2,2,3-Tribromopropanal as a versatile reagent in the skraup-type synthesis of 3-bromoquinolin-6-ols

Article abstract of DOI:10.1055/s-0033-1340670

2,2,3-Tribromopropanal, a reagent which almost became forgotten in the chemical literature after its first application in the 1950s, is used for the one-step transformation of diversely substituted 4-nitro- and 4-methoxyanilines into 3-bromo-6-nitroquinolines and 3-bromo-6-methoxyquinolines. These intermediates are then converted, in one further step, into 3-bromoquinolin-6- ols, which may carry additional substituents at positions 7 and 8. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340670

858▌
LETTER
letter
2,2,3-Tribromopropanal as a Versatile Reagent in the Skraup-Type Synthesis
of 3-Bromoquinolin-6-ols
Skraup-Type Synthesis of 3-Bromoquinolin-6-ols
Clemens Lamberth,*a Fiona Murphy Kessabi,a Renaud Beaudegnies,a Laura Quaranta,a Stephan Trah,a
Guillaume Berthon,a Fredrik Cederbaum,a Thomas Vettiger,b CS Prasannac
a
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland
Fax +41(62)8660860; E-mail: clemens.lamberth@syngenta.com
b
Syngenta Crop Protection AG, Process Development, Breitenloh 5, 4333 Münchwilen, Switzerland
c
Syngenta Research and Technology Centre, Santa Monica Works, Corlim, Ilhas, Goa 401 110, India
Received: 09.12.2013; Accepted after revision: 03.01.2014
bromination at C-3 of the quinoline,13,18,19 and finally ex-
Abstract: 2,2,3-Tribromopropanal, a reagent which almost became
change of the fluoro or nitro functions in the resulting
forgotten in the chemical literature after its first application in the
3-bromo-6-fluoroquinolines13
or
3-bromo-6-nitro-
1950s, is used for the one-step transformation of diversely substitut-
ed 4-nitro- and 4-methoxyanilines into 3-bromo-6-nitroquinolines
and 3-bromo-6-methoxyquinolines. These intermediates are then
converted, in one further step, into 3-bromoquinolin-6-ols, which
may carry additional substituents at positions 7 and 8.
quinolines18 with a hydroxy function.
For a research program, we required an efficient access to
a whole series of diversely substituted 3-bromoquinolin-
6-ols, many of them further functionalized at positions 7
and/or 8. We realized that the Skraup reaction would be
the most appropriate cyclization method for our purposes,
the reason being that for the preparation of a 3-bromo-
quinoline with two substituents at positions 6 and 8, the
Skraup reaction starts from a trisubstituted phenyl ring
(disubstituted aniline), whereas several alternative quino-
line syntheses would require tetrasubstituted benzene
derivatives (Friedlaender: disubstituted 2-aminobenzalde-
hyde; Pfitzinger: disubstituted isatin), which are less fre-
quently available. During our search for a shorter access
to 3-bromoquinolin-6-ols, we came across a single exam-
ple in the literature from the 1950s which used 2,2,3-tri-
bromopropanal as a three-carbon synthon for the Skraup
reaction of anilines, simultaneously achieving the ring-
closure and introduction of the desired bromine atom at C-3
of the quinoline.20 Two further examples of such a Skraup
cyclization–bromination have been described employing
2-bromoacrolein and bromine.21 Although not mentioned
in these papers, it can be assumed that these Skraup reac-
tions proceed via in situ formed 2,2,3-tribromopropanal.
Key words: anilines, quinolone, heterocycle, cyclization, Skraup
reaction, kinase inhibitor, fungicide
The quinoline is undoubtedly one of the most important
heterobicyclic scaffolds in organic chemistry.1 Several
different methods have been developed for the synthesis
of such 2,3-benzannelated pyridines, these include the
Combes,2 Friedlaender,3 Pfitzinger,4 Povarov5 and
Skraup–Doebner–Miller quinoline syntheses.6 Also, the
existence of active ingredient families which are based on
the quinoline nucleus, such as the quinoline antimalarials7
(e.g., chloroquine), and the quinolone antibiotics8 (e.g.,
ciprofloxacin), testifies to the importance of this heterocy-
clic system. 3-Bromoquinolin-6-ols have attracted our at-
tention as versatile intermediates for an experimental
class of agrochemical fungicides (Figure 1).9 Quinolines
with this special substitution pattern have also been used
as building blocks in the synthesis of c-Met selective ki-
nase inhibitors,10 monoamine neurotransmitter re-uptake
inhibitors11 and dynemicin A type anticancer agents.12
We decided to prepare 2,2,3-tribromopropanal from the
bulk chemical acrolein, instead of 2-bromoacrolein,
which turned out to be easily possible with bromine.22 As
the reaction partner for the subsequent Skraup cyclization,
we had anticipated a 4-nitroaniline, which indeed forms a
3-bromo-6-nitroquinoline under heating in acetic acid.
Reduction of the nitro function under Bechamp conditions
with iron powder and concentrated hydrochloric acid de-
livered the amino group, which was hydrolyzed into the
desired phenol with phosphoric acid at high temperature
under high pressure in a tantalum autoclave (Scheme 1,
method A).23 Although this procedure was used in the
small- and large-scale synthesis of several different 3-bro-
moquinolin-6-ols, the harsh conditions and special equip-
ment required for the last step prompted us to look for an
alternative. A more practical approach was found in the
Skraup cyclization of the same 1,3-dielectrophile, 2,2,3-
OH
Br
N
R
Figure 1 General structure of 3-bromoquinolin-6-ols
The few 3-bromoquinolin-6-ols, which so far have been
described in the literature, have been prepared in a three-
step sequence via Skraup quinoline synthesis of diverse 4-
fluoro-, 4-methoxy- or 4-nitro-substituted anilines with
glycerol,13,14 1,3-propanediol,15 3-aminopropan-1-ol,16 or
tris(3-hydroxypropyl)amine,17 subsequent regioselective
SYNLETT 2014, 25, 0858–0862
Advanced online publication: 10.02.2014
DOI: 10.1055/s-0033-1340670; Art ID: ST-2013-B1123-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Skraup-Type Synthesis of 3-Bromoquinolin-6-ols
859
NO2
H2N
1. Fe, HCl
2. H3PO4, H2O
NO2
Br
Me
method A
67%
77%
N
OH
O
Me
Br
O
Br2
3
Br
H
H
84%
N
Br Br
OMe
Me
Br
5
45%
1
2
84%
HBr
method B
OMe
N
Me
4
H2N
Me
Scheme 1 Skraup cyclization of 2,2,3-tribromopropanal with a 4-nitroaniline (method A) and a 4-methoxyaniline (method B), delivering
3-bromo-8-methylquinolin-6-ol (5)
tribromopropanal, with 4-methoxyanilines to give 3-bro- mixtures from which the polar 3-bromoquinolin-6-ols
mo-6-methoxyquinolines, followed by ether cleavage to were often very difficult to isolate.
give the corresponding 3-bromoquinolin-6-ols (Scheme
Several different derivatives of 3-bromoquinolin-6-ol
1, method B).23 Although the yields of the Skraup quino-
(Table 1, entry 1) could be prepared using these two dif-
line synthesis steps in both methods are modest, these ap-
ferent methods, amongst them examples with an addition-
proaches present the advantage of furnishing the key
al substituent at the C-8 position (Table 1, entries 2–7), at
intermediate in a single step from readily available re-
C-7 (entries 8–10), and also with two substituents at posi-
agents. An attempt to perform the Skraup cyclization di-
tions C-7 and C-8 (Table 1, entries 11 and 12).
rectly using 4-aminophenols led to complex reaction
Table 1 Novel 3-Bromoquinolin-6-ols with Analytical Data and Yields of the Skraup-Type Cyclization Step
Entry 3-Bromoquinolin-6-ol
1H NMR (400 MHz, DMSO)
LC–MS
Method
(yield)
OH
OH
Br
Br
7.14 (d, J = 2.0 Hz, 1 H), 7.35 (dd, J = 2.0 Hz, 7.8 Hz,
1 H), 7.87 (dd, J = 1.9 Hz, 8.1 Hz, 1 H), 8.49 (d, J = 1.9
Hz, 1 H), 8.67 (d, J = 2.1 Hz, 1 H), 10.49 (s, 1 H)
tR = 1.42 min; MS: m/z = 225
A
(67%)
1
2
[M + 1]+, 227 [M + 3]+
N
N
7.02 (d, J = 1.9 Hz, 1 H), 7.19 (dd, J = 1.9 Hz, 8.0 Hz,
1 H), 8.61 (d, J = 2.2 Hz, 1 H), 8.73 (d, J = 2.2 Hz, 1
H), 10.55 (s, 1 H)
tR = 1.45 min; MS: m/z = 242
[M]+, 244 [M + 2]+, 245 [M
+3 ]+
B
(58%)
F
OH
OH
OH
OH
Br
Br
Br
Br
7.16 (d, J = 2.0 Hz, 1 H), 7.52 (d, J = 2.1 Hz, 1 H), 8.61
(d, J = 2.4 Hz, 1 H), 8.77 (d, J = 2.4 Hz, 1 H), 10.60 (s,
1 H)
tR = 1.75 min; MS: m/z = 258
[M]+, 260 [M + 2]+, 262 [M +
4]+
A
(61%)
3
4
5
6
N
N
N
N
Cl
Br
I
7.26 (d, J = 2.3 Hz, 1 H), 7.78 (d, J = 2.2 Hz, 1 H), 8.67
(d, J = 1.9 Hz, 1 H), 8.86 (d, J = 2.0 Hz, 1 H), 10.52 (s,
1 H)
tR = 1.54 min; MS: m/z = 302
[M]+, 304 [M + 2]+, 305 [M
+3 ]+
A
(63%)
7.21 (d, J = 2.2 Hz, 1 H), 7.97 (d, J = 2.3 Hz, 1 H), 8.53
(d, J = 2.0 Hz, 1 H), 8.74 (d, J = 2.1 Hz, 1 H), 10.51 (s,
1 H)
tR = 1.68 min; MS: m/z = 350
[M]+, 352 [M + 2]+, 353 [M +
3]+
A
(60%)
A
(77%)
B
2.64 (s, 3 H), 6.99 (d, J = 2.1 Hz, 1 H), 7.22 (d, J = 2.1
Hz, 1 H), 8.47 (d, J = 2.2 Hz, 1 H), 8.69 (d, J = 2.3 Hz,
1 H), 10.13 (s, 1 H)
tR = 1.78 min; MS: m/z = 238
[M]+, 239 [M + 1]+
(45%)
Me
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 858–862

860
C. Lamberth et al.
LETTER
Table 1 Novel 3-Bromoquinolin-6-ols with Analytical Data and Yields of the Skraup-Type Cyclization Step (continued)
Entry 3-Bromoquinolin-6-ol
1H NMR (400 MHz, DMSO)
LC–MS
Method
(yield)
OH
Br
7.17 (d, J = 2.2 Hz, 1 H), 7.69 (d, J = 2.2 Hz, 1 H), 8.20
(d, J = 2.0 Hz, 1 H), 8.81 (d, J = 1.9 Hz, 1 H), 10.32 (s,
1 H)
tR = 1.73 min; MS: m/z = 292
[M]+, 294 [M + 2]+, 295 [M +
3]+
A
(72%)
7
N
CF3
OH
Br
Br
7.34 (dd, J = 1.9 Hz, 7.8 Hz, 1 H), 7.77 (dd, J = 2.0 Hz,
8.0 Hz, 1 H), 8.58 (d, J = 2.1 Hz, 1 H), 8.74 (d, J = 2.1
Hz, 1 H), 10.93 (s, 1 H)
tR = 1.43 min; MS: m/z = 242
[M]+, 244 [M + 2]+, 245 [M +
3]+
B
(61%)
8
9
F
N
N
1.25 (t, J = 7.5 Hz, 3 H), 2.72 (q, J = 7.3 Hz, 2 H), 7.13
(d, J = 2.1 Hz, 1 H), 7.72 (d, J = 2.1 Hz, 1 H), 8.48 (d,
J = 1.9 Hz, 1 H), 8.63 (d, J = 2.0 Hz, 1 H), 10.37 (s, 1
H)
OH
tR = 1.63 min; MS: m/z = 252
[M]+, 254 [M + 2]+, 255 [M +
3]+
B
(68%)
Et
1.29 (d, J = 7.0 Hz, 6 H), 4.23 (sept, J = 6.9 Hz, 1 H)
7.12 (d, J = 2.1 Hz, 1 H), 7.73 (d, J = 2.1 Hz, 1 H), 8.46
(d, J = 1.9 Hz, 1 H), 8.65 (d, J = 2.0 Hz, 1 H), 10.39 (s,
1 H)
OH
Br
Br
tR = 1.72 min; MS: m/z = 266
[M]+, 268 [M + 2]+, 269 [M +
3]+
B
(59%)
10
11
12
i-Pr
N
N
OH
tR = 1.71 min; MS: m/z = 292
[M]+, 294 [M + 2]+, 296 [M +
4]+
7.37 (s, 1 H), 8.72 (d, J = 2.0 Hz, 1 H), 8.86 (d, J = 2.0
Hz, 1 H), 11.49 (s, 1 H)
B
(66%)
Cl
Cl
OH
F
Br
2.70 (s, 3 H), 7.18 (dd, J = 2.1 Hz, 8.3 Hz, 1 H), 8.53
(d, J = 2.0 Hz, 1 H), 8.76 (d, J = 1.9 Hz, 1 H), 10.77 (s,
1 H)
tR = 1.68 min; MS: m/z = 256
[M]+, 258 [M + 2]+, 259 [M +
3]+
B
(63%)
N
Me
The broad variability of the different anilines which could droxy function include the ether 14 and the ester 17. The
be transformed into 3-bromoquinoline derivatives C-5 position can be functionalized, for example, by the in-
prompted us to try a similar Skraup cyclization with 2- troduction of a second hydroxy group to give diol 10, or
amino-5-methoxypyridine (6). Instead of the desired 3- by regioselective Claisen rearrangement of an intermedi-
bromo-6-methoxy[1,8]naphthyridine (7), only the 3-for- ate allyl ether to afford 11. Finally, the ring nitrogen of 3-
mylimidazo[1,2-a]pyridine 8 was isolated, which results bromoquinolin-6-ol (13) can be successfully converted
from a double alkylation–dehydrobromination sequence, into the corresponding N-oxide 16.
in which both nitrogen atoms of 6 are involved (Scheme
2).
In conclusion, we have developed a general synthesis of
3-bromoquinolin-6-ols, which can be prepared in only
The 3-bromoquinolin-6-ols are perfectly suited for further two steps from either a 4-nitroaniline or a 4-methoxyani-
transformations (Scheme 3). As demonstrated by the di- line, via a Skraup-type cyclization with 2,2,3-tribromo-
substituted quinoline 13, not only can the bromo and hy- propanal and subsequent installation of the hydroxy
droxy functions be exchanged, it is also possible to function. Additional substituents are easily introduced at
introduce additional substituents at positions 1 and 5. The positions 1, 3, 5, and 6 of the quinoline, either by manip-
bromine at position 3 can be replaced by several different ulation of the starting aniline, or by further reactions of 3-
groups, for instance by an amino function as in product 9, bromoquinolin-6-ol. Furthermore, the bromo and hydroxy
by another halogen such as fluorine (as in 12), or by a car- moieties are perfectly suited for transformation into other
bon substituent such as ethynyl (as in 15). Examples of functional groups.
successful alkylation and acylation of the phenolic hy-
OMe
BrH2CCBr2CHO (2)
OMe
OMe
Br
N
N
AcOH
+
O
H2N
N
N
N
H
6
7
8
0%
18%
Scheme 2 Attempted Skraup synthesis of bromonaphthyridines
Synlett 2014, 25, 858–862
© Georg Thieme Verlag Stuttgart · New York

LETTER
Skraup-Type Synthesis of 3-Bromoquinolin-6-ols
861
OH
OH
Br
OH
Br
OH
H2N
N
N
10
11
N
9
59%
76%
Pd2(dba)3
1. BrCH2CH=CH2, NaH
1. IBX
2. NaBH4
37%
2. Δ
[(t-Bu)3PH]BF4, Li2N(TMS)2
O
ClCH2CO2Me
K2CO3
1. BuLi
OH
OH
Br
F
O
Br
2. (PhSO2)2NF
63%
OMe
73%
N
N
N
13
12
14
1.
CH CC(Me)2OH
PhCOCl
Pd(PPh3)2Cl2 (0.05 equiv)
MCPBA
71%
Et3N
CuI (0.1 equiv), EtNi-Pr2
74%
88%
2. KOH
OH
O
Br
OH
Br
+
N
O
N
N
O–
17
15
16
Scheme 3 Modifications of 3-bromoquinolin-6-ol (13) at positions 1, 3, 5 and 6
Elsevier: Amsterdam, 2007, 567–596. (b) Park, H.-R.; Kim,
T. H.; Bark, K.-M. Eur. J. Med. Chem. 2002, 37, 443.
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LETTER
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3-Bromo-8-methylquinolin-6-ol (5)
Reduced Fe powder (15 g, 0.27 mol) was added in portions
to a suspension of 3-bromo-8-methyl-6-nitroquinoline (3)
(20.6 g, 77 mmol) in a mixture of EtOH (400 mL) and 37%
aq HCl (2 mL) at r.t. The mixture was heated at reflux
temperature for 2 h, during which time the color of the
suspension changed from grey–yellow to red–brown. The
mixture was cooled to 40 °C, filtered through Celite, and the
filtrate diluted with EtOH, treated with silica gel and
concentrated under reduced pressure. The residue was
purified by chromatography on silica gel, using EtOAc and
CH2Cl2 as eluents to deliver 6-amino-3-bromo-8-
methylquinoline. This intermediate was suspended in a
mixture of 85% aq phosphoric acid (125 mL) and H2O (12
mL), and heated to 180 °C in a tantalum pressure vessel for
72 h. Subsequently, the mixture was cooled to r.t. and added
to H2O (250 mL). To this solution, 30% aq NaOH solution
was added until a pH between 2–4 was reached. The
resulting precipitate was filtered, washed with cold H2O and
dried to give 3-bromo-8-methylquinolin-6-ol (5) (12.3 g, 52
mmol, 67%).
(22) 2,2,3-Tribromopropanal (2)
Br2 (103 mL, 319 g, 2.0 mol) was added dropwise over 2 h
to a solution of acrolein (1) (131 mL, 112 g, 2.0 mol) in DCE
(320 mL) at r.t. During the addition, the color changed from
colorless to orange and the reaction temperature was kept in
the range 20–40 °C. Following addition, the mixture was
stirred for 2 h at r.t., then another equivalent of Br2 (103 mL,
319 g, 2.0 mol) was added dropwise over 2 h. The red–
brown mixture was stirred for 16 h at r.t., evaporated under
reduced pressure, and the residue purified by Vigreux
column distillation to deliver 2,2,3-tribromopropanal (2)
(494 g, 1.68 mol, 84%) as a slightly yellowish liquid.
Bp 80–85 °C (0.02 mbar); 1H NMR (400 MHz, CDCl3):
δ = 4.23 (s, 2 H), 9.16 (s, 1 H).
1H NMR (400 MHz, DMSO-d6): δ = 2.64 (s, 3 H), 6.99 (d,
J = 2.1 Hz, 1 H), 7.22 (d, J = 2.1 Hz, 1 H), 8.47 (d, J = 2.2
Hz, 1 H), 8.69 (d, J = 2.3 Hz, 1 H), 10.13 (s, 1 H).
Method B
3-Bromo-6-methoxy-8-methylquinoline (4)
2,2,3-Tribromopropanal (2) (50.0 g, 0.18 mol) was added
slowly to a suspension of 4-methoxy-2-methylaniline (25.0
g, 0.18 mol) in glacial AcOH (300 mL). The mixture was
stirred for 6 h at r.t., then diluted with EtOAc (300 mL) and
washed with H2O (2 × 100 mL), brine (100 mL) and 2 M
NaOH solution (100 mL). The organic layer was dried over
MgSO4 and evaporated under reduced pressure. The residue
was purified by chromatography on silica gel, using EtOAc
and heptane as eluents to yield 3-bromo-6-methoxy-8-
methylquinoline (4) (20.5 g, 81 mmol, 45%).
(23) 3-Bromo-8-methylquinolin-6-ol (5); Typical Procedures
Method A
3-Bromo-8-methyl-6-nitroquinoline (3)
2,2,3-Tribromopropanal (2) (29.4 g, 0.1 mol) was added
slowly to a suspension of 2-amino-5-nitrotoluene (15.2 g,
0.1 mol) in glacial AcOH (200 mL). The mixture was heated
to 110 °C for 1 h, cooled to r.t. and filtered. The remaining
solid was washed with Et2O, then suspended in H2O (150 mL)
and treated with aq sat. NaHCO3 solution until a pH of 9 was
reached. The suspension was transferred to a separating
funnel and extracted with EtOAc (2 × 200 mL). The organic
phase was dried over MgSO4 and evaporated under reduced
pressure. The residue was purified by chromatography on
silica gel, using EtOAc and heptane as eluents to afford 3-
bromo-8-methyl-6-nitroquinoline (3) (20.7 g, 77 mmol,
77%) as yellow crystals.
1H NMR (400 MHz, CDCl3): δ = 2.73 (s, 3 H), 3.90 (s, 3 H),
6.82 (d, J = 2.0 Hz, 1 H), 7.21 (d, J = 2.1 Hz, 1 H), 8.17 (d,
J = 1.9 Hz, 1 H), 8.76 (d, J = 2.0 Hz, 1 H).
3-Bromo-8-methylquinolin-6-ol (5)
A mixture of 3-bromo-6-methoxy-8-methylquinoline (4)
(14.0 g, 55 mmol) in 48% HBr (250 mL) was slowly heated
to 110 °C, and kept at this temperature for 20 h.
Subsequently, the mixture was cooled and filtered. The
residue was washed with H2O, taken up in sat. aq NaHCO3
solution and filtered again. The solid was washed with H2O
and dried under high vacuum to afford 3-bromo-8-
methylquinolin-6-ol (5) (11.1 g, 47 mmol, 84%). The 1H
NMR spectroscopic data of the sample of compound 5 was
identical to that obtained using method A.
1H NMR (400 MHz, CDCl3): δ = 2.86 (s, 3 H), 8.35 (d,
J = 2.1 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.54 (d, J = 2.2
Hz, 1 H), 9.06 (d, J = 2.1 Hz, 1 H).
Synlett 2014, 25, 858–862
© Georg Thieme Verlag Stuttgart · New York

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