Bis(amido)magnesium mediated aldol additions: First structural characterisation of an amidomagnesium aldolate intermediate

Article abstract of DOI:10.1039/a903784e

Bis(hexamethyldisilazido)magnesium has successfully been used to mediate aldol additions of selected ketones and aldehydes in hydrocarbon media, and the structure of an intermediate amido(aldolate), [{(Me₃Si)₂NMg[μ-OC(Me)-Bu(t)CH

Full text of DOI:10.1039/a903784e

Bis(amido)magnesium mediated aldol additions: first structural
characterisation of an amidomagnesium aldolate intermediate
John F. Allan, Kenneth W. Henderson* and Alan R. Kennedy
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, UK G1 1XL.
E-mail: k.w.henderson@strath.ac.uk
Received (in Basel, Switzerland) 11th May 1999, Accepted 2nd June 1999
Bis(hexamethyldisilazido)magnesium has successfully been
used to mediate aldol additions of selected ketones and
aldehydes in hydrocarbon media, and the structure of an
intermediate amido(aldolate), [{(Me3Si)2NMg[m-OC(Me)-
ButCH2C(But) = O]}2] 17, produced by the self-coupled
reaction of pinacolone has been characterised by X-ray
crystallography.
turn, reactions with pinacolone 2, acetophenone 3, hexan-2-one
4, 3-methylbutan-2-one 5 and cyclohexanone 6 were performed
(Scheme 1), and Table 1 lists the results of the aldol addition
reactions mediated by 1.†
Isolated yields from the ketone/aldehyde reactions compare
favourably with lithium-mediated additions (reactions 1–5).2 In
most instances the reaction of the ketone enolates with
Addition of the a carbon of an aldehyde or ketone to a second
carbonyl unit is known as the aldol addition and has become one
of the cornerstone reactions of modern synthetic chemistry.1
Several methods have been developed to mediate this trans-
formation, one of the most useful being the formation of a metal
enolate by abstraction of a proton a to the carbonyl using a
strong base. This is most commonly achieved through the use of
lithium reagents and more specifically bulky lithium amides
such as lithium diisopropylamide (LDA) and lithium hexame-
thyldisilazide (LHMDS).2 We are interested in exploring the
utility of amidomagnesium compounds as reagents to perform
similar transformations since they are less reactive, more
thermally stable and, in some instances, more selective than
their lithium counterparts.3 Magnesium has previously been
used to mediate aldol additions via transmetallation of pre-
formed lithium enolates with magnesium halides.2 Reactions of
this type have proved problematic due to ‘salt-effects’.4 In this
respect, we have recently reported the presence of Schlenk-type
equilibria for Hauser bases (R2NMgX) and halomagnesium
enolates, which complicates their use.5 In comparison, bis(ami-
do)magnesium compounds [(R2N)2Mg] have scarcely been
studied as reagents.6 In part this is due to complications with
their synthesis, leading to troublesome side reactions of in situ
prepared complexes.7 These experimental problems have
recently been overcome and we now report the use of
bis(amido)magnesium compounds as reagents.8 Herein we
exploit an ether-free preparation of the bis(amide)
[Mg{N(SiMe3)2}2] 1, and examine its utility in the aldol
addition reaction.
Table 1 Aldol addition reactions mediated by 1
Carbonyl added
(mol. equiv.)
Entry
1
Ketone
Major product
OH
Yield (%)
86
O
O
PhCHO (1.5)
But
But
7
O
OH
Ph
O
2
3
4
PhCHO (2)
PhCHO (2)
PhCHO (2)
86
94
82
Ph
Ph
8
O
O
OH
Ph
9
O
O
O
OH
Ph
10
O
OH
Ph
5
PhCHO (2)
90
11
O
OH
But
6
7
8
9
2
3
4
5
2 (1)
3 (1)
4 (1)
5 (1)
56
38
80
63
But
Ph
12
OH
Ph
A mixture of commercially available Bu2Mg and 2 equiva-
lents of hexamethyldisilazane was heated to reflux in heptane
solution for several hours, and slow cooling to room tem-
perature resulted in the crystallisation of 1 in high yield.9
Crystalline 1 was then isolated and used as a stock reagent. In
O
13
O
OH
OMgN(SiMe3)2
Bun
Mg{N(SiMe3)2}2
+
R1MeC=O
R1
CH2
14
R1MeC=O
O
OH
PhCHO
15
O
OMgN(SiMe3)2
O
OMgN(SiMe3)2
R1
Me
O
Ph
H
R1
R1
10
6
6 (1)
62
OH
Where R1 = But, Ph, Bun, Pri
16
Scheme 1
Chem. Commun., 1999, 1325–1326
1325

boat conformation are found in a ratio of 80.5(3):19.5(3).
Chelate isomers are also found in aldolate derivatives of
lithium,13 zinc,14 titanium15 and aluminium.16 These isomers
adopt half-boat, chair, half-chair and twist boat structures,
illustrating the shallow energy surface separating these con-
formations.
We would like to thank The Royal Society for a University
Research Fellowship (K. W. H.), and Professor Robert E.
Mulvey and Dr William J. Kerr for helpful discussions during
the preparation of this manuscript.
Notes and references
† Base 1 (2 mmol) was suspended in 10 ml of hexane and cooled to 278 °C.
Aldehyde (4 mmol) or alternatively ketone (2 mmol) was then added,
followed by dropwise addition of the ketone (2 mmol). The aldehyde
reactions were stirred at 278 °C for 30 min then quenched with 1 M HCl.
The self-coupled reactions were warmed to room temperature and stirred for
48–72 h before quenching in 1 M HCl. Improved yields of 12 and 13 were
obtained on heating the mixtures to reflux for several hours. Further
improvements in yields are expected on optimising the reaction condi-
tions.
‡ Crystal data for 17: C36H82Mg2N2O4Si4, M = 768.02, T = 123(2) K,
¯
triclinic space group, P1, a = 9.610(3), b = 11.381(2), c = 12.024(4) Å,
Fig. 1 Molecular structure of the major isomer of 17 with hydrogen atoms
omitted for clarity. Key bond lengths (Å) and angles (°): Mg(1)–O(1)
1.9540(15), Mg(1)–O(1*) 1.9881(15), Mg(1)–N(1) 1.9920(19), Mg(1)–
O(2*) 2.0619(15), O(1)–Mg(1)–O(1*) 85.90(6), O(1)–Mg(1)–N(1)
126.96(7), O(1*)–Mg(1)–N(1) 129.57(7), O(1)–Mg(1)–O(2*) 111.60(7),
O(1*)–Mg(1)–O(2*) 87.18(6), N(1)–Mg(1)–O(2*) 108.51(7), C(7)–O(1)–
Mg(1) 144.29(16), C(7)–O(1)–Mg(1*) 116.06(13), Mg(1)-O(1)–Mg(1*)
94.10(6), C(14)–O(2)-Mg(1*) 130.27(12).
a = 98.90(2), b = 104.00(2), g = 105.996(19)°, U = 1191.5(5) Å3, Z =
1, m(Mo-Ka) = 0.185 mm21, Dc = 1.070 Mg m23, 2qmax = 56°, 6084
reflections collected, 5746 unique, (Rint = 0.0173) all were used in the
calculations. The minor disorder component was treated isotropically with
no hydrogen atoms attached. All other non-hydrogen atoms were treated
anisotropically and all other hydrogens included in a riding model. The final
wR(F2) was 0.1417 and conventional R was 0.0488. Programs were
standard diffractometer control software and members of the SHELX
family (G. M. Sheldrick, University of Göttingen, Germany). The structure
was solved using direct methods and refined by full-matrix least-squares
refinement on F2. A single crystal of 17 was mounted in inert oil and
transferred to the cold N2 gas stream of the diffractometer.
benzaldehyde resulted in a small quantity (4–16%) of self-
addition products. Significantly, this problem was overcome by
adding 2 equivalents of the aldehyde to a solution of 1 before
addition of the ketone. Also, no aldimine formation was
detected.10 Analogies with Corey’s internal quench method for
formation of silyl enol ethers are clear.11
It is known that ketone–ketone aldol coupling is usually less
favourable than ketone–aldehyde additions. Using high tem-
perature conditions (25–70 °C) the self-aldol reactions were
found to proceed in reasonable yields (reactions 6–10).12 The
ability to perform these reactions at higher temperatures
contrasts appreciably with the lithium analogues, where the
aldolates commonly undergo retro-aldol reactions above
230 °C or eliminate LiOH to give enones.2 With the systems
reported here, the enone only becomes the major product after
extended reflux. Furthermore, reactivity of both amide func-
tions bonded to magnesium is suggested by reaction of 4
equivalents of 2 with 1 which yielded 55% of aldol product 12
(calculated with respect to ketone).
CCDC 18/1286. See http://www.rsc.org/suppdata/cc/1999/1325/ for
crystallographic files in .cif format.
1 C. H. Heathcock, in Asymmetric Synthesis, ed. J. D. Morrison,
Academic Press, New York, 1983, vol. 3, pp. 111–212.; D. A. Evans,
ibid., pp. 2–110; C. H. Heathcock, Aldrichim. Acta, 1990, 23, 99.
2 H. O. House, D. S. Crumrine, A. Y. Teranishi and H. D. Olmstead,
J. Am. Chem. Soc., 1973, 95, 3310; F. Gaudemar-Bardone and M.
Gaudemar, J. Organomet. Chem., 1976, 104, 281.
3 P. E. Eaton, C. H. Lee and Y. Xiong, J. Am. Chem. Soc., 1989, 111,
8016.
4 A. Loupy and B. Tchoubar, Salt Effects in Organic and Organometallic
Chemistry, VCH, New York, 1991.
5 J. F. Allan, W. Clegg, K. W. Henderson, L. Horsburgh and A. R.
Kennedy, J. Organomet. Chem., 1998, 559, 173.
6 D. Bonafoux, M. Bordeau, C. Biran, P. Cazeau and J. Dunogues, J. Org.
Chem., 1996, 61, 5532; D. Bonafoux, M. Bordeau, C. Biran, and J.
Dunoguès, J. Organomet. Chem., 1995, 493, 27.
It should be noted that when polar donor solvents such as
THF or HMPA were present, the yield of aldolate was
significantly reduced ( < 10% for entry 6). This is consistent
with the observation that, in lithium-mediated reactions,
increasing the solvent polarity increases yields of enolisation
but disfavours addition. However, this effect appears to be more
dramatic for magnesium, since the lithium reactions are
commonly performed in THF solution. This may be a
consequence of the magnesium centres being more sterically
crowded than those of lithium, resulting in blocking of the
incoming carbonyl.
The intermediate from the pinacolone self-coupled reaction,
[{(Me3Si)2NMg[m-OC(Me)ButCH2C(But)NO]}2] 17, was char-
acterised by X-ray crystallography (Fig. 1).‡ The centrosym-
metric structure is based on a trans-6,4,6-fused ring system in
which each aldolate acts as both bridge and chelate.
7 K. W. Henderson, J. F. Allan and A. R. Kennedy, Chem. Commun.,
1997, 1149.
8 M. Westerhausen, Trends Organomet. Chem., 1997, 2, 89.
9 This is a variation of the method from L. M. Engelhardt, B. S. Jolly, P. C.
Junk, C. L. Raston, B. W. Skelton and A. H. White, Aust. J. Chem.,
1986, 39, 1337.
10 D. J. Hart, K. Kanai, D. G. Thomas and T. K. Yang, J. Org. Chem.,
1983, 48, 289.
11 E. J. Corey and A. W. Gross, Tetrahedron Lett., 1984, 25, 495.
12 Magnesium anions have been used for the thermodynamic equilibration
of aldolates: K. A. Swiss, W. B. Choi, D. C. Liotta, A. F. Abdel-Magid
and C. A. Maryanoff, J. Org. Chem., 1991, 56, 5978.
13 P. G. Williard and J. M. Salvino, Tetrahedron Lett., 1985, 26, 3931.
14 S. C. Goel, M. Y. Chiang and W. E. Buhro, J. Am. Chem. Soc., 1991,
113, 7069.
15 P. G. Cozzi, C. Floriani, A. Chiesivilla and C. Rizzoli, Organometallics,
1994, 13, 2131.
16 M. B. Power, A. W. Apblett, S. G. Bott, J. L. Atwood and A. R. Barron,
Organometallics, 1990, 9, 2529.
Two superimposed isomers are present within the crystal
lattice of 17. The isomers differ in the conformation of the six-
membered aldolate chelate rings where half-chair and twist-
Communication 9/03784E
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Chem. Commun., 1999, 1325–1326