Lewis acid catalyst free electrophilic alkylation of silicon-capped π donors in 1,1,1,3,3,3-hexafluoro-2-propanol

Article abstract of DOI:10.1002/anie.200803927

(Figure Presented) A credit to donation: A diverse range of electrophilic addition reactions, conventionally carried out using Lewis acid catalysts, have been performed in electrophilic media without acidic reagents. 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) acts as an efficient hydrogen-bond donor and highly polar solvent for a wide range of substrates in reactions with Si-capped π donors.

Full text of DOI:10.1002/anie.200803927

Angewandte
Chemie
DOI: 10.1002/anie.200803927
Electrophilic Reaction Media
Lewis Acid Catalyst Free Electrophilic Alkylation of Silicon-Capped
p Donors in 1,1,1,3,3,3-Hexafluoro-2-propanol**
Maxim O. Ratnikov, Vasily V. Tumanov, and William A. Smit*
The electrophilic alkylation of p donors most often implies
the use of Lewis acid catalysts for the generation of reactive
electrophilic species from covalent precursors.[1] A promising
alternative to this procedure has recently been suggested in
studies by Mayr and co-workers.[2,3] In particular, it was
disclosed that cationic intermediates generated by solvolysis
of SN1-active substrates in polar solvents, such as acetone/
water, acetonitrile/water, 2,2,2-trifluoroethanol (TFE), or
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), can be trapped by
p nucleophiles (activated arenes, heteroarenes, or enol
ethers) provided the nucleophilicity of the latter is higher
than that of the solvent system.[3]
imental data also attests to the usefulness of HFIP as a
À
medium for synthetically useful reactions, such as C O
cleavage of oxiranes with O, N, or S nucleophiles under
neutral conditions,[6a] or in certain C C bond-forming trans-
À
formations such as arene p-methoxybenzylation,[3a] Diels–
Alder cycloaddition,[6a] or cationic cyclization.[15]
As was demonstrated in previous studies by our group, the
interaction of b-chloroalkyl arylthioethers with Lewis acids
leads to the formation of electrophilic species capable of
reacting with a number of silicon-capped p donors, to give the
respective products of b-arylthioalkylation (Scheme 1,
[Eq. (1)]).[5a]
Herein[4], we show that a similar approach can be
extended well beyond the scope of purely solvolytic reactions,
and might also be applicable for elaboration of the Lewis acid
free protocols for a diverse set of reactions, such as b-
arylthioalkylation of p donors,[5a] Hosomi–Sakurai acetal
allylation,[5b] the Mukaiyama aldol reaction,[5c] and Sakurai–
Mukaiyama conjugate additions.[5d–f]
Since the use of HFIP as a reaction medium was found to
be a factor of crucial importance for performing these
transformations (see below), it is appropriate to briefly
discuss the specific physical properties of HFIP and some
aspects of its preparative utilization relevant to this sub-
ject.[6a,b]
Scheme 1. b-Arylthioalkylation of Si-capped p donors. TMS=trimethyl-
silyl; HFIP=1,1,1,3,3,3-hexafluoro-2-propanol.
HFIP is well-known as a polar solvent[7] of high ionizing
power[8] and low nucleophilicity.[9] Notably, in sharp contrast
to the majority of other polar solvents, HFIP is capable of
strongly solvating anions but not cations, as was deduced from
both conductometric studies[10] and gas-phase determination
of the anion-binding energy.[11] HFIP also serves as a powerful
hydrogen-bond donor, as was demonstrated not only by the
spectral studies and calorimetric measurements,[12] but also by
the isolation of extremely stable complexes with a number of
nucleophilic species.[13]
Owing to the low nucleophilicity and highly ionizing
properties of HFIP, complemented by its capacity to effec-
tively solvate chloride anions, it might be anticipated that this
solvent could be useful both as a medium and as a Lewis acid
substitute in this reaction. The validity of these expectations
was fully confirmed for the model reaction of the adduct 1
(formed in situ by the interaction of styrene with p-chloro-
phenylsulfenyl chloride) with 2-silyloxypropene 2. The intro-
duction of an excess of HFIP to a solution of these
components in CH2Cl2 at 208C resulted in a rapid, slightly
exothermic reaction, furnishing the b-arylthioalkylation
adduct 3 as the sole product, isolated in 88% yield
(Scheme 1, [Eq. (2)]).
The above properties of HFIP make it an optimal solvent
for the generation of persistent carbocations and cationic
radicals from various precursors and under a fairly diverse set
of reaction conditions.[14] A considerable amount of exper-
Further experiments revealed that a similar procedure is
also applicable for the preparation of a wide range of
compounds analogous to adduct 3, following the route
represented in Scheme 1, [Eq. (1)].[16] Attempts to substitute
HFIP for TFE as the reaction medium resulted in a dramatic
decrease in the yields of the target products, owing to a side
reaction leading to the formation of solvoadducts, such as
ArSCH2CH(Ph)OCH2CF3. This side product was prepared in
nearly quantitative yield upon the treatment of 1 in a CH2Cl2/
TFE mixture (1:4) with a hindered base, 2,6-di-tert-butylpyr-
[*] M. O. Ratnikov, V. V. Tumanov, Prof. Dr. W. A. Smit
N. D. Zelinsky Institute of Organic Chemistry
47 Leninsky Prospect, Moscow, Russia, 119991
Fax: (+7)495-135-53-28
E-mail: smt@ioc.ac.ru
[**] We would like to thank Prof. H. Mayr for helpful discussions which
stimulated our interest in research in this field. Financial support
from RFBR (project No 06-03-33016) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803927.
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Table 1: HFIP-mediated reactions of acetals and carbonyl compounds
with p donors.
idine, and was shown to be totally unreactive toward the
selected p donors, even after prolonged heating in the
CH2Cl2/TFE medium. Notably, in HFIP medium, no com-
peting formation of the respective solvoadducts occurred.
We then investigated the applicability of HFIP as both
medium and activator for a number of classical reactions of
carbonyl compounds and their acetals, as shown in Table 1
[Eqs. (3–5)], which are carried out using Lewis acid cata-
lysts.[5b–e] Pleasingly, all of these reactions proceeded in HFIP/
CH2Cl2, under mild conditions without any catalysts, to give
the respective adducts in good-to-excellent yields. These
results are summarized in Table 1.
The adducts listed were prepared earlier using various
Lewis acids and a range of diverse preparative procedures.[1,5f]
It is therefore remarkable that, regardless of the nature of the
reaction and identity of the reactants, the preparation of all of
these adducts was achieved under essentially identical con-
ditions, by merely adding a nucleophile into the solution of
the electrophilic component in a CH2Cl2/HFIP mixture (1:4)
at ambient temperature. Reaction progress was monitored by
thin-layer chromatography (for the preparation of 12, 13, 22,
and 34), GC/MS (for 14 and 28–33), or 1H NMR spectroscopy
(for 10, 11, and 19–21), which reveal that, as a rule, complete
conversion of the starting electrophile occurred in several
minutes. The simple workup required no special treatments
and practically pure products could be obtained after removal
of the solvent and excess of nucleophile.
Entry
1
Substrate
Nu
Product
Yield
83%
2
3
4
52%[a]
69%
7
7
82%
(d.r. 1:1)
4
5
5
61%
6
7
8
51%[a]
88%
15
15
8
Hosomi-Sakurai acetal allylation[5b] proceeded smoothly
for dimethyl acetals of aliphatic and aromatic aldehydes
(Table 1, entries 1–3) as well as for cycloalkanone acetals
(Table 1, entry 5). The similar reaction of silyl enol ethers
resulted in the formation of an aldol-like product. The use of
prochiral nucleophile 9 in this reaction afforded the respec-
tive adduct 13 as a 1:1 mixture of diastereoisomers (Table 1,
entry 4). Reactions of aldehydes, both aliphatic and aromatic,
with trimethylsilyl-protected p donors (Mukaiyama aldol
reaction[5c]), regardless of the nature of the latter, is accom-
panied by the transfer of the trimethylsilyl group to give
either b-trimethylsiloxycarbonyl compounds (Table 1,
entries 6, 8, and 9) or silylated homoallyl alcohols (Table 1,
entry 7). Very little diastereoselectivity was detected in the
reaction of aldehydes 15 and 16 with silyloxycyclopentene
(Table 1, entries 8 and 9). Both cyclic and acyclic conjugated
ketones reacted with various p donors under the aforemen-
tioned conditions, furnishing the corresponding adducts in
good yields (Table 1, entries 10–14). HFIP also promoted
reactions with acrylate acceptors (Table 1, entries 15 and 16).
No transfer of the trimethylsilyl group occurred in these
conjugate addition reactions.
The above results represent proof-of-principle evidence
attesting to the promise of the utilizing HFIP as a “magic”
solvent to facilitate a range of Friedel–Crafts-type reactions,
using covalent reagents in the absence of a Lewis acid
catalyst, under essentially neutral conditions. Indeed, HFIP
was shown to be a competent substitute for the standard
Lewis acid catalysts in promoting two major types of electro-
philic additions to p donors; namely, the dissociative type,
which involves the removal of the nucleofuge from the
covalent precursors (acetals or b-arylthioalkyl ethers), and
76%
(d.r. 1.1:1)
93%
(d.r. 1.5:1)
9
18
10
89%
11
12
23
23
17
8
53%[a]
83%
13
14
26
18
26
80%
24
25
77%[a]
15
16
61%
25%[a]
[a] The low yield of the adduct is due to the occurrence of side reactions
(see Scheme 2).
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the associative type, which requires the activation of the
carbonyl compounds (aldehydes or a,b-unsaturated enones or
enoates).
The observed phenomenon of a remarkably high proto-
=
nating capacity of HFIP towards C C bonds seems to be
rather nontrivial and, as such, it merits further in-depth
investigation.
It may be assumed that this unprecedented activity
pattern of HFIP is primarily a result of its well-documented
capacity to serve as a very efficient hydrogen-bond donor
towards a number of acceptors.[12,13] It is tempting to speculate
that the transformation of the starting covalent compounds
into the polarized, H-bonded species[17] resulted in a sub-
stantial enhancement of their activity as electrophilic
reagents. Furthermore, the interaction of these reagents
with the covalent p donors should be facilitated by efficient
stabilization of the polar transition state by the solvation
effects of HFIP, as a highly polar and ionizing solvent.
In the course of this study we came across a rather
unexpected reactivity profile of HFIP. Hitherto, HFIP has
been known to be an H-bond provider for heteroatomic
functional groups.[6a] We disclosed that a similar donation
In summary, the concept, advanced and validated in the
presented study, has potential applicability in a number of
other synthetically useful reactions, which are conventionally
Lewis acid mediated procedures. Our current studies are
aimed at the evaluation of the scope and preparative
ramifications of the described novel Lewis acid free protocol
for the electrophilic alkylation of various p donors.
Received: August 8, 2008
Published online: November 3, 2008
Keywords: electrophilic addition · hydrogen bonds · Lewis acids ·
silanes · solvent effects
.
=
toward a nucleophilic C C bond may result in a consumption
[1] M. Santelli, J.-M. Pons, Lewis Acids and Selectivity in Organic
Chemistry, CRC, Boca Raton, 1996, p. 334; see also A. D.
Dilman, S. L. Ioffe, Chem. Rev. 2003, 103, 733.
of the p nucleophiles because of the competing side reactions,
namely, protodesilylation (Scheme 2, path A) and electro-
[2] For a discussion of the basic concepts of this approach, see:
a) S. S. Minegishi, S. Kobayashi, H. Mayr, J. Am. Chem. Soc.
2004, 126, 5174; b) B. Denegri, S. Minegishi, O. Kronja, H. Mayr,
Angew. Chem. 2004, 116, 2353; Angew. Chem. Int. Ed. 2004, 43,
2302; c) H. Mayr, B. Kempf, A. F. Ofial, Acc. Chem. Res. 2003,
36, 66.
[3] a) M. Hofmann, N. Hampel, T. Kanzian, H. Mayr, Angew. Chem.
2004, 116, 5518; Angew. Chem. Int. Ed. 2004, 43, 5402; b) M.
Westermaier, H. Mayr, Org. Lett. 2006, 8, 4791.
[4] Preliminary results of this study were presented at ESOC-2007,
Dublin, Ireland (Book of Abstracts, 342).
[5] a) W. A. Smit, M. I. Lazareva, I. P. Smolyakova, R. Caple, Russ.
Chem. Bull. Int. Ed. 2001, 50, 1949; b) A. Hosomi, Acc. Chem.
Res. 1988, 21, 200; c) T. Mukaiyama, Angew. Chem. 1977, 89,
858; Angew. Chem. Int. Ed. Engl. 1977, 16, 817; d) T.
Mukaiyama, M. Murakami, Synthesis 1987, 1043; e) H.
Hosomi, H. Sakurai, J. Am. Chem. Soc. 1977, 99, 1673; f) K.
Narasaka, K. Soai, T. Mukaiyama, Chem. Lett. 1974, 1223; T.
Mukaiyama, Y. Sagawa, S. Kobayashi, Chem. Lett. 1986, 1017;
g) P. Perlmutter, Conjugate Addition Reactions in Organic
Synthesis, Pergamon, Oxford, 1992, p. 373.
Scheme 2. The protonation of a carbon–carbon double bond by HFIP,
and subsequent desilylation (A) or electrophilic alkylation (B).
[6] For a review, see: a) J.-P. Bꢀguꢀ, D. Bonnet-Delpon, B. Crousse,
Synlett 2004, 18; b) I. A. Shuklov, N. V. Dubrovina, A. Bꢁrner,
Synthesis 2007, 2925.
[7] As was calculated from the solvatochromic measurements, the
empirical parameter of solvent polarity, ETN = 1.068 for HFIP.
Among 360 solvents tested, HFIP is the sole solvent outside of
the range of the scale defined by the limiting values ETN = 0 (for
Me4Si) and ETN = 1 (for water), see: C. Reichardt, Chem. Rev.
1994, 94, 2319.
philic alkylation of a second molecule of the p donor
(Scheme 2, path B), with the formation of dimeric products.
The dimeric adducts 35 and 36 were isolated as by-products in
significant yields in the reactions of acetal 4 with methallylsi-
lane 8 (Table 1, entry 2), and of acrylate 25 with enolate 27
(Table 1, entry 16), respectively. The formation of products
resulting from path A (isobutylene from 8 and acetophenone
1
from 27) was ascertained by H NMR spectroscopy of the
[8] From the data of solvolytic studies, the ionizing power Y for
HFIP is 3.61 (cf. Y= 3.04 for HCOOH), see: F. L. Schadt, T. W.
Bentley, P. von R. Schleyer, J. Am. Chem. Soc. 1976, 98, 7667.
[9] According to recent estimates by Mayr and co-workers, the
magnitude of the nucleophilicity parameter N ꢀ À2.4 for HFIP,
which is much lower than N values for the majority of other polar
solvents and synthetically useful p donors (see Refs. [2a, 3a]).
[10] M. A. Matesich, J. Knoefel, H. Feldman, D. F. Evans, J. Phys.
Chem. 1973, 77, 366.
[11] G. W. Caldwell, J. A. Massuchi, M. G. Ikonomou, Org. Mass
Spectrom. 1989, 24, 8.
[12] HFIP was shown to be a much stronger hydrogen-bond donor
than phenol towards various acceptors, regardless of the
reaction mixtures.
Monitoring of the solutions of Si-capped nucleophiles, in a
CD2Cl2/HFIP mixture at room temperature, by 1H NMR
spectroscopy revealed that their half-lives in these conditions
vary from several minutes (for 17, 26, and 27) up to several
hours (for the less-reactive 7 and 8) and the ratio of
desilylated (path A) and dimeric (path B) products depends
on the nature of the p nucleophile. The ease with which these
reactions occur is especially surprising in view of the low
acidity of HFIP (pKa = 9.3, compared to pKa = 4.8 for acetic
acid).
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experimental parameters used to measure this property (calo-
maximum (Dlmax = 54–60 nm) was detected for the methoxycar-
benium ion derived from 5 following treatment with boron
trihalide or a structurally similar cationic complex of 16 with
boron trihalide (c.f. data in H. Mayr, G. Gorath, J. Am. Chem.
Soc. 1995, 117, 7862). The results of the comparative studies of
1H and 13C NMR spectra for the solutions of 5 or 16 in neat
CD2Cl2 and a CD2Cl2/HFIP (1:10) mixture revealed deshielding
effects both for 1H (Dd = 0.2–0.4 ppm for all protons of 5 and 16,
except CHO in 16, which underwent an upfield shift, Dd =
0.15 ppm) and 13C signals (Dd = 3.0 ppm for CH(OMe)2 in 5
and 4.8 ppm for CHO in 16). Although the cause of these effects
is far from clear, it is noteworthy that the transformation of 5 or
16 into the respective cationic derivatives resulted in much more
dramatic changes in the NMR spectra (see the data in the
reference cited above). A noticeable trend was observed upon
the comparison of 13C NMR spectra of 23 in neat CD2Cl2 and a
CD2Cl2/HFIP (1:5) mixture. The addition of HFIP resulted in a
substantial downfield shift of C1 and C3 signals (Dd = 7.0 and
5.7 ppm, respectively) and an upfield shift for the C2 signal
(Dd = 1.1 ppm). Similar, but substantially more strongly
expressed, effects were observed earlier for the complexes of
conjugated carbonyl compounds with various Lewis acids (for
example, Dd = 8.3, À3.3, and 26.1 ppm for C1, C2, and C3,
respectively, for the crotonaldehyde–boron trifluoride complex,
see: R. F. Childs, D. L. Mulholland, A. Nixon, Can. J. Chem.
1982, 60, 801).
À
rimetric data, shift in O H-stretching frequency, hydrogen-bond
chemical shifts; see K. F. Purcell, J. A. Stikeleather, S. D. Brunk,
J. Am. Chem. Soc. 1969, 91, 4019). Calculations based upon the
Kamlet-Taft generalized solvatochromic equation point to the
much higher hydrogen-bond-donor ability of HFIP (a = 1.96)
than such proton donors as methanol (a = 0.93) or acetic acid
(a = 1.09); see: M. J. Kamlet, J.-L. Abboud, M. H. Abrham,
R. W. Taft, J. Org. Chem. 1983, 48, 2877.
[13] For example, a 1:1 complex of HFIP with THF was stable
enough to tolerate distillation at 1008C; recovery of the alcohol
from this complex required its treatment with 20% oleum; see:
W. J. Middleton, R. V. Lindsey, Jr., J. Am. Chem. Soc. 1964, 86,
4948.
[14] L. Eberson, M. P. Hartshorn, O. Persson, F. Radner, Chem.
Commun. 1996, 2105, and references therein.
[15] P. H. Ferber, G. E. Gream, Aust. J. Chem. 1981, 34, 2217.
[16] A full account of the studies, dealing with elaboration of the
preparative methods, will be published shortly.
[17] Studies were carried out, aimed at the evaluation of the effects of
HFIP on the parameters of UV/Vis and/or NMR spectroscopy of
benzaldehyde acetal 5, p-methoxybenzaldehyde 16, or cyclo-
pentenone 23. UV/Vis spectroscopy of solutions of 5 or 16 in
HFIP did not disclose any substantial changes indicative of the
formation of ionized species. There was a very small shift of the
maximum, as compared to the basic spectra in CH2Cl2 (Dlmax
=
8–9 nm), whereas the appearance of an intense red-shifted
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