Synthesis of bromocyclopropylpyridines via the Sandmeyer reaction

Article abstract of DOI:10.1016/j.tetlet.2017.03.029

The reactions of 2-amino-5-cyclopropylpyridine with organic nitrites in the presence of copper(II) halides in various organic solvents were investigated. Optimal reaction conditions for the Sandmeyer reaction were developed and successfully applied to the synthesis of useful building blocks, bromo and chlorocyclopropylpyridines. Aminocyclopropylpyridines were synthesized in high yields from the corresponding aminobromopyridines under standard Suzuki coupling conditions.

Full text of DOI:10.1016/j.tetlet.2017.03.029

Accepted Manuscript
Synthesis of bromocyclopropylpyridines via the Sandmeyer reaction
Romualdas Striela, Gintaras Urbelis, Jurgis Sūdžius, Sigitas Stončius, Rita
Sadzevičienė, Linas Labanauskas
PII:
S0040-4039(17)30324-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.029
TETL 48730
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 January 2017
28 February 2017
8 March 2017
Please cite this article as: Striela, R., Urbelis, G., Sūdžius, J., Stončius, S., Sadzevičienė, R., Labanauskas, L.,
Synthesis of bromocyclopropylpyridines via the Sandmeyer reaction, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.03.029
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Tetrahedron Letters
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Synthesis of bromocyclopropylpyridines via the Sandmeyer reaction
Romualdas Striela, Gintaras Urbelis, Jurgis Sūdžius, Sigitas Stončius, Rita Sadzevičienė and Linas
Labanauskas∗
Center for Physical Sciences and Technology, Akademijos 7, LT-08412 Vilnius, Lithuania
ARTICLE INFO
ABSTRACT
Article history:
Received
The reactions of 2-amino-5-cyclopropylpyridine with organic nitrites in the presence of
copper(II) halides in various organic solvents were investigated. Optimal reaction conditions for
the Sandmeyer reaction were developed and successfully applied to the synthesis of useful
building blocks, bromo and chlorocyclopropylpyridines. Aminocyclopropylpyridines were
synthesized in high yields from the corresponding aminobromopyridines under standard Suzuki
coupling conditions.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Aminopyridine
Cyclopropylpyridine
Sandmeyer reaction
Copper catalysis
Suzuki reaction
The cyclopropylpyridine scaffold is widely used in the
development of biologically active substances. Compounds
containing the 2-substituted 5-cyclopropylpyridine moiety have
been reported as inhibitors of interleukin receptor-associated
kinases,1,2 type 1a growth hormone secretagogue receptor (GHS-
R1a) inverse agonists3 and voltage-gated sodium channel
blockers.4,5 2-Substituted 3- or 4-cyclopropylpyridines were used
for the synthesis of canabinoid receptor 2 agonists6-8 or PDE4
enzyme inhibitors.9 Compounds containing the 4-substituted 3-
cyclopropylpyridine moiety possess similar biological
activities.10,11
The synthesis of cyclopropylpyridine derivatives is usually
based on the palladium catalyzed coupling of halogenated
cyclopropylpyridines.1-11 Several reaction pathways to these
attractive building blocks have been reported, including from the
corresponding cyclopropylpyridines by rearrangement of N-
oxides in PBr3,6,7 by halogenation using BuLi chemistry11 or
direct bromination of an activated pyridine ring.12 The latter
pathway is problematic due to the lability of the cyclopropyl ring.
Another methodology is based on introduction of the cyclopropyl
group to the pyridine ring using Suzuki12-15 or Kumada16 coupling
interested in the synthesis of bromocyclopropylpyridines and, in
particular, 2-bromo-5-cyclopropylpyridine. To the best of our
knowledge, synthesis of the latter compound as well as the other
three isomers, i.e. 2-bromo-3-cyclopropyl-, 2-bromo-4-
cyclopropyl- and 4-bromo-3-cyclopropylpyridine, has not been
reported.
The
synthesis
of
2-halogeno-5-cyclopropylpyridines
employing Suzuki coupling reactions appears to be limited to 2-
fluoro and 2-chloroderivatives,17,18 whereas the Negishi coupling
reaction of 2,5-dibromopyridine affords the isomeric 5-bromo-2-
cyclopropylpyridine.23 This encouraged us to investigate the
possibility to synthesize bromocyclopropylpyridines from
aminobromopyridines using an alternative route, e.g. Suzuki
coupling followed by the Sandmeyer reaction. The latter reaction
is a widely used method for the preparation of aryl halides from
aryl amines. Aryl diazonium halides, obtained from aryl amines
by diazotization using sodium nitrite/hydrohalic acid in water24 or
alkyl nitrites,25 react with copper halides to form the
corresponding halides in average to good yields. However, in the
case of substituted 2-aminopyridines, especially those possessing
acid sensitive groups, the Sandmeyer reaction gives only average
yields or even no reaction under standard conditions.26,27
reactions
of
dihalogenopyridines.
Nevertheless,
both
modifications of this method are often concomitant with low to
average yields and purification problems due to the formation of
side-products.17-19 Cyclization of the 3-hydroxypropyl group20
and other methods of cyclopropyl ring formation21-22 provide low
to average yields or are unsuitable for the synthesis of
monosubstituted cyclopropanes.
Doyle and co-workers25 reported the rapid conversion of aryl
amines into aryl chlorides and aryl bromides using alkyl nitrites
and anhydrous copper(II) halides in acetonitrile. Herein, we
present
a study on the copper catalyzed reactions of
aminocyclopropylpyridines with alkyl nitrites in organic
solvents.
As part of an ongoing research program regarding the
synthesis of cyclopropyl-substituted building blocks, we became
———
∗ Corresponding author. Tel.: +370 615 20561; fax: +370 5260 2317; e-mail: linas.labanauskas@ftmc.lt

2
Tetrahedron Letters
Table 1. Sandmeyer reaction of 2-amino-5-cyclopropylpyridine 1a: optimization of the reaction conditionsa
Entry
CuX2 (eq.)
RONO (eq.)
Solvent
Time (h)
Product distribution (%)b
1a
3
9
1
2
1
1
0
1
1
1
0
0
0
0
2
8
0
2a, 3a
4a–4e
5a–5b
6
0
0
0
2
1
2
1
4
5
2
3
3
9
4
2
1
1
1c
2
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (1.2)
CuBr2 (0.5)
CuBr2 (0.5)
CuBr2 (0.5)
CuBr2 (0.1)
CuBr2 (0.05)
CuCl2 (0.5)
AmylONO (1.2)
AmylONO (1.2)
AmylONO (1.2)
AmylONO (1.2)
AmylONO (1.2)
AmylONO (1.2)
AmylONO (1.2)
AmylONO (1.2)
AmylONO (1.2)
t-BuONO (1.2)
AmylONO (1.2)
AmylONO (1.1)
AmylONO (1.1)
t-BuONO (1.1)
AmylONO (1.1)
AmylONO (1.1)
AmylONO (1.1)
MeCN
72
72
16
3
2a, 21
4a, 58
5a, 1
5a, 1
0
MeCN
2a, 26
4a, 57 (52)d
3
MeOH
2a, 17
4b, 80
4
THF
2a, 45
4c, 49
5a, 1
5a, 1
5a, 2
5a, 1
5a, 15
5a, 8
5b, 2
5a, 3
5a, 4
5a, 7
5b, 5
5a, 8
5a, 10
5a, 3
5
Dioxane
C6H5Cl
CH2Cl2
C2H5Br
1,2-C2H4Br2
1,2-C2H4Br2
CH2Br2
CH2Br2
CH2Br2
CH2Br2
CH2Br2
CH2Br2
CH2Cl2
16
72
6
2a, 42
4d, 55 (21)d
6
2a, 75
4e, 17
7
2a, 60; 3a, 36
2a, 80
0
0
0
0
0
0
0
0
0
0
0
8
72
72
72
16
24
1
9
2a, 86
10
11
12
13c
14
15
16
17
2a, 95
2a, 94
2a, 93 (76)d
2a, 80
24
120
170
24
2a, 90
2a, 81 (51)d
2a, 79
3a, 95 (74)d
a Reaction carried out on a 1 mmol scale in the corresponding solvent (6 mL) at 25 °C, unless stated otherwise.
b GC-MS data.
c Reaction carried out at 65 °C.
d Isolated yield.
Aminocyclopropylpyridines 1a, 1c and 1e were synthesized from the corresponding aminobromopyridines and
cyclopropylboronic acid using standard Suzuki coupling conditions28 (Pd(OAc)2, tricyclohexylphosphine, K3PO4, toluene/water).29
Initial attempts to prepare 2-bromo-5-cyclopropylpyridine 2a from 2-amino-5-cyclopropylpyridine 1a using copper(II) bromide
and amyl nitrite in acetonitrile at 65 °C produced (pyridin-2-yl)acetamide 4a as the major product (Table 1, entry 1). Decreasing the
reaction temperature to 25 °C did not significantly affect the chemoselectivity or ratio of products (Entry 2). Other solvents, such as
methanol, THF and dioxane (Entries 3-5), also gave substantial amounts of the corresponding by-products 4b-d.
None of these solvents reacted with 1a in the absence of copper(II) bromide; control experiments in the presence of CuBr2 but
without amyl nitrite in acetonitrile also did not produce 4a from 1a. It is generally accepted that the Sandmeyer reaction is catalyzed
by copper(I) halides and proceeds by a radical mechanism, where the diazonium salt is reduced to a diazonium radical via single
electron-transfer, which quickly loses dinitrogen to afford an aryl radical. Final ligand transfer from the copper(II) salt completes
the catalytic cycle and regenerates the copper(I) species. Nevertheless, the 2-pyridinediazonium ion derived from 1a is apparently
unstable in rather polar solvents (Entries 1-5) and undergoes heterolytic cleavage.30 The produced highly reactive cation reacts with
any available nucleophile. In the case of cyclic ethers (Entries 4, 5), the reaction most likely proceeds via a transient oxonium
species, which undergo subsequent ring opening reaction to furnish ethers 4c-d (Scheme 1).

3
Scheme 1. Plausible mechanism for the formation of 4d.
The radical pathway, however, cannot be completely rejected, as the Sandmeyer reaction of 1a in chlorobenzene (Table 1, entry
6) produced a non-negligible amount of arylated pyridine 4e as a mixture of two isomers. Moreover, a substantial amount of
chloropyridine 3a was produced in dichloromethane (Entry 7), suggesting the intermediacy of radical rather than cationic species.
The latter result prompted us to investigate the Sandmeyer reaction of 1a in bromoalkanes, which could serve both as a non-
nucleophilic reaction media and a source of bromine. Thus, clean conversions were attained in bromoethane and 1,2-dibromoethane
using amyl- or tert-butyl nitrite (Entries 8-10), however, the reaction proved to be rather sluggish. The best results were obtained in
dibromomethane (Entry 11). Under the optimal reaction conditions using 0.5 equiv. of CuBr2 and 1.1 equiv. of amyl nitrite at 25 °C,
bromopyridine 2a was produced in 76% isolated yield (Entry 12).31 Lower temperatures were beneficial, as the reaction at 65 °C
produced more impurities (Entry 13), whereas the use of tert-butyl nitrite as the diazotization reagent (Entry 14) offered no
advantages. The CuBr2 loading could be further reduced to 10 or even 5 mol% (Entries 15-16), albeit at the expense of reaction rate.
The combination of dichloromethane and CuCl2 (0.5 equiv.) was equally effective and furnished the desired chloropyridine 3a in
74% yield (Entry 17).
With the optimal reaction conditions in hand, the substitutive deamination reaction of several aminocyclopropylpyridines and
aminopyridines 1b-e was explored (Table 2).
Table 2. Synthesis of bromopyridines 2b-ea
Entry
1
Product
Time (h)
16
GC-MS (isolated) (%)
83 (41)
2
24
24
1
96 (51)
3
0
4b
95 (55)
94 (57)
5b
4
a Reaction carried out on a 1 mmol scale in dibromomethane (6 mL) in the presence of CuBr2 (0.5 mmol) and amyl nitrite (1.1 mmol) at 25 °C, unless stated
otherwise.
b Reaction carried out at 65 °C.
In comparison with 2-aminopyridine congeners 1a-c, 4-aminopyridines 1d-e exhibited notably lower reactivity and required
elevated temperatures (Table 2, entries 3-5). The corresponding bromopyridines 2b-e were obtained in good yields.31 The
Sandmeyer reaction of 1d-e produced practically no ether by-products analogous to 5a (Table 1); pyridine and 3-
cyclopropylpyridine, respectively, were the major by-products (up to 5%). Interestingly, these products of reductive deamination
were absent in the crude mixtures from the Sandmeyer reaction of 2-aminopyridines 1a-c.
In conclusion, we have developed an efficient conversion of 2-amino-5-cyclopropylpyridine 1a to 2-bromo- and 2-chloro-5-
cyclopropylpyridines in a non-aqueous media. The optimized procedure involves the treatment of 1a with the corresponding
copper(II) halide and amyl nitrite in dibromomethane (or dichloromethane), which serve as both a non-nucleophilic reaction media
and the halogen source. In other solvents, such as methanol, THF or dioxane, reaction of the 2-pyridinediazonium ion derived from

4
Tetrahedron Letters
1a follows a different route which likely involves cationic rather than radical species as an intermediate. The optimized method was
successfully applied to the synthesis of other bromopyridines, including previously unreported 2-bromo- and 4-bromo-3-
cyclopropylpyridines 2c, 2e.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/.
References and notes
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water (1 mL) were added and reaction mixture stirred for 10 min under an argon flow. Tricyclohexylphosphine (10 mol%) and Pd(OAc)2 (5
mol%) were added and reaction mixture stirred at reflux until GC-MS analysis of the reaction mixture indicated full consumption of the starting
material. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, diluted with EtOAc (25 mL), washed with water
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31. General procedure for preparation of halogenopyridines 2, 3. Aminopyridine (1 mmol) and corresponding Cu(II) halide (0.5 mmol) were
dissolved dibromo(chloro)methane (6 mL) at 25 °C under an argon atmosphere. Alkyl nitrite (1.1 mmol) was added dropwise over 5 min and
reaction mixture stirred at the appropriate temperature (Table 1 and 2) until GC-MS analysis of the reaction mixture indicated full consumption of
the starting material. The reaction mixture was poured into 1 N NaOH (20 mL), stirred for 1 h and extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried (Na2SO4) and evaporated to dryness. The crude product was purified by column chromatography on silica
gel.

5
Graphical Abstract
Synthesis of bromocyclopropylpyridines via
the Sandmeyer reaction
Leave this area blank for abstract info.
Romualdas Striela, Gintaras Urbelis, Jurgis Sūdžius, Sigitas Stončius, Rita Sadzevičienė and Linas Labanauskas
CuBr2
AmylONO, CH2Br2
NH2
N
N
Br

6
Tetrahedron Letters
•
An efficient method for the synthesis of bromo- and
chlorocyclopropylpyridines was developed.
Dibromo- and dichloromethane serve as a source of
halogen in the Sandmeyer reaction.
•
•
•
Copper(II) halides can be used in catalytic amounts.
In other solvents the reaction likely involves cationic
species as an intermediate.