Oxidation of methyl heteroaryls with molecular oxygen: A facile synthesis of 2-[N-(tert-butoxycarbonyl)amino]-4-pyridinecarbaldehyde

Article abstract of DOI:10.1055/s-2007-983817

Oxidation of nitrogen-based methyl heteroaryls with molecular oxygen resulted in the formation of the corresponding benzyl alcohols. While experimentally easy and amenable to large-scale preparations, this approach has limitations with respect to the particular nature of heterocyclic substrates. Using this methodology, the title compound, 2-[N-(tert-butoxycarbonyl)amino]-4- pyridinecarbaldehyde, considered to be a versatile pharmaceutical intermediate, was prepared on a multigram scale. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983817

PAPER
2529
Oxidation of Methyl Heteroaryls with Molecular Oxygen: A Facile Synthesis
of 2-[N-(tert-Butoxycarbonyl)amino]-4-pyridinecarbaldehyde
Oxidation of Methyl
H
i
e
teroar
c
yls hael Berlin,* Robert Aslanian, Manuel de Lera Ruiz, Kevin D. McCormick
The Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA
Fax +1(908)7407152; E-mail: michael.berlin@spcorp.com
Received 30 January 2007; revised 17 May 2007
scribed use of the dianion derived from 2-[N-(tert-but-
Abstract: Oxidation of nitrogen-based methyl heteroaryls with
molecular oxygen resulted in the formation of the corresponding
benzyl alcohols. While experimentally easy and amenable to large-
scale preparations, this approach has limitations with respect to the
oxycarbonyl)amino]-4-methylpyridine (1) in reactions
with electrophiles.7 We investigated the applicability of
this approach toward our goal of obtaining alcohol 2 in a
particular nature of heterocyclic substrates. Using this methodolo- convenient large-scale procedure.
gy, the title compound, 2-[N-(tert-butoxycarbonyl)amino]-4-pyri-
dinecarbaldehyde, considered to be a versatile pharmaceutical
intermediate, was prepared on a multigram scale.
When predried molecular oxygen was passed through a
–78 °C suspension of the dianion derived from 1, the dark
orange color quickly changed to bright yellow. After sev-
eral hours, the reaction mixture was quenched with two
equivalents of acetic acid together with an excess of dim-
ethyl sulfide. The crude mixture was stirred for an addi-
tional 48 hours at room temperature, as it appeared by
TLC that formation of alcohol 2, presumably from its hy-
droperoxide precursor, was still being completed during
this time. Gratifyingly, the desired alcohol 2 was isolated
in 52% yield (Scheme 1). Conversion into aldehyde 3 was
effected in high yield under NaOCl/TEMPO conditions.
Key words: oxidation, oxygen, methyl heteroaryls, benzyl anion,
benzyl alcohols
Despite rising interest in the 2-aminopyridine motif as a
building block for biologically active molecules,1 meth-
ods available for its incorporation into more complex
structures are rather limited. 2-Amino-4-hydroxymeth-
ylpyridine has been prepared from the corresponding ami-
no acid N-acetyl derivative2 and is now commercially
available. In conceptually similar, although somewhat
lengthy approaches, Boc-protected 2-amino-4-hydroxy-
methylpyridine 2 was prepared in three steps from the
same 2-acetylamino-4-pyridinecarboxylic acid3 and in 4
steps from 2-chloro-4-pyridinecarboxylic acid.4 Boc-pro-
tected 3-amino-5-pyridinecarbaldehyde was obtained in
three steps from 3,5-pyridinedicarboxylic acid with the
apparent implication that the same method was used to ac-
cess 2-amino-4-pyridinecarboxaldehyde 3.5 However, an
option of direct access to benzyl alcohol and/or aldehyde
from the 2-amino-4-methylpyridine precursor without in-
voking carboxylic acid intermediates would be desirable.
More straightforward in nature, this approach has the po-
tential to be cheaper and more amenable to large scale
synthesis. In a general sense, it may also offer the advan-
tage of applicability to heterocycles for which no benzoic
esters are commercially available and better compatibility
with certain functional groups, in contrast to metal hy-
drides required for ester reduction. We describe here our
efforts towards direct oxygenation of Boc-protected 2-
amino-4-methylpyridine 1 and other nitrogen-containing
heterocycles.
OH
1. BuLi (2 equiv), THF
2. O2, –78 °C
3. Me2S, AcOH
N
NHBoc
N
NHBoc
52%
1
2
CHO
N
NaOCl, TEMPO (cat.)
CH2Cl2
84%
NHBoc
3
Scheme 1 Synthesis of aldehyde 3
The moderate yield of alcohol formation is not easy to ex-
plain, as no obvious side products have been isolated.
However, the efficiency of the procedure, ease of scale-up
and purification, as well as the low cost of starting 2-ami-
no-4-methylpyridine appear to offer a viable option to the
previously mentioned reductive methods.
Heterocycle variation in a series of biologically active an-
alogues stimulated our interest in the application of this
oxidative approach to the synthesis of other heteroaryl-de-
rived benzyl alcohols. From the outset, however, we had
to consider conceptual limitations of this strategy. In par-
ticular, electron-poor nitrogen heteroaryls can be expect-
ed to be susceptible to nucleophilic attack from alkylmetal
bases8 or aryllithium intermediates, possibly arising from
Attempts at direct oxidation of compound 1 with oxidants
of moderate strength (e.g., SeO2) were not successful, and
complex mixtures containing largely unreacted starting
material were obtained.6 Ihle and co-workers have de-
SYNTHESIS 2007, No. 16, pp 2529–2533
x
x.
x
x
.
2
0
0
7
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983817; Art ID: M00607SS
© Georg Thieme Verlag Stuttgart · New York

2530
M. Berlin et al.
PAPER
the direct ring metalation.9 Replacement of butyllithium
with LDA did not change the outcome, as adducts with
pyrimidines and pyridazines (e.g., LDA adduct with 4)
were isolated in both cases. Direct ring metalation can
also shift the reactivity from the methyl group to the het-
eroaryl nucleus,10 although intermediate quenching of the
more reactive ring position with a removable blocking
group can potentially be envisioned. Functional group
compatibility with reaction conditions was not systemati-
cally investigated, but complex mixtures were formed
with specific substrates 5 and 6 (Figure 1). In the case of
nitro substitution ortho to the methyl group (compound
7), the easily formed deep blue benzylic anion was com-
pletely unreactive towards oxygen, and starting material
was fully recovered. Similarly, subjecting ethylpyridine 8
to the reaction conditions returned unchanged starting ma-
terial.
F
N
N
NHBoc
N
N
N
F
13
14
15
Figure 2 Compounds 13–15
Table 1 Benzylic Oxidations of Methyl Heteroarylsa
Starting material
Product
Isolated yield (%)
49
OH
N
N
N
NHBoc
N
NHBoc
9
10
33
49
OH
F
N
N
N
O
N
NHBoc
N
F
N
F
4
5
6
11
OH
O2N
N
N
N
NHBoc
N
NHBoc
12
7
8
a
Procedures analogous to the conversion 1 into 2 were used. One
Figure 1 Unsuccessful benzylic oxygenation substrates
equiv of BuLi was used in the syntheses of 11 and 12. Anion of
2-fluoro-4-methylpyridine was maintained at –78 °C throughout the
reaction.
However, when the methodology was applied to the 4-
amino-6-methylpyrimidine,11 the desired alcohol 10 was
isolated in 49% yield (Table 1). The approach also proved
moderately successful in the case of 2-fluoro-4-
methylpyridine12 which produced the desired alcohol
11,13 but also 2-fluoro-4-methylpyridine dimer 13
(Figure 2) in comparable 31% yield. Oxidation of 3,4-lu-
tidine occurred selectively at the 4-methyl group to yield
4-hydroxymethyl-3-methylpyridine (12),14 in contrast to
the previously reported unsuccessful approach to 4-hy-
droxymethyl-2-methylpyridine under similar condi-
tions.15 Dimer formation (compound 14),16 however, was
also observed (15%) although in a lower yield compared
to the 2-fluoro analogue 13. Interestingly, attempted oxi-
dation of 2-(tert-butoxycarbonyl)amino-4,6-dimethylpyr-
idine (15) (Figure 2) resulted in intractable mixture.
tions into the process of methyl heteroaryl dimer forma-
tion will be reported in due course.
Having established an efficient and reliable synthetic
route to aldehyde 3, we explored its use as a pharmaceuti-
cal intermediate. The 2-amino-4-pyridyl motif can be
variably linked into more complex structures with the na-
ture of connection dependent on the functional elabora-
tion of the initial aldehyde 3 (Scheme 2). The 2-
aminopyridine motif often conveys unique biological
properties to the targets of interest. Information in this re-
gard will be reported in due course.
All reactions were carried out under N2 with anhyd solvents (Sigma-
Aldrich) under anhydrous conditions, unless otherwise noted. Re-
While the mechanism of dimer formation is not quite clear agents were purchased at the highest commercial quality and used
without further purification, unless otherwise stated. Flash chroma-
at this point, formation of 13 appears to be attributable to
the reaction of the starting 2-fluoro-4-methylpyridine
with the alcohol 11 under the workup conditions. This was
demonstrated by the full conversion of starting methyl
heteroaryl into the dimer 13 (as followed by TLC) upon
exposure to equimolar amount of the corresponding alco-
tography was carried out with EM science Silica gel 60 (neutral,
230–400 mesh). 1H NMR and 13C NMR spectra were recorded on a
Bruker Avance 500 NMR Spectrometer with chemical shifts mea-
sured relative to residual or deuterated solvent and reported in ppm
relative to external TMS. HRMS was recorded on a Micromass QT
of Ultima API US mass spectrometer by FAB. IR spectra were re-
hol 11 and catalytic amount of acetic acid. However, sub- corded on ATI Mattson Genesis FTIR spectrometer. Elemental
analyses were performed by Quantitative Technologies Inc., White-
house, NJ, USA. Melting points were measured on Thomas Hoover
capillary melting point apparatus, Thomson Scientific, USA.
jecting a mixture of 3,4-dimethylpyridne and alcohol 12
to similar conditions did not lead to 14. Further investiga-
Synthesis 2007, No. 16, 2529–2533 © Thieme Stuttgart · New York

PAPER
Oxidation of Methyl Heteroaryls
2531
to afford 15.97 g (84%) of aldehyde 3 as an off-white solid; mp
125–126 °C.
F3C
OH
CO2H
IR (neat): 3206, 1725, 1580, 1535, 1432, 1290 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.56 (s, 9 H), 7.37 (dd, J = 5.0, 1.5
Hz, 1 H), 8.47 (br s, 1 H), 8.50 (br d, J = 5.0 Hz, 1 H), 9.75 (br s, 1
H, NH), 10.04 (s, 1 H).
N
NHBoc
N
NHBoc
16
17
13C NMR (75 MHz, CDCl3): d = 28.30, 81.57, 113.78, 114.90,
NaClO2, NaH2PO4
2-methylbut-2-ene
CF3SiMe3, TBAF
66%
143.91, 148.74, 152.66, 154.33, 191.66.
94%
HRMS-FAB: m/z calcd for C11H15N2O3 [M + H]+: 223.1083; found:
3
223.1079.
Anal. Calcd for C11H14N2O3: C, 59.45; H, 6.35; N, 12.61. Found: C,
59.37; H, 6.23; N, 12.70.
Bu2NH, NaBH(OAc)3
80%
NBu2
4-(tert-Butoxycarbonylamino)-6-methylpyrimidine (9)
The mixture containing 4-amino-6-methylpyrimidine (1.04 g, 9.50
mmol), di-tert-butyl dicarbonate (2.71 g, 12.4 mmol) and DMAP
(0.122 g, 1.00 mmol) in t-BuOH (25 mL) was stirred for 6 h at r.t.
With starting material still present, an additional amount of di-tert-
butyl dicarbonate (1.00 g, 4.58 mmol) was added, and the mixture
was stirred at r.t. overnight. The mixture was concentrated, the res-
idue dry-loaded on silica gel, and flash-chromatographed (5–12%
acetone–CH2Cl2) to afford 0.73 g (37%) of pyrimidine 9 as a white
solid.
N
NHBoc
18
Scheme 2 Synthetic transformations of aldehyde 3
1H NMR (300 MHz, CDCl3): d = 1.55 (s, 9 H), 2.49 (s, 3 H), 7.84
2-(tert-Butoxycarbonylamino)-4-hydroxymethylpyridine (2)
To a –78 °C solution of picoline 1 (35.96 g, 173 mmol) in THF (1.4
L), was added a 1.4 M BuLi solution in hexanes (272 mL, 381
mmol) in portions over 30 min. The mixture was then allowed to
warm up and stirred for 2 h at r.t., which resulted in the formation
of an orange precipitate. The mixture was cooled back to –78 °C,
and predried O2 (passed through a Drierite column) was bubbled
through the suspension for 6 h while the temperature was main-
tained at –78 °C. The color of the mixture changed to yellow during
this time. It was then quenched at –78 °C with Me2S (51.4 mL, 700
mmol) followed by AcOH (22 mL, 384 mmol). The mixture was al-
lowed to warm up and stirred for 48 h at r.t. Dilution with H2O (3 L)
and extraction with EtOAc (2 × 500 mL) were followed by concen-
tration and flash chromatography of the residue (0–15% acetone–
CH2Cl2) to provide 20.15 g (52%) of alcohol 2 as a pale yellow sol-
id; mp 133–134 °C.
(s, 1 H), 8.73 (s, 1 H), 8.82 (br s, 1 H, NH).
HRMS-FAB: m/z calcd for C10H16N3O2 [M + H]+: 210.1243; found:
210.1245.
Anal. Calcd for C10H15N3O2: C, 57.40; H, 7.23; N, 20.08. Found: C,
57.53; H, 7.39; N, 20.18.
4-(tert-Butoxycarbonylamino)-6-hydroxymethylpyrimidine
(10)
In a procedure analogous to that described for 2, pyrimidine 9 (350
mg, 1.67 mmol) yielded 185 mg (49%) of pyrimidine alcohol 10.
1H NMR (500 MHz, CD3OD): d = 1.57 (s, 9 H), 4.64 (s, 2 H), 8.16
(s, 1 H), 8.64 (s, 1 H).
13C NMR (125 MHz, CD3OD): d = 27.44, 63.78, 81.62, 104.51,
152.81, 157.29, 160.20, 171.18.
HRMS-FAB: m/z calcd for C10H16N3O3 [M + H]+: 226.1192; found:
226.1181.
IR (neat): 3434, 3206, 1727, 1618, 1579, 1540, 1432, 1293 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52 (s, 3 H), 3.04 (br s, 1 H, OH),
4.71 (s, 1 H), 6.98 (d, J = 5.5 Hz, 1 H), 7.95 (s, 1 H), 8.26 (d, J = 5.5
Hz, 1 H), 9.39 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 28.29, 63.65, 80.89, 109.60,
115.67, 147.60, 152.66, 152.73, 152.91.
Anal. Calcd for C10H15N3O3: C, 53.32; H, 6.71; N, 18.66. Found: C,
53.22; H, 6.63; N, 18.40.
2-Fluoro-4-hydroxymethylpyridine (11) and 1,2-Bis(2-fluoro-4-
pyridyl)ethane (13)
HRMS-FAB: m/z calcd for C11H17N2O3 [M + H]+: 225.1239; found:
To a –78 °C solution of 2-fluoro-4-methylpyridine (4.1 g, 36.9
mmol) in THF (150 mL), was added dropwise a 2.4 M solution of
BuLi in hexanes (15.4 mL 36.9 mmol). The mixture was stirred for
2 h at –78 °C, after which predried O2 was passed through the solu-
tion for 4 h. The mixture was then quenched with AcOH (2.2 mL,
38.7 mmol) and Me2S (5.1 mL, 70 mmol) and allowed to warm to
r.t. The mixture was concentrated, the residue was dry-loaded on
silica gel and subjected to flash chromatography (2% acetone–
CH2Cl2) to give 1.5 g (33%) of 1113 and 1.25 g (31%) of 13.
225.1236.
Anal. Calcd for C11H16N2O3: C, 58.91; H, 7.19; N, 12.49. Found: C,
58.91; H, 7.26; N, 12.34.
2-(tert-Butoxycarbonylamino)-4-pyridinecarbaldehyde (3)
To a solution of the alcohol 2 (19.15 g, 85.5 mmol) in CH2Cl2 (640
mL) was added aq sat. NaHCO3 [prepared from 8.62 g (103 mmol)
of NaHCO3 in H2O (90 mL)] and NaBr (444 mg, 4.3 mmol). The
mixture was cooled to 0 °C, and TEMPO (140 mg, 0.90 mmol) was
introduced. Commercial bleach solution (5.25% in NaOCl, 122 mL
of 0.7 M, 85.4 mmol) was added, in portions, to the vigorously
stirred mixture over 40 min. After additional 20 min at 0 °C, the
mixture was quenched with aq sat. Na2S2O3 (200 mL) and allowed
to warm to r.t. Dilution with H2O (600 mL) and extraction with
CH2Cl2 (200 mL) were followed by concentration and flash chro-
matography (from 30% hexanes–CH2Cl2 to 0–2% acetone–CH2Cl2)
Compound 13:
1H NMR (500 MHz, CDCl3): d = 3.02 (s, 2 H), 6.76 (s, 1 H), 6.99
(d, J = 5.1 Hz, 1 H), 8.15 (d, J = 5.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 35.12, 109.08 (d, J = 37 Hz),
121.42 (d, J = 4 Hz), 147.69 (d, J = 16 Hz), 154.93 (d, J = 7 Hz),
164.05 (d, J = 239 Hz).
Synthesis 2007, No. 16, 2529–2533 © Thieme Stuttgart · New York

2532
M. Berlin et al.
PAPER
HRMS-FAB: m/z calcd for C12H11F2N2 [M + H]+: 221.0890; found:
221.0905.
Anal. Calcd for C12H15F3N2O3: C, 49.32; H, 5.17; N, 9.59; F, 19.50.
Found: C, 49.83; H, 5.12; N, 9.71; F, 18.95.
Anal. Calcd for C12H10F2N2: C, 65.45; H, 4.58; N, 12.72; F, 17.25.
Found: C, 65.23; H, 4.52; N, 12.32; F, 17.04.
2-(tert-Butoxycarbonylamino)-4-(N,N-dibutylaminomethyl)py-
ridine (18)
To a solution of the aldehyde 3 (344 mg, 1.55 mmol) and Bu2NH
(261 mL, 1.86 mmol) in CH2Cl2 (10 mL) was added AcOH (1 drop).
The mixture was stirred for 1 h at r.t., after which NaBH(OAc)3
(493 mg, 2.33 mmol) was added. The mixture was stirred for 20 h
at r.t., subjected to aq NaHCO3 [30 mL of a sat. soln diluted with
H2O (30 mL)] workup and CH2Cl2 extraction (2 × 40 mL). The or-
ganic phase was dried, concentrated, and the residue was flash-
chromatographed (0–2% 2.3 M NH3 in MeOH–CH2Cl2) to afford
415 mg (80%) of amine 18 as a clear oil which solidified under vac-
uum.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, J = 7.2 Hz, 6 H), 1.22–1.35
(m, 4 H), 1.37–1.48 (m, 4 H), 2.39 (t, J = 7.1 Hz, 4 H), 3.53 (s, 2 H),
7.06 (d, J = 5.2 Hz, 1 H), 7.90 (s, 1 H), 8.25 (d, J = 5.2 Hz, 1 H),
9.28 (br s, 1 H, NH).
4-Hydroxymethyl-3-methylpyridine (12)
To a –78 °C solution of 3,4-lutidine (10.0 mL, 89 mmol) in THF
(400 mL), was added dropwise a 2.5 M solution of BuLi in hexanes
(35.7 mL, 89 mmol). The resulting mixture was stirred at –78 °C for
25 min and then slowly warmed up to r.t. over 1.5 h. The mixture
was cooled back to –78 °C, and predried O2 was bubbled through
the solution for 1 h. The mixture was warmed up to r.t. over 1 h
while the stream of O2 was maintained. The mixture was cooled to
–30 °C, and Me2S (26 mL, 350 mmol) was added, followed by Et3N
(50 mL, 360 mmol). The resulting mixture was warmed to r.t. and
stirred for an additional 20 h. The mixture was diluted with H2O
(800 mL), extracted with EtOAc (2 × 150 mL), the combined organ-
ic phases were dried (Na2SO4), and concentrated. The brown oily
residue was subjected to flash chromatography (5% of 0.4 M NH3
in MeOH–CH2Cl2) to afford 5.35 g (49%) of alcohol 1214 as white
crystals.
13C NMR (75 MHz, CDCl3): d = 14.06, 20.55, 28.38, 29.29, 53.91,
58.24, 80.58, 112.12, 118.28, 147.33, 151.91, 152.52, 152.82.
HRMS-FAB: m/z calcd for C19H34N3O2 [M + H]+: 336.2651; found:
336.2647.
1H NMR (500 MHz, CD3OD): d = 2.26 (s, 3 H), 4.67 (s, 2 H), 7.51
(d, J = 5.0 Hz, 1 H), 8.26 (s, 1 H), 8.35 (d, J = 5.0 Hz, 1 H).
13C NMR (125 MHz, CD3OD): d = 14.4, 60.5, 121.0, 131.4, 146.8,
149.1, 150.6.
Anal. Calcd for C19H33N3O2: C, 68.02; H, 9.91; N, 12.53. Found: C,
68.00; H, 9.87; N, 12.40.
HRMS-FAB: m/z calcd for C7H10NO [M + H]+: 124.0762; found:
124.0756.
References
2-(tert-Butoxycarbonylamino)-4-pyridinecarboxylic Acid (16)
To a solution of the aldehyde 3 (2.07 g, 9.32 mmol) in t-BuOH (80
mL) was added aq sat. NaH2PO4 (5.75 g, 47.9 mmol) and 2-methyl-
but-2-ene (6 mL, 56.6 mmol), followed by NaClO2( 3.38 g, 37.3
mmol). The mixture was stirred overnight at r.t., concentrated, and
the residue was dry-loaded on silica gel and flash-chromatographed
(30–50% MeOH–CH2Cl2) to afford 2.08 g (94%) of acid 16 as a
white solid.
1H NMR (300 MHz, CD3OD): d = 1.53 (s, 9 H), 7.44 (dd, J = 5.6,
2.3 Hz, 1 H), 8.27 (dd, J = 5.6, 1.1 Hz, 1 H), 8.28 (br s, 1 H).
13C NMR (75 MHz, CD3OD): d = 28.58, 81.70, 113.63, 118.97,
146.83, 148.90, 154.36, 171.27.
(1) (a) Biftu, T.; Feng, D.; Fisher, M.; Liang, G.-B.; Qian, X.;
Scribner, A.; Dennis, R.; Lee, S.; Liberator, P.; Brown, C.;
Gurnett, A.; Leavitt, P.; Thompson, D.; Mathew, J.; Misura,
A.; Samaras, S.; Tamas, T.; Sina, J.; McNulty, K.;
McKnight, C.; Schmatz, D.; Wyvratt, M. Bioorg. Med.
Chem. Lett. 2006, 16, 2479. (b) Bilodeau, M.; Hartman, G.
PCT Int. Appl. WO 2003000687, 2003; Chem. Abstr. 2003,
138, 73254. (c) Chuang, C.-Y.; Wickens, P.; Hong, Z.;
Brennan, C.; Dixon, J.; Kluender, H.; Kreiman, C.;
Kumarasinghe, E. PCT Int. Appl. WO 2006096338, 2006;
Chem. Abstr. 2006, 145, 314983. (d) Honda, T.; Tajima, H.;
Kawashima, K.; Okamoto, K.; Yamamoto, M.; Inaba, T.;
Takeno, Y. PCT Int. Appl. WO 2005085201, 2005; Chem.
Abstr. 2005, 143, 286294. (e) Wagner, G.; Kotschenreuther,
D.; Zimmermann, W.; Laufer, S. J. Org. Chem. 2003, 68,
4527.
(2) (a) Selwood, D.; Brummell, D.; Budworth, J.; Burtin, G.;
Campbell, R.; Chana, S.; Charles, I.; Fernandez, P.; Glen, R.;
Goggin, M.; Reynolds, K.; Spacey, G.; Stables, J.; Tatlock,
M.; Wheeler, K.; Wishart, G.; Woo, C.-K. J. Med. Chem.
2001, 44, 78. (b) Feng, D.; Fisher, M.; Liang, G.-B.; Qian,
X.; Brown, C.; Gurnett, A.; Leavitt, P.; Liberator, P.;
Mathew, J.; Misura, A.; Samaras, S.; Tamas, T.; Schmatz,
D.; Wyvratt, M.; Biftu, T. Bioorg. Med. Chem. Lett. 2006,
16, 5978.
(3) Polla, M.; Tottie, L.; Norden, C.; Linschoten, M.; Müsil, D.;
Trumpp-Kallmeyer, S.; Aukrust, I.; Ringom, R.; Holm, K.;
Neset, S.; Sandberg, M.; Thurmond, J.; Yu, P.; Hategan, G.;
Anderson, H. Bioorg. Med. Chem. 2004, 12, 1151.
(4) Kuramochi, T.; Kakefuda, A.; Yamada, H.; Tsukamoto, I.;
Taguchi, T.; Sakamoto, S. Bioorg. Med. Chem. 2005, 13,
4022.
(5) Nakayama, K.; Ishida, Y.; Ohtsuka, M.; Kawato, H.;
Yoshida, K.; Yokomizo, Y.; Hosono, S.; Ohta, T.; Hoshino,
K.; Ishida, H.; Yoshida, K.; Renau, T.; Leger, R.; Zhang, J.;
Lee, V.; Watlins, W. Bioorg. Med. Chem. Lett. 2003, 13,
4201.
HRMS-FAB: m/z calcd for C11H15N2O4 [M + H]+: 239.1032; found:
239.1035.
2-(tert-Butoxycarbonylamino)-4-[(2,2,2-trifluoro-1-hy-
droxy)ethyl]pyridine (17)
To the solution of the aldehyde 3 (1.11 g, 5.0 mmol) in THF (10
mL) was added a 0.5 M solution of CF3SiMe3 in THF (20 mL, 10.0
mmol), followed by a 1 M solution of TBAF in THF (10 mL, 10.0
mmol) predried over 4 Å MS. The mixture was stirred overnight at
r.t., and subjected to aq NH4Cl [100 mL of a sat. soln diluted with
H2O (200 mL)] workup and EtOAc extraction (2 × 100 mL). The
combined organic phases were dried (Na2SO4) and concentrated,
and the residue was flash-chromatographed (5–8% acetone–
CH2Cl2) to afford 0.96 g (66%) of alcohol 17 as a white foam.
1H NMR (300 MHz, CD3OD): d = 1.53 (s, 9 H), 5.05 (q, J = 7.0 Hz,
1 H), 7.14 (d, J = 5.5 Hz, 1 H), 8.04 (s, 1 H), 8.24 (d, J = 5.5 Hz, 1
H).
13C NMR (75 MHz, CD3OD): d = 28.59, 72.09 (q, J = 32 Hz),
81.81, 112.63, 118.26, 125.80 (q, J = 282 Hz), 148.33, 148.79,
154.08, 154.38.
HRMS-FAB: m/z calcd for C12H16F3N2O3 [M + H]+: 293.1113;
found: 293.1108.
Synthesis 2007, No. 16, 2529–2533 © Thieme Stuttgart · New York

PAPER
(6) cf.: Tagawa, Y.; Yamashita, K.; Higuchi, Y.; Goto, Y.
Oxidation of Methyl Heteroaryls
2533
(11) (a) Marshall, J.; Walker, J. J. Chem. Soc. 1951, 1004.
Heterocycles 2003, 60, 953.
(b) van der Plas, H. Recl. Trav. Chim. Pays-Bas 1965, 84,
1101.
(12) Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.;
Watanabe, M.; Yokoyama, K. Chem. Pharm. Bull. 1990, 38,
2446.
(13) Pesti, J.; Huhn, G.; Yin, J.; Xing, Y.; Fortunak, J.; Earl, R. J.
Org. Chem. 2000, 65, 7718.
(14) Armarego, W.; Milloy, B.; Sharma, S. J. Chem. Soc., Perkin
Trans. 1 1972, 2485.
(15) Ragan, J.; Jones, B.; Meltz, C.; Texeira, J. Jr. Synthesis 2002,
483.
(16) Tomasik, P.; Woszezyk, A.; Abramovitch, R. J. Heterocycl.
Chem. 1979, 16, 1283.
(7) Ihle, N.; Krause, A. J. Org. Chem. 1996, 61, 4810.
(8) (a) Lucchesini, F. Tetrahedron 1992, 48, 9951.
(b) Pankiewicz, J.; Decroix, B.; Fugier, C.; Morel, J.;
Pastour, P. J. Chem. Res., Synop. 1978, 133. (c) Letsinger,
R.; Lasco, R. J. Org. Chem. 1956, 21, 812.
(9) (a) Wilson, W. D.; Strekowski, L.; Tanious, F.; Watson, R.;
Mokrosz, J.; Strekowska, A.; Webster, G.; Neidle, S. J. Am.
Chem. Soc. 1988, 110, 8292. (b) Kramer, R.; Fritsky, I. Eur.
J. Org. Chem. 2000, 3505. (c) Mitschker, A.; Brandl, U.;
Kauffmann, T. Tetrahedron Lett. 1974, 15, 2343. (d) van
der Stoel, R.; van der Plas, H. Recl. Trav. Chim. Pays-Bas
1978, 97, 116.
(10) Konoike, T.; Kanda, Y.; Araki, Y. Tetrahedron Lett. 1996,
37, 3339.
Synthesis 2007, No. 16, 2529–2533 © Thieme Stuttgart · New York