Arylation, alkenylation, and alkylation of 2-halopyridine N-oxides with Grignard reagents: A solution to the problem of C2/C6 regioselective functionalization of pyridine derivatives

Article abstract of DOI:10.1021/jo302511s

A facile arylation, alkenylation, and alkylation of functionalized 2-halopyridine N-oxides with various Grignard reagents was developed. It represented a highly efficient and selective C-H bond functionalization of pyridine derivatives in the presence of reactive C-Cl or C-Br bonds. Using Cl or Br as a blocking group, C2/C6 site-controllable functionalization of pyridine derivatives has been achieved. Various pyridine compounds can be prepared as illustrated in the total syntheses of Onychine, dielsine, and PARP-1 inhibitor GPI 16539.

Full text of DOI:10.1021/jo302511s

Note
pubs.acs.org/joc
Arylation, Alkenylation, and Alkylation of 2‑Halopyridine N‑Oxides
with Grignard Reagents: A Solution to the Problem of C2/C6
Regioselective Functionalization of Pyridine Derivatives
Song Zhang, Lian-Yan Liao, Fang Zhang, and Xin-Fang Duan*
College of Chemistry, Beijing Normal University, Beijing 100875, China
S
* Supporting Information
ABSTRACT: A facile arylation, alkenylation, and alkylation of
functionalized 2-halopyridine N-oxides with various Grignard
reagents was developed. It represented a highly efficient and
selective C−H bond functionalization of pyridine derivatives in
the presence of reactive C−Cl or C−Br bonds. Using Cl or Br
as a blocking group, C2/C6 site-controllable functionalization
of pyridine derivatives has been achieved. Various pyridine
compounds can be prepared as illustrated in the total syntheses
of Onychine, dielsine, and PARP-1 inhibitor GPI 16539.
yridines are among the most widespread heterocyclic
on previous reports: (1) the replacement of chlorine by the R-
Pstructural units in natural products, pharmaceuticals, or Ar-group of Grignard reagents10 and (2) the exchange
reaction between bromine and magnesium.11 Due to these
reactions, direct arylation or alkylation of 2-halopyridine N-
oxides using Grignard reagents to obtain the corresponding 6-
substituted 2-halopyridine N-oxides can be remarkably
challenging, and to the best of our knowledge, there has been
no report on such functionalizations to date.12 Recently we
have discovered a facile condition for the arylation and
alkylation of nitropyridine N-oxides with Grignard reagents.3b
We rationalize that the mild procedure with high chemo-
selectivity may be suitable for the desired functionalization of 2-
halopyridine N-oxides.
In a preliminary experiment, a complex mixture was obtained
when 2-chloro-3-ethoxycarbonyl-pyridine N-oxide (1a) was
treated with PhMgBr or EtMgBr at −50 °C and quenched with
water. A similar result was obtained when the reactions were
worked up by heating the resulting mixture in DMF or Ac2O.3f
The complexity of the products could be due to the instability
of the chlorine-containing adduct dihydropyridine N-oxides
under those workup conditions, and next we attempted to
aromatize the dihydropyridine N-oxides into the corresponding
pyridine N-oxides in situ using DDQ.13 As expected, the desired
2-chloro-3-ethoxycarbonyl-6-phenylpyridine N-oxide (3aa) and
2-chloro-3-ethoxycarbonyl-6-ethylpyridine N-oxide (3ae) were
obtained in 83% and 95%, respectively (Table 1, entries 1 and
5). This finding demonstrated that the pyridine N-oxides
bearing an electron-withdrawing group were sufficiently
reactive for the nucleophilic addition of Grignard reagents,
biologically active compounds, and functional materials.1
Pyridine N-oxides often serve as important intermediates for
the activation and functionalization of pyridine by virtue of
their high reactivity, ease of synthesis, and ready availability.2
Numerous efforts have been devoted to developing efficient
methods for the arylation, alkenylation, and alkylation of
pyridine N-oxides. Among the reported methods, arylation or
alkylation using Grignard reagents3 and palladium-catalyzed
direct arylation via C−H activation4 represent the major
strategies.5 However, functionalization of 3-substituted pyridine
N-oxides using these procedures would confront the problem
of regiochemistry because of a competition between the two
reactive positions C2 and C6,6−8 and thus an efficient and
general method to address this regioselectivity is highly desired.
To this end, we herein report a simple transition-metal-free
arylation, alkenylation, and alkylation of functionalized 2-
halopyridine N-oxides. Since the halogen atom can block the
otherwise competing reactive sites and can be subsequently
removed, replaced, or used in a cross-coupling reaction, this
one-pot procedure provides a practicable and general method
for site-controllable functionalization of pyridine derivatives at
C2 or C6.
Due to its high electrophilicity, 2-halopyridine N-oxide
functions as one of key intermediates for the introduction of
substituents at 2-position of pyridine derivatives. Usually the
halogen atoms at the 2/6 positions of pyridine N-oxides are
more reactive relative to those at other positions and thus can
be preferentially transformed into other functionalities.9 The
highly reactive halogen atoms at the 2-position of pyridine N-
oxides can also react with Grignard reagents in two ways based
Received: December 1, 2012
© XXXX American Chemical Society
A
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Note
remarkable tolerance toward different functional groups such as
ester (1a−1c, 1h, 1i), cyano (1d), or nitro group (1g and 1k).
Besides, the highly functionalized oxide, 2,5-dibromo-4-nitro-
pyridine N-oxide (1k), could also be arylated with Grignard
reagents (Table 1, entries 27 and 28). Even more interesting is
the fact that the arylation, alkenylation, and alkylation with
Grignard reagents proceeded smoothly in the presence of a
ketone group such as CH3CO and PhCO (Table 1, entries 14−
18, 25, and 26). The selective addition of Grignard reagents to
C2 or C6 of pyridine N-oxides in the presence of a ketone
group has been observed for the first time, and this should help
to further understand and better utilize the high reactivity of
pyridine N-oxides toward the nucleophilic addition of Grignard
reagents.
Compared with many transition-metal-catalyzed C−H
activation reactions, the procedure described herein had the
advantage that an efficient arylation, alkenylation, or alkylation
of pyridine N-oxides could be achieved in the presence of
activated C−Cl or C−Br bonds. Hence it can provide a
solution to the problem of C2/C6 regioslective functionaliza-
tion of pyridine derivatives by using Cl or Br as a blocking
group that could then be removed or transformed into other
desired groups. To further probe its synthetic potentials, total
syntheses of two natural products (onychine15 and dielsine16)
and PARP-1 inhibitor GPI 1653917 using this method as the
key step are outlined in Schemes 1 and 2. In Scheme 1, methyl
Table 1. Arylation, Alkenylation, and Alkylation of
Functionalized 2-Chloro- or Bromopyridine N-Oxides with
a
Various Grignard Reagents
b
yield
entry
1 (X, R)
2 (R′)
2a (Ph)
product
(%)
1
1a (Cl, 3-COOMe)
3aa
3ab
3ac
3ad
3ae
3af
83
91
87
93
95
98
98
76
78
90
68
96
88
85
78
75
86
90
90
65
70
72
78
70
75
75
80
82
2
1a
2b (2-MeOC6H4)
3
1a
2c (2-MeOOCC6H4)
4
1a
2d (thiophen-2-yl)
5
1a
2e (Et)
6
1a
2f (n-Bu)
7
1a
2g (cyclopentyl)
3ag
3ah
3ai
8
1a
2h (vinyl)
9
1a
2i (styryl)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1b (Cl, 4-COOMe)
2f
3bf
3ca
3dj
3dg
3ek
3el
1c (Cl, 5-COOMe)
2a
1d (Cl, 3-CN)
2j (3-CF3C6H4)
1d
2g
1e (Cl, 5-PhCO)
2k (4-MeC6H4)
1e
2l (i-Pr)
1f (Cl, 3-CH3CO)
2c
3 fc
3fm
3fn
3gp
3hq
3hm
3ib
3if
1f
2m (prop-1-enyl)
Scheme 1. Total Syntheses of Onychine and Dielsine
1f
2n (cyclohexyl)
1g (Cl, 3-NO2)
2p (4-FC6H4)
1h (Br, 3-COOMe)
2q (n-Pr)
1h
2m
2b
2f
1i (Br, 4-COOMe)
1i
1i
2h
2p
2q
3ih
3jp
3jq
3kd
3kp
1j (Br, 5-PhCO)
1j
1k (Br, 4-NO2-5-Br) 2d
1k 2p
a
2-Halopyridine N-oxide was treated with Grignard reagent (1.2
equiv) in THF at −50 °C. After the addition reaction was completed
(1−3 h), DDQ (1.2 equiv) was added. The mixture was allowed to
b
warm to room temperature and stirred for additional 4−6 h. Yield of
isolated product.
and it is critical to choose appropriate workup conditions for
the conversion of the adduct dihydropyridine N-oxides into
more stable pyridine N-oxides.
2-chloro-4-methyl-5-nicotinate N-oxide (1l) was phenylated
and deoxygenated in one pot to give methyl 2-chloro-4-methyl-
6-phenyl-5-nicotinate (4) in 86% yield. Compound 4 was
annulated with PPA to afford the key precursor (5) to onychine
and dielsine. The chlorine atom of 5, which was originally fixed
as a blocking group,18 was later removed or translated into
hydroxyl group to furnish onychine and dielsine in a total yield
of 74% or 68%, respectively.
The reported total synthesis of PARP-1 inhibitor GPI 16539
started with a nonregioselective Suzuki coupling of 2,6-
dichloro-3-nitropyridine with 2-diisopropylcarbamoylphenyl-
boronic acid leading to the mixture of the desired 2-arylated
intermediate in 42% and the other isomer in 38%, and the
target molecule was obtained in only 14% overall yield.17b,19 By
using our protocol (Scheme 2) a facile arylation of readily
available 2-chloro-5-nitropyridine N-oxide (1m) with 2-
methoxycarbonylphenylmagnesium chloride20 afforded the
The above reaction represents a very simple yet highly
efficient protocol for arylation and alkylation of 2-halopyridine
N-oxides. It was thus further explored with the results
summarized in Table 1. For the functionalized 2-chloropyridine
N-oxides (1a−1g), arylation, alkenylation, and alkylation with
Grignard reagents went smoothly (Table 1, entries 1−19), and
neither the deprotonation at the 6-position14 nor the
displacement of Cl with R′ group10 was observed. Notably
the functionalized 2-bromopyridine N-oxides (1h−1k) could
be readily arylated, alkenylated, and alkylated as well (Table 1,
entries 20−28).
Interestingly, heteroaryl or functionalized aryl magnesium
reagents could also be used for the corresponding arylation,
leading to the expected products in 75−93% yields (Table 1,
entries 3, 4, 12, 16, and 27). Overall the reactions also showed a
B
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Note
3aa. Yield 437 mg, 83%; mp = 148−149 °C; IR (cm−1, KBr) 1729;
1H NMR (400 MHz, CDCl3) δ 7.84−7.82 (m, 2H), 7.70 (d, J = 8.3
Hz, 1H), 7.50 (t, J = 3.2 Hz, 3H), 7.42 (d, J = 8.3 Hz, 1H), 4.00 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 132.8, 131.9, 130.5, 129.4,
129.1, 129.0, 128.7, 128.4, 126.6, 125.9, 123.9, 120.3, 51.6; MS (ESI)
[M + H]+ (m/z, 264). Anal. Calcd for C13H10ClNO3: C, 59.22; H,
3.82; N, 5.31. Found: C, 58.97; H, 3.65; N, 5.17.
Scheme 2. Total Synthesis of PARP-1 Inhibitor GPI 16539
3ab. Yield 534 mg, 91%; mp = 125−128 °C; IR (cm−1, KBr) 1736;
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.3 Hz, 1H), 7.49−7.45
(m, 1H), 7.40−7.36 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 8.3
Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
163.8, 157.3, 151.7, 143.1, 131.7, 130.5, 128.8, 125.3, 125.1, 121.5,
120.6, 111.4, 55.9, 53.3; MS (ESI) [M + H]+ (m/z, 294). Anal. Calcd
for C14H12ClNO4: C, 57.25; H, 4.12; N, 4.77. Found: C, 56.98 H,
3.91; N, 4.56.
3ac. Yield 559 mg, 87%; mp = 138−140 °C; IR (cm−1, KBr) 1732;
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 1H), 7.74 (d, J =
8.2 Hz, 1H), 7.67−7.63 (m, 1H), 7.59−7.55 (m, 1H), 7.35−7.32 (m,
2H), 4.00 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
166.4, 163.5, 153.9, 142.6, 132.9, 132.4, 131.1, 130.2, 130.0, 129.9,
128.7, 126.0, 125.9, 122.9, 53.2, 52.4; MS (ESI) [M + H]+ (m/z, 322).
Anal. Calcd for C15H12ClNO5: C, 55.99; H, 3.73; N, 4.35. Found: C,
55.81; H, 3.86; N, 4.28;
desired arylated product (3mc) in 80% yield. Displacement of
the chlorine atom of the intermediate 3mc with N-
methylpiperazine gave the key precursor 6, which was subjected
to reduction with iron powder yielding GPI 16539. This total
synthesis involved only three steps, and the overall yield was
77%. Here the reagents used in our syntheses are readily
available, and corresponding procedures were very straightfor-
ward. Once again this total synthesis has demonstrated that the
problem of C2/C6 regioslective functionalization of pyridine
derivatives could be circumvented by using Cl or Br as a
blocking group, which could be readily transformed into other
substituents.
In summary, we have developed a one-pot arylation,
alkenylation, and alkylation of 2-chloro or bromopyridine N-
oxides with various Grignard reagents. Since highly reactive
halogen atoms can seldom be tolerated in many known
transition-metal-catalyzed couplings and direct C−H function-
alization, the procedure described herein can be viewed as a
highly selective C−H functionalization of pyridine N-oxides in
the presence of reactive Cl or Br atoms. In addition, these
halogen atoms were used as an easily transformable blocking
group and thus provide a general and practicable approach to
circumvent the problem of C2/C6 regioslective functionaliza-
tion of pyridine derivatives. Given the simplicity, efficiency, and
tolerance toward functional groups such as ester, cyano, nitro,
and ketone groups, this protocol can find wide applications in
building various pyridine compounds including pyridine-based
natural products and bioactive complex molecules.
3ad. Yield 501 mg, 93%; mp = 123−125 °C; IR (cm−1, KBr) 1736;
1H NMR (400 MHz, CDCl3) δ 7.97−7.94 (m, 2H), 7.81 (d, J = 8.8
Hz, 1H), 7.70 (d, J = 5.0 Hz, 1H), 7.29−7.26 (m, 1H), 4.00 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 163.4, 146.3, 143.3, 133.1, 131.2,
129.4, 126.8, 126.6, 125.2, 118.6, 53.2; MS (ESI) [M + H]+ (m/z,
270). Anal. Calcd for C11H8ClNO3S: C, 48.99; H, 2.99; N, 5.19.
Found: C, 48.70; H, 2.79; N, 4.94.
3ae. Yield 409 mg, 95%; mp = 115−116 °C; IR (cm−1, KBr) 1735;
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 1H), 7.26 (d, J =
8.2 Hz, 1H), 3.98 (s, 3H), 3.03 (q, J = 7.4 Hz, 2H), 1.35 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 155.7, 142.5, 125.3,
124.4, 122.0, 53.0, 24.6, 10.4; MS (ESI) [M + H]+ (m/z, 216). Anal.
Calcd for C9H10ClNO3: C, 50.13; H, 4.67; N, 6.50. Found: C, 49.89;
H, 4.49; N, 6.34.
3af. Yield 477 mg, 98%; mp = 66−67 °C; IR (cm−1, KBr) 1739; 1H
NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.2
Hz, 1H), 3.97 (s, 3H), 2.99 (t, J = 7.7 Hz, 2H), 1.73 (m, J = 7.6 Hz,
2H), 1.45 (m, J = 7.4 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 163.6, 157.0, 142.8, 127.5, 125.8, 121.8, 53.2,
31.5, 27.8, 22.5, 13.8; MS (ESI) [M + H]+ (m/z, 244). Anal. Calcd for
C11H14ClNO3: C, 54.22; H, 5.79; N, 5.75. Found: C, 53.98; H, 5.61;
N, 5.60.
3ag. Yield 501 mg, 98%; mp = 92−93 °C; IR (cm−1, KBr) 1728; 1H
NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 1.0
Hz, 1H), 3.97 (s, 3H), 3.78 (m, 1H), 2.29−2.22 (m, 2H), 1.81−1.75
(m, 4H), 1.62−1.60 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 163.7,
160.6, 142.8, 127.1, 125.7, 119.7, 53.2, 53.1, 40.8, 30.7, 25.3; MS (ESI)
[M + H]+ (m/z, 256). Anal. Calcd for C12H14ClNO3: C, 56.37; H,
5.52; N, 5.48. Found: C, 56.11; H, 5.39; N, 5.31.
3ah. Yield 325 mg, 76%; mp = 75−76 °C; IR (cm−1, KBr) 1732, 1H
NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.3
Hz, 1H), 7.39 (dd, J1 = 11.3 Hz, J2 = 18.2 Hz, 1H), 6.20 (d, J = 17.8
Hz, 1H), 5.80 (d, J = 11.3 Hz, 1H), 3.98 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 163.4, 151.2, 143.1, 127.9, 125.6, 123.7, 119.6, 53.2;
MS (ESI) [M + H]+ (m/z, 214). Anal. Calcd for C9H8ClNO3: C,
50.47, H, 3.74; N, 6.54. Found: 50.37; H, 3.72, N, 6.47.
EXPERIMENTAL SECTION
■
General Procedure for Arylation, Alkenylation, and Alkyla-
tion of Functionalized 2-Halopyridine N-Oxides with Grignard
Reagents. A dry argon-flushed 250-mL flask, equipped with a
magnetic stirrer and a septum, was charged with 2-halopyridine N-
oxide21 (3.2 mmol). Dry THF (80 mL) was added, the resulting
solution was cooled to −50 °C, and RMgX (3.8 mmol, titrated before
use22) was then added slowly using a syringe during 1 h. The mixture
was stirred at that temperature for 1−1.5 h until the 2-halopyridine N-
oxide was consumed (checked by TLC). DDQ (860 mg, 3.8 mmol)
was added. The mixture was then allowed to come to room
temperature and stirred for 4 h. The reaction was quenched with a
20% solution of Na2CO3 (20 mL), and THF was removed by
distillation in vacuo. The aqueous phase was extracted with CH2Cl2 (5
× 40 mL), and the organic fractions were dried (Na2SO4) and
concentrated in vacuo. The crude residue was purified by flash
chromatography to yield the desired oxide.
3ai. Yield 452 mg, 78%; mp = 110−122 °C; IR (cm−1, KBr) 1739;
1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 16.6 Hz, 1H), 7.68−7.58
(m, 5H), 7.41−7.37 (m, 3H), 3.98 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.5, 151.3, 138.4, 135.7, 129.9, 129.0, 127.8, 125.7, 119.4,
118.6, 53.2; MS (ESI) [M + H]+ (m/z, 290). Anal. Calcd for
C15H12ClNO3: C, 62.19; H, 4.17; N, 4.83. Found: C, 61.89; H, 4.10;
N, 4.73.
3bf. Yield 438 mg, 90%; mp = 55−56 °C; IR (cm−1, KBr) 1723; 1H
NMR (400 MHz, CDCl3) δ 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.0
Hz, 1H), 3.96 (s, 3H), 2.96 (t, J = 7.7 Hz, 2H), 1.74−1.69 (m, 2H),
C
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Note
1.49−1.42 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.7, 154.7, 142.6, 125.2, 124.4, 122.9, 53.0, 31.1, 27.9,
22.5, 13.8; MS (ESI) [M + H]+ (m/z, 244). Anal. Calcd for
C11H14ClNO3: C, 54.22; H, 5.79; N, 5.75. Found: C, 53.96; H, 5.60;
N, 5.89.
Anal. Calcd for C11H6ClFN2O3: C, 49.18; H, 2.25; N, 10.43. Found:
C, 48.94; H, 1.99; N, 10.26.
3hq. Yield 356 mg, 65%; mp = 79−80 °C; IR (cm−1, KBr) 1735; 1H
NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 6.8
Hz, 1H), 3.97 (s, 3H), 2.98 (t, J = 7.5 Hz, 2H), 1.83−1.74 (m, 2H),
1.04 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3, 156.4,
134.4, 130.9, 125.3, 122.7, 53.2, 19.1, 13.8; MS (ESI) [M + H]+ (m/z,
275). Anal. Calcd for C10H12BrNO3: C, 43.82; H, 4.41; N, 5.11.
Found: C, 43.81; H, 4.44; N, 5.01.
3ca. Yield 358 mg, 68%; mp = 79−81 °C; IR (cm−1, KBr) 1738; 1H
NMR (400 MHz, CDCl3): 7.63−7.58 (m, 2H), 7.49−7.47 (m, 3H),
7.42−7.39 (m, 2H), 3.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.1, 151.6, 145.4, 131.4, 129.7, 129.5, 129.1, 128.3, 125.4, 125.0,
52.8; MS (ESI) [M + H]+ (m/z, 264). Anal. Calcd for C13H10ClNO3:
C, 59.22; H, 3.82; N, 5.31. Found: C, 58.96; H, 3.67; N, 5.13.
3dj. Yield 573 mg, 96%; mp = 123−126 °C; IR (cm−1, KBr) 2246;
1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H),
7.80 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 8.3 Hz,
1H), 7.52 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 152.7,
146.2, 132.6, 131.7, 131.4, 131.1, 129.2, 127.8, 127.7, 127.4, 126.4,
126.3, 126.3, 126.2, 125.0, 124.8, 122.3, 113.0; MS (ESI) [M + H]+
(m/z, 299). Anal. Calcd for C13H6ClF3N2O: C, 52.28; H, 2.03; N,
9.38. Found: C, 51.98; H, 1.87; N, 9.12.
3hm. Yield 381 mg, 70%; mp = 102−103 °C; IR (cm−1, KBr) 1731;
1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.5 Hz, 1H), 7.44 (d, J =
8.3 Hz, 1H),7.13 (d, J = 16.2 Hz, 1H), 6.81−6.72 (m, 1H), 3.97 (s,
3H), 2.44 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.2,
151.1, 137.5, 134.8, 130.2, 125.3, 122.8, 120.2, 53.1, 18.4; MS (ESI)
[M + H]+ (m/z, 273). Anal. Calcd for C10H10BrNO3: C, 44.14, H,
3.70, N, 5.15. Found: C, 43.85; H, 3.58; N, 5.01.
3ib. Yield 487 mg, 72%; mp = 125−127 °C; IR (cm−1, KBr) 1731;
1H NMR (400 MHz, CDCl3) δ 8.26−8.10 (m, 1H), 7.93−7.90 (m,
1H), 7.48−7.44 (m, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz,
1H), 7.01 (t, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 163.6, 157.3, 149.6, 131.6, 130.5, 129.5, 126.9,
126.2, 125.7, 124.8, 120.6, 111.2, 55.8, 52.9; MS (ESI) [M+Na]+ (m/z,
361). Anal. Calcd for C14H12BrNO4: C, 49.73; H, 3.58; N, 4.14.
Found: C, 49.48; H, 3.41; N, 3.98.
3dg. Yield 392 mg, 88%; mp = 151−153 °C; IR (cm−1, KBr) 2236;
1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.3 Hz, 1H), 7.32 (d, J =
8.3 Hz, 1H), 3.76 (m, J = 8.3 Hz, 1H), 2.29−2.22 (m, 2H), 1.84−1.74
(m, 4H), 1.63−1.60 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.8,
144.9, 127.3, 120.8, 113.4, 110.8, 40.7, 30.7, 25.3; MS (ESI) [M + H]+
(m/z, 223). Anal. Calcd for C11H11ClN2O: C, 59.33; H, 4.98; N,
12.58. Found: C, 59.04; H, 4.72; N, 12.29.
3if. Yield 449 mg, 78%; mp = 55−56 °C; IR (cm−1, KBr) 1720; 1H
NMR (400 MHz, CDCl3) δ 8.16 (d, J = 1.8 Hz, 1H), 7.80 (s, 1H),
3.95 (s, 3H), 2.96 (t, J = 7.7 Hz, 2H), 1.76−1.68 (m, 2H), 1.50−1.41
(m, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
163.6, 154.5, 133.5, 128.2, 125.3, 124.4, 122.9, 52.9, 31.5, 28.0, 22.5,
13.8; MS (ESI) M+ (m/z, 288). Anal. Calcd for C11H14BrNO3: C,
45.85, H, 4.90; N, 4.86. Found: C, 45.65; H, 4.75; N, 4.77.
3ih. Yield 361 mg, 70%; mp = 79−80 °C; IR (cm−1, KBr) 1728; 1H
NMR (400 MHz, CDCl3) δ 8.16 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 2.4
Hz, 1H), 7.33 (dd, J1 = 17.8 Hz, J2 = 11.4 Hz, 1H), 6.19 (dd, J1 = 17.8
Hz, J2 = 6.3 Hz, 1H), 5.75 (dd, J1 = 11.3 Hz, J2 = 8.8 Hz, 1H), 3.97 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 163.3, 149.5, 133.7, 128.6,
127.8, 125.4, 122.6, 121.9, 52.9; MS (ESI) [M + H]+ (m/z, 259). Anal.
Calcd for C9H8BrNO3: C, 41.89; H, 3.12; N, 5.43. Found: C, 41.66; N,
3.07; N, 5.38.
3ek. Yield 550 mg, 85%; mp = 211−212 °C; IR (cm−1, KBr) 1682;
1H NMR (400 MHz, CDCl3) δ 7.61−7.59 (m, 3H), 7.48 (t, J = 7.4
Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.27−7.23 (m, 3H), 7.05 (d, J = 7.8
Hz, 2H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.1, 149.8,
144.1, 140.1, 136.9, 135.8, 133.8, 130.1, 129.7, 128.9, 128.5, 127.2,
125.3, 123.7, 21.4; MS (ESI) [M + H]+ (m/z, 324). Anal. Calcd for
C19H14ClNO2: C, 70.48; H, 4.36; N, 4.33. Found: C, 70.19; H, 4.02;
N, 4.07.
3el. Yield 430 mg, 78%; mp = 116−117 °C; IR (cm−1, KBr) 1668;
1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 2H), 7.69−7.65
(m, 1H), 7.54−7.47 (m, 3H), 6.99 (d, J = 8.3 Hz, 1H), 3.38−3.31 (m,
1H), 1.37 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 193.5,
155.9, 144.0, 136.0, 135.9, 134.6, 130.2, 129.0, 123.9, 122.8, 31.7, 17.7;
MS (ESI) [M + H]+ (m/z, 276). Anal. Calcd for C15H14ClNO2: C,
65.34, H, 5.12, N, 5.08. Found: C, 65.53; H, 5.19, N, 4.86.
3 fc. Yield 458 mg, 75%; mp = 143−144 °C; IR (cm−1, KBr) 1726;
1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 7.7 Hz, 1H), 7.66 (t, J =
7.5 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.37 (d,
J = 8.1 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 3.79 (s, 3H), 2.73 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 196.3, 166.5, 153.3, 140.1, 136.9,
132.4, 131.0, 131.3, 130.1, 129.9, 124.1, 123.5, 52.5, 30.3; MS (ESI)
[M + H]+ (m/z, 306). Anal. Calcd for C15H12ClNO4: C, 58.93; H,
3.96; N, 4.58. Found: C, 58.71; H, 4.02; N, 4.38;
3jp. Yield 558 mg, 75%; mp = 134−137 °C; IR (cm−1, KBr) 1672;
1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.3 Hz, 1H), 7.58 (d, J =
7.6 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.40−7.32 (m, 4H), 7.22 (d, J =
8.3 Hz, 1H), 6.93 (t, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
192.9, 164.6, 162.1, 148.5, 137.8, 135.6, 134.1, 132.5, 132.4, 129.6,
129.5, 128.7, 126.3, 124.5, 115.5, 115.3; MS (ESI) M+ (m/z, 372).
Anal. Calcd for C18H11BrFNO2: C, 58.09; H, 2.98; N, 3.76. Found: C,
57.83; H, 2.79; N, 3.58.
3jq. Yield 480 mg, 75%; IR (cm−1, KBr) 1671; 1H NMR (400 MHz,
CDCl3) δ 7.80 (d, J = 7.4 Hz, 2H), 7.67 (t, J = 7.2 Hz, 2H), 7.52 (t, J =
7.6 Hz, 2H), 7.00 (t, J = 8.8 Hz, 1H), 2.90 (t, J = 7.7 Hz, 2H), 1.78−
1.66 (m, 2H), 0.96−0.91 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
193.2, 153.3, 136.3, 135.9, 134.5, 130.2, 129.1, 129.0, 127.5, 123.4,
58.5, 31.7, 19.7, 14.2; MS (ESI) [M + H]+ (m/z, 321). Anal. Calcd for
C15H14BrNO2: C, 56.27; H, 4.41; N, 4.37; Found: C, 56.49; H, 4.42;
N, 4.29.
3fm. Yield 364 mg, 86%; mp = 102−103 °C; IR (cm−1, KBr) 1700;
1HNMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 1H), 7.54 (d, J =
8.3 Hz, 1H), 7.12 (d, J = 18.0 Hz, 1H), 6.82−6.73 (m, 1H), 2.68 (s,
3H), 2.04 (d, J = 5.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 196.3,
150.9, 140.8, 137.6, 135.1, 124.1, 122.4, 120.0, 30.4, 18.4; MS (ESI)
[M + H]+ (m/z, 212). Anal. Calcd for C10H10ClNO2: C, 56.75; H,
4.76; N, 6.62. Found: C, 57.01; H, 4.82, N, 6.47.
3kd. Yield 608 mg, 80%; mp = 140−141 °C; IR (cm−1, KBr) 1547,
1
1357; H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.70 (dd, J = 5.0
3fn. Yield 456 mg, 90%; mp = 75−76 °C; IR (cm−1, KBr) 1712; 1H
NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.2
Hz, 1H), 3.53 (dd, J = 2.8 Hz, J = 13.6 Hz, 1H), 2.67 (s, 3H), 2.08 (d,
J = 13.6 Hz, 2H), 1.88 (d, J = 13.2 Hz, 2H), 1.80−1.46 (m, 2H), 1.33−
1.27 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 196.5, 160.0, 140.0,
135.4, 123.8, 120.4, 38.5, 30.4, 30.2, 26.1, 26.0; MS (ESI) [M + H]+
(m/z, 254). Anal. Calcd for C13H16ClNO2: C, 61.54; H, 6.36; N, 5.52.
Found: C, 61.68; H, 6.33; N, 5.49.
Hz, J = 0.8 Hz, 1H), 7.56 (dd, J1 = 1.6 Hz, J2 = 0.8 Hz, 1H), 7.21 (dd,
J1 = 5.0 Hz, J2 = 3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 147.9,
144.5, 132.8, 132.7, 130.7, 130.5, 126.5, 123.5, 113.9; MS (ESI) [M +
H]+ (m/z, 381). Anal. Calcd for C9H4Br2N2O3S: C, 28.45, H, 1.06; N,
7.37. Found: C, 28.18; H, 1.09; N, 7.30.
3kp. Yield 621 mg, 82%; mp = 197−198 °C; IR (cm−1, KBr) 1547,
1
1347; H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.37−7.34 (m,
2H), 7.27−7.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.0,
162.5, 152.7, 143.8, 132.9, 131.6, 131.5, 127.9, 124.5, 116.5, 114.1; MS
(ESI) [M + H]+ (m/z, 392). Anal. Calcd for C11H5Br2FN2O3: C,
33.71; H, 1.29; N, 7.15. Found: C, 33.49; H, 1.03; N, 6.98.
3gp. Yield 483 mg, 90%; mp = 149−151 °C; IR (cm−1, KBr) 1531,
1346; 1H NMR (400 MHz, CDCl3) δ 7.87−7.84 (m, 2H), 7.78 (d, J =
8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.22 (t, J = 8.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 165.4, 162.9, 152.6, 146.1, 139.3, 131.7,
127.0, 123.3, 119.8, 116.0, 115.8; MS (ESI) [M + H]+ (m/z, 269).
3mc. Yield 984 mg, 80% mp = 133−134 °C; IR (cm−1, KBr) 1722,
1
1536, 1349; H NMR (400 MHz, CDCl3) δ 8.24−8.22 (dd, J = 0.8
D
dx.doi.org/10.1021/jo302511s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 7.68 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.71−7.61 (m, 3H), 7.24
(d, J = 0.8 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.8, 148.9, 146.7, 145.2, 133.4, 131.0, 130.6, 130.4, 129.5, 128.8,
124.7, 119.7, 52.5; MS (ESI) [M + H]+ (m/z, 309). Anal. Calcd for
C13H9ClN2O5: C, 50.58; H, 2.94; N, 9.08. Found: C, 50.73; H, 3.09;
N, 9.02.
6. To a solution of 3mc (500 mg, 1.6 mmol) in THF (20 mL) were
added triethylamine (0.3 mL, 2.1 mmol) and N-methyl-piperazine (0.4
mL, 3.6 mmol). The mixture was stirred and heated at reflux until the
compound 3mc was consumed (monitored by TLC). After
evaporation to dryness in vacuo, the residue was taken up with
CH2Cl2 (300 mL) and washed with saturated aqueous Na2CO3
solution (25 mL). The organic fractions were dried (Na2CO3) and
concentrated in vacuo. The residue was purified by flash
chromatography (petroleum ether/ethyl acetate = 1:2) to give 6 in
98% yield (591 mg): yellow solid, mp > 220 °C (dec); IR (cm−1, KBr)
1720, 1565, 1334; 1H NMR (400 MHz, CD3SOCD3) δ 8.08 (t, J = 9.8
Hz, 2H), 7.70 (d, J = 6.1 Hz, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.33(d, J =
6.6 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 3.66 (s, 3H), 3.37 (br s, 4H),
2.51 (br s, 4H), 2.23 (s, 3H); 13C NMR (100 MHz, CD3SOCD3) δ
165.4, 156.9, 147.2, 138.8, 133.1, 132.6, 129.8, 129.2, 121.9, 112.2,
55.9, 53.9, 52.1, 46.7, 45.5, 18.5; MS (ESI) [M + H]+ (m/z, 373).
Anal. Calcd for C18H20N4O5: C, 58.06; H, 5.41; N, 15.05. Found: C,
58.21; H, 5.62; N, 15.32.
4. A solution of 1l (10 mmol) in THF (250 mL) was treated with
phenyl magnesium chloride (2a, 12 mmol) and then DDQ (15 mmol)
as described in the general procedure. Upon completion of the
reaction (monitored by TLC), the mixture was warmed to 0 °C, and
PCl3 (15 mmol) was added dropwise. The mixture was allowed to
come to room temperature and stirred for 2 h. The mixture was
treated with saturated aqueous Na2CO3 solution (80 mL), and THF
was removed by distillation in vacuo. The aqueous phase was extracted
with CH2Cl2 (5 × 80 mL), and the organic fractions were dried
(Na2CO3) and concentrated in vacuo. The residue was purified by
flash chromatography (petroleum ether/ethyl acetate = 10:1) to give 4
in 86% yield (2.30g): white solid, mp = 94−95 °C; IR (cm−1, KBr)
1730; 1H NMR (400 MHz, CDCl3) δ 7.52−7.49 (m, 2H), 7.35−7.33
(m, 3H), 7.12 (s, 1H), 3.58 (s, 3H), 2.33 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 167.6, 156.2, 150.4, 147.9, 137.5, 128.2, 127.4, 127.2,
126.7, 122.6, 51.4, 18.4; MS (ESI) [M + H]+ (m/z, 262). Anal. Calcd
for C14H12ClNO2: C, 64.25; H, 4.62, N, 5.35. Found: C, 64.43; H,
4.46; N, 5.54.
GPI 16539.17b Compound 6 (150 mg, 0.4 mmol) was dissolved in
acetic acid (20 mL), and iron powder (200 mg, 3.6 mmol) was added.
The mixture was stirred and heated at 100 °C until the reaction was
completed (monitored by TLC). The resulting mixture was
neutralized with saturated aqueous Na2CO3 solution and extracted
with CH2Cl2 (5 × 80 mL), and the organic fractions were dried
(Na2CO3) and concentrated in vacuo. The residue was purified by
flash chromatography (ethyl acetate) to give the title compound in
98% yield (110 mg): yellow solid, mp = 280−283 °C; IR (cm−1, KBr)
5.16b Compound 4 (300 mg, 1.2 mmol) was dissolved in 12 mL of
PPA and heated at 210 °C until the reaction was completed (checked
by TLC). The mixture was poured onto ice and neutralized with
saturated aqueous Na2CO3 solution. The aqueous phase was extracted
with CH2Cl2 (3 × 80 mL), and the organic fractions were dried
(Na2CO3) and concentrated in vacuo. The residue was purified by
flash chromatography (petroleum ether/ethyl acetate = 10:2) to give 5
in 92% yield (242 mg): white solid, mp = 190−191 °C; IR (cm−1,
1
1656; H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H); 8.71 (d, J = 8.0
Hz, 1H); 8.43 (d, J = 7.9 Hz, 1H); 7.77 (t, J = 8.0 Hz, 1H); 7.60 (t, J =
8.0 Hz, 1H); 7.42 (d, J = 9.0 Hz, 1H); 6.85 (d, J = 9.0 Hz, 1H); 3.65
(s, 4H); 2.56 (s, 4H); 1.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
162.5, 155.4, 135.9, 134.0, 132.5, 128.7, 127.5, 127.0, 126.5, 124.7,
123.8, 109.7, 54.9, 46.3, 45.7; MS (ESI) [M + H]+ (m/z, 295). Data
was consistent with that reported in the literature.17b
1
KBr) 1714; H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.4 Hz, 1H),
7.70 (d, J = 7.3 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.5 Hz,
1H), 7.04 (s, 1H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
191.9, 166.4, 155.8, 149.9, 141.9, 135.1, 135.0, 131.4, 125.4, 124.6,
123.9, 131.3, 17.3; MS (ESI) [M + H]+ (m/z, 230). IR, NMR, and MS
data was consistent with that reported in the literature.16b
ASSOCIATED CONTENT
■
S
* Supporting Information
General information and copies of 1H and 13C NMR spectra for
all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Onychine.15b Compound 5 (103 mg, 0.45 mmol) was dissolved in
CH3OH (15 mL). Anhydrous sodium acetate (410 mg, 0.5 mmol) and
palladium on carbon (10%, 100 mg) were added, and the mixture was
stirred under 1 atm of H2 at ambient temperature. After compound 5
was consumed (monitored by TLC), the reaction mixture was filtered
and evaporated to dryness. The residue was purified by column
chromatography (petroleum ether/ethyl acetate = 5:1) to give the title
product in 94% yield (82 mg): white solid, mp = 100−102 °C; IR
(cm−1, KBr) 1668; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 5.3 Hz,
1H), 7.84 (d, J = 7.4 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.59 (t, J = 7.4
Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 5.3 Hz, 1H), 2.64 (s,
3H); 13C NMR (400 MHz, CDCl3) δ 193.2, 165.6, 152.8, 147.7,
143.1, 135.1, 135.0, 130.9, 126.0, 125.9, 123.7, 120.8, 17.3; MS (ESI)
[M + H]+ (m/z, 196). Data was consistent with that reported in the
literature.15b
AUTHOR INFORMATION
Corresponding Author
*E-mail: xinfangduan@vip.163.com.
■
Notes
Notes. The authors declare no competing financial interest.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Science Foundation of
China (21072022), Specialized Research Fund for the Doctoral
Program of Higher Education (20100003110010).
Dielsine.16b NaH (22 mg, 0.9 mmol) was dissolved in a solution of
phenylmethanol (146 mg, 1.35 mmol) in DMF (15 mL), and
compound 5 (103 mg, 0.45 mmol) was added. The mixture was
heated at 70―90 °C until compound 5 was consumed (monitored
by TLC). To the resulting mixture were added acetic acid (60 mg, 1.0
mmol) and palladium on carbon (10%, 100 mg), and the mixture was
stirred under 1 atm of H2 at ambient temperature. Upon completion of
the debenzylation (monitored by TLC), the mixture was filtered and
evaporated to dryness. The residue was purified by column
chromatography (ethyl acetate) to give the title product in 86%
yield (82 mg): white solid, mp > 300 °C; IR (cm−1, KBr) 1701, 1638;
1H NMR (400 MHz, CDCl3) δ 8.07−7.85 (m, 1H); 7.59−7.02 (m,
4H); 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 191.1, 165.4,
154.4, 150.2, 141.0, 135.5, 134.5, 131.8, 125.5, 124.2, 123.7, 120.9,
16.6; MS (ESI) M+ (m/z, 211). Data was consistent with that reported
in the literature.16b
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■
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