N-Trimethylsilyloxyenamines as new aldehyde enolate synthons: General, efficient and diastereoselective aldol reaction with ketals and acetals

Article abstract of DOI:10.1039/b924880c

(E)-N-Trimethylsilyloxyenamines, easily accessible from aldonitrones, proved to be excellent nucleophiles in TMSOTf-induced diastereoselective aldol reaction, both with ketals and acetals, proceeding via an extended transition state and leading to a new aldol C-C-bond in the aldonitrone products, that can be readily hydrolysed to the corresponding aldehydes.

Full text of DOI:10.1039/b924880c

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N-Trimethylsilyloxyenamines as new aldehyde enolate synthons: general,
efficient and diastereoselective aldol reaction with ketals and acetalsw
b
a
Manoj R. Sonawane,a Ivana Cı
´
sarova and Ilya M. Lyapkalo*
´
Received (in Cambridge, UK) 26th November 2009, Accepted 1st February 2010
First published as an Advance Article on the web 19th February 2010
DOI: 10.1039/b924880c
(E)-N-Trimethylsilyloxyenamines, easily accessible from
aldonitrones, proved to be excellent nucleophiles in TMSOTf-
induced diastereoselective aldol reaction, both with ketals and
acetals, proceeding via an extended transition state and leading
to a new aldol C–C-bond in the aldonitrone products, that can be
readily hydrolysed to the corresponding aldehydes.
of the enamines 1 described in literature7 were prepared
by silylation of the corresponding aldonitrones,7,8 with no
reactivity being reported until recently.9
Noteworthy, the enamines 1b–e are formed as pure
E-isomers, in contrast to the silyl enol ethers obtained by
silylation of aliphatic aldehydes normally in modest to good
Z-selectivity.
The most relevant study exploring N-hydroxy-enamine
intermediates as aldol nucleophiles in the reaction with
activated ketones only was carried out by Jørgensen et al.10
After careful scrutiny of the existing data on the b-nucleophilic
reactivity of the enamines derived from aldonitrones,y
we decided to commence our study on application of the
enamines 1 in aldol chemistry by attempting the TMSOTf
catalysed reaction11 with dimethyl acetals or ketals under the
conditions initially described for silyl enol ethers by Noyori et al.12
Our initial attempt to react the enamine 1a with
PhCH(OMe)2 employing a catalytic (20 mol%) quantity of
TMSOTf led to very low (ca. 6%) conversion to the desired
nitrone product 2a regardless of the reaction time, with the
starting materials recovered essentially intact. Gratifyingly, a
stoichiometric amount of TMSOTf furnished complete
conversion to the nitrone 2a (Table 1) thus paving a way to
the first high-yielding reaction of N-trimethylsilyloxyenamines
as b-nucleophiles.
The presence of a stoichiometric quantity of TMSOTf
necessitated careful optimisation of the quenching conditions
to prevent uncontrolled generation of highly acidic TfOH in the
organic phase that may trigger undesired side reactions of the
products 2. Homogeneous quenching with MeONa in MeOH at
low temperature was found to be optimal for rendering high
yields of the b-methoxy aldonitrones 2 (Table 1).
The enamine 1a turned out to be an excellent synthetic
equivalent of acetaldehyde, a simplest enolisable carbonyl
compound whose nucleophilic reactivity is regarded to be
particularly challenging.3,13,14 It reacts cleanly with both
acetals and ketals to afford nitrones 2a–f,r which are convenient
precursors to the corresponding a-unsubstituted b-methoxy
aldehydes as demonstrated by high-yielding synthesis of 3c,e
(see Table 2).
The aldol reaction has achieved the status of an indispensable
tool for stereoselective assemblage of carbon–carbon bonds.1
In order to obtain a good stereocontrol, high reaction conversion
and isolated yield of the desired aldol product, two necessary
(though not sufficient) prerequisites must be observed:
sufficient thermodynamic ‘‘push’’2 and kinetic stability of the
aldol product under the reaction conditions. These prerequisites
ultimately determined the traditional development of the
stereoselective aldol reaction as between aldehyde electrophilesz
and enolate nucleophiles from ketones and carboxylate
derivatives. Aldehyde nucleophiles proved challenging since
the aldol products derived thereof bear a reactive aldehyde
functionality which is involved in side reactions under the
reaction conditions.
A seminal extension of the traditional scope of the aldol
methodology was achieved after the successful implementation
of the controlled stereoselective cross-aldol reaction. Selected
approaches include utilization of vinyl tris(trimethylsilyl)silyl
ether as an acetaldehyde enolate nucleophile,3 interaction of
aldehyde-derived trichlorosilyl enol ethers with aldehydes
under the nucleophilic catalysis by chiral phosphamides,4
and proline catalysis for the direct cross-aldol reaction of
aldehydes pioneered by MacMillan et al.5
In the latter version, likely intermediacy of the enamine
nucleophile6 arising from the condensation of aldehyde with
proline alludes to a promise of success in application of
rationally designed enamines as aldehyde enolate synthons in
the controlled aldol reaction of a wider applicability in regard
to both the carbonyl electrophile and aldehyde nucleophile.
To this end, we envisaged and obtained N-tert-butyl-N-
trimethylsilyloxyenamines (1) (Scheme 1). Two representatives
a Institute of Organic Chemistry and Biochemistry Academy of
Sciences of the Czech Republic, v. v. i., Flemingovo nam. 2,
16610 Prague 6, Czech Republic.
E-mail: ilya.lyapkalo@uochb.cas.cz; Fax: +420 220183578;
Tel: +420 220183420
b Department of Inorganic Chemistry, Charles University,
Hlavova 2030, 128 40 Prague 2, Czech Republic
w Electronic supplementary information (ESI) available: Experimental
details, single-crystal X-ray and spectroscopic data, including original
1H and 13C NMR spectra. CCDC 755320 (2m), 755321 (2p) and
755322 (2s). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b924880c
Scheme 1 Synthesis and isolated yields of the enamines 1. 1a: R = H,
94% (36%7); 1b: R = Me, 95%; 1c: R = n-C5H11, 91%; 1d: R = Ph,
89%; 1e: R = rac-Ph(Me)CH, 91%. For experimental details, physical
and spectroscopic data, see ESI.w
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Table 1 Diastereoselective aldol-type reaction of the enamines 1a–e
with acetals and ketals induced by TMSOTf (1.2 equiv.). Unless
stated otherwise diastereomeric ratio (dr) was determined by
1H NMR of the crude products 2 before chromatographic purification
whereas yield (%) refers to that of the isolated products after
the purification
Table 2 Synthesis of aldehydes 3 from aldonitrones 2. Hydrolysis
conditions: r.t., (i) aq. H3PO4/hexane, (ii) aq. HCl, MeOH
Nitrone 2 (dr), Aldehyde 3 (dr), Nitrone 2 (dr), Aldehyde 3 (dr),
conditions
yield (%)
conditions
yield (%)
2c (—), i
2e (—), i
2g (—), i
2i (—), ii
2l (3 : 1), i
3c (—), 97
3e (—), 96
3g (—), 5a
3i (—), 89
2m (7 : 1), i
2n (20 : 1), i
2s (17 : 1), ii
2u (12 : 1), ii
2w (20 : 1), ii
3m (6.7 : 1), 83b
3n (11 : 1), 98
3s (10 : 1), 85b
3u (15 : 1), 90
c
3l (2.6 : 1), 86b
—
a
As
a
mixture
with
b
95%
elimination
product
Me3CC(Me)QCHCHQO. Obtained from the enamines 1 without
isolation of the corresponding nitrones 2. Very slow conversion
leading to PhC(O)Me that is indicative of the retro-aldol reaction.
c
The (E)-N-tert-butyl-N-trimethylsilyloxyenamines 1b–d
react with acetals and ketals to produce nitrones 2 in excellent
yield and with high diastereoselectivity. The syn-configuration
of the major diastereomers shown in Table 1 is unequivocally
established by single-crystal X-ray analysis for the nitrones
2m,p,s (see Fig. 1 in ESIw)15 or by exact matching the NMR
data for the parent aldehydes syn-/anti-3l16 and syn-3n17 from
2l and 2n respectively with those given in literature. For the
products 2o,w it is assigned arbitrarily based on the structural
similarity with 2m,s.z
The reaction is applicable to dibenzyl ketals as exemplified
by the synthesis of b-benzyloxyaldonitrone 2h0. However, no
reaction occurred between heptaldehyde dibenzyl acetal and
the enamines 1b or 1d under the standard conditions. Our
attempts to prepare starting dibenzyl ketals from aryl alkyl
ketones met so far with limited success (see ESIw). Clearly,
more efforts are required to fully extend this methodology
to the synthetically more versatile but chemically less stable
b-benzyloxy aldonitrones.
Assuming the intermediacy of the methyl carboxonium
electrophile generated from the acetals or ketals and TMSOTf,12
the syn-stereoselectivity of the new aldol-type reaction could be
rationalized by proposing an extended transition state (TS) that
leads to the N-trimethylsilyloxyimmonium intermediate A. The
stereocontrol in TS is attained via minimisation of steric repulsion
between the bulkiest substituent RL (Ar 4 Et/Me 4 H) of the
electrophile and R of the enamine 1 and electrostatic repulsion
between the partial positive charges (d+) on the heteroatoms as
shown in Scheme 2.
The proposed transition state TS exhibits stereochemical
relevance to that reported for the related reaction of
a 6% (estimated by 1H NMR) with 0.2 equiv. of TMSOTf. b Readily
eliminated MeOH upon storage to give the unsaturated nitrone
bearing a conjugated CQC bond. c For the reaction carried out in a
4 : 1 blend of 1,2-dimethoxyethane and hexane instead of CH2Cl2.
Scheme
2 Putative extended transition state leading to the
syn-diastereoselectivity in formation of the intermediate N-trimethyl-
silyloxyimmonium cation A followed by the product 2.
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trimethylsilyl enol ethers by Noyori et al.12 It is also geometrically
similar to that of the Lewis acid induced addition of alken-2-
yl(tri-n-butyl)stannanes and related nucleophiles to carbonyl
compounds yielding syn-homoallyl alcohols.18 The TS features
a synclinal arrangement of the fragment bearing bulky TMS
group and the most sterically demanding substituent RL of the
electrophile. However, it does not appreciably destabilise the TS
because the TMS group in the enamines 1 is located one bond
further away from the reaction centre compared to trimethylsilyl
enol ethers or alken-2-yl(tri-n-butyl)stannanes and oriented away
from the approaching electrophile. This may account for higher
dr values obtained with the enamines 1 as compared with
trimethylsilyl enol ethers.12
Notes and references
z Important exceptions were activated ketones such as a-keto esters
and a-diketones1e and ketals activated by Lewis acids.1b,12
y Jørgensen et al. reported orienting experiments on aldol addition of
N-benzyl-O-(trimethylsilyl)-N-vinylhydroxylamine to an activated ketone
resulting in a mixture of addition and condensation products;10 Aurich
et al.8b found that Mannich-type addition–cyclisation of nitrones with
their N-hydroxyenamine tautomers is a reversible solvent-dependent
process. Hence, we reasoned that Noyori’s TMSOTf methodology12
offering robust C–C-coupling under intrinsically kinetic conditions may
be the best option for the enamines 1 to begin with.
z Although syn-configuration of major diastereomers for 2q,t,u,v,x is
very likely, we refrain from indicating it here. Further structural
elucidation is in progress.
1 Selected reviews: (a) T. Mukaiyama, Org. React. (N. Y.), 1982, 28,
203; (b) T. Mukaiyama and M. Murakami, Synthesis, 1987,
1043–1054; (c) S. G. Nelson, Tetrahedron: Asymmetry, 1998, 9,
357–389; (d) R. Mahrwald, Chem. Rev., 1999, 99, 1095–1120;
(e) J. S. Johnson and D. A. Evans, Acc. Chem. Res., 2000, 33,
325–335; (f) C. Palomo, M. Oiarbide and J. M. Garcia, Chem.
Soc. Rev., 2004, 33, 65–75; (g) L. M. Geary and P. G. Hultin,
Tetrahedron: Asymmetry, 2009, 20, 131–173.
It is intriguing that the diastereoselectivity level in reactions
of the enamines 1 with ketals is higher than with acetals (see
Table 1) and is unprecedented for the ketone electrophiles in
the aldol reaction.
Circumstantial evidence for the extended transition state
(Scheme 2) comes from the comparative analysis of the results
obtained by Denmark et al.4 who reported excellent anti-
selectivity for the (E)-isomers of silyl enol ethers that undergo
2 J. P. Guthrie, Can. J. Chem., 1978, 56, 962–973.
3 M. B. Boxer and H. Yamamoto, J. Am. Chem. Soc., 2006, 128, 48–49.
4 S. E. Denmark and S. K. Ghosh, Angew. Chem., Int. Ed., 2001, 40,
4759–4762.
5 A. B. Northrup and D. W. C. MacMillan, J. Am. Chem. Soc.,
2002, 124, 6798–6799.
aldol reaction through
a chairlike transition structure
organized around a silicon centre.19
The reaction efficiency in conjunction with the exceptionally
wide scope and a lack of subsequent side reactions can likely be
attributed to the enhanced b-C-nucleophilicity of the enamines 1
and kinetic stability of the N-trimethylsilyloxyimmonium inter-
mediate A under the reaction conditions. In these respects, the
new aldol-type reaction of 1 compares favourably with the
related reaction of N,N-bis(silyloxy)enamines reported earlier.20
Accessibility of the b-methoxy aldehydes 3 is exemplified by
high-yielding conversion of a series of aldonitrones 2 under
acidic conditions as shown in Table 2.
6 B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc.,
2000, 122, 2395–2396.
7 K. Torssell and O. Zeuthen, Acta Chem. Scand., Ser. B, 1978, 32b,
118–124.
8 (a) A. Padwa, D. Dean and T. Oine, J. Am. Chem. Soc., 1975, 97,
2822–2829; (b) H. G. Aurich, J. Eidel and M. Schmidt, Chem. Ber.,
1986, 119, 18–35; (c) C. H. Cummins and R. M. Coates, J. Org.
Chem., 1983, 48, 2070–2076. We routinely employed CCl4 as a
reaction solvent following the original procedure described in
ref. 8a; other non-protogenic solvents including CH2Cl2,7,8b,c
CHCl3,8b benzene or hexane (this work) can be employed with
comparable efficiency.
9 (a) M. J. S. Gomes, L. Sharma, S. Prabhakar, A. M. Lobo and P.
M. C. Gloria, Chem. Commun., 2002, 746–747; (b) H.-J. Song,
C. J. Lim, S. Lee and S. Kim, Chem. Commun., 2006, 2893–2895.
10 A. Bøgevig, K. V. Gothelf and K. A. Jørgensen, Chem.–Eur. J.,
2002, 8, 5652–5661.
11 Relevant review: A. D. Dilman and S. L. Ioffe, Chem. Rev., 2003,
103, 733–772.
12 S. Murata, M. Suzuki and R. Noyori, Tetrahedron, 1988, 44, 4259–4275.
13 J. W. Yang, C. Chandler, M. Stadler, D. Kampen and B. List,
Nature, 2008, 452, 453–455.
14 S. E. Denmark and T. Bui, J. Org. Chem., 2005, 70, 10190–10193.
15 For description of the X-ray method, see ESIw.
Only insignificant erosion of diastereoselectivity was
observed during the hydrolysis. A surprising propensity of
2g and 3g to elimination of MeOH (see footnotes to Tables 1
and 2) is likely attributable to conformational effects.
To demonstrate the synthetic utility of the new aldol-type
reaction, synthesis of the aldehydes 3l,m,s was successfully
carried out without isolation of the corresponding nitrones 2.
The yields of the one-pot reactions are typically 5–10% higher
than the overall yields of the two-step protocol.
In summary, we have documented the first general and
diastereoselective reaction of hitherto scarcely described
N-trimethylsilyloxyenamines 1, new highly efficient and
geometrically defined nucleophilic aldehyde equivalents easily
accessible from the corresponding aldonitrones. The aldol-type
addition to the electrophiles generated from acetals or ketals
required stoichiometric quantities of TMSOTf to proceed.
This apparent drawback may be turned to the advantage by
exploiting the promising versatility and stereocontrol offered
by the N-trimethylsilyloxyimmonium intermediates A.21
Extension of the reaction to free carbonyl and Mannich
electrophiles, use of chiral auxiliaries for chirality induction,
and exploration of the reactivity pathways of the type A
intermediates are currently underway.
16 S. Kiyooka, Tetrahedron: Asymmetry, 2003, 14, 2897–2910.
17 D. A. Evans, S. J. Miller and M. D. Ennis, J. Org. Chem., 1993, 58,
471–485.
18 The formation of syn-products via a putative extended transition
state is typically, albeit not exclusively (cf. ref. 18c), observed for
the reactions induced by BF3ꢁOEt2, see: (a) Y. Yamamoto, Acc.
Chem. Res., 1987, 20, 243–249; (b) M. Yasuda, K. Hirata,
M. Nishino, A. Yamamoto and A. Baba, J. Am. Chem. Soc.,
2002, 124, 13442–13447; (c) C. K. Z. Andrade, N. R. Azevedo and
G. R. Oliveira, Synthesis, 2002, 928–936.
19 (a) S. E. Denmark and R. A. Stavenger, Acc. Chem. Res., 2000, 33,
432–440; (b) S. E. Denmark and G. L. Beutner, Angew. Chem., Int.
Ed., 2008, 47, 1560–1638.
20 A. D. Dilman, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko and
V. A. Tartakovsky, J. Org. Chem., 2000, 65, 8826–8829.
21 Nucleophilic additions to CQN bond of nitrones induced by
TMSOTf are precedented: (a) C. Camiletti, D. D. Dhavale,
F. Donati and C. Trombini, Tetrahedron Lett., 1995, 36,
7293–7296; (b) M. Gianotti, M. Lombardo and C. Trombini,
Tetrahedron Lett., 1998, 39, 1643–1646; (c) M. Lombardo and
C. Trombini, Curr. Org. Chem., 2002, 6, 695–713.
We thank the IOCB (Grant No. Z4 055 0506) and the
Ministry of Education (Grant No. MSM0021620857 for I. C.)
for financial support.
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This journal is The Royal Society of Chemistry 2010
2658 | Chem. Commun., 2010, 46, 2656–2658