Efficient synthesis of tert-Butyl (6-Formylpyridin-2-yl)carbamic acid

Article abstract of DOI:10.1080/00397911.2011.625291

We have developed an efficient four-step synthesis of tert-butyl (6-formylpyridin-2-yl)carbamic acid (1) in 80% overall yield using inexpensive starting material and reagents and no air-sensitive reagents. Column chromatography was not required for purification of the intermediates or the final product.

Full text of DOI:10.1080/00397911.2011.625291

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Efficient Synthesis of tert-Butyl (6-
Formylpyridin-2-yl)carbamic Acid
a
a
a
Helena Majgier-Baranowska , Bing Li & Norton P. Peet
a
Microbiotix, Inc. , Worcester , Massachusetts , USA
Accepted author version posted online: 29 Feb 2012.Published
online: 21 Feb 2013.
To cite this article: Helena Majgier-Baranowska , Bing Li & Norton P. Peet (2013) Efficient
Synthesis of tert-Butyl (6-Formylpyridin-2-yl)carbamic Acid, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:8, 1173-1180, DOI:
10.1080/00397911.2011.625291
To link to this article: http://dx.doi.org/10.1080/00397911.2011.625291
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1
Synthetic Communications , 43: 1173–1180, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.625291
EFFICIENT SYNTHESIS OF tert-BUTYL
6-FORMYLPYRIDIN-2-yl)CARBAMIC ACID
(
Helena Majgier-Baranowska, Bing Li, and Norton P. Peet
Microbiotix, Inc., Worcester, Massachusetts, USA
GRAPHICAL ABSTRACT
Abstract We have developed an efficient four-step synthesis of tert-butyl (6-formylpyridin-2-
yl)carbamic acid (1) in 80% overall yield using inexpensive starting material and reagents
and no air-sensitive reagents. Column chromatography was not required for purification of
the intermediates or the final product.
Keywords 6-Aminopyridine-2-carboxaldehyde; 6-aminopyridine-2-carboxylic acid; bis-
Boc protection; building block synthesis; carbamate protection
INTRODUCTION
Pyridine is frequently found as the core structure or a component in a variety
[
1]
[2]
of drugs, for example, ethionade, etoricoxib, dimetindene, brompheniramine,
[3]
[4]
[
5]
[6]
isoniazid, and metyrapone (Fig. 1). Consequently, there has been significant
effort directed toward the design of new and efficient syntheses for pyridine-
containing building blocks.
The specific pyridine-containing building block that we required for preparation
of a designed compound library was tert-butyl (6-formylpyridin-2-yl)carbamic acid
[7]
(
in small quantities from limited sources (CAS number: 956523-98-1). The synthesis of
1), as shown in Scheme 1, which was quite expensive and commercially available only
[8a]
compound 1 has been previously reported starting from 2-amino-6-bromopyridine
2) as shown in Scheme 1. Boc-protection of the amino group of 2-amino-6-bromo-
(
pyridine (2) gave an inseparable mixture of mono-Boc-protected compound 3 and
di-Boc-protected compound 4, in a ratio of 4:1. The mixture of mono-Boc and di-Boc
esters 3 and 4 was treated with i-PrMgCl.LiCl to give mono-Boc-protected
compound 3 in 68% yield. Treatment of compound 3 with methyllithium and
Received September 12, 2011.
Address correspondence to Norton P. Peet, Microbiotix, Inc., One Innovation Drive, Worcester,
MA 01605, USA. E-mail: npeet@microbiotix.com
1
173

1174
H. MAJGIER-BARANOWSKA, B. LI, AND N. P. PEET
Figure 1. Structures of selected pyridine-containing drugs.
n-butyllithium to produce the metallated dianion, followed by treatment with
1
dimethylformamide (DMF), provided compound 1 (yield and H NMR spectra were
not reported). Even though the reported synthesis is only three steps, this procedure
requires an expensive starting material and air-sensitive magnesium and lithium
reagents, chromatography is required, and the overall yield is poor.
[
8b]
Shown in Scheme 2 is an alternate, lengthier procedure reported for the prep-
aration of aldehyde 1. This procedure was not attractive to us because of its length
and overall poor yield. Starting with 2-acetamido-6-methylpyridine (5), which is also
costly from many suppliers, the five-step procedure gives only 6.9% yield of aldehyde
1
. It was clear, therefore, that a new, concise procedure that did not use expensive
starting materials or reagents, or air-sensitive reagents, and that was amenable to
large-scale production was needed.
To prepare multigram quantities of building block 1 to support the preparation
of our focused library, we developed a new synthesis, which is efficient and
[
8a]
Scheme 1. Literature synthesis of compound 1.
ꢀ
Reagents and conditions: (a) (Boc)
ꢀ
2
O, DMAP, TEA,
DCM, 0 C, 5 h, column chromatography; (b) iso-PrMgCl ꢁ LiCl, THF, 0 C, 30 min; and (c) CH
3
Li,
ꢀ
and then n-BuLi, DMF, THF, ꢂ78 C, 30 min and then 1 h, rt.

TERT-BUTYL (6-FORMYLPYRIDIN-2-YL)CARBAMIC ACID
1175
[
10b]
ꢀ
Scheme 2. Literature synthesis of compound 1.
(b) 2 M NaOH, reflux, 180 min; (c) H
Reagents and conditions: (a) KMnO , water, 80 C;
N, THF, 60 C, 9 h, column
4
ꢀ
2
SO
4
, EtOH, reflux, 23 h; (d) (Boc)
ꢀ
2
O, Et
3
chromatography; and (e) DIBAL, THF, ꢂ78 C, column chromatography.
cost-effective, requires no chromatography, is scalable, and high yielding, and
importantly avoids air-sensitive reagents. This synthesis, which contains an impor-
tant and rather unusual bis-Boc intermediate (compound 10), is shown in Scheme 3.
We envisioned that esterification of 6-amino-2-picolinic acid (7) would proceed
smoothly to produce 6-amino-2-picolinic acid ethyl ester (8) as shown in Scheme 3.
Indeed, by employing a modified procedure where 6-amino-2-picolinic acid (7) was
[
9c]
treated with SOCl in absolute EtOH at reflux
2
for 72 h, we obtained the corre-
[
9a,b]
sponding ester 8 as a hydrochloride salt in 97% yield.
8
Preparation of compound
from 7 has also been reported by using the following conditions: 4 N HCl in
[
9d]
[9e]
[9f]
1,4-dioxane,
9g]
H SO
HCl or oxalyl chloride in dichloromethane (DCM),
followed by EtOH. All of these procedures give modest yields of esterified
and
[
2
4
product. The corresponding methyl ester has also been synthesized using methanolic
[
9h]
hydrogen chloride.
-picolinic acid (9) from ester 8 (Scheme 2) using reported conditions were unsuc-
Our efforts to obtain ethyl 6-[(tert-butyloxycarbonyl)amino]-
9c]
[
2
cessful; a mixture of compounds was produced, which contained mono-Boc and
di-Boc products, as well as the starting material 8. The mono-Boc and di-Boc product
mixture was extremely difficult to separate using silica-gel column chromatography.
However, we noticed that reduction of a mixture of mono-Boc and di-Boc esters with
a metal hydride led solely to mono-Boc alcohol 11. Therefore, we decided to directly
prepare the di-Boc compound 10 and then reduce the ester group to directly produce
alcohol 11, which would be the immediate precursor to the desired aldehyde 1, as
shown in Scheme 3.
Scheme 3. New synthesis of compound 1. Reagents and conditions: (a) SOCl
ꢀ
2
, EtOH, reflux 72 h;
, EtOH, 0 C, 90 min, and then rt,
(
b) tert-BuOH, acetone, (Boc)
2
O, DMAP, rt, 77 h; (c) NaBH , CaCl
Cl (1:4), rt, 90 min.
2
4
2
9
0 min; and (d) pyridine-SO , DMSO-CH
3
2

1176
H. MAJGIER-BARANOWSKA, B. LI, AND N. P. PEET
[
10a]
Scheme 4. Literature synthesis of compound 11.
ꢀ
Reagents and conditions: (a) DPPA, TEA, tert-
ꢀ
BuOH, toluene, 100 C, overnight, column chromatography; and (b) CaCl
2
, NaBH CN, EtOH, 0 C, 2 h.
3
Treatment of compound 8 with Boc anhydride, in the presence of dimethylami-
nopyridine (DMAP), either in an acetone=tert-BuOH solution or in dichloro-
methane, produced only bis-Boc intermediate 10, in 88% or 82% yield, respectively.
The product was recovered by crystallization from the reaction mixture, at low tem-
peratures, and no mono-Boc-protected product was detected after crystallization.
Next, compound 10 was treated with Ca(BH ) , generated in situ from CaCl
2
4
2
ꢀ
and NaBH , in absolute EtOH at 0 C to give the corresponding tert-butyl
4
[
6-(hydroxymethyl)pyridin-2-yl]carbamic acid (11) in 99% yield. Note that under
the reduction conditions, the di-Boc-protected amino group was simultaneously
transformed to the mono-Boc-protected amino group.
[
10a]
Synthesis of compound 11 has previously been reported
using several
approaches, starting from expensive 6-(ethoxycarbonyl)-2-picolinic acid (12, CAS
number: 21855-16-3) with variable yields. For example, under Curtis rearrangement
conditions, compound 12 was converted to ethyl 6-[(tert-butyloxycarbonyl)amino]-
2
reduced the ester to produce alcohol 11 (quantitative yield).
-picolinic acid (9); subsequent treatment of 9 with NaBH CN=CaCl efficiently
2
3
10a]
[
Other reduction con-
[
10bꢂe]
ditions for the conversion of 9 to 11 have also been used,
[
including NaBH4=
Synthesis of alcohol 11 has also been reported from
10b,c]
[9a]
CaCl2
aldehyde 1 by reduction with NaBH4.
and LiAlH4.
[8a]
Our attempt to oxidize alcohol 11 to aldehyde 1 with the Dess–Martin reagent
was inefficient; only 9% of the desired compound 1 was produced. Finally, the
corresponding aldehyde 1 was obtained in excellent yield (95%) from oxidation of
alcohol 11 at room temperature in dimethylsulfoxide (DMSO)–CH Cl (1:4) by
2
2
[
11]
employing the inexpensive Parikh–Doering reagent (pyridine-SO3) in the presence
of Et N. The final crude product 1 was purified simply by elution with 2:3 EtOAc–
hexanes through a plug of silica gel to remove traces of pyridine.
3
In summary, we have developed a practical and efficient four-step synthesis of
tert-butyl (6-formylpyridin-2-yl)carbamic acid (1) in 80% overall yield. The synthesis
started from inexpensive 6-amino-2-picolinic acid (7). All four synthetic steps were
performed with inexpensive, non-air-sensitive chemical reagents, and purification of
the intermediates and the final product avoided silica-gel column chromatography.
Compound 1 is a useful two-point scaffold and building block for the synthesis of
compound libraries with potential biological activity.
EXPERIMENTAL
Ethyl 6-Amino-2-picolinic Acid (8)

TERT-BUTYL (6-FORMYLPYRIDIN-2-YL)CARBAMIC ACID
1177
A heterogeneous mixture of 6-amino-2-picolinic acid (7) (25 g, 0.181 mol) in absolute
ꢀ
ethanol (190 mL) was cooled in an acetone–dry ice bath (0 C) and carefully treated
with SOCl (15 mL) under an argon atmosphere with stirring. The reaction mixture
2
ꢀ
was heated in an oil bath at 85 C. Additional SOCl was added to the reaction
2
mixture after 21 h (16 mL) and 45 h (10 mL), and heating was continued for an
additional 24 h. The reaction mixture was cooled to rt, diluted with ethyl ether
ꢀ
(
200 mL), and stored in a refrigerator (þ5 C) overnight. The solid that formed
was collected by filtration, washed with ethyl ether, and air dried to give a cream-
colored solid as the hydrochloride salt of 8. This hydrochloride salt was suspended
in CH Cl and treated with saturated aqueous NaHCO until the phases were clear.
2
2
3
The organic layer was separated, washed with water and brine, dried over Na SO ,
2
4
and co-evaporated with hexanes, and the residue was triturated with hexanes and
collected to give 8 as a cream-colored solid (24.69 g, 97%), R ¼ 0.33 (1:1 EtOAc–
f
ꢀ
1
hexanes), mp 115.7–116.2 C, LC=MS=m=z 166 (M þ 1). H NMR (300 MHz,
CDCl ) d ¼ 7.56–7.45 (m, 2H), 6.67 (dd, J ¼ 0.9, 8.1 Hz, 1H), 4.94 (bs, 2H), 4.42
3
1
(
4
q, J ¼ 7.2 Hz, 2H), 1.41 (t, J ¼ 7.2 Hz, 3H) (reported H NMR spectrum at
[
9i]
00 MHz).
Ethyl Bis-(N,N-tert-butyloxycarbonyl)-6-amino-2-picolinic Acid (10)
Method A. A mixture of ethyl 6-amino-2-picolinic acid (8) (19.0 g, 114 mmol),
tert-BuOH (100 mL) and acetone (65 mL) was treated with DMAP (2.79 g, 228 mmol)
and a solution of di-tert-butyl dicarbonate (53.9 g, 247 mmol) in tert-BuOH (35 mL)
and stirred at room temperature for 48 h. The reaction mixture was diluted with hex-
ꢀ
anes (600 mL) and cooled to ꢂ60 C for 3 h. A white solid was collected by filtration,
washed with cold hexanes, and dried in air. The filtrate was evaporated to dryness.
The residue was dissolved in a minimal amount of CH Cl , diluted with hexanes,
2
2
ꢀ
and cooled to ꢂ20 C. The second crop was collected by filtration, washed with cold
hexanes to give, in total, 10 as a white solid (36.8 g, 88%), R ¼ 0.75 (1:1 EtOAc–
f
ꢀ
1
hexanes), mp 112–116 C; LC=MS=m=z 367.4 (M þ 1). H NMR (300 MHz, CDCl )
3
d ¼ 8.03 (d, J ¼ 7.8 Hz, 1H), 7.87 (t, J ¼ 8.1 Hz), 7.47 (d, J ¼ 7.2 Hz), 4.45 (q, J ¼
7
.2 Hz, 2H), 1.46 (s, 18H), 1.41 (t, J ¼ 6.9 Hz, 3H).
Method B. Di-tert-butyl dicarbonate (1.24 g, 5.68 mmol) and DMAP (63 mg,
.534 mmol) were added to a stirred solution of 6-amino-2-picolinic acid ethyl ester
0
(
8) (300 mg, 1.80 mmol) in CH Cl (5 mL). After stirring for 18 h, additional di-tert-
2 2
butyl dicarbonate (169.1 mg, 0.775 mmol) was added, and stirring was continued
for 12 h. Additional di-tert-butyl dicarbonate (170.4 mg, 0.781 mmol) was again
added, and stirring was continued for another 12 h. The solution was passed through
a pad of silica gel and concentrated. The solid residue was dissolved in a minimum
ꢀ
volume of hexanes and refrigerated (þ5 C) overnight to give white crystals that were
collected by filtration and dried in air and then under high vacuum to give compound
1
0 as a white powder (0.541 g, 1.48 mmol, 82%), R ¼ 0.75 (1:1 EtOAc–hexanes),
f

1178
H. MAJGIER-BARANOWSKA, B. LI, AND N. P. PEET
ꢀ
1
mp 112 ꢂ 116 C; LC=MS=m=z 367.4 (M þ 1). H NMR (300 MHz, CDCl ) d ¼ 8.02
3
(
d, J ¼ 7.8 Hz, 1H), 7.86 (t, J ¼ 7.8 Hz), 7.47 (d, J ¼ 8.1 Hz, 1H), 4.45 (q, J ¼ 7.2 Hz,
2
H), 1.46 (s, 18H), 1.41 (t, J ¼ 6.9 Hz, 3H).
tert-Butyl [6-(Hydroxymethyl)pyridin-2-yl]carbamic Acid (11)
A sonicated suspension of 93% CaCl (12.1 g, 109 mmol) in EtOH (70 mL) was added
2
followed by the portionwise addition of solid NaBH (10.3 g, 273 mmol), sequentially,
4
over 20 min to a solution of ethyl bis-(N,N-tert-butyloxycarbonyl)-6-amino-2-pico-
linic acid (10) (10 g, 27.3 mol) in absolute ethanol (250 mL) cooled in an ice-water
ꢀ
bath. The heterogeneous mixture was stirred at 0 C for 90 min and then at room
temperature for an additional 90 min. The suspension was filtered, and the precipitate
was washed with absolute ethanol. The filtrate was evaporated to give a transparent,
gelatinous residue. The residue was dissolved in CHCl and washed with 1 N NaOH.
3
The resulting white suspension was filtered, and the precipitate was washed with
chloroform. The filtrate was extracted with chloroform, and the combined organic
layers were washed with brine, dried over Na SO , and evaporated to give a glassy
2
4
residue 11 (6.05 g, 99%), R ¼ 0.56 (1:1 EtOAc–hexanes), LC=MS=m=z 255.4
f
1
(
1
M þ 1). H NMR (300 MHz, CDCl ) d ¼ 7.82 (d, 8.4 Hz, 1H), 7.65 (t, J ¼ 7.8 Hz,
3
H), 7.23 (bs, 1H), 6.89 (dd, J ¼ 0.6, 7.5 Hz, 1H), 4.65 (d, J ¼ 4.8 Hz, 2H), 3.40
1
[10c]
(t, J ¼ 5.1 Hz, 1H), 1.53 (s, 9H) (reported H NMR).
tert-Butyl (6-Formylpyridin-2-yl)carbamic Acid (1)
Et N (17.3 mL) followed by the portionwise addition of pyridine-SO (11.9 g,
3
3
7
pyridin-2-yl)carbamic acid (11) (5.58 g, 24.9 mmol) in CH Cl (250 mL) and dry
4.8 mmol) was added at rt to a stirred solution of tert-butyl (6-(hydroxymethyl)
2
2
DMSO (62 mL). Stirring was continued for 1.5 h, and the reaction solution was
quenched with water (600 mL) and extracted with EtOAc (4 ꢃ 600 mL). The organic
layer was washed with water and brine, dried over Na SO , and evaporated to give a
2
4
crude product. The crude product was applied to a thick pad of silica and eluted with
:3 EtOAc–hexanes to remove a trace of pyridine. Evaporation of the solvents gave
2
the desired product 1 as a honey-colored solid (5.26 g, 95%), R ¼ 0.66 (2:3 EtOAc–
f
ꢀ
1
hexanes), mp 156 C (dec). LC=MS=m=z 224 (M þ 1). H NMR (300 MHz, CDCl )
3
d ¼ 9.89 (s, 1H), 8.20 (d, J ¼ 8.4 Hz, 1H), 7.84 (t, J ¼ 7.5 Hz, 1H), 7.62 (dd, J ¼ 0.6,
1
.5, 1H), 7.48 (bs, 1H), 1.54 (s, 9H) (reported H NMR at 400 MHz).
[8b]
7

TERT-BUTYL (6-FORMYLPYRIDIN-2-YL)CARBAMIC ACID
1179
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4
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