5
264
F. Xu et al. / Tetrahedron Letters 57 (2016) 5262–5265
Table 1
1
H (500 MHz) NMR data for 3a, 5a, 6a, and 7a (CD
3
OD, d in ppm, J in Hz)
Position
3a
5a
6a
7a
2
3
4
5
6
7
8
8.62 (1H, s)
—
—
8.17 (1H, d, J = 7.9)
7.63–7.70 (1H, overlap)
7.63–7.70 (1H, overlap)
7.99 (1H, d, J = 7.9)
8.83 (1H, d, J = 3.0)
7.56 (1H, dd, J = 8.5, 4.0)
8.72 (1H, d, J = 8.5)
—
8.80 (1H, d, J = 4.4)
7.59 (1H, dd, J = 8.4, 4.1)
8.49 (1H, d, J = 8.4)
—
8.84 (1H, d, J = 4.2)
7.44 (1H, dd, J = 8.1, 4.4)
8.31 (1H, d, J = 8.1)
7.79 (1H, d, J = 8.9)
7.34 (1H, d, J = 8.9)
—
—
—
7.55 (1H, d, 9.0)
7.68 (1H, d, 9.0)
7.58 (1H, d, J = 9.0)
7.94 (1H, d, J = 9.0)
—
Table 2
1
3C (125 MHz) NMR data for 3a, 5a, 6a, and 7a (CD
3
OD, d in ppm)
Position
3a
5a
6a
7a
2
3
4
4
5
6
7
8
8
142.5 (CH)
148.2 (C)
102.9 (C)
107.3 (C)
122.5 (CH)
127.9 (CH)
126.9 (CH)
128.2 (CH)
102.2 (C)
149.9 (CH)
120.6 (CH)
131.7 (CH)
126.5 (C)
156.4 (C)
94.8 (C)
119.8 (CH)
130.7 (CH)
143.8 (C)
147.9 (CH)
122.1 (CH)
130.4 (CH)
126.9 (C)
112.0 (C)
151.2 (C)
121.3 (CH)
129.6 (CH)
144.0 (C)
150.2 (CH)
119.2 (CH)
137.3 (CH)
124.1 (C)
127.3 (CH)
118.8 (CH)
155.3 (C)
113.8 (C)
145.2 (C)
a
a
including the proton signals at d 7.55 (d) and d 7.68 (d). Thus, we
concluded that that one of the protons of the benzene ring was
substituted by a chlorine atom. The large coupling constant of
Cl
OH
5
4
6
OH
Cl
9
.0 Hz indicated that the two CH groups are ortho to each other.
7
N
N
8
1
Accordingly, the possibility of C-7 halogenation can be ruled out.
Based on the HMBC correlations of both proton signals at d 7.55
and 7.68 to C-8a at d 143.8 (Fig. 4), the chlorination site was deter-
mined to be at C-6. Thus, this product was identified as 5-hydroxy-
6-chloroquinoline.
3
-Hydroxy-4-chloroquinoline (3a)
5-Hydroxy-6-chloroquinoline (5a)
Cl
HO
4a
HO
N
8a
N
1
Cl
The H and DEPTQ-135 NMR spectra of 6a are similar to those of
5
-Chloro-6-hydroxyquinoline (6a)
7-Hydroxy-8-chloroquinoline (7a)
5
a. The signal of H-2 was located in the low field at d 8.80. With
this signal, the spin system of H-2/H-3/H-4 was identified by the
H– H COSY correlations (Fig. 4). The other spin system consists
1
1
H- H COSY
HMBC
1
1
Figure 4. Selected 1H– H COSY and HMBC correlations of 3a, 5a, 6a and 7a.
1
of two doublet signals from the benzene ring that belongs to H-7
and H-8, as suggested by the large coupling constant of 9.0 Hz.
Accordingly, it can be deduced that C-5 of 6 was chlorinated. This
was confirmed by the HMBC correlations of H-4 (d 8.49, d) and H-7
(d 7.58, d) to C-5 at d 112.0. Therefore, 6a was characterized as
5-chloro-6-hydroxyquinoline.
1
each product, H (Figs. S3–S6), DEPTQ-135 (Figs. S7–S10), HSQC,
1
1
HMBC, and H– H COSY spectra were recorded. The proton and
carbon signals were assigned and are listed in Tables 1 and 2.
1
1
The H NMR spectrum of 3a showed five proton signals, includ-
The H NMR spectrum of 7a showed five proton signals. The
1
1
ing two doublet proton signals (d 7.99 and 8.17), an overlapped sig-
nal (2H, d 7.63–7.70), and a singlet (d 8.62). This is one proton less
than the substrate, indicating that one of the CH of 3-hydrox-
yquinoline was chlorinated. The 1H– H COSY spectra showed a
spin system that consists of the two doublet signals and two over-
lapped proton signals, which suggested that the halogenation did
not occur on the benzene ring and thus one of the protons on the
pyridine ring was substituted by a chlorine atom. This was sup-
ported by the presence of the singlet signal, which was assigned
to H-2 according to the HMBC correlations (Fig. 4) of this proton
to C-4 (d 102.9) and C-8a (d 102.2). Thus, it can be deduced that
the halogenation occurred at C-4 position, which is ortho to the
hydroxyl group (Fig. 4). This was further supported by the HMBC
correlations of H-5 (d 8.17) to C-4. Thus, 3a was identified as
presence of a CH–CH–CH spin system in the H– H COSY spectrum
(Fig. 4) indicated that none of the protons on the pyridine ring was
1
1
chlorinated. The H– H COSY correlations of H-5 to H-6, which are
doublet signals at d 7.79 and 7.34 with a coupling constant of
8.9 Hz, respectively, indicated that Rdc2 introduced a chlorine
atom to C-8. The structure was thus characterized as 7-hydroxy-
8-chloroquinoline, which was supported by the HMBC correlations
shown in Figure 4. 7a is a new compound.
1
Structural identification of the products 3a, 5a, 6a, and 7a sug-
gested that among the seven tested hydroxyquinolines, four were
taken by Rdc2 as substrates to form the corresponding monochlo-
rinated products. The chlorination reaction is highly specific as the
position where the chlorine atom was introduced is ortho to
the hydroxyl group of the four substrates. This is consistent with
the results for isoquinolines in our previous studies. A number of
pharmaceutically important molecules contain a hydroxylated or
chlorinated quinoline moiety, such as quinine, quinidine, chloro-
quine, and montelukast shown in Figure 1. Thus, the hydroxyl
group and chlorine atom attached to quinoline represent impor-
tant functional groups. In this work, we generated four quinoline
derivatives that contain both functional groups at different
positions.
3
-hydroxy-4-chloroquinoline.
1
The H and DEPTQ-135 NMR of 5a also showed five CH signals,
confirming that one proton of the substrate 5 was chlorinated. The
signal of H-2 can be easily located in the low field at d 8.83. Two
spin systems were observed in the 1H- H COSY spectrum (Fig. 4).
The CH–CH–CH system belongs to the pyridine ring, which
includes H-2 (d 8.83, d), H-3 (d 7.56, dd), and H-4 (d 8.72, d). The
CH-CH system consists of two protons from the benzene ring,
1