specifically, p. 110.
treated with HAlCl2Á(THF)2 (1.4 equiv.) and Cp*2ZrCl2 (0.05 equiv.) at 14 P. Cottet, D. Mu¨ller and A. Alexakis, Org. Lett., 2013, 15, 828.
80 1C (2 h) in THF followed by solvent removal and the addition of MeLi 15 J. F. Teichert and B. L. Feringa, Angew. Chem., Int. Ed., 2010, 49, 2486.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 1655--1657 | 1657