Chichibabin-type direct alkylation of pyridyl alcohols with alkyl lithium reagents

Article abstract of DOI:10.1021/ol3024117

Direct C(6) alkylation of pyridyl alcohols can be achieved following an initial deprotonation of the hydroxy group. This transformation, which is believed to occur by a Chichibabin-type alkylation, avoids lateral deprotonation prior to pyridine ring alkylation and gives increased regioselectivity for C(6) over C(4) alkylation.

Full text of DOI:10.1021/ol3024117

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Chichibabin-Type Direct Alkylation of
Pyridyl Alcohols with Alkyl Lithium
Reagents
Jenna L. Jeffrey and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720,
United States
rsarpong@berkeley.edu
Received August 30, 2012
ABSTRACT
Direct C(6) alkylation of pyridyl alcohols can be achieved following an initial deprotonation of the hydroxy group. This transformation, which is
believed to occur by a Chichibabin-type alkylation, avoids lateral deprotonation prior to pyridine ring alkylation and gives increased
regioselectivity for C(6) over C(4) alkylation.
The pyridine heterocycle has emerged as an impor-
tant structural motif in complex natural products,1aꢀc
pharmaceuticals,1d,e and designer ligands for catalysis.2
The efficient preparation and study of pyridine-containing
molecules depends on general and direct methods for
the functionalization of pyridines and their correspond-
ing picoline derivatives. Not surprisingly, numerous ap-
proaches have been established for the direct C(2) and C(6)
functionalization of the pyridine nucleus,3 which include
the introduction of heteroatoms (e.g., the Chichibabin
reaction),4 as well as the installation of halogens and
carbon substituents (e.g., using deprotonation/functiona-
lization or the Minisci process).5,6 However, several unmet
challenges are inherent in the direct C(6) functionalization
of picoline derivatives (e.g., A, Figure 1).7 These challenges
include competing functionalization at C(4) (e.g., via C),
as well as lateral functionalization of the picoline group.
This latter competing process, which may be initiated by
deprotonation of the pseudobenzylic position (see E),7g,h
plagues many attempts to directly functionalize picoline
(1) (a) Holliday, B. J.; Mirkin, C. A. Angew. Chem., Int. Ed. 2001, 40,
2022–2043. (b) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627–646.
(c) Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459–2482.
(d) Henry, G. D. Tetrahedron 2004, 60, 6043–6061. (e) Uenishi, J.;
Takagi, T.; Ueno, T.; Hiraoka, T.; Yonemitsu, O.; Tsukube, H. Synlett
1999, 41–44.
(5) A recent review: Bull, J. A.; Mousseau, J. J.; Pelletier, G.;
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(2) (a) Conti, S.; Falorni, M.; Giacomelli, G.; Soccolini, F. Tetra-
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Pitacco, G.; Rigo, P.; Benedetti, F. J. Org. Chem. 2009, 74, 3547–3550.
(c) Lyle, M. P. A.; Narine, A. A.; Wilson, P. D. J. Org. Chem. 2004, 69,
5060–5064. (d) Zimmermann, N.; Keenan, M.; Hayashi, M.; Kaiser, S.;
Goddard, R.; Pfaltz, A. Angew. Chem., Int. Ed. 2004, 43, 70–74. (e) Liu,
Q.-B.; Yu, C.-B.; Zhou, Y.-G. Tetrahedron Lett. 2006, 47, 4733–4736. (f)
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Herrmann, W. A. Organometallics 2007, 26, 6290–6299. (g) Bianchini,
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431–455.
(3) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Black-
well Science Ltd.: Oxford, U.K., 2000; p 66. (b) Abramovitch, R. A.;
Sacha, J. G. Adv. Heterocycl. Chem. 1966, 6, 229–345.
(4) (a) Chichibabin, A. E.; Zeide, O. A. J. Russ. Phys. Chem. Soc.
1914, 46, 1216–1236. (b) Chichibabin, A. E. Ber 1923, 56B, 1879–1885.
(c) McGill, C. K.; Rappa, A. Adv. Heterocycl. Chem. 1988, 44, 1–79.
(6) (a) Minisci, F.; Galli, R.; Malatesta, V.; Caronna, T. Tetrahedron
1970, 26, 4083–4091. (b) Minisci, F.; Vismara, E.; Fontana, F. Hetero-
cycles 1989, 28, 489–519. (c) For a recent variant, see: Seiple, I. B.; Su, S.;
Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran,
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992. (b) Francis, R. F.; Wisener, J. T.; Paul, J. M. Chem. Commun. 1971,
1420. (c) Francis, R. F.; Davis, W.; Wisener, J. T. J. Org. Chem. 1974, 39,
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J. Chem. Soc., Perkin Trans. 1 1985, 213–219. (h) Vedernikov, A. N.;
Pink, M.; Caulton, K. G. J. Org. Chem. 2003, 68, 4806–4814. (i) For an
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see: Denmark, S. E.; Fan, Y. Tetrahedron: Asymmetry 2006, 17, 687–
707.
r
10.1021/ol3024117
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derivatives. In many cases, competing deprotonation leads
to a lack of productive reactivity (e.g., via E) or decom-
position (e.g., via D).7a,e,f
Figure 1. Challenges with direct C(6) functionalization of pico-
line derivatives by alkyl nucleophile addition.
Recently, a series of metal-mediated approaches to
achieve C(6) functionalization of picolines has been intro-
duced, which addresses many of the functional group and
regioselectivity challenges inherent in traditional meth-
odologies for pyridine functionalization.8,9 However, the
direct C(6) alkylation of hydroxylated variants of picoline
derivatives (pyridyl alcohols) remains unsolved. In this
manuscript, we describe a solution to this challenge that
relies on a Chichibabin-type alkylation.
Pyridyl alcohols (e.g., 1, Figure 2) represent a unique
class of picoline derivatives, which has proven broadly
useful in the synthesis of ligands for the enantioselective
hydrogenation of unactivated olefins (e.g., F, Figure 2)10
orfor Pd-catalyzed allylic substitution reactions (e.g., G).11
Additionally, pyridyl alcohols have been found to self-
assemble in the presence of certain metal salts to form
double-stranded helicates (e.g., H).12 As such, methods
that provide direct access to alkylated variants of pyridyl
alcohols would be highly valuable. An attractive option to
achieve the direct alkylation of pyridyl alcohols would be
to employ an alkylative variant of the Chichibabin reac-
tion, which has been previously used in the direct alkyla-
tion of pyridines.7
Figure 2. Examples of pyridyl alcohol utility.
For example, during investigations on the reactivity of
indolizinones,13 we required efficient access to an alkylated
variant of pyridyl alcohol 1 (Figure 2). After extensively
investigating various methods for the introduction of a
butyl group at C(6) of 1, it was determined that only the
direct, Chichibabin-type reaction with n-BuLi furnished
the desired product. We postulated that pyridyl alcohols
could offer a general solution to the traditional challenges
associated with an alkylative Chichibabin-type process.
First, by deprotonation of the alcohol group (e.g., in 2,
Scheme 1) with an appropriate base, an alkoxide inter-
mediate would be formed (see 3), which would be slow to
undergo lateral deprotonation (e.g., upon treatment with
an alkyl lithium reagent). Second, a potential interaction
between the alkoxide countercation (M) and the pyridine
nitrogen of 3 would enhance the electrophilicity at C(6)
and also increase the basicity of the alkoxide lone pairs.
This potential increase in basicity of the alkoxide was
expected to enhance interactions with organometals (see
3a), which would in turn increase the nucleophilicity of the
organometallic toward the pyridine nucleus and also direct
its delivery to the proximal C(6) position of 3 (in preference
(8) Nakao, Y. Synthesis 2011, 3209–3219.
(9) (a) Guan, B.-T.; Hou, Z. J. Am. Chem. Soc. 2011, 133, 18086–
18089. (b) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A.
ꢀ
J. Am. Chem. Soc. 2008, 130, 14926–14927. (c) Larivee, A.; Mousseau,
J. J.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 52–54. (d) Cho, S. H.;
Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254–9256. (e)
Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020–18021. (f) Murakami, M.; Hori, S. J. Am. Chem. Soc. 2003,
125, 4720–4721.
(14) A three-dimensional depiction of 3a reveals a potential proxi-
mity-guided addition of R0Li to C(6).
(10) (a) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew. Chem., Int. Ed.
2006, 31, 5194–5197. (b) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res.
€
2007, 40, 1402–1411. (c) Woodmansee, D. H.; Muller, M.-A.; Neuburger,
M.; Pfaltz, A. Chem. Sci. 2010, 1, 72–78.
(11) Uenishi, J.; Hamada, M. Tetrahedron: Asymmetry 2001, 12,
2999–3006.
(12) (a) Telfer, S. G.; Sato, T.; Kuroda, R. Angew. Chem., Int. Ed.
2004, 43, 581–584. (b) Telfer, S. G.; Kuroda, R. Chem.;Eur. J. 2005, 11,
57–68.
(15) This method is especially attractive if one considers the alter-
native Boekelheide oxidation of substrates where R and R0 are similar,
which is likely to be nonselective:
(13) Hardin Narayan, A. R.; Sarpong, R. Org. Biomol. Chem. 2012,
10, 70–78.
B
Org. Lett., Vol. XX, No. XX, XXXX

to C(4)).14 Finally, loss of LiH and protonation would
provide the desired C(6)-alkylated pyridyl alcohol (5).15
nucleophiles (see 18) led to reduced yields of the adducts
(in the latter case, presumably due to competing lithiation
of the newly introduced benzene ring).7b
Scheme 1. Proposed Facilitation of Chichibabin-Type Alkyla-
tion of Pyridyl Alcohols (2)
Table 1. Optimization of the Direct Alkylation of 1
entry
base
conditionsa
conversion (%)b
1
2
3
4
5
6
n-BuLi
n-BuLi
n-BuLi
NaH
EtMgBrc
n-BuMgClc
23 °C, 44 h
60 °C, 24 h
110 °C, 24 h
110 °C, 24 h
110 °C, 24 h
110 °C, 24 h
65
67
71
10
0
0
a All reactions were performed in PhMe in a Schlenk tube under a N2
atmosphere. b Determined by 1H NMR. c Alkylmagnesium halides were
insoluble under the reaction conditions.
To test this hypothesis, we initiated our studies on the
direct alkylation of pyridyl alcohols with 1 (see Table 1),
which was prepared from commercially available 2,3-
cycloheptenopyridine using a Boekelheide oxidation
sequence.10a Pyridyl alcohol 1 was treated sequentially
with a range of bases followed by n-BuLi as the alkyl
nucleophile. Thus, using n-BuLi as the base (23 °C, 0.5 h),
followed by an additional 1.1 equiv of n-BuLi as the
nucleophile, and stirring at 23 °C for 44 h resulted in
65% conversion to 6 after quenching (with MeOH) and a
standard workup (entry 1). Increasing the temperature to
60 °C (entry 2) led to 6 in essentially the same conversion
but in a shorter reaction time period (24 h). Upon heating
the reaction mixture to 110 °C (entry 3), conversion to 6
(71%) was also observed, along with some byproducts.
Interestingly, employing NaH (entry 4) as the base resulted
in only 10% conversion, whereas the use of EtMgBr (entry 5)
or n-BuMgCl (entry 6) as base did not lead to a produc-
tive reaction and resulted in the recovery of the starting
material.
The optimal reaction conditions (outlined in Table 1,
entry 3) were applied to a range of substrates, as illustrated
in Figure 3 (see 7ꢀ18; only products are shown). Notably,
in the absence of the hydroxy group, polymerization or
decomposition was observed for the majority of substrates
(e.g., 7a or 11a), suggesting an important role for the
hydroxy group.16 Acyclic pyridyl alcohols gave modest
to good isolated yields of the alkylated products (see 7b;
8ꢀ12). For cyclic pyridyl alcohols, only the seven- and
eight-membered ring substrates gave satisfactory yields
of the alkylated products (compare 13 to 14ꢀ17). Pri-
mary and secondary alkyl lithium reagents were compe-
tent nucleophiles (e.g., see 14 and 15, respectively),
whereas tertiary alkyl lithiums (see 16) and aryl lithium
Figure 3. Products of the direct alkylation of selected pyridyl
alcohols. as-BuLi was used as the base. bt-BuLi was used as the
base. cMeLi was used as the base. dPhLi was used as the base.
(16) It has been reported (ref 7b, 7c) that, in the presence of an excess
of tert-butyl lithium, pyridine gives a mixture of alkylated products,
including 2,4,6-tri-tert-butylpyridine (33% yield in refluxing hexane and
76% yield in refluxing heptane).
To better understand the mechanism and explore the
scope of these direct alkylation processes, a series of
Org. Lett., Vol. XX, No. XX, XXXX
C

experiments, as outlined in eqs 1ꢀ4, was undertaken.
Pyridyl alcohol 1 was treated with n-BuLi (1.0 equiv),
followed by s-BuLi (1.1 equiv) as the nucleophile. The
product, containing ans-butyl group at C(6) (15, eq 1), was
isolated in 63% yield, which suggests that, in principle,
only 1.0 equiv of the nucleophile is required. Therefore, for
cases where a precious alkyl substituent is required, n-BuLi
could be employed as the sacrificial base.
deprotonation (see 3, Figure 1). However, thefacilityof the
alkylation reaction (i.e., conversion of 23 to 6) suggests
that deprotonation of the carbinol center, or of the newly
introduced pseudobenzylic position, may occur following
alkylation (perhaps by the generated LiH). Support for
this hypothesis was obtained by performing the alkylation
reaction of 23 in deuterated toluene, followed by quench-
ing with deuterated methanol. Analysis of the resulting
product showed the presence of deuterium at both pseu-
dobenzylic positions of 6, i.e., at the carbinol center and at
the pseudobenzylic position of the n-butyl chain.
When methyl ether 19 (eq 2)17 was subjected to the
alkylation conditions, only a trace amount (2%) of the
n-butylated product (20) was obtained, with the remainder
of the mass balance accounted for by unreacted 19 and a
complex mixture of unidentified byproducts. This obser-
vation suggests that the deprotonation of the hydroxy
group is crucial for alkylation. Replacing the oxygen atom
of 19 with nitrogen (see methylamine 21, eq 3) led to a 15%
yield of the C(6)-alkylated product (see 22, eq 3).18 This
observation further emphasizes the seemingly special role
of the proximal alkoxide as compared to an amido group.
In conclusion, the direct alkylation of pyridyl alcohols
using alkyl lithium reagents has been accomplished. The
reaction is thought to proceed via the intermediacy of a
lithium alkoxide intermediate, which enhances the C(6)-
alkylation of the pyridine ring. Despite the modest yield of
these direct functionalization reactions, they represent an
effective one-step alternative to multistep methods that
have been previously employed for the synthesis of the
target compounds.10a,c
Acknowledgment. We thank Dr. Alison Narayan
(University of Michigan) for initial studies on these alkyla-
tionreactionsand for insightful discussions. Thisworkwas
supported by a grant from the NIH (NIGMS R01 084906).
R.S. is a Camille Dreyfus Teacher-Scholar. J.L.J. is grate-
ful to the NSF for a graduate fellowship.
When deuterated substrate 23 (eq 4)17 was subjected to
the alkylation conditions, analysis of the resulting product
(i.e., 6) revealed complete replacement of the pseudo-
benzylic deuterium by proton. This result is contrary to
our prediction that the carbinol proton is protected from
Supporting Information Available. Experimental de-
tails and copies of 1H and 13C spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) For details on the preparation of 19, 21, and 23, see the
Supporting Information.
(18) The yield was determined by 1H NMR analysis of the crude
reaction mixture using 1 mg/mL methenamine as an internal standard.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX