[1,2]-Anionic rearrangement of 2-benzyloxypyridine and related pyridyl ethers

Article abstract of DOI:10.1021/jo901707x

(Chemical Equation Presented) An anionic rearrangement of 2-benzyloxypyridine is described. Pyridine-directed metalation of the benzylic carbon leads to 1,2-migration of pyridine via a postulated associative mechanism (addition/elimination). Several aryl pyridyl carbinols were obtained in high yields. A formal synthesis of carbinoxamine, an antihistamine drug used for the treatment of seasonal allergies and hay fever, emerges from this methodology.

Full text of DOI:10.1021/jo901707x

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involving carbon-oxygen-bond homolysis and recombination
[1,2]-Anionic Rearrangement of 2-Benzyloxypyridine
and Related Pyridyl Ethers
of the resulting pair of intermediate radicals.4 The [1,2]-Wittig
process provides insight into the reactivity profile of reactive
carbanion intermediates, but its value in synthesis5 is limited due
to difficulties associated with guiding complex molecular systems
along the high-energy radical reaction pathway.
Jingyue Yang and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State
University, Tallahassee, Florida 32306-4390
SCHEME 1. Representative [1,2]-Anionic Rearrangements
gdudley@chem.fsu.edu
Received August 5, 2009
In the [1,2]-Brook rearrangement,6 it is a silyl group that
migrates between the carbinol center to the adjacent oxygen
atom. Silyl migration is reversible (see the retro-Brook7
reaction) and likely proceeds via a pentavalent silicate inter-
mediate (Scheme 1B). This reaction is enjoying renewed
interest, in part due to acylsilane methodologies that produce
R-silyl alcohol substrates for the [1,2]-Brook reaction.8
The [1,2]-anionic rearrangement of 2-alkoxypyridines
(Scheme 1C) was identified while studying the synthetic chem-
istry of 2-benzyloxypyridine (1a, Scheme 2)9 as part of our
interest in developing electrophilic reagents for the synthesis of
arylmethyl ethers and esters.10 We had envisioned making
derivatives of 1a via directed metalation using the complex-
induced proximity effect (CIPE),11 followed by trapping with
electrophiles (1a f 4 f 5, Scheme 2, not observed). Instead,
prior to addition of the electrophile, we observed an unex-
pected product: phenyl(2-pyridyl)methanol (2a, Scheme 2).
Rearrangement of benzyllithium 4 accounts for the forma-
tion of R-pyridyl alcohol 2a. The mechanism likely involves an
associative process, akin to the Brook pathway, in which the
An anionic rearrangement of 2-benzyloxypyridine is de-
scribed. Pyridine-directed metalation of the benzylic car-
bon leads to 1,2-migration of pyridine via a postulated
associative mechanism (addition/elimination). Several
aryl pyridyl carbinols were obtained in high yields. A
formal synthesis of carbinoxamine, an antihistamine drug
used for the treatment of seasonal allergies and hay fever,
emerges from this methodology.
[1,2]-Anionic rearrangements such as those pioneered by
Wittig1 and Brook2 are important tools for altering the
complexity of molecules at hand. Rearrangement reactions
interconvert pairs of structural isomers; this interconversion
is especially valuable if one of the two isomers is more
accessible than the other. Parallels can be drawn between
the Wittig and Brook reactions and the anionic rearrange-
ment of pyridyl ethers described herein (Scheme 1).
The [1,2]-Wittig rearrangement3 involves conversion of an R-
alkoxy-carbanion into a more stable oxyanion with concomitant
migration of the alkyl group (Scheme 1A). Experimental evi-
dence generally points to a stepwise, dissociative mechanism
(6) Reviews on the [1,2] Brook rearrangement: (a) Brook, A. G. Acc.
Chem. Res. 1974, 7, 77–84. (b) Brook, A. G.; Bassindale, A. G. Molecular
rearrangements of organosilicon compounds. In Rearrangements in Ground and
Excited States; de Mayo, P., Ed.; Academic Press: New York, 1980; Vol. 2, pp
149-227. (c) Jankowski, P.; Raubo, P.; Wicha, J. Synlett 1994, 985–992.
(7) West, R.; Lowe, R.; Stewart, H. F.; Wright, A. J. Am. Chem. Soc.
1971, 93, 282–283.
(1) Wittig, G.; Lohmann, L. Liebigs Ann. 1942, 550, 260–268.
(2) (a) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886–1889. (b) Brook,
A. G.; Warner, C. M.; McGriskin, M. E. J. Am. Chem. Soc. 1959, 81, 981–
983.
(8) Moser, W. H. Tetrahedron 2001, 57, 2065–2084.
(3) Reviews on the [1,2]-Wittig rearrangement: (a) Marshall, J. A. The
Wittig rearrangement. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 3, pp 975-1014. (b)
Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. 1997, 1275–1281.
(4) Lansbury, P. T.; Pattison, V. A.; Siler, J. D.; Bieber, J. B. J. Am. Chem.
Soc. 1966, 88, 78–84.
(5) (a) Giampietro, N. C.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc.
2009, 131, 12556–12557. (b) Bertrand, M. B.; Wolfe, J. P. Org. Lett. 2008, 8,
4661–4663. (c) Hameury, T.; Guillemont, J.; Van Hijfte, L.; Bellosta, V.;
Cossy, J. Synlett 2008, 2345–2347. (d) Tomooka, K.; Yamamoto, H.; Nakai,
T. Angew. Chem., Int. Ed. 2000, 39, 4500–4502. (e) Tomooka, K.; Kikuchi,
M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem., Int. Ed.
2000, 39, 4502–4505. (f) Schreiber, S. L.; Goulet, M. T.; Schulte, G. J. Am.
Chem. Soc. 1987, 109, 4718–4720.
(9) (a) Serio Duggan, A. J.; Grabowski, E. J. J.; Russ, W. K. Synthesis
1980, 573–575. (b) Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Org. Synth.
2007, 84, 295–305. (c) Lopez, S. S.; Dudley, G. B. Beilstein J. Org. Chem. 2008,
4, No. 44, doi:10.3762/bjoc.4.44.
(10) (a) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923–3927.
(b) Nwoye, B. O.; Dudley, G. B. Chem. Commun. 2007, 1436–1437. (c)
Tummatorn, J.; Albiniak, P. A.; Dudley, G. B. J. Org. Chem. 2007, 72, 8962–
8964. (d) Albiniak, P. A.; Amisial, S. M.; Dudley, G. B.; Hernandez, J. P.;
House, S. B.; Matthews, M. B.; Nwoye, B. O.; Reilly, M. K.; Tlais, S. F.
Synth. Commun. 2008, 38, 656–665. (e) Albiniak, P. A.; Dudley, G. B.
Tetrahedron Lett. 2007, 48, 8097–8100. (f) Tlais, S. F.; Lam, H.; House,
S. E.; Dudley, G. B. J. Org. Chem. 2009, 74, 1876–1885.
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7998 J. Org. Chem. 2009, 74, 7998–8000
Published on Web 09/17/2009
DOI: 10.1021/jo901707x
r
2009 American Chemical Society

Yang and Dudley
JOCNote
SCHEME 2. Discovery of the Anionic Rearrangement of 1a
TABLE 1. Optimization of the n-Butyllithium-Promoted [1,2]-Anionic
Rearrangement of 2-Benzyloxypyridine (1)
entry
n-BuLi
temp
recovery of 1aa
5-10%
yield of 2a
1
2
3
4
5
6
7
1.1 equiv
1.2 equiv
2.0 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.3 equiv
-78 °C to rt
-78 °C to rt
-78 °C to rt
-78 °C
nd
b
-
77%
ndc
nd
85%
nd
77%
b
-
42%
b
-60 °C
-
17%
-40 °C
b
migrating carbon atom transiently expands to a tetrahedral
(sp3) intermediate (cf. 6, Scheme 2) that is hypervalent relative
to the trigonal planar (sp2) ground state structure. Complexa-
tion between the pyridine nitrogen and the lithium ion is
maintained throughout the nucleophilic aromatic substution
(addition/elimination) of the electron-deficient pyridine ring.
Related [1,2]-anionic rearrangements of R-carbamoyloxy-car-
banions (from directed metalation of carbamates) are known,12
as is the [1,4]-migration of pyridine rings onto urea-derived
R-amino-carbanions.13
-60 °C
-
aEstimated by 1H NMR spectroscopy. bComplete consumption of 1a.
cSignificant decomposition was apparent in the TLC analysis of the
reaction mixture.
TABLE 2. Substituent Effects and an Alternative Set of Conditions for
Promoting the [1,2]-Anionic Rearrangement
R-Pyridyl alcohols (2) are of general interest in synthesis
and medicinal chemistry,14 and we wanted to gain access to
them via the [1,2]-anionic rearrangement pathway. To the
best of our knowledge, the [1,2]-anionic rearrangement of
2-alkoxypyridines has not been observed previously.15
Key experiments related to identifying optimal conditions
for the n-butyllithium-promoted rearrangement of 2-benzy-
loxypyridine are recounted in Table 1. The efficiency of the
reaction is highly sensitive to minor changes in the reaction
protocol. Full conversion requires a slight molar excess of n-
BuLi (1.2 equiv), but too much base is detrimental (cf. entries
1-3 and 7).16 When using specifically 1.2 equiv of n-BuLi, a
reaction temperature of -60 °C provides results superior to
when temperatures slightly higher or lower are employed (cf.
entries 4-6). Optimally, treatment of 2-benzyloxyridine (1a)
entry
Ar
R
yield of 1 base
temp
yield of 2
48%a (2b)
33%a (2c)
1
2
3
4
2-MeO-C6H4
4-MeO-C6H4
C6H5
H
90% (1b) n-BuLi -60 °C
92% (1c) n-BuLi -60 °C
H
Me 96% (1d) n-BuLi -60 °C to rt 24%b (2d)
95% (2d)
C6H5
Me 96% (1d) LDAc rt
aMass balance was recovered starting material (52% of 1b and 67% of
1a). bStarting material and undesired byproduct recovered. c1.3 equiv of
LDA employed.
in THF17 with 1.2 equiv of n-BuLi at -60 °C furnishes
phenyl(2-pyridyl)methanol (1a f 2a) in 85% yield (entry
5). The delicate balance of reaction conditions required for
optimal results is indicative of a complicated reaction path-
way. It appears that n-BuLi competitively metallates both
the substrate and the product.16
Changing the substrate from 2-benzyloxypyridine to related
derivatives changes the kinetic profile of the reaction; the
conditions described in entry 5 of Table 1 are not generalizable
(Table 2). For example, the reaction conversion drops signifi-
cantly for methoxy-substituted ethers 1b and 1c, likely due to
competing metalation pathways, although the yields of 2 based
on recovered starting material remain high (estimated >95%,
entries 1 and 2). R-Branching in 1d was detrimental in other
ways (entry 3): conversion to tertiary alcohol 2d was incom-
plete, and a new byproduct emerged, resulting from addition of
n-butyllithium to the pyridine ring.18
(12) (a) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935–1937.
(b) Zhang, P.; Gawley, R. E. J. Org. Chem. 1993, 58, 3223–3224. (c)
Worayuthakarn, R.; Boonya-udtayan, S.; Arom-oon, E.; Ploypradith, P.;
Ruchirawat, S.; Thasana, N. J. Org. Chem. 2008, 73, 7432–7435. (d)
Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.; Ruchirawat, S. Tetra-
hedron Lett. 2003, 44, 1019–1021.
(13) (a) Clayden, J.; Hennecke, U. Org. Lett. 2008, 10, 3567–3570. (b) For
related migrations of other arene rings, see: Clayden, J.; Farnaby, W.;
Grainger, D. M.; Hennecke, U.; Mancinelli, M.; Tetlow, D. J.; Hillier, I. H.;
Vincent, M. A. J. Am. Chem. Soc. 2009, 131, 3410–3411.
(14) For recent studies into the medicinal chemistry of R-pyridyl alcohols
(2-pyridinemethanol derivatives), see: Ducharme, Y.; Friesen, R. R.; Blouin,
^ ꢀ
ꢀ
ꢀ
M.; Cote, B.; Dube, D.; Ethier, D.; Frenette, R.; Laliberte, F.; Mancini, J. A.;
Masson, P.; Styhler, A.; Young, R. N.; Girard, Y. Bioorg. Med. Chem. Lett.
2003, 13, 1923–1926.
(15) (a) Anionic rearrangement of 4-benzyloxypyridine was noted during
studies on the directed metalation of pyridine rings: LaMunyon, D. H.; , The
synthetic utility of methoxypyridines. M.S. Thesis, Utah State University, Logan,
UT, 1989. We thank Professor Daniel L. Comins (now at North Carolina State
University) for alerting us to this work. (b) For recent developments and leading
references into the directed metalation of pyridines, as opposed to metalations
directed by pyridine that are the focus of the present study, see: Ondachi, P. W.;
Comins, D. L. Tetrahedron Lett. 2008, 49, 569–572.
Rather than attempt to reoptimize the reaction protocol
for each substrate (1 f 2) individually, a unified set of
(18) The byproduct was determined to be 2-butyl-6-(1-phenylethoxy)-
pyridine (shown below), from addition of n-butyllithium to the pyridine ring
followed by autoxidation.
(16) Deuterium is incorporated to a minor extent into the product alcohol
(at the carbinol carbon) when the reaction is quenched with MeOD. Thus, in
situ metalation of the product must be occurring, which consumes
n-butyllithium and explains the need for a precise excess of n-butyllithium
for optimal results. Further mechanistic experiments are in progress.
(17) A brief screening of other solvents and/or cosolvents;Et2O, to-
luene, hexane, HMPA, DMPU;failed to identify a superior option.
J. Org. Chem. Vol. 74, No. 20, 2009 7999

Yang and Dudley
JOCNote
TABLE 3. Scope and Limitations of the LDA-Promoted [1,2]-Anionic
Rearrangement of Arylalkoxypyridines
SCHEME 3. Synthesis of Carbinoxamine
entry
Ar
C6H5
2-MeO-C6H4
4-MeO-C6H4
4-CF3-C6H4
4-Cl-C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
R
yield of 1
yield of 2
1
2
3
4
5
6
7
8
9
10
H
H
H
H
95% (1a)
90% (1b)
92% (1c)
75% (1e)
93% (1f)
96% (1d)
96% (1g)
63% (1h)
57% (1i)
99% (1j)
98% (2a)
99% (2b)
99% (2c)
0%
70% (2f)
95% (2d)
86%a (2g)
20%a (2h)
0%a
the resolution of which is accomplished with use of
d-tartaric acid.21,22 Carbinoxamine is an antihistamine drug
(histamine H1 antagonist) used for the treatment of seasonal
allergies and hay fever.23
H
Me
Et
Cyb
t-Bu
Ph
In conclusion, a [1,2]-anionic rearrangement of 2-benzy-
loxypyridine and its derivatives is reported. According to our
postulated mechanism, pyridine-directed metalation at the
benzylic position triggers an intramolecular nucleophilic
aromatic substitution reaction (addition/elimination) via
an intermediate spiroepoxide (6, Scheme 2). This new dis-
covery provides a link between two disparate reaction path-
ways: the [1,2]-Wittig rearrangement (in which arene
migration is rare) and the tandem directed metalation/
nucleophilic acyl substitution methodologies developed by
Snieckus, Gawley, Clayden, and others.12,13 Pyridyl ethers 1
are readily available from the corresponding alcohols and 2-
97% (2j)
aMass balance was recovered starting material (1). bCy = cyclohexyl
conditions with applicability across a broader range of
substrates was sought. Lithium diisopropylamide (LDA)
was the preferred chioce from among several19 potential
bases (Table 2, entry 4).
The reaction conditions involving LDA as the base instead
of n-BuLi were then used to explore the scope of the
rearrangement reaction (Table 3). The title substrate (2-
benzyloxypyridine, 1a) rearranged to 2a in 98% yield
(entry 1). Electron-donating groups on the benzene ring
are well tolerated: rearrangement of substrates with either
an o-methoxy (1b) or p-methoxy (1c) substituent proceeded
each in 99% yield (entries 2 and 3). The yield of 2 decreased
to 70% when the electron-withdrawing p-chloro substituent
was in place (1f f 2f, entry 5), and p-trifluoromethylated
substrate 1e decomposed under the reaction conditions
(entry 4).
For making tertiary R-pyridyl alcohols (entries 6-10), the
anionic rearrangement seems to depend on whether or not
metalation occurs. Sterics and kinetic acidity play an im-
portant role (entries 6-9); the reaction conversion of alkyl-
substituted pyridyl ethers and the isolated yield of the
R-pyridyl alcohol relate inversely to the size of the branching
substituent at the benzylic ether position. The relevance of
thermodynamic acidity can be inferred from entry 10;
2-(diphenylmethoxy)pyridine (1j), presumably the most
acidic of the substrates included in Table 3, furnishes tertiary
alcohol 2j in 97% yield.
chloropyridine.
A variety of secondary and tertiary
R-pyridyl alcohols were prepared in good to excellent yield.
Experimental Section
General Procedure: [1,2] Anionic Rearrangement. To a solu-
tion of LDA (1.3 equiv) in THF at room temperature was added
benzyloxypyridines 1 (100 mg, 1.0 equiv) in THF (1 mL)
dropwise, and the solution was stirred overnight or until all
the starting material was consumed. The resulting mixture was
diluted with H2O (5 mL) and extracted with EtOAc (4 Â 5 mL).
The combined organic extract was then washed with brine, dried
(Na2SO4), filtered, concentrated under vacuum, and purified on
silica gel to yield pyridine alcohols 2.
Acknowledgment. We thank the FSU Department of
Chemistry and Biochemistry and the FSU Research Foun-
dation (GAP Award) for support of this work, the NMR
Facility for spectroscopic support, and Dr. Umesh Goli for
assistance with mass spectrometry. We thank Professor
Daniel L. Comins (North Carolina State University) for
helpful insights and discussions.
R-Pyridyl alcohol (()-2f (see Table 3, entry 5) has been
converted in one step into (()-carbinoxamine20 (Scheme 3),
Supporting Information Available: Detailed experimental
procedures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) The bases included s-BuLi, t-BuLi, PhLi, BnLi, Ph3CLi, LDA,
LiHMDS, LiDMSO, LiN(OMe)Me, LiTMP, LiH, and alkyl Grignard
reagents. LDA was sufficiently reactive to promote the rearrangement, and
no competing addition to the pyridine ring was observed. After brief
optimization (not shown) and screening against multiple substrates, 1.3
equiv of LDA at rt emerged as the optimal set of conditions.
(20) Reddy, M. S.; Reddy, B. K.; Reddy, C. K.; Kumar, M. K.; Rajan,
S. T.; Eswaraiah, S.; Mummadi, V. Orient. J. Chem. 2007, 23, 691–694.
(21) Braker, W. British Patent 905 995, Sept. 19, 1962: Chem. Abstr. 1963,
58, 5644a.
(22) Enantioselective synthesis of carbinoxamine (6 steps, 24% yield):
Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675–5678.
(23) (a) Physicians’ Desk Reference, 60th ed.; Thompson PDR: Montvale,
NJ, 2006, pp 739-740. (b) Barouh, V.; Dall, H.; Patel, D.; Hite, G. J. Med. Chem.
1971, 14, 834–836.
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