Pyridine-directed organolithium addition to an enol ether

Article abstract of DOI:10.1002/adsc.201000495

A previously reported anionic rearrangement of benzyl 2-pyridyl ethers can now be accessed by a distinct and unusual mechanism: addition of alkyllithium reagents to α-(2-pyridyloxy)-styrene triggers an anionic rearrangement to afford tertiary pyridyl carbinols. The process is explained by invoking a contra-electronic, pyridine-directed carbolithiation of the enol ether π-system. Copyright

Full text of DOI:10.1002/adsc.201000495

UPDATES
DOI: 10.1002/adsc.201000495
Pyridine-Directed Organolithium Addition to an Enol Ether
Jingyue Yanga and Gregory B. Dudleya,*
a
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, U.S.A.
Fax : (+1)-850-644-8281; phone: (+1)-850-644-2333; e-mail: gdudley@chem.fsu.edu
Received: June 25, 2010; Revised: October 10, 2010; Published online: December 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000495.
Abstract: A previously reported anionic rearrange-
ment of benzyl 2-pyridyl ethers can now be ac-
cessed by a distinct and unusual mechanism: addi-
tion of alkyllithium reagents to a-(2-pyridyloxy)-
styrene triggers an anionic rearrangement to afford
tertiary pyridyl carbinols. The process is explained
by invoking a contra-electronic, pyridine-directed
carbolithiation of the enol ether p-system.
The observation is as follows: addition of 1.3 equiv-
alents of n-butyllithium to a solution of a-pyridyloxy-
styrene 1 in THF provides an 84% yield of tertiary
pyridyl carbinol 2a [Eq. (1)]. To explain this, one
must account for (i) C C bond formation at the b-
carbon of the enol ether, and (ii) migration of the pyr-
idyl group from oxygen to the a-carbon.
ꢀ
Given that directed metallation of benzyl pyridyl
ethers triggers an anionic rearrangement to give terti-
ary pyridyl carbinols [e.g., Eq (2)],[6] the simplest ex-
planation[7] involves carbolithiation of enol ether 1
{1![Ia], Eq. (1)}.
Keywords: anionic rearrangement; contra-electron-
ic carbolithiation; electron transfer; enol ethers;
pyridine; reactive intermediates
The presumed carbolithiation (1![Ia]) is the first
example to the best of our knowledge of the enol
ether p-system reacting with an electron-rich (nucleo-
philic) reagent.[1] Moreoever, the nucleophilic attack
In this update, we present indirect evidence of a occurs at the more electron-rich terminus of the enol
unique and unexpected carbolithiation of an enol ether.[8,9]
ether [pyridyl ether 1, Eq (1)],[1] in which organolithi-
The contra-electronic organolithium addition to 1
um nucleophiles[2] add inter-molecularly across the proceeded to the exclusion of alternative potential re-
electron-rich alkene in a manner opposite to the action pathways [Eq (3) and Eq. (4)]. Namely, pyri-
normal polarization preferences of an enol ether dine-directed carbolithiation could be envisioned to
(contra-electronically).[3] This observation provides in- occur in alignment with the polarization of enol 1, but
sight into the unusual behavior of highly reactive spe- the expected products of such a process [4 and 5, Eq.
cies[4,5] and reveals an alternative entry into our re- (3), arising from b-elimination of the lithium alkox-
ported anionic rearrangement of benzyloxypyridines ide] could not be detected. Another “reasonable” re-
[Eq (2)].[6]
action process would be for the alkyllithium reagent
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Pyridine-Directed Organolithium Addition to an Enol Ether
the 2-position of pyridine. Likewise and as expected,
a-methoxystyrene[11] (13) is completely unreactive
under these conditions [Eq. (7)].
These data, coupled with our earlier report [cf. Eq.
(2)],[6] support the reaction pathway outlined in Eq.
(1): pyridine-directed addition of n-butyllithium to
enol ether 1 triggers anionic rearrangement of the re-
sulting a-(2-pyridyloxy)benzyllithium, [Ia]. The ques-
tion is: Why does the apparently contra-electronic ad-
to attack the electron-deficient pyridine ring [addition dition pathway predominate? Given that addition to
at C-2, followed by elimination of the enolate, Eq. enol ether 1 occurs, why does the n-butyl group
(4)]. Although nucleophilic aromatic substitutions at attack the b-carbon and not the a-carbon, which
the 2-position of pyridine are well known, no such would generate a primary organolithium intermediate
products are observed in this process.
{[II], Eq. (3)} and trigger facile b-elimination of
The central importance of the 2-pyridyloxy group lithio-acetophenone?
in directing the alkyllithium addition to 1 is supported
In considering reasonable mechanisms for this un-
by the control experiments shown in Eq. (5), Eq. (6) usual addition/rearrangement sequence (1!2), we
and Eq. (7). Although carbolithiation of styrene de- favour a process in which carbolithiation (1![I],
rivatives is known,[10] this is not an example of a Scheme 1) leads directly into the previously reported
phenyl substitutent overriding the normal reactivity anionic rearrangement[6] ([I]!2). To explain the appa-
profile of an enol ether. The 2-pyridyloxy group, not rently contra-electronic carbanion addition, it is help-
the phenyl, controls the regioselectivity of the pro- ful to invoke the electron-transfer properties of highly
cess: n-butyllithium reacts with stilbene derivative 8 reactive organolithium nucleophiles.[12] Precomplexa-
to produce tertiary alcohol 9 [i.e., by the addition/re- tion between the lithium reagent and the pyridine ni-
arrangement process, cf. Eq. (1)] to the exclusion of trogen ([IV], Scheme 1) produces the proximity
10, the expected product of regioisomeric addition effect[13] necessary for directed carbolithiation, which
and elimination [cf. Eq. (3)]. 4-Pyridyloxy analogue is thermodynamically favourable.[14] We postulate that
11, in which pyridine complexation does not produce carbolithiation of enol ether 1 may involve rate-deter-
a proximity effect, does not undergo the same addi- mining electron-transfer to produce a transient enol
tion/rearrangement process [Eq. (6)]. Instead, starting ether radical anion [V], followed almost instantane-
material is recovered along with small amounts of ously by radical recombination to [I]. The observed
products derived from addition of n-butyllithium to regioselectivity would then be consistent with radical
recombination ([V]![I])[15] guided by sterics and/or
proximity effects. Pyridyloxylithium [I] undergoes
anionic rearrangement, as described previously.[6]
a-Pyridyloxystyrene 1 was prepared as shown in
Scheme 2. Oxidation of monoglyme and addition of
phenylmagnesium bromide to the resulting aldehyde
provided benzyl alcohol derivative 15, which was con-
verted into pyridyl ether 16 using nucleophilic aro-
matic substitution of 2-chloropyridine.[16] LDA-pro-
moted elimination of 2-methoxyethanol from 16[17]
provides a-pyridyloxystyrene 1.
A brief screening of organolithium nucleophiles re-
vealed a correlation between organolithium reactivity
and reaction efficiency (Table 1). Methyllithium react-
ed with 1 along the presumed carbolithiation and
anionic rearrangement pathway to give 2b in 84%
yield (entry 1), which is comparable to the 84% yield
observed in the reaction of 1 with n-butyllithium
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Jingyue Yang and Gregory B. Dudley
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Scheme 1. Postulated mechanism: alkyllithium addition (1![I]) triggers an anionic rearrangement[6] ([I]!2).
Scheme 2. Preparation of a-(2-pyridyloxy)styrene (1).
(entry 3). Methylmagnesium bromide, on the other
Table 1. Scope of the nucleophilic addition to a-pyridyloxy-
styrene 1.[a]
hand, was unreactive under similar conditions
(entry 2). The more reactive secondary and tertiary
butyllithium isomers produced higher yields of terti-
ary alcohol product:[18] s-BuLi, 86%, entry 4; t-BuLi,
97%, entry 5. Reaction of 1 with phenyllithium, which
is less nucleophilic than most alkyllithium reagents,
gave rise to alcohol 2e in a relatively modest 75%
yield (entry 6), and the hydride reagent produced a
mixture of products including acetophenone (6),
which presumably arises from hydride addition to pyr-
idine at C-2 [cf. Eq. (4)].
ACHTUNGTRENNUNG
In summary, organolithium addition to an enol
ether has been observed within the context of a previ-
ously reported anionic rearrangement of lithiated
benzyl pyridyl ethers.[6] Specifically, pyridine-directed,
contra-electronic addition of reactive alkyllithium re-
agents to a-(2-pyridyloxy)-styrene (1) triggers the
anionic rearrangement to provide tertiary pyridyl car-
binols. We postulate a mechanism in which the orga-
nolithium reagent attacks 1 in a dipole-opposed (con-
traelectronic) fashion, perhaps via a single electron
transfer mechanism, with the carbanionic moiety re-
acting at the more electron-rich terminus of the enol
ether. Further exploration of this novel reaction path-
way will be reported in due course.
[a]
Styrene 1 in THF treated with organometallic reagent at
room temperature under nitrogen.
[b]
[c]
No reaction.
1H NMR spectroscopic analysis of the crude reaction
mixture revealed a complex mixture of products, includ-
ing starting material and acetophenone [cf. Eq (4)].
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Pyridine-Directed Organolithium Addition to an Enol Ether
Clayden, M. Donnard. J. Lefranc, A. Minassi and D. J.
Tetlow, J. Am. Chem. Soc. 2010, 132, 6624 (vinyl ureas).
[2] a) Organolithium compounds/solvated electrons, (Ed.:
N. M. Alpatova), Springer-Verlag, New York, Berlin,
1987; b) The Chemistry of Organolithium Compounds,
(Ed.: B. J. Wakefield), Pergamon Press, Oxford, New
York, 1974.
Experimental Section
a-Pyridyloxystyrene 1 (20 mg, 1 equiv.) was dissolved in
1 mL of dry THF under nitrogen at room temperature and
n-butyllithium (1.3 equiv.) was added dropwise. The reaction
mixture was stirred overnight (or until TLC analysis of the
reaction mixture showed complete consumption of the enol
ether), then diluted with H2O (5 mL) and extracted with
EtOAc (4ꢁ5 mL). The combined organic extracts were
washed with brine, dried (Na2SO4), filtered, concentrated
under vacuum, and purified on silica gel to obtain 1-phenyl-
1-pyridylhexanol (2a); yield: 84%.
[3] The Chemistry of Alkenes, (Ed.: S. Patai), Interscience
Publishers, London, New York, 1964, Vol. 1.
[4] Carbolithiation of ethylene, see: a) P. D. Bartlett, S.
Friedman, M. Stiles, J. Am. Chem. Soc. 1953, 75, 1771;
b) P. D. Bartlett, S. J. Tauber, W. P. Weber, J. Am.
Chem. Soc. 1969, 91, 6362.
Calculations were performed at the B3LYP 6-31+GACTHUNTGRNEUNG(d,p)
[5] Intramolecular carbolithiation (cyclization) reactions of
electron-rich alkenes are less unusual, although no less
noteworthy. For reviews, see: a) W. F. Bailey, T. V.
Ovaska, in: Advances in Detailed Reaction Mechanisms,
Vol. 3, (Ed.: J. M. Coxon), JAI Press, Greenwich, CT,
1994, pp 251–273; b) M. J. Mealy, W. F. Bailey, J. Orga-
nomet. Chem. 2002, 646, 59; c) J. Clayden, Organolithi-
ums: Selectivity for Synthesis Pergamon Press, New
York, 2002, pp 293–335; recent papers: d) W. F. Bailey,
X. L. Jiang, Tetrahedron 2005, 61, 3183; e) I. Coldham,
K. N. Price, R. E. Rathmell, Org. Biomol. Chem. 2003,
1, 2111.
level, for results, see Figure 1 and Figure 2.
Figure 1. Calculated p-bond polarization (in italics) and se-
lected net atomic charges (in bold) for 2-pyridyloxystyrenes
1, complex [IV], and a-methoxystyrene (13).
[6] J. Yang, G. B. Dudley, J. Org. Chem. 2009, 74, 7998.
[7] Ockhamꢂs (Occamꢂs) razor favours the simplest explan-
ation, but it is not an irrefutable principle of logic.
[8] Calculations at the B3LYP 6-31+GACTHNUTRGNEUNG(d,p) level suggest
that the pyridyloxy group, like the methoxy group, is
electron-releasing. Although the pyridyloxy group is a
weaker donor than methoxy, the majority (51.46%) of
the alkene p-electron density is localized near the b-
carbon of 1 (Figure 1). A similar pattern is calculated
for [IV], after complexation of the alkyllithium.
Figure 2. Relative energies calculated for [IV], [I], and
[VII].
[9] This unusual reaction would not be classified as an
“umpolung” process. The term “umpolung” (meaning,
“reversed polarity”) refers to an altered form of a
common functional group that displays reactivity oppo-
site to that of the normal pattern (e.g., lithiated 1,3-di-
thiane vs. aldehyde). In contrast, Eq. (1) represents a
rare example in which the unaltered functional group –
in this case, an enol ether – displays reactivity opposite
to the expected pattern. For a discussion on umpolung
reactivity strategies, see: D. J. Ager, in: Umpoled Syn-
thons: A Survey of Sources and Uses in Synthesis, (Ed.:
T. A. Hase), John Wiley & Sons, New York, 1987,
pp 19–72.
Acknowledgements
We thank the FSU Research Foundation (GAP Award) for
generous financial support and the FSU High Performance
Computing group for assistance with the calculations.
References
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enol ether has not been observed previously. For select-
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Jingyue Yang and Gregory B. Dudley
UPDATES
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[14] The relative energies of alkyllithium [IV], benzyllithi-
um [I], and lithium alkoxide [VII] were calculated at
[16] a) A. J. Serio Duggan, E. J. J. Grabowski, W. K. Russ,
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[17] Incidentally, this reaction was originally designed and
performed as a competition experiment between E2
elimination and the anionic rearrangement described
previously (ref.[6]). It shows, not surprisingly, that elimi-
nation of the lithium alkoxide is faster than the anionic
rearrangement [cf. Eq. (2)]. In one compromised run
of this competition experiment, we used LDA that was
the B3LYP 6-31+GACHTNUGTRNEUNG(d,p) level (R=n-Bu, Figure 2).
Both the addition and the rearrangement appear to be
highly exothermic. We thank a referee for suggesting
that we examine the energetics of the conversion of
[IV]![I]!
G
contaminated with a small amount n-butyllithium,
which resulted in isolation of 2a and identification of
the contra-electronic alkyllithium addition reaction.
[18] Similar reactivity trends have been documented for
other directed carbolithiation reactions; see refs.[1a,1d,4]
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Adv. Synth. Catal. 2010, 352, 3438 – 3442