Novel method of synthesizing various five membered heterocycles from an aryl tribromomethyl group

Article abstract of DOI:10.1080/00397911.2012.679331

Synthesis of five membered heterocycles from an aryl tribromomethyl functional group is discussed. Exposing a tribromomethyl group to subsequent nucleophilic attacks by a 1,2-di-nucleophilic species promotes the cyclization of five membered heterocycles. Such heterocycles as oxadiazoles, thiadiazole, benzimidazole, benzothioazole, and benzoxazole were synthesized in moderate to good yields. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.679331

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Novel Method of Synthesizing Various
Five Membered Heterocycles from an
Aryl Tribromomethyl Group
Robert Tynebor a & Elizabeth Millings b
a Medicinal Chemistry, Merck and Company, West Point, New York,
USA
b Department of Chemistry, State University of New York at Stony
Brook, Stony Brook, New York, USA
Published online: 05 Apr 2013.
To cite this article: Robert Tynebor & Elizabeth Millings (2013) Novel Method of Synthesizing Various
Five Membered Heterocycles from an Aryl Tribromomethyl Group, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:14, 1902-1908,
DOI: 10.1080/00397911.2012.679331
To link to this article: http://dx.doi.org/10.1080/00397911.2012.679331
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Synthetic Communications1, 43: 1902–1908, 2013
Copyright # Merck and Company
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.679331
NOVEL METHOD OF SYNTHESIZING VARIOUS FIVE
MEMBERED HETEROCYCLES FROM AN ARYL
TRIBROMOMETHYL GROUP
Robert Tynebor1 and Elizabeth Millings2
1Medicinal Chemistry, Merck and Company, West Point, New York, USA
2Department of Chemistry, State University of New York at Stony Brook,
Stony Brook, New York, USA
GRAPHICAL ABSTRACT
Abstract Synthesis of five membered heterocycles from an aryl tribromomethyl functional
group is discussed. Exposing a tribromomethyl group to subsequent nucleophilic attacks
by a 1,2-di-nucleophilic species promotes the cyclization of five membered heterocycles.
Such heterocycles as oxadiazoles, thiadiazole, benzimidazole, benzothioazole, and benzox-
azole were synthesized in moderate to good yields.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Cyclization; heterocycles; tribromomethyl
INTRODUCTION
Recent work on a medicinal chemistry program required the conversion of
dibromobenzyl derivative 1 to aldehyde 3 using a previously published procedure.[1]
However, during the process it was apparent that minor amounts of overbrominated
starting material 2 led to formation of amide 4 (Scheme 1). This conversion of a
tribromomethyl group to an amide was not noted in the procedure, but a literature
search revealed previous articles describing this particular transformation with
limited examples.[2]
More recently, Ellis employed mild conditions to convert a tribromide sub-
strate into an amide by refluxing in acetonitrile with the appropriate amine and
diisopropylethyl amine (DIPEA) for 6 h in moderate to good yields (48–72%).[3]
In our laboratory we independently discovered that potassium carbonate and
Received December 15, 2011.
Address correspondence to Robert Tynebor, Medicinal Chemistry, Merck and Company, 770
Sumneytown Pike, P. O. Box 4, West Point, NY 19486, USA. E-mail: robert_tynebor@merk.com
1902

FIVE-MEMBERED HETEROCYCLES
1903
Scheme 1. Treating a mixture of 1 and 2 with dimethyl amine yields products 3 and 4.
N-methyl-2-pyrrolidone (NMP) produced better yields for our particular substrate.
Both reaction conditions were probed together using the commercially available
2-(tribromomethyl)quinoline (5) (Scheme 2). Benzyl amine and piperidine amide
derivatives 6a and 6b were synthesized by treating 5 with an amine (2 eq), potassium
carbonate (3 eq), and NMP at 70 ꢀC to yield 52% and 54% of 6a and 6b. Treating 5
with acetonitrile=DIPEA afforded 41% and 40% of 6a and 6b, respectively (Table 1).
For this particular tribromomethyl substrate, acetonitrile=DIPEA led to a slower
reaction time and also produced more of the dimer by-product 7. Another advantage
to using the NMP=K2CO3 method is the potential to heat the reaction higher to
drive subsequent reactions to completion.
To further develop the synthetic utility of an aryl tribromomethyl functional
group, we explored the possibility of removing any residual water that presumably
leads to the amide functional group and treat proposed methanimine intermediate
8 with an additional nucleophile (Scheme 3). If the second nucleophile attacks the
imine of 8, the product formed would be a five membered ring. As a result, various
1,2-di-nucleophiles could theoretically produce a diverse range of five membered
heterocycles (9).
Synthesis of 1,3,4-oxadiazole 10 and 1,3,4-thiadiazole 11[4] required the
reaction of benzohydrazide or benzenecarbothiohydrazide with tribromide 5 using
identical NMP=K2CO3 conditions prescribed for amides 6a and b (Table 2). In both
cases the reactions progressed faster than the synthesis of the amides and a full
conversion was observed within 90 min.
3-substituted 1,2,4-oxadiazoles 12 and 13 were synthesized by the reaction of
N0-hydroxycarboximidamides and tribromide 5. N0-Hydroxybenzenecarboximida-
mide yielded 50% of the 3-phenyl-substituted oxadiazole 13 and only required
1.5 h of heating at 70 ꢀC. Methyl derivative 12 also required 3 h of heating at
70 ꢀC and yielded 32% of the desired product.
To further define the reaction scope, 2-[4-(tribromomethyl)phenyl] pyridine
(14) was synthesized and treated with di-nucleophiles. This particular substrate
was chosen to determine if the reaction requires a nitrogen a to the tribromo methyl
Scheme 2. Synthesis of amides 6a and b from tribromomethyl 5.

1904
R. TYNEBOR AND E. MILLINGS
Table 1. Reaction of tribromomethylquinoline 5 with amines at 70 ꢀC
Product yield
Product yield
Condition
6a
7
h
6b
7
h
(10)b
(53)
9
7
54
40
(43)
10c
4
4d
a
NMP=K2CO3
CAN=DIPEAa
52
41
a3 eq of base.
bParentheses indicate LCMS conversion of 7 with respect to intensity of 6a and b.
cIsolated yield of 7.
dRecovered 34% of 5.
Scheme 3. Proposed synthesis of five membered heterocycles from an aryl tribromomethyl group.
Table 2. Reaction of tribromomethylquinoline 5 with various 1,2 di-nucleophiles
Compound
10
Nucleophile
Product
Yield (%)
Temp. (ꢀC)
Time(h)
1.5
70
70
11
12
13
42
32
50
70
70
70
1
3
1.5

FIVE-MEMBERED HETEROCYCLES
1905
Table 3. Reaction of tribromomethylphenyl 14 with various a,b bis-nucleophiles
Yield
(%)
Temp.
(ꢀC)
Time
(h)
Compound
Nucleophile
Product
15
56
36
70
4.0
5.0
16
70
group as previous examples suggest.[2,3] Tribromomethyl 14 was synthesized by
refluxing 2-(4-methylphenyl)pyridine in the presence of NBS (3.3 eq) and benzoyl
peroxide (0.1 eq) in CCl4 to afford 37% of the desired product. Oxadiazoles 15
and 16 were synthesized in a manner similar to 10 and 13 with slightly reduced yields
(Table 3). Because the yields of 15 and 16 were similar to their quinoline counter-
parts, we can assume the a nitrogen has no significant role in the reaction mechanism
(Scheme 4).
Initial attempts to synthesize fused bicyclic systems 17 and 20 yielded a mixture
of desired product and amide at 70 ꢀC (Scheme 5). For example, the reaction
between 1,2-phenyldiamine and 5 at 70 ꢀC yielded 52% of the 2-aminephenyl amide
=
21 (x ¼ N) and only a trace of the desired product 18 (X N). However, increasing
the reaction temperature to 130 ꢀC for 5 h facilitated ring closure and produced ben-
zimidazole 18 in good yield (Table 4). Benzothioazole 17 and benzoxazole 19 were
synthesized in poor to moderate yield because of a 1:1 mixture of product–amide
forming at 130 ꢀC. Treating 14 with 2-aminobenzenethiol and heating the reaction
mixture to 130 ꢀC afforded 37% of benzothiazol 20 after 2 h. The lower yield
observed for the bicyclic systems 17–20 could potentially be due to the increased
Scheme 4. Synthesis of heterocycles 15 and 16 by treating 2-[4-(tribromomethyl)phenyl]pyridine (14) with
di-nucleophiles.
Scheme 5. Synthesis of fused 5,6-bicyclic hetereocycles 17–20.

1906
R. TYNEBOR AND E. MILLINGS
Table 4. Reaction of tribromides 5 and 14 with 1,2 di-nucleophilic benzenes
Compound R-Br3
Nucleophile
Product
Yield (%) Temp (ꢀC) Time (h)
17
18
5
5
35
49
130
130
2
5
19
20
5
23
37
130
130
1.5
2
14
steric hindrance between the aryl tribromide group and the phenyl group and also
due to the limited flexibility of the 1,2-substituted phenyl groups to facilitate the
second nucleophilic attack.
To eliminate thermal cyclization of the amide intermediate 21 as a mechanism
for synthesizing benzimidazole 18, a couple of different reaction conditions were
explored. Synthesizing amide 21 by using 1-[bis(dimethylamino)methylene)-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and heating the puri-
fied product at 130 ꢀC for 5 h in only NMP yielded a trace of the cyclized product.
Treating amide 21 with K2CO3 in NMP and heating to 130 ꢀC for 5 h also failed to
yield more than 5% of product by liquid chromatography–mass spectrometry (LCMS)
analysis. An alternative approach to test the amide intermediate cyclization hypothesis
was to form 21 by heating the reaction in Scheme 5 at 50ꢀC for 48h to produce a 21:18
ratio of 5.9:1. At this point the reaction temperature was increased to 130ꢀC to mimic
the conditions and environment for the formation of 18 in Table 4. After 8 h of heating
at 130 ꢀC, the reaction mixture still maintained a 4.2:1 ratio of compounds 21:18.
Because neither of the conditions employed facilitated any substantial conversion of
amide 21 to benzimidazole 18 it can therefore be understood that the amide is not
a precursor to cyclization for 5,6-fused biaryl heterocyclic systems and therefore
proceeds through a different mechanism.
In summary, treating an aryl tribromomethyl group with various 1,2
di-nucleophiles led to the development of a one-step procedure to synthesize several
five membered heterocycles. This new methodology further increases the accessibility
of five membered heterocycles for synthesizing biologically relevant molecules.
EXPERIMENTAL
Proton nuclear magnetic resonance spectra (1H NMR) data was obtained using
a Varian 400-MHZ instrument. High resolving power accurate mass measurements
were acquired by use of a Bruker Daltonics 7 T Fourier transform ion cyclotron

FIVE-MEMBERED HETEROCYCLES
1907
resonance (FTICR) mass spectrometer. Samples were dissolved in acetonitrile–
water–acetic acid (50:50:0.1% v=v), and ionized by use of electrospray ionization
(ESI). External calibration was accomplished with oligomers of polypropylene glycol
(PPG, average molecular weight 425 Da). Column chromatography was performed
using Biotage 12-g snap columns.
Conversion of 2-(Tribromomethyl)quinoline into Amides 6a and b
Representative procedure: N-Benzylquinoline-2-carboxamide 6a. Benzyl
amine (28 mg, 0.26 mmol) was added to a stirring mixture of potassium carbonate
(54.6 mg, 0.39 mmol) and 2-(tribromomethyl)quinoline (50 mg, 0.13 mmol) in NMP
(1.3 mL). The reaction mixture was heated to 70 ꢀC for 9 h. The reaction was cooled
to rt, quenched with water, and extracted with EtOAc (2ꢁ). The combined organic
layers were washed with water (3ꢁ) and brine (2ꢁ), dried over MgSO4, filtered, and
evaporated. The crude residue was purified by silica-gel chromatography using
5–50% EtOAc=Hex to yield the product (18 mg, 52%).
Data. 1H NMR (CHCl3) d 4.74 (2 H, d, J ¼ 6.14 Hz), 7.27–7.45 (4 H, m),
7.56–7.63 (1 H, m), 7.74 (1 H, ddd, J ¼ 8.54, 6.84, 1.48 Hz), 7.87 (1 H, d, J ¼ 8.20 Hz),
8.06 (1 H, d, J ¼ 8.51 Hz), 8.27–8.38 (2 H, m), 8.60 (1 H, s). MS m=z (M þ H)
263.1175 found; 263.1179 required.
Piperidin-1-yl(Quinolin-2-yl)methanone 6b
Piperidine (11 mg, 0.26 mmol) was added to a stirring mixture of DIPEA
(54.6 mg, 0.39 mmol) and 2-(tribromomethyl)quinoline (50 mg, 0.13 mmol) in
acetonitrile (ACN) (1.3 mL). The reaction mixture was heated to 70 ꢀC for 4 h. The
reaction was cooled to rt, quenched with water, and extracted with EtOAc (2ꢁ).
The combined organic layers were washed with water (3ꢁ) and brine (2ꢁ), dried over
MgSO4, filtered, and evaporated. The crude residue was purified by silica-gel chro-
matography using 0–100% EtOAc=Hex to yield the product (13 mg, 40%).
1H NMR (CHCl3) d 1.56–1.79 (6 H, m), 3.47–3.52 (2 H, m), 3.76–3.81 (2 H, m),
7.58 (1 H, t, J ¼ 7.50 Hz), 7.64 (1 H, d, J ¼ 8.42 Hz), 7.71–7.76 (1 H, m), 7.83 (1 H, d,
J ¼ 8.16 Hz), 8.09 (1 H, d, J ¼ 8.51 Hz), 8.23 (1 H, d, J ¼ 8.43 Hz). MS m=z (M þ H)
241.1332 found; 241.1335 required.
Conversion of an Aryl Tribromomethyl into Oxadiazoles (10, 12, 13
15, 16) and Thiadiazole (11)
Representative procedure: 2-(5-Phenyl-1,3,4-oxadiazol-2-yl)quinoline
10. Benzohydrazide (35.8 mg, 0.26 mmol) was added to a stirring mixture of potass-
ium carbonate (54.6 mg, 0.39 mmol) and 2-(tribromomethyl)quinoline (50 mg,
0.13 mmol) in NMP (1.3 mL). The reaction mixture was heated to 70 ꢀC for 1.5 h.
The reaction was cooled to rt, quenched with water, and extracted with EtOAc
(2ꢁ). The combined organic layers were washed with water (3ꢁ) and brine (2ꢁ), dried
over MgSO4, filtered, and evaporated. The crude residue was purified by silica-gel
chromatography using 0–50% EtOAc=Hex to yield the product (25 mg, 70%).

1908
R. TYNEBOR AND E. MILLINGS
Data. 1H NMR (CHCl3) d 7.52–7.56 (2 H, m), 7.63 (1 H, t, J ¼ 7.52 Hz),
7.77–7.82 (1 H, m), 7.88 (1 H, d, J ¼ 8.19 Hz), 8.24–8.28 (3 H, m), 8.29–8.41 (2 H,
m). MS m=z (M þ H) 274.0970 found; 274.0975 required.
Conversion of an Aryl Tribromomethyl into Fused 5,6 Bicyclic
Heterocycles (17–20)
Representative
procedure:
2-(1,3-Benzothiazol-2-yl)quinoline
17. 2-Aminobenzenethiol (33.0 mg, 0.26 mmol) was added to a stirring mixture of
potassium carbonate (54.6 mg, 0.39 mmol) and 2-(tribromomethyl)quinoline
(50 mg, 0.13 mmol) in NMP (1.3 mL). The reaction mixture was heated to 130 ꢀC
for 2 h. The reaction was cooled to rt, quenched with water, and extracted with
EtOAc (2ꢁ). The combined organic layers were washed with water (3ꢁ) and brine
(2ꢁ), dried over MgSO4, filtered, and evaporated. The crude residue was purified
by silica-gel chromatography using 10–100% EtOAc=Hex to yield the product
(12 mg, 35%).
Data. 1H NMR (CHCl3) d 7.39–7.45 (1 H, m), 7.46–7.53 (1 H, m), 7.54–7.60
(1 H, m), 7.71–7.79 (1 H, m), 7.85 (1 H, d, J ¼ 8.16 Hz), 7.97 (1 H, d, J ¼ 7.92 Hz),
8.11 (1 H, d, J ¼ 8.22 Hz), 8.18 (1 H, d, J ¼ 8.50 Hz), 8.28 (1 H, d, J ¼ 8.56 Hz),
8.47 (1 H, d, J ¼ 8.53 Hz). MS m=z (M þ H) 263.0635 found, 263.0637 required.
Complete spectral details are available online in the Supplemental Materials.
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N-bromosuccinimide. Bull. Chem. Soc. Jpn., 1994, 67, 1113–1119.
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