Preparation and chemical behavior of 2-(tert-butoxycarbonyl)amino-3- bromomethyl pyridine, a novel alkylating agent

Article abstract of DOI:10.1080/00397910500334371

Synthesis of a novel heterocyclic alkylating agent has been developed. Its instability toward elevated temperatures and/or polar media can be used to prepare 8-aza-1,4-dihydrobenzo[1,3-d]oxazin-2-one. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500334371

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Preparation and Chemical Behavior of
2‐(tert‐Butoxycarbonyl)amino‐3‐bromomethyl
Pyridine, a Novel Alkylating Agent
Mikhail Krasavin a , Sergey Shkavrov a & Dmitry Kravchenko a
a Chemical Diversity Research Institute , Moscow Reg., Russia
Published online: 15 Aug 2006.
To cite this article: Mikhail Krasavin , Sergey Shkavrov & Dmitry Kravchenko (2006) Preparation and Chemical
Behavior of 2‐(tert‐Butoxycarbonyl)amino‐3‐bromomethyl Pyridine, a Novel Alkylating Agent, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:2,
181-186, DOI: 10.1080/00397910500334371
To link to this article: http://dx.doi.org/10.1080/00397910500334371
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Synthetic Communicationsw, 36: 181–186, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500334371
Preparation and Chemical Behavior
of 2-(tert-Butoxycarbonyl)amino-
3-bromomethyl Pyridine, a Novel
Alkylating Agent
Mikhail Krasavin, Sergey Shkavrov, and Dmitry Kravchenko
Chemical Diversity Research Institute, Moscow, Russia
Abstract: Synthesis of a novel heterocyclic alkylating agent has been developed. Its
instability toward elevated temperatures and/or polar media can be used to prepare
8-aza-1,4-dihydrobenzo[1,3-d]oxazin-2-one.
Keywords: Alkylating agents, bis-functional reagents, cyclic carbamates
Heteroatom alkylation remains a common tool for rapid “scaffold decoration”
in combinatorial chemistry.[1] This, in turn, fuels the continued interest in
novel alkylating agents (such as heteroarylmethyl halides) that incorporate
pharmaceutically relevant heterocyclic moieties and, ideally, contain other
orthogonally reactive groups.
In reviewing the currently available arsenal of heteroarylmethyl halides
(HetCH2Hal) for combinatorial library design, we became particularly inter-
ested in a series of isomeric bromomethyl 2-(tert-butoxycarbonyl)aminopyri-
dines 1–4. These alkylating agents were considered because of their
ambiphilic character and the potential for convenient and SAR-informative
diversification of the library compounds via initial alkylation, subsequent Boc
group removal, and further “capping” of the free amino group. The initial
presence ofthe protectiveBoc groupisessential asitreduces(bothelectronically
and sterically) the nucleophilicity of the 2-aminopyridine moiety and, hence, the
Received in Poland June 14, 2005
Address correspondence to Mikhail Krasavin, Chemical Diversity Research
Institute, 2a Rabochaya St. Khimki, Moscow Reg. 114401, Russia.
Tel.: þ7(095)995-4942; Fax: þ7(095)926-9780; E-mail: myk@chemdiv.com
181

182
M. Krasavin, S. Shkavrov, and D. Kravchenko
tendency of this type of reagents to self-alkylation.[2] We were surprised to learn,
however, that of these four alkylating agents, only for one—2-(tert-butoxycar-
bonyl)amino-3-bromomethyl pyridine (1) (or any other protected form
thereof)—there was no preparative protocol described in the literature. A
similar chloride was reported in Ref.[3] However, we found that its use is
limited to the described in situ alkylation of thiolate anions.
Because radical bromination of corresponding methylpyridines using
N-bromosuccinimide (NBS) with common initiators (such as benzoyl
peroxide,[4] AIBN,[5] heat,[6] or microwave irradiation[7]) was the principal
method found in the literature to prepare 2–4, we proceeded to examine its
applicability to bromination of 2-(Boc-amino)-3-methyl pyridine. In all
instances, treatment of the latter with NBS resulted in predominant ring-bro-
mination and led to complex mixtures of products. Similar results were
obtained using photochemical bromination with molecular bromine in CCl4.
Attempts to C-lithiate the same material with 2.5 equiv. of n-BuLi and sub-
sequent treatment with sources of electrophilic bromine (BrCN, Br2) also
did not present a promising synthetic approach.
We therefore turned our attention to preparation and utilization of the cor-
responding hydroxymethyl derivative 7. Double Boc-protection of the amino
group in methyl 2-aminonicotinate (5) provided good yield of the ester 6.
Treatment of the latter with 2 equiv. of LiAlH4 at 08C resulted in reduction
of the ester functionality and concomitant removal of one of the two Boc
groups (Scheme 1). Lower reduction temperatures led to incomplete
removal of one of the Boc groups: the resulting impurity is indistinguishable
1
from the desired product in the H NMR spectrum but highly complicates
product purification in the subsequent step.
After an unsuccessful attempt to convert the alcohol 7 into its mesyl
derivative (with intention to treat the latter with LiBr in acetone)[8] we
Scheme 1.

2-(tert-Butoxycarbonyl)amino-3-bromomethyl Pyridine
183
Scheme 2.
found that the target bromide 1 could be obtained in fair yield by reacting the
alcohol 7 with CBr4-triphenyl phosphine in THF (Scheme 2).
This crystalline material can be stored neat indefinitely at room
temperature. However, it was discovered that at elevated temperatures (even
as low as 408C) and/or with polar solvents (such as acetonitrile and
DMSO) the bromide 1 is quantitatively converted into hitherto unreported
8-aza-1,4-dihydrobenzo[1,3-d]oxazin-2-one (8), presumably via the loss of
tert-butyl bromide. [The presence of tert-butyl bromide in the crude
1
reaction mixture was established by examination of its H NMR spectrum
(singlet at 1.12 ppm)]. Interestingly, simple heating of the alcohol 7 in aceto-
nitrile at reflux temperature for 2 h provided only poor yield of 8 (Scheme 3).
The synthetic utility of this novel heterocycle is being currently investigated
and will be reported in due course.
In summary, we have developed a synthesis of the novel bis-functional
alkylating agent 1. It was observed that this material is unstable when
exposed to a polar medium and/or elevated temperatures. These conditions
lead to quantitative conversion to an unknown cyclic carbamate 8 and can
serve as a method for its preparation.
EXPERIMENTAL
All reactions were run in oven-dried glassware in an atmosphere of nitrogen.
Melting points were measured with a Buchi B-520 melting-point apparatus
and are not corrected. Analytical thin-layer chromatography was carried
out on EM Separations Technology F254 silica-gel plates. Compounds were
visualized with short-wavelength UV light. 1H NMR and 13C NMR
spectra were recorded on Bruker DPX-300 spectrometers in DMSO-d6 or
CDCl3 using TMS as an internal standard. Mass-spectral analyses were
obtained on a PE SCIEX API 150EX mass spectrometer. All solvents and
Scheme 3.

184
M. Krasavin, S. Shkavrov, and D. Kravchenko
reagents were obtained from commercial sources and used without
purification.
Methyl 2-[bis(tert-butoxycarbonyl)amino]nicotinate (6)
A solution of methyl 2-aminonicotinate (15.2 g, 0.10 mol) in anhydrous DCM
(90 mL) was added dropwise to a solution of di-tert-butyl dicarbonate (44.0 g,
0.202 mmol) and 4-dimethylaminopyridine (0.45 g, 3.7 mmol) in anhydrous
DCM (90 mL). [Methyl 2-aminonicotinate is commercially available or can
be prepared easily from cheap 2-aminonicotinic acid using the following
simple protocol: A suspension of 2-aminonicotinic acid (25 g) in methanol
(300 mL, freshly distilled over CaO) was carefully treated with concentrated
sulfuric acid (40 mL). The mixture was heated at reflux for 20 h and then
cooled down to room temperature. The mixture was concentrated to a
volume of ꢀ100 mL and poured into a mixture of ice (1 kg) and 25%
NH4OH (140 mL). The resulting precipitate was collected by filtration and
air-dried to provide 15.2 g of methyl 2-aminonicotinate (55%).] The
resulting solution was stirred at ambient temperature for 36 h. It was then
passed through a pad of silica gel and concentrated in vacuo. The residue
was dissolved in a minimum volume of hexane (50–75 mL) and was refriger-
ated overnight. The crystals formed were filtered off and air-dried to provide
26.4 g (75%) of 6 as white shiny solid: mp ¼ 152–1538C (decomp.). 1H NMR
(300 MHz, d6-DMSO) d 9.38 (dd, J ¼ 3.2, 6.1 Hz, 1H), 8.68 (dd, J ¼ 3.2,
6.8 Hz, 1H), 7.21 (dd, J ¼ 6.1, 6.8 Hz, 1H), 3.62 (s, 3H), 1.46 (s, 18H);
13C NMR (75 MHz, d6-DMSO) d 167.6 (COOMe), 152.6, 149.3 (NCOO),
149.1, 143.5, 117.9, 115.7, 77.7 [C(CH3)3], 51.9 (OCH3), 27.6 [C(CH3)3];
LCMS m/z 353 (M þ Hþ); Anal. calcd. for C17H24N2O6: C, 57.94; H, 6.86;
N, 7.95. Found: C, 57.90; H, 6.81; N, 7.92.
2-(tert-Butoxycarbonyl)amino-3-hydroxymethyl Pyridine (7)
A solution of methyl 2-[bis(tert-butoxycabronyl)amino]nicotinate (6, 23.8 g,
67.6 mmol) in anhydrous THF (180 mL) was cooled to 08C and treated with
a 1 M solution of LiAlH4 in THF (135 mL, 2 equiv.). The reaction mixture
was stirred at 08C for 2 h, warmed to room temperature, and stirred for an
additional 30 min. The reaction mixture was slowly added to a concentrated
.
aqueous solution of KNaC2O4 4H2O (500 mL) with vigorous stirring. The
organic layer was separated, and the aqueous layer was extracted with ethyl
acetate (3 ꢀ 150 mL). The combined organic extracts were dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The product was
purified by column chromatography on silica gel (50 ! 100% ethyl acetate
in hexane) to afford crystalline 7 (9.85 g, 65%): mp ¼ 138–1398C. 1H
NMR (300 MHz, d6-DMSO) d 8.45 (br s, 1H), 8.30 (dd, J ¼ 1.7, 4.8 Hz,

2-(tert-Butoxycarbonyl)amino-3-bromomethyl Pyridine
185
1H), 7.66 (dd, J ¼ 1.7, 7.4 Hz, 1H), 7.02 (dd, J ¼ 4.8, 7.4 Hz, 1H), 4.57
(s, 2H), 1.50 (s, 9H); 13C NMR (75 MHz, d6-DMSO) d 153.6, 149.7
(C55O), 147.2, 138.8, 127.7, 120.1, 91.0 [C(CH3)3], 61.9 (CH2OH), 28.1
[C(CH3)3]; LCMS m/z 225 (M þ Hþ); Anal. calcd. for C11H16N2O3:
C, 58.91; H, 7.19; N, 12.49. Found: C, 58.96; H, 7.23; N, 12.55.
2-(tert-Butoxycabonyl)amino-3-bromomethyl Pyridine (1)
Carbon tetrabromide (4.8 g, 14.5 mmol) was added to a solution of 2-(tert-
butoxycarbonyl)amino-3-hydroxymethyl pyridine (7, 2.0 g, 8.92 mmol) in
anhydrous THF (10 mL). After full dissolution of the carbon tetrabromide,
the mixture was treated with triphenylphosphine (2.6 g, 10.0 mmol) to cause
a slight exothermic reaction. The reaction mixture was stirred at room temp-
erature for 3.5 h and then loaded onto a silica-gel column. Elution with 20%
THF in hexane provided the bromide 1 (1.3 g, 52%) as white crystalline
solid: mp ¼ 1448C (decomp.). 1H NMR (300 MHz, CDCl3) d 8.39
(d, J ¼ 4.5 Hz, 1H), 7.78 (d, J ¼ 7.5 Hz, 1H), 7.12 (dd, J ¼ 4.5, 7.5, 1H),
4.59 (s, 2H), 1.51 (s, 9H); 13C NMR (75 MHz, CDCl3) d 152.8, 149.0
(C55O), 148.0, 140.0, 125.9, 120.7, 81.3 [C(CH3)3], 30.0 (CH2Br), 28.2
[C(CH3)3]; LCMS m/z 288 (M þ Hþ); Anal. calcd. for C11H15BrN2O2:
C, 46.01; H, 5.27; Br, 27.83; N, 9.76. Found: C, 45.95; H, 5.22; Br, 27.77;
N, 9.73.
8-Aza-1,4-dihydrobenzo[1,3-d]oxazin-2-one (8)
2-(tert-Butoxycabonyl)amino-3-bromomethyl
pyridine
(1,
500 mg,
1.74 mmol) was dissolved in anhydrous acetonitrile (5 mL) and stirred at
ambient temperature for 1 h. Concentration in vacuo and purification by
column chromatography on silica gel (25% ethyl acetate in hexanes)
afforded 8 (260 mg, quant.) as white amorphous solid: mp ¼ 156–1578C.
1H NMR (300 MHz, d6-DMSO) d 10.65 (s, 1H), 8.16 (d, J ¼ 5.1 Hz, 1H),
7.61 (d, J ¼ 7.3 Hz, 1H), 7.04 (dd, J ¼ 5.1, 7.3 Hz, 1H), 5.30 (s, 2H); 13C
NMR (75 MHz, d6-DMSO) d 151.8, 149.4 (C55O), 147.7, 133.1, 118.5,
113.7, 66.3 (CH2O); LCMS m/z 151 (M þ Hþ); Anal. calcd. for
C7H6N2O2: C, 56.00; H, 4.03; N, 18.66. Found: C, 56.05; H, 4.07; N, 18.70.
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