A simple Cu-catalyzed coupling approach to substituted 3-pyridinol and 5-pyrimidinol antioxidants

Article abstract of DOI:10.1021/jo801501e

(Chemical Equation Presented) A convenient approach to 3-pyridinols and 5-pyrimidinols via a two-step Cu-catalyzed benzyloxylation/catalytic hydrogenation sequence is presented. The corresponding 3-pyridinamines and 5-pyrimidinamines can be prepared in an analogous sequence utilizing benzylamine in lieu of benzyl alcohol. The radical-scavenging ability of these derivatives are preliminarily explored and reveal that the increased acidities of the pyridinols and pyrimidinols render them susceptible to more significant kinetic solvent effects when compared to phenols.

Full text of DOI:10.1021/jo801501e

A Simple Cu-Catalyzed Coupling Approach to Substituted
3-Pyridinol and 5-Pyrimidinol Antioxidants
Susheel J. Nara, Mukund Jha, Johan Brinkhorst, Tony J. Zemanek, and Derek A. Pratt*
Department of Chemistry, Queen’s UniVersity, Kingston, ON, Canada K7L 3N6
pratt@chem.queensu.ca
ReceiVed July 21, 2008
A convenient approach to 3-pyridinols and 5-pyrimidinols via a two-step Cu-catalyzed benzyloxylation/
catalytic hydrogenation sequence is presented. The corresponding 3-pyridinamines and 5-pyrimidinamines
can be prepared in an analogous sequence utilizing benzylamine in lieu of benzyl alcohol. The radical-
scavenging ability of these derivatives are preliminarily explored and reveal that the increased acidities
of the pyridinols and pyrimidinols render them susceptible to more significant kinetic solvent effects
when compared to phenols.
Introduction
generates the superoxide radical anion, rendering the phenol a
pro-oxidant, rather than an antioxidant (Scheme 1).
Phenols, ubiquitous in Nature and industry, constitute the most
widely used and arguably most effective class of radical-
scavenging chain-breaking antioxidants. The archetypical phe-
nolic antioxidant, R-tocopherol (R-TOH, the most potent form
of vitamin E), is believed to be the most effective natural
compound of this class, reacting with peroxyl radicals with a
rate constant around 3 × 106 M-1 s-1 at ambient temperature
in nonpolar solvents.1 It has long been the goal of many
academic and industrial researchers to develop synthetic radical-
scavenging antioxidants with even greater activities than R-TOH.
Attempts to maximize the antioxidant activity of phenolic
compounds have been based largely upon the extensive
structure-reactivity studies of Mahoney, Ingold and Pedulli,
which clearly show that electron-donating substituent groups
on the aromatic ring weaken the phenolic O-H bond, leading
to greater rates of H-atom transfer to autoxidation chain-carrying
peroxyl radicals.2 Unfortunately, studies with phenols that are
more electron-rich than the substituted benzochromanol found
in R-TOH have been disappointing since these compounds are
generally reactive with air.3 This reaction is undesired from two
perspectives: first, it depletes the antioxidant, and second, it
In recent years, we have demonstrated that phenolic com-
pounds containing nitrogen in lieu of carbon at the 3 or 3 and
5 positions have an unprecedented balance between radical-
scavenging chain-breaking antioxidant activity and stability to
air oxidation.4,5 For example, 2-amino-5-pyrimidinols such as
1 and 6-amino-3-pyridinols such as 2 react 2-fold and 5-fold
faster with peroxyl radicals than R-TOH. Most importantly, 1
and 2 are indefinitely stable to degradation when exposed to
air, conditions under which the equivalently substituted phenols
rapidly decompose.
Unfortunately, detailed structure-reactivity studies with
3-pyridinols and 5-pyrimidinols beyond 1, 2 and closely related
(3) (a) Burton, G. W.; Doba, T.; Gabe, E.; Hughes, L.; Lee, F. L.; Prasad,
L.; Ingold, K. U. J. Am. Chem. Soc. 1985, 107, 7053. (b) Barclay, L. R. C.;
Vinqvist, M. R.; Mukai, K.; Itoh, S.; Morimoto, H. J. Org. Chem. 1993, 58,
7416.
* To whom correspondence should be addressed. Tel: 613-533-3287. Fax:
613-533-6669.
(4) (a) Pratt, D. A.; DiLabio, G. A.; Brigati, G.; Pedulli, G. F.; Valgimigli,
L. J. Am. Chem. Soc. 2001, 123, 4625. (b) Valgimigli, L.; Brigati, G.; Pedulli,
G. F.; DiLabio, G. A.; Mastragostino, M.; Arbizzani, C.; Pratt, D. A. Chem.sEur.
J. 2003, 9, 4997.
(5) (a) Wijtmans, M.; Pratt, D. A.; Valgimigli, L.; DiLabio, G. A.; Pedulli,
G. F.; Porter, N. A. Angew. Chem., Int. Ed. 2003, 42, 4370. (b) Wijtmans, M.;
Pratt, D. A.; Brinkhorst, J.; Swerza, R.; Valgimigli, L.; Pedulli, G. F.; Porter,
N. A. J. Org. Chem. 2004, 69, 9215.
(1) (a) Burton, G. W.; Ingold, K. U. J. Am. Chem. Soc. 1981, 103, 6472. (b)
Burton, G. W.; Ingold, K. U. Acc. Chem. Res. 1986, 19, 194.
(2) See, e.g.: Mahoney, L. R.; DaRooge, M. A J. Am. Chem. Soc. 1975, 97,
4722. (b) Brigati, G.; Lucarini, M.; Mugaini, V.; Pedulli, G. F. J. Org. Chem.
2002, 67, 4828. (c) Pratt, D. A.; DiLabio, G. A.; Mulder, P.; Ingold, K. U. Acc.
Chem. Res. 2004, 37, 334.
9326 J. Org. Chem. 2008, 73, 9326–9333
10.1021/jo801501e CCC: $40.75 2008 American Chemical Society
Published on Web 11/01/2008

Simple Preparation of 3-Pyridinols and 5-Pyrimidinols
SCHEME 1. Desired Peroxyl Radical Trapping Reaction of r-Tocopherol (r-TOH) and the Competing Undesired Reaction
with Molecular Oxygen
SCHEME 2. Previous Routes to 2-Amino-5-Pyrimidinols 1
and 6-Amino-3-Pyridinols 2a
SCHEME 3. Benzyloxylation/Hydrogenation Sequence to
3-Pyridinols and 5-Pyrimidinolsa
a Key: (a) BnOH, Cs2CO3, CuI, 1,10-phenanthroline, toluene, 110 °C,
overnight; (b) H2, Pd/C, MeOH, rt, 2 h. b Isolated yield.
phenyl counterparts, we enthusiastically pursued this chemistry.
Our attempts centered on the use of tert-butyl alcohol or benzyl
alcohol to facilitate mild removal of the tert-butyl or benzyl
moiety in a subsequent step and included a variety of different
commercially available Pd sources and ligand combinations in
differing catalyst loadings. Unfortunately, this approach did not
afford encouraging results, with only trace amounts of product
formed from either 3-bromopyridine or 5-bromopyrimidine.
We next turned our attention to a Cu-catalyzed approach. The
Cu-mediated Ullmann ether synthesis8 is a classical method to
effect aryl carbon-heteroatom bond formation and Buchwald
has shown that it can be done catalytically with aryl iodides.9
Again, we hoped that the increased electron deficiency of the
pyridine and pyrimidine rings would make the accessible pyridyl
and pyrimidyl bromides good substrates for this reaction. Indeed,
we found that 3-bromopyridine and 5-bromopyrimidine are
smoothly converted to their cooresponding benzyl ethers
(Scheme 3) and that catalytic hydrogenation to remove the
benzyl group and yield the 3-pyridinol and 5-pyrimidinol is
quantitative. In comparison, bromobenzene could not be con-
verted to benzyl phenyl ether under the same conditions.
Monosubstituted Pyri(mi)dyl Halides as Substrates. To our
surprise, exploring the substrate scope of this approach in order
to prepare a series of pyridinols and pyrimidinols for detailed
structure-reactivity studies required the de novo preparation
of almost all of the pyridyl halides and pyrimidyl halides we
examined since many were not available through commercial
suppliers, nor were synthetic routes for their preparation
described in the literature. We desired a wide range of
substitution: electron-donating groups such as amino, alkoxy,
and alkyl and electron-withdrawing groups such as halo, cyano
and nitro. Furthermore, we hoped to prepare them all via
2-aminopyri(mi)dine, one of the most inexpensive monofunc-
tionalized pyri(mi)dines. The transformations are summarized
in Scheme 4.
a Key: (a) NaOAc, DMF, 100 °C, 4 h, 30%4; (b) (i) BuLi, THF, -78
°C, 30 min, (ii) 2-nitro-m-xylene, THF, -78 °C, 2 h, (iii) aq HCl, 25-63%.5
compounds have yet to be carried out, and their suitability for
various applications has yet to be explored because of a lack of
commercial availability and convenient synthetic routes for their
preparation. For example, the approaches we employed to
prepare 1 and 2 (Scheme 2) are restrictive in the substitution
that they tolerate, they are low-yielding (ca. 20-30% for most
examples) and can be quite costly.
While the aryl bromide to aryl alcohol conversion employed
to prepare 2 was low yielding, this type of approach was most
desirable because we could then make use of the vast substitu-
tion chemistry known to pyridines and pyrimidines to construct
precursors to a wide variety of pyridinols and pyrimidinols and
then convert them to the aryl alcohols in a final step.
Unfortunately, efforts to improve the lithiation/oxidation se-
quence by changes in reaction conditions were futile. Herein
we present the results of our attempts to find a more general,
inexpensive and higher yielding approach to convert pyridyl
and pyrimidyl halides to pyridyl and pyrimidyl alcohols for the
detailed kinetic and thermodynamic studies we have long desired
to carry out.
Results and Discussion
Pyri(mi)dyl Halides to Pyri(mi)dyl Alcohols. We envisioned
a two-step sequence involving the formation of an aryl ether
followed by cleavage of the ether to yield the desired aryl
alcohol. Hartwig6 and Buchwald7 have shown that the Pd-
catalyzed etherification of electron-poor aryl bromides can be
accomplished in good yields and given the greater electron-
deficiency of the pyridine and pyrimidine rings relative to their
(6) See, e.g.: Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem.
Soc. 2000, 122, 10718.
(7) See, e.g.: Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 10770.
(8) Ullman, F. Chem. Ber. 1904, 37, 853. For a general review, see: Lindley,
J. Tetrahedron 1984, 40, 1433.
(9) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002,
4, 973.
J. Org. Chem. Vol. 73, No. 23, 2008 9327

Nara et al.
SCHEME 4. Preparation of Substrates for Cu-Catalyzed Benzyloxylation of Pyridines and Pyrimidinesa
a Key: (a) pyr: NBS, CH3CN, rt, overnight, 87%; pym: NBS, CH3CN, reflux, overnight, 85%; (b) HIO4-2H2O, I2, HOAc, H2SO4, 80 °C, 4 h, pyr: 83%;
pym: 63%; (c) pyr: HCO2H, formalin, reflux, overnight, 45%; pym: NaH, MeI, DMF, 4h, 82%; (d) concd H2SO4, H2O2, 5 °C, rt, overnight, pyr: 62%; pym:
no reaction; (e) Et3(Bn)NCl, t-BuONO, CH2Cl2, rt, 1-12 h, pyr: 79-85%; pym: 35-40%; (f) Me3(Bn)NBr, t-BuONO, CH2Br2, rt, 1-12 h, pyr: 80-85%;
pym: 35-40%; (g) NaOMe, MeOH, rt, overnight, pyr: 69%; pym: 77%; (h) Et2Zn, 2 mol % of PdCl2 and dppf, dioxane, 50°C, overnight, pyr: 42%; pym:
36%; (i) pyr: ref 10; pym: NaCN, Et3(Bn)NCl, DMF, rt, 7 h, 52%. Complete details are provided in the Supporting Information.
2-Aminopyridine was first brominated with NBS in CH3CN
or iodinated with I2/HIO4 in HOAc to provide the handle for
the eventual Cu-catalyzed benzyloxylation/hydrogentation se-
quence. The amine could be reductively alkylated with form-
aldehyde to yield the 2-N,N-dimethylaminopyridine or oxidized
with Caro’s acid to yield the 2-nitropyridine. To provide a handle
for nucleophilic substitution or cross-coupling, the aminopyri-
dine could be easily halo-dediazotized under nonaqueous
conditions to yield the 2-chloro or 2-bromo species. Subsequent
treatment with NaOMe and NaCN lead to the 2-cyanopyridine
and 2-methoxypyridine, respectively, while the 2-ethylpyridine
was obtained by Pd-catalyzed cross-coupling with diethylzinc.
The nonaqueous diazotization improves the yield over traditional
Sandmeyer approaches due to both better conversion and ease
of workup and isolation.
(entries 2 and 4, respectively) presumably due to deprotonation,
and therefore, deactivation under the basic conditions employed.
2-Aminopyridine has a pKa of 14.3 (measured in CH3CN),11
and 2-hydroxypyridine (2-pyridone) has a pKa of 11.6 (in
H2O).12 This further prevented efficient couplings of base-labile
protected precursors (e.g., acylated amines or alcohols) due to
alcoholysis. In the end, we found that an amine protected as
the 2,5-dimethylpyrrole13 could be efficiently coupled and then
the amine readily deprotected as in Scheme 5.14 Any O-
protecting group stable to base would presumably be useful for
the preparation of the pyridinone, but this was not explored.
The other problematic pyridyl halide, 5-bromo-2-nitropyridine
(entry 10), surprisingly underwent ipso substitution of benzyloxy
for the nitro group, yielding 2-benzyloxy-5-bromopyridine in
55% yield.
The pyrimidyl halide substrates could be prepared in a similar
fashion from 2-aminopyrimidine, but with a few notable
differences due to the lower inherent nucleophilicity of the
amino group. First, reductive alkylation with formaldehyde was
quite slow and abandoned in favor of treatment with NaH/MeI.
The reduced reactivity also precluded the oxidation of the
2-aminopyrimidine to the 2-nitropyrimidinesa transformation
that has yet to be reported in the literature. Not surprisingly,
the halo-dediazotizations were consistently lower yielding, but
the subsequent substitutions and cross-couplings were quite
facile. With these substrates in hand, we explored the generality
of the Cu-catalyzed benzyloxylation approach. The results are
presented in Table 1.
To our satisfaction, essentially all of the pyridyl halides were
good substrates for this reaction. Conventionally, aryl iodides
are the best substrates for the Ullmann reaction and, indeed,
for electron-rich pyridines, such as the 2-N,N-dialkylamino- and
2-alkoxy-substituted compounds, iodides were found to be much
better substrates than bromides. However, in the case of the
less electron-rich pyridines, such as the 2-alkyl-, unsubstituted,
and 2-halosubstituted compounds, bromides proved to be good
substrates as well.
While some of the pyrimidyl halides were also good
substrates for the Ullmann reaction (2-dialkylamino, 2-alkyl,
unsubstituted), any which presented a reasonable leaving group
at the activated 2-position (alkoxide, halide, cyanide) underwent
preferential substitution at this position, leading to 2,5-diben-
zyloxy substituted compounds. In order to access the pyrimidine
derivatives with these groups intact at the 2-position, the 2,5-
dibenzyloxypyrimidine (24) then had to be subjected to nu-
cleophilic substitutions, e.g. with NaOMe to yield the 2-methoxy-
5-benzyloxy derivative (77% yield).
Ortho Alkylated Pyri(mi)dyl Halides as Substrates. Many
of the radical-scavenging chain-breaking phenolic antioxidants
used in industry and found in Nature contain alkyl substitution
in the ortho positions relative to the phenolic hydroxyl group,
e.g., methyl in R-TOH and tert-butyl in butylated hydroxytolu-
ene (BHT). Hence, we expanded our studies of the substrate
(10) Song, J. J.; Yee, N. K.; Tan, Z.; Xu, J.; Kapadia, S. R.; Senanayake,
C. H. Org. Lett. 2004, 6, 4905.
(11) Kaljurand, I.; Rodina, T.; Leito, I.; Koppel, I. A.; Schwesinger, R. J.
Org. Chem. 2000, 65, 6202.
(12) Albert, A.; Phillips, J. N. J. Chem. Soc. 1956, 1294.
(13) Lu¨tzen, A.; Hapke, M.; Staats, H.; Bunzen, J. Eur. J. Org. Chem. 2003,
394, 8–3957.
(14) Alternatively, one could envision a Pd-amination of the 6-halo-3-
benzyloxypyridine to arrive at the 6-amino-3-benzyloxypyridine, but this approach
is not useful for the pyrimidines, Vide infra.
The halogenated 2-aminopyridine and 2-hydroxypyridine (the
keto tautomer predominates in the latter) were poor substrates
9328 J. Org. Chem. Vol. 73, No. 23, 2008

Simple Preparation of 3-Pyridinols and 5-Pyrimidinols
TABLE 1. Copper-Catalyzed Benzyloxylation of 3-Halopyridines
and 5-Halopyrimidinesa
SCHEME 5. Preparation of Substrates for Cu-Catalyzed
Benzyloxylation of Pyridines and Pyrimidinesa
a Key: (a) 2,5-hexanedione, p-TsOH, toluene, Dean-Stark, overnight,
pyr: 82%; pym: 91%; (b) 10 equiv of BnOH, 1.5 equiv of Cs2CO3, 10 mol
% of CuI, 20 mol % of 1,10-phenanthroline, toluene, pyr: 86%; pym: 82%;
(c) NH2OH·HCl, Et3N, EtOH, water, reflux, 20 h, pyr: 81%; pym: 76%.
scavenging chain-breaking antioxidants, and we have wondered
if incorporating nitrogen atoms in the aromatic ring of these
compounds would help stabilize them to air oxidation, as we
have demonstrated for phenols.4,5 This would allow the prepara-
tion of more effective aromatic amine antioxidants, since they
would tolerate substitution with more electron-donating groups
without being too reactive to air to be useful. Unfortunately,
there is a paucity of precedent to these classes of compounds
in the literature. We are therefore encouraged that the benzy-
loxylation/hydrogenation approach can be extended to prepare
the analogous arylamines from the same halogenated precursors
in a two-step process involving first a Cu-catalyzed coupling
to benzylamine followed by catalytic hydrogenation. We found
that changing the base, solvent, and ligand to K3PO4, DMSO,
and proline, respectively, as suggested by Zhang and co-
workers,17 resulted in better yields for the preparation of the
N-benzylamines and subsequent catalytic hydrogenation often
proceeded better at higher temperatures with ammonium formate
as the reductant.18 For example, we prepared the N,N-dimethy-
lamino-substituted pyridyl and pyrimidyl N-benzylamines 34
and 35 in 80% and 81% yield, respectively, and subsequently
debenzylated them to give the pyri(mi)dinamines 36 and 37.
The approach is contrasted with that used to prepare the
analogous pyri(mi)dinols 38 and 39 in Scheme 6.
Pyri(mi)dyl Halides to Pyri(mi)dyl Thiols. We also inves-
tigated whether this approach could be applied to the synthesis
of the analogous arylthiols from the same halogenated precur-
sors. A recent computational study has recommended that
3-pyridinethiols be pursued as antioxidants based on their low
S-H bond strengths.19 Indeed, the Cu-catalyzed coupling of
the N,N-dimethylamino-substituted pyridyl and pyrimidyl io-
dides with benzyl mercaptan was possible (isolated yields, pyr:
87%, pym: 65%), but cleavage of the resulting S-benzyl
thioethers 40 and 41 was cumbersome (Scheme 7). While it
could be accomplished for the pyridine using titanocene
a Conditions: 10 equiv of BnOH, 1.5 equiv of Cs2CO3, 10 mol % of
CuI, 20 mol % of 1,10-phenanthroline, toluene, 110 °C, 24 h. b Isolated
yield following purification. c Substitution occurs at both the 2- and
5-positions to yield 2,5-dibenzyloxypyrimidine (24). d Substitution
occurs at both the 2- and 5-positions to yield 24. Reactions at 60 °C led
to 2-benzyloxy-5-iodopyrimidine 25. e Substitution occurs at both the 2-
and 5-positions to yield the 2,5-dibenzyloxypyridine (26). Reactions at
60 °C led to 2-benzyloxy-5-iodopyridine (27). f Substitution occurs only
at the 2-position to give 2-benzyloxy-5-bromopyridine (28).
scope of the Cu-mediated benzyloxylation to include pyridyl
and pyrimidyl halides with o-methyl and tert-butyl substitution.
In doing so, we discovered that even electron rich pyrimidyl
and pyridyl halides with methyl substitution at the ortho position
were reasonable substrates for the two-step conversion to
pyridinols and pyrimidinols. For example, the benzyl ethers 31
and 32 could be prepared from the corresponding aryl iodides
and subsequently converted to pyridinol 2 and pyrimidinol 1 in
68% and 62% isolated yield over both steps. Unfortunately, tert-
butylated substrates such as the accessible pyrimidine 3315
proved too hindered for the Cu-catalyzed coupling reaction (or
a Cu-catalyzed halogen exchange16 to afford the corresponding
aryl iodide).
Pyri(mi)dyl Halides to Pyri(mi)dyl Amines. Aromatic
amines are probably the most important industrial radical-
(17) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(18) Siya, R.; Spicer, L. D. Synth. Commun. 1987, 17, 415.
(19) Nam, P. C.; Nguyen, M. T.; Chandra, A. K. J. Phys. Chem. A 2006,
110, 10904.
(15) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323.
(16) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844.
J. Org. Chem. Vol. 73, No. 23, 2008 9329

Nara et al.
TABLE 2. Second-Order Rate Constants for the Reactions of
SCHEME 6. Comparing the Benzylamination/
Hydrogenation Sequence to 3-Pyridinamines and
5-Pyrimidinamines and the Benzyloxylation/Hydrogenation
Sequence to 3-Pyridinols and 5-Pyrimidinolsa
2-N,N-Dimethylamino-Substituted Pyri(mi)dinol and
Pyri(mi)dineamine with Peroxyl Radicals in Benzene and
Propionitrile at 25 °C
kROO ·(M-1 s-1
)
H-atom donor
benzene
propionitrile
pyridinol 38
3.7 × 106
1.4 × 106
1.3 × 106
4.0 × 105
3.4 × 106
2.1 × 105
6.7 × 104
5.0 × 104
7.5 × 103
3.8 × 105
pyrimidinol 39
pyridinamine 36
pyrimidinamine 37
R-TOH25
stable monosubstituted phenols. This is due to the slightly
stronger phenolic O-H bond in pyrimidinols compared to
equivalently substituted pyridinols (i.e., 78.2 kcal/mol4 in 1 and
77.0 kcal/mol5 in 2). The arylamine analogues 36 and 37,
prepared similarly from 2-aminopyridine and 2-aminopyrimi-
dine, respectively, react roughly 3-fold slower with peroxyl
radicals than the corresponding pyridinols and pyrimidinols in
benzene. This is a similar difference in kinetics to those of
reactions of phenols and anilines with radicals and is ascribed
to the slightly stronger N-H bond in anilines as compared to
the O-H bond in phenols.26
a Key: (a) BnNH2, K3PO4, CuI, proline, DMSO, 80 °C, 48 h; (b) pyr:
NH4HCO2, Pd/C, HOAc, rt, 16h, 80%; pym: NH4HCO2, Pd/C, MeOH,
reflux, 30 min, 81%; (c) BnOH, Cs2CO3, CuI, 1,10-phenanthroline, toluene,
110 °C, overnight, pyr: 92%; pym: 95%; (d) H2, Pd/C, MeOH, rt, overnight,
pyr: 89%; pym: 93%.
SCHEME 7. Benzylthiolation of
2-N,N-Dimethylaminopyri(mi)dyl Iodidea
The kinetics of H-atom transfer reactions of phenols and
anilines are known to be sensitive to the nature of the medium.
Ingold and co-workers have clearly demonstrated that the kinetic
solvent effect (KSE) on these reactions can be well described
by a mechanism wherein the H-bond donating (HBD) abilities
of phenols (ArOH, Scheme 9) or anilines render them less
reactive in H-bond accepting (HBA) solvents (S) since the
phenolic O-H (or anilinic N-H) is tied up in an H-bond and
not free to react (Scheme 9).27
To date, there is no data on the KSEs on the H-atom transfer
reactions of pyridinols and little on the pyrimidinols.4b This is
particularly relevant for these classes of antioxidants since the
increased electron-deficiency of the pyridine and pyrimidine
rings would be expected to yield a more acidic O-H bond,
increasing their H-bond donating ability relative to phenols, and
decreasing their rates of reaction. The preliminary data we have
gathered here support this idea. For example, where the rate
constant for R-TOH drops by roughly 10-fold on going from
benzene to propionitrile, that for pyridinol 38 drops 17-fold and
that for pyrimidinol 39 drops 21-fold. This is presumably due
to the greater acidity of the O-H bond along the phenol-
pyridinol-pyrimidinol series (i.e., pKa’s of R-TOH, 38, and 39
are 11.9,28 9.22 ( 0.09,29 and 8.15 ( 0.04,29 respectively),
which leads to greater H-bonding interactions between the
H-atom donor and the solvent. This will be explored in detail
in a future manuscript.
a Key: (a) BnSH, Cs2CO3, CuI, 1,10-phenanthroline, toluene, 110 °C,
overnight, pyr: 87%; pym: 65%; (b) pyr: Ti(Cp)2Cl2, Bu2Mg, diglyme, 0°C,
1 h, 23%; pym: (i) Bu3SnH, AIBN, benzene, reflux, 3 h, (ii) 6 M HCl, rt,
2 h, 10%.
dichloride and dibutylmagnesium,20 the product thiol was readily
oxidized to the corresponding disulfide, which was solely
isolated. Where titanocene dichloride and dibutylmagnesium
failed to cleave the pyrimidyl thioether, treatment with tributyltin
hydride/AIBN21 followed by either concentrated acid or tet-
rabutylammonium fluoride22 was successful, but again yielded
only the disulfide.
Preliminary Kinetics Investigations. We have carried out
preliminary studies of the reactivity of pyri(mi)dinols 38 and
39 and pyri(mi)dinamines 36 and 37 with peroxyl radicals using
a newly developed peroxyl radical clock approach.23,24 This
approach involves the kinetic competition between the unimo-
lecular ꢀ-fragmentation of the nonconjugated peroxyl radical I
derived from peroxyester 42, which occurs with a rate constant
of 1.4 × 105 s-1, and its trapping by a H-atom donor (XH) to
yield a nonconjugated hydroperoxide (Scheme 8). Rate constants
determined for XH ) 36-39, determined in benzene and
propionitrile, are given in Table 2.
The pyridinol 38, prepared in four straightforward steps from
2-aminopyridine (halogenation, alkylation, benzyloxylation, and
hydrogenolysis), was found to be indefinitely air stable and
slightly more reactive toward peroxyl radicals than R-TOH in
benzene. Consistent with our previous results, the corresponding
pyrimidinol 39 prepared in exactly the same way, but starting
from 2-aminopyrimidine, had slightly lower reactivity compared
to pyridinol 38 and R-TOH but was more reactive than air-
Surprisingly, the KSEs on the reactions of the arylamines 36
and 37 were found to be even larger than those on the reactions
of the pyri(mi)dinols, as seen when comparing the rate constants
for the reactions in propionitrile to those in benzene (i.e., rate
constants drop 26-fold and 53-fold for 36 and 37, respectively).
Since anilines are less acidic than phenols, we had expected
the pyri(mi)dinamines to have weaker interactions with HBA
solvents than the pyri(mi)dinols, and consequently smaller KSEs.
This will also be explored in detail in a future manuscript.
(20) Akao, A.; Nonoyama, N.; Yasuda, N. Tetrahedron Lett. 2006, 47, 5337.
(21) Gutierrez, C. G.; Summerhays, L. R. J. Org. Chem. 1984, 49, 5206.
(22) Harpp, D. N.; Gingras, M. J. Am. Chem. Soc. 1988, 110, 7737.
(23) Roschek, B.; Tallman, K. A.; Rector, C. L.; Gillmore, J. G.; Pratt, D. A.;
Punta, C.; Porter, N. A. J. Org. Chem. 2006, 71, 3527.
(24) Jha, M.; Pratt, D. A. Chem. Comm. 2008, 1252.
(25) Valgimigli, L.; Banks, J. T.; Lusztyk, J.; Ingold, K. U. J. Org. Chem.
1999, 64, 3381.
(26) MacFaul, P. A.; Ingold, K. U.; Lusztyk, J. J. Org. Chem. 1996, 61,
1316.
(27) Litwinienko, G.; Ingold, K. U. Acc. Chem. Res. 2007, 40, 222.
(28) Steenken, S.; Neta, P. J. Phys. Chem. 1982, 86, 3661.
(29) Cooper, T.; Nara, S. J.; Pratt, D. A., to be published.
9330 J. Org. Chem. Vol. 73, No. 23, 2008

Simple Preparation of 3-Pyridinols and 5-Pyrimidinols
SCHEME 8. Peroxyester-Based Approach for the Determination of Peroxyl Radical Kinetics23,24
SCHEME 9. Kinetic Solvent Effects on H-Atom Transfer
Reactions of Phenols
7.16-7.19 (dd, J ) 8.8, 3.2 Hz, 1H), 7.33-7.44 (m, 5H), 7.85-7.86
(d, J ) 2.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 71.5,
109.4, 127.0, 127.6, 128.1, 128.6, 134.5, 136.8, 148.7, 153.2 ppm.
HRMS (ES+) calcd (M) 200.0950, obsd 200.0952. Yield: 35% from
coupling. Yield: 81% from deprotection of pyrrole 24 (vide infra).
2-Amino-5-benzyloxypyrimidine (8). 1H NMR (400 MHz,
CDCl3): δ 4.85 (bs, 2H), 5.04 (s, 2H), 7.35-7.42 (m, 5H), 8.10 (s,
2H) ppm. 13C NMR (100 MHz, CDCl3): δ 72.2, 127.7, 128.4, 128.7,
136.1, 146.6, 146.64, 158.4 ppm. HRMS (ES+) calcd (M) 201.0902,
obsd 201.0903. Yield: 0% from coupling. Yield: 76%. From
deprotection of pyrrole 25 (vide infra).
In conclusion, we have explored the use of a simple Cu-
catalyzed coupling approach to 3-pyridinols and 5-pyrimidinols
and the analogous arylamines. This two-step sequence, along
with the means to prepare a variety of pyri(mi)dyl halide
precursors, now permits us to pursue detailed studies of the
exciting radical-scavenging activities of these compounds, in
particular, the importance of kinetic solvent effects on their
reactivities.
2-Methoxy-5-benzyloxypyridine (9). 1H NMR (400 MHz,
CDCl3): δ 3.81 (s, 3H), 4.97 (s, 2H), 6.59-6.62 (d, J ) 9.2 Hz,
1H), 7.17-7.35 (m, 6H), 7.79-7.80 (dd, J ) 2.8 Hz, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ 53.6, 71.3, 111.1, 127.6, 127.9,
128.2, 128.7, 132.4, 136.6, 150.2, 158.9 ppm. HRMS (ES+) calcd
(M) 215.0946, obsd 215.0947. Yield: 88%.
2-Methoxy-5-benzyloxypyrimidine (10). 1H NMR (400 MHz,
CDCl3): δ 3.98 (s, 3H), 5.11 (s, 2H), 7.42-7.43 (m, 5H), 8.26 (s,
2H) ppm. 13C NMR (100 MHz, CDCl3): δ 53.0, 69.8, 125.6, 126.5,
126.8, 133.7, 144.7, 146.6, 158.6 ppm. HRMS (ES+) calcd (M)
216.0899, obsd 216.0906. Yield: 77% from NaOMe treatment of
2,5-dibenzyloxypyrimidine (24, vide infra).
Experimental Section
General Procedure for Benzyloxylation of Pyri(mi)dyl
Halides. To a mixture of CuI (0.40 mmol), 1,10-phenanthroline
(0.80 mmol), cesium carbonate (6.00 mmol), and bromo- or
iodopyri(mi)dine (4.00 mmol) in a dry Schlenk flask (evacuated
and nitrogen purged) were added 5 mL of toluene and benzyl
alcohol (40 mmol) and heated in an oil bath at 110 °C for 24 h.
The reaction mixture was filtered through a silica plug and solvent
removed under reduced pressure. The crude residue obtained was
subjected to flash chromatography (eluent: ethyl acetate/hexanes)
and the purified product characterized by 1H NMR, 13C NMR, and
mass spectrometry.
2-Ethyl-5-benzyloxypyridine (13). 1H NMR (400 MHz, CDCl3):
δ 1.23-1.27 (t, J ) 7.6 Hz, 3H), 2.58-2.63 (q, J ) 7.6 Hz, 2H),
5.40 (s, 2H), 6.77-6.80 (d, J ) 8.4 Hz, 1H), 7.32-7.50 (m, 6H),
8.03 (d, J ) 2.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ
15.6, 25.2, 67.6, 110.9, 127.8, 127.9, 128.5, 132.3, 137.5, 138.8,
145.3, 162.0 ppm. HRMS (ES+) calcd (M) 213.1154, obsd
213.1152. Yield: 84%.
2-Ethyl-5-benzyloxypyrimidine (14). 1H NMR (500 MHz,
CDCl3): δ 1.25-1.28 (t, J ) 6.0 Hz, 3H), 2.58-2.62 (q, J ) 6.0
Hz, 2H), 5.45 (s, 2H), 7.31-7.34 (m, 2H), 7.37-7.40 (m, 2H),
7.50-7.52 (d, J ) 6.0 Hz, 2H), 8.39 (s, 2H) ppm. 13C NMR (100
MHz, CDCl3): δ 15.2, 22.7, 68.9, 127.9, 128.4, 129.1, 130.0, 136.8,
158.5, 163.8 ppm. HRMS (ES+) calcd (M) 214.1106, obsd
214.1106. Yield: 74%.
3-Benzyloxypyridine (3). The characterization data is consistent
with literature values.30 Yield: 86%.
5-Benzyloxypyrimidine (4). 1H NMR (400 MHz, CDCl3): δ 5.14
(s, 2H), 7.34-7.41 (m, 5H), 8.46 (s, 2H), 8.85 (s, 1H) ppm. 13C
NMR (100 MHz, CDCl3): δ 70.7, 127.4, 128.9, 129.7, 135.2, 144.0,
151.7, 152.8 ppm. HRMS (ES+) calcd (M) 186.0793, obsd
186.0795. Yield: 88%.
2-Chloro-5-benzyloxypyridine (15). 1H NMR (400 MHz,
CDCl3): δ 5.11 (s, 2H), 7.23-7.28 (m, 2H), 7.36-7.43 (m, 5H)
8.15-8.16 (d, J ) 2.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
δ 70.9, 124.5, 125.4, 127.5, 128.5, 128.8, 135.7, 137.1, 142.8, 154.1
ppm. HRMS (ES+
2-N,N-Dimethylamino-5-benzyloxypyridine (5). 1H NMR (400
MHz, CDCl3): δ 3.04 (s, 6H), 5.03 (s, 2H), 6.49-6.51 (d, J ) 9.2,
1H), 7.19-7.22 (dd, J ) 9.2, 3.2), 7.33-7.45 (m, 5H), 7.99-8.00
(d, J ) 9.2, 2.8 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 38.8,
71.7, 106.5, 126.5, 127.6, 128.0, 128.6, 135.0, 137.2, 147.0, 155.4
ppm. HRMS (ES+) calcd (M) 228.1263, obsd 228.1255. Yield:
92%.
) calcd (M) 219.0451, obsd 219.0446. Yield: 83%
from 2-chloro-5-bromopyridine and 91% from 2-chloro-5-iodopy-
ridine.
2-Cyano-5-benzyloxypyridine (21). 1H NMR (400 MHz,
CDCl3): δ 5.20 (s, 2H), 7.30-7.33 (dd, J ) 8.8, 3.2 Hz, 1H)
7.38-7.46 (m, 5H), 7.64-7.66 (d, J ) 8.8 Hz, 1H), 8.46-8.47 (d,
J ) 2.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 70.8, 117.4,
120.9, 125.6, 127.6, 128.8, 128.9, 129.5, 134.8, 140.7, 157.0 ppm.
HRMS (ES+) calcd (M) 210.0793, obsd 210.0800. Yield: 91%.
2,5-Dibenzyloxypyrimidine (24). 1H NMR (400 MHz, CDCl3):
δ 5.10 (s, 2H), 5.41 (s, 2H), 7.28-7.50 (m, 10H), 8.27 (s, 2H)
ppm. 13C NMR (100 MHz, CDCl3): δ 69.2, 71.7, 127.6, 127.9,
127.9, 128.4, 128.6, 128.8, 135.7, 136.8, 146.7, 148.7, 159.9 ppm.
HRMS (ES+) calcd (M) 292.1212, obsd 292.1216. Yield: 88% from
1
2-N,N-Dimethylamino-5-benzyloxypyrimidine (6). H NMR
(400 MHz, CDCl3): δ 3.15 (s, 6H) 5.02 (s, 2H), 7.40-7.41 (m,
5H), 8.14 (s, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 37.6, 72.6,
127.7, 128.3, 128.7, 136.5, 144.7, 146.6, 158.7 ppm. HRMS (ES+)
calcd (M) 229.1215, obsd 229.1217. Yield: 95%.
2-Amino-5-benzyloxypyridine (7). 1H NMR (400 MHz, CDCl3):
δ 4.35 (bs, 2H), 5.03 (s, 2H), 6.48-6.50 (d, J ) 8.8 Hz, 1H),
(30) Cherng, Y.-.J Tetrahedron 2002, 58, 4931–4935.
J. Org. Chem. Vol. 73, No. 23, 2008 9331

Nara et al.
1
2-bromo-5-iodopyrimidine, 85% from 2-chloro-5-iodopyrimidine,
89% from 2-ethoxy-5-iodopyrimidine, 85% from 2-methoxy-5-
bromopyrimidine, 79% from 2-chloro-5-bromopyrimidine.
2-Benzyloxy-5-iodopyrimidine (25). 1H NMR (400 MHz,
CDCl3): δ 5.43 (s, 2H), 7.33-7.41 (m, 3H), 7.47-7.49 (d, J ) 7.2
Hz, 2H), 8.67 (s, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 69.5,
82.6, 128.0, 128.2, 128.5, 136.0, 164.0, 164.4 ppm. HRMS (ES+)
calcd (M) 311.9760, obsd 311.9747. Yield: 97% at 60 °C from
2-chloro-5-iodopyrimidine, 98% at 60 °C from 2-bromo-5-iodopy-
rimidine.
5-N-Benzylamino-2-N,N-dimethylaminopyrimidine (35). H
NMR (300 MHz, CDCl3): δ 3.11 (s, 6H) 3.52 (bs, 1H), 4.23 (s,
2H), 7.25-7.35 (m, 5H), 7.93 (s, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ 38.2, 50.3, 128.1, 128.2, 129.4, 133.5, 139.6, 145.4, 158.7
ppm. HRMS (ES+) calcd (M) 228.1375, obsd 228.1373. Yield:
82%.
General Procedure for Hydrogenolysis of 5-Benzyl-
aminopyri(mi)dines. A mixture of 5-benzylaminopyri(mi)dine (1.0
mmol), ammonium formate (5.0 mmol, 216 mg), and Pd-carbon
(10 mol%) in methanol (10 mL) was refluxed for 30 min. The
reaction mixture was filtered over Celite and washed with methanol
(10 mL). The filtrate was concentrated and residue was resuspended
in diethyl ether (50 mL). The insoluble particles were filtered off,
and the filtrate was concentrated. The residue was subjected to flash
chromatography (eluent: ethyl acetate/hexanes). The purified prod-
uct was characterized by 1H NMR, 13C NMR, and mass spectrom-
etry. Although the conversion was quantitative in all the cases, the
purification and isolation of the polar derivatives led to slightly
reduced yields.
2,5-Dibenzyloxypyridine (26). 1H NMR (400 MHz, CDCl3): δ
4.96 (s, 2H), 5.24 (s, 2H), 6.65-6.68 (d, J ) 8.8, 1H) 7.16-7.37
(m, 11H), 7.79-7.80 (d, J ) 2.8, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ 67.8, 71.3, 111.5, 127.6, 127.8, 127.86, 127.9, 128.2,
128.5, 128.7, 132.4, 136.7, 137.6, 150.4, 158.4 ppm. HRMS (ES+)
calcd (M) 291.1259, obsd 291.1259. Yield: 88%.
2-Benzyloxy-5-iodopyridine (27). 1H NMR (400 MHz, CDCl3):
δ 5.40 (s, 2H), 6.66-6.68 (d, J ) 8.4 Hz, 1H), 7.32-7.46 (m,
5H), 7.80-7.83 (dd, J ) 8.8, 2.4 Hz, 1H), 8.36-8.37 (d, J ) 2.0
Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 67.9, 82.3, 113.7,
128.0, 128.0, 128.5, 136.9, 146.5, 152.6, 163.0 ppm. HRMS (ES+)
calcd (M) 310.9807, obsd 310.9806. Yield: 10%.
5-Amino-2-N,N-dimethylaminopyridine (36). The characteriza-
tion data was consistent with the literature.31 Yield: 80%.
5-amino-2-N,N-dimethylaminopyrimidine (37). 1H NMR (400
2-Benzyloxy-5-bromopyridine (28). 1H NMR (400 MHz,
CDCl3): δ 5.37 (s, 2H), 6.74-6.76 (d, J ) 9.2 Hz, 1H) 7.33-7.48
(m, 5H), 7.66-7.69 (dd, J ) 8.8, 2.4 Hz, 1H) 8.24 (d, J ) 2.4 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3): δ 68.0, 111.9, 113.0, 128.0,
128.0, 128.5, 136.9, 141.2, 147.4, 162.4 ppm. MS (m/z, % intensity)
91 (100), 262 (9), 264 (8). Yield: 55%
MHz, CDCl3): δ 3.02 (bs, 2H), 3.13 (s, 6H), 8.00 (s, 2H) ppm. 13
C
NMR (100 MHz, CDCl3): δ 37.6, 129.9, 146.6, 158.3 ppm. HRMS:
calcd (M) 138.0905, obsd 138.0905. Yield: 81%
General Procedure for Hydrogenolysis of 5-Benzyloxy-
pyri(mi)dines. A solution of 2-substituted and unsubstituted
5-benzyloxypyri(mi)dine (0.175 mmol) in 5 mL of MeOH was
treated with 10% Pd on C (0.01 g), and the resulting black
suspension was stirred at rt under H2 atmosphere (1 atm) overnight.
The catalyst was removed by filtration through a pad of Celite,
and the filtrate was concentrated under reduced pressure. The
residue was subjected to flash chromatography (eluent: ethyl acetate/
2-N-(2,5-Dimethylpyrrolo)-5-benzyloxypyridine (29). 1H NMR
(400 MHz, CDCl3): δ 2.11 (s, 6H), 5.18 (s, 2H), 5.90 (s, 2H),
7.16-7.18 (d, J ) 8.4 Hz, 1H), 7.40-7.50 (m, 6H), 8.37-8.38 (d,
J ) 2.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 13.0, 70.8,
106.4, 122.5, 123.5, 127.7, 128.5, 128.7, 128.8, 135.9, 137.1, 145.2,
154.0 ppm. HRMS (ES+) calcd (M) 278.1419, obsd 278.1414.
Yield: 86%.
hexanes). The purified product was characterized by 1H NMR, 13
NMR, and mass spectrometry. Although the conversion was
quantitative in all the cases, the purification and isolation of the
polar derivatives led to slightly reduced yields.
C
2-N-(2,5-Dimethylpyrrolo)-5-benzyloxypyrimidine (30). 1H
NMR (400 MHz, CDCl3): δ 2.37 (s, 6H), 5.21 (s, 2H), 5.98 (s,
2H), 7.46-7.52 (m, 5H), 8.56 (s, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ 14.1, 71.2, 107.8, 127.7, 128.8, 128.9, 129.4, 135.3,
145.0, 150.6, 151.8 ppm. HRMS (ES+) calcd (M) 279.1372, obsd
279.1369. Yield: 82%.
1
6-N,N-Dimethylamino-3-pyridinol (38). H NMR (400 MHz,
CDCl3): δ 3.04 (s, 6H) 6.50-6.52 (d, J ) 9.2 Hz, 1H) 7.18-7.21
(dd, J ) 8.8, 2.8 Hz, 1H) 7.81 (d, J ) 2.8 Hz, 1H), 8.45 (bs, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 39.3, 108.1, 128.5, 132.6,
145.1, 153.7 ppm. HRMS (ES+) calcd (M) 138.0793, obsd
138.0790. Yield: 89%.
5-Benzyloxy-4,6-dimethyl-2-N,N-dimethylaminopyridine
1
(31). H NMR (400 MHz, CDCl3): δ 2.26 (s, 3H), 2.45 (s, 3H),
3.07 (s, 6H), 4.77 (s, 2H), 6.22 (s, 1H), 7.37-7.50 (m, 5H) ppm.
13C NMR (100 MHz, CDCl3): δ 16.6, 19.5, 38.4, 74.9, 105.2, 128.0,
128.03, 128.6, 137.6, 141.3, 143.8, 149.2, 155.8 ppm. HRMS (ES+)
calcd (M) 256.1576, obsd 256.1576. Yield: 81%.
2-N,N-Dimethylamino-5-pyrimidinol (39). 1H NMR (400 MHz,
DMSO-d6): δ 3.03 (s, 6H) 8.00 (s, 2H), 9.03 (s, 1H) ppm. 13C NMR
(100 MHz, DMSO-d6): δ 37.2, 142.9, 145.2, 157.4 ppm. HRMS
(ES+) calcd (M) 139.0746, obsd 139.0739. Yield: 93%.
5-Benzyloxy-4,6-dimethyl-2-N,N-dimethylaminopyrimidine
General Procedure for Benzylthiolation of Pyri(mi)dyl
Halides. To the mixture of CuI (0.40 mmol), 1,10-phenanthroline
(0.80 mmol), cesium carbonate (6.00 mmol), and 2-N,N-dimethy-
lamino-5-iodopyri(mi)dine (4.00 mmol) in a dry Schlenk flask
(evacuated and nitrogen purged) were added 5 mL of toluene and
benzyl mercaptan (40 mmol) and the mixture heated in an oil bath
at 110 °C for 24 h. After the completion of reaction, as judged by
TLC, the reaction was quenched by filtering the reaction mixture
through silica plug and the filtrate concentrated in vacuo. The crude
residue obtained was subjected to flash chromatography (eluent:
ethyl acetate/hexanes). The purified product was characterized by
1H NMR, 13C NMR, and mass spectrometry.
1
(32). H NMR (400 MHz, CDCl3): δ 2.35 (s, 6H), 3.18 (s, 6H),
4.75 (s, 2H), 7.37-7.47 (m, 5H) ppm. 13C NMR (100 MHz,
CDCl3): δ 19.3, 37.3, 75.4, 128.1, 128.3, 128.6, 137.1, 141.6, 158.5,
160.1 ppm. HRMS (ES+) calcd (M) 257.1528, obsd 257.1524.
Yield: 78%.
General Procedure for Benzylamination of Pyri(mi)dyl
Halides. A mixture of 5-bromo-2-N,N-dimethylaminopyri(mi)dine
(1.49 mmol, 0.30 g), copper iodide (0.15 mmol, 0.029 g, 10 mol%),
K3PO4 (3.0 mmol, 0.63 g), and L-proline (0.17 mmol, 0.02 g) in
DMSO was stirred at 80 °C for 48 h under nitrogen. The reaction
mixture was diluted with 20 mL of ethyl acetate and filtered through
Celite. The filtrate was concentrated under reduced pressure, and
the residue obtained was purified using flash column chromatog-
raphy (solvent: ethyl acetate) to give the title compound.
5-N-Benzyamino-2-N,N-dimethylaminopyridine (34). 1H NMR
(300 MHz, CDCl3): δ 3.00 (s, 6H) 4.28 (s, 2H), 6.47-6.51 (d, J )
8.9 Hz, 1H), 6.94-6.98 (dd, J ) 8.9, 3.0 Hz, 1H) 7.30-7.40 (m,
5H), 7.76-7.77 (d, J ) 2.5 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ 39.6, 50.3, 107.6, 125.5, 127.9, 128.2, 129.3, 134.2,
136.3, 140.2, 154.9 ppm. HRMS (ES+) calcd (M) 227.1422, obsd
227.1419. Yield: 80%.
5-S-Benzylthio-2-N,N-dimethylaminopyridine (40). 1H NMR
(400 MHz, CDCl3): δ 3.23 (s, 6H), 4.00 (s, 2H), 6.51-6.53 (d, J
) 8.8 Hz, 1H), 7.26-7.28 (d, J ) 6.4 Hz, 2H), 7.33-7.38 (m,
3H), 7.42-7.45 (dd, J ) 8.8, 2.4 Hz, 1H) 8.26 (d, J ) 2.0 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 38.1, 42.3, 105.7, 116.1,
127.0, 128.4, 129.0, 138.3, 143.2, 153.3, 158.7 ppm. HRMS (ES+)
calcd (M) 244.1034, obsd 244.1040. Yield: 87%.
(31) Seydel, J. J. Med. Chem. 1971, 14, 724–729.
9332 J. Org. Chem. Vol. 73, No. 23, 2008

Simple Preparation of 3-Pyridinols and 5-Pyrimidinols
5-S-Benzylthio-2-N,N-dimethylaminopyrimidine (41). 1H NMR
(400 MHz, CDCl3): δ 3.27 (s, 6H), 3.92 (s, 2H), 7.22-7.24 (d, J
) 6.8 Hz, 2H), 7.25-7.39 (m, 3H), 8.23 (s, 2H) ppm. 13C NMR
(100 MHz, CDCl3): δ 37.2, 42.3, 114.1, 127.2, 128.5, 129.0, 137.8,
161.3, 163.0 ppm. HRMS (ES+) calcd (M) 245.0987, obsd
245.0977. Yield: 65%.
Rate Constants for Reactions with Peroxyl Radicals. Stock
solutions of H-atom donors (0.05-0.5 M) and tert-butyl 4-phe-
nylperbutenoate (42, 0.1 M) were prepared in benzene. The various
concentrations of H-atom donor were mixed with tert-butyl-4-
phenylperbutenoate (0.01 M, 10 µL of 0.1 M) and diluted up to
100 µL with benzene in 2.0 mL HPLC vials. The reaction mixtures
were irradiated at 300 nm for 30 min at 25 °C. After irradiation,
the mixtures were reduced with PPh3 (50 µL of 1.0 M in benzene)
and diluted up to 1.8 mL with hexanes. The products of photolysis
were measured by GC/FID analysis of the nonconjugated and
conjugated alcohols as in ref 24. The ratio of products (conjugated/
nonconjugated) was plotted versus the reciprocal of H-atom donor
concentration to determine the rate constants as in ref 24.
Acknowledgment. We thank Jason Hanthorn for his as-
sistance in the characterization of some of the new compounds
described here and for helpful discussions. This work was
supported by grants from the Natural Sciences and Engineering
Research Council of Canada and Queen’s University. D.A.P.
also acknowledges support of the Canada Research Chairs
program.
Note Added after ASAP Publication. A correction was
made to a Table 2 column heading in the version published on
November 11, 2008.
Supporting Information Available: Details of the prepara-
tion and characterization of the substrates for the Cu-catalyzed
couplings in Table 1 and Scheme 5 and raw data used to
determine the rate constants given in Table 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO801501E
J. Org. Chem. Vol. 73, No. 23, 2008 9333