Synthesis of substituted pyridines and quinolines

Article abstract of DOI:10.1055/s-2007-965940

A variety of N-vinyl and N-aryl amides were converted to the corresponding pyridine and quinoline derivatives, respectively. Amide activation and nucleophilic addition of copper(I) (trimethylsilyl)acetylide efficiently provided the desired alkynyl imines. Ruthenium-catalyzed protodesilylation and cycloisomerization of these imines gave the corresponding azaheterocycles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965940

PRACTICAL SYNTHETIC PROCEDURES
1115
Synthesis of Substituted Pyridines and Quinolines
S
ynthesis of Substitute
a
d
Pyridines
t
and Q
t
uinolin
h
es ew D. Hill, Mohammad Movassaghi*
Department of Chemistry, Massachusettes Institute of Technology, Cambridge, MA 02139, USA
Fax +1(617)2521504; E-mail: movassag@mit.edu
Received 23 November 2006
PSP
No80
Abstract: A variety of N-vinyl and N-aryl amides were converted to the corresponding pyridine and quinoline derivatives, respectively.
Amide activation and nucleophilic addition of copper(I) (trimethylsilyl)acetylide efficiently provided the desired alkynyl imines.
Ruthenium-catalyzed protodesilylation and cycloisomerization of these imines gave the corresponding azaheterocycles.
Key words: amide, imine, pyridine, quinoline, vinylidene
Tf2O, 2-ClPyr
–78→0 °C, CH2Cl2;
CpRu(PPh3)2Cl
SPhos, NH4PF6
O
N
N
N
TMSC≡CCu, THF
–78→23 °C
97%
H
105 °C, toluene
91%
TMS
1
2
3
Scheme 1
suggest a superb electrophilic activation of the amide sub-
strates using this reagent combination11c that has enabled
Introduction
Pyridines and quinolines are important classes of azahet- the use of a wide range of nucleophiles. Related to the
erocycles and are found in many pharmaceuticals, natural chemistry at hand, these conditions have allowed the di-
products, and fine materials.1,2 Their significance has in- rect addition of copper(I) (trimethylsilyl)acetylide to a va-
spired many synthetic methods for their synthesis and de- riety of amides to give the corresponding alkynyl imines
rivatization. Most syntheses of these azaheterocycles in good yield.
involve either condensation of amines and carbonyl deriv-
Table 1 Conversion of Amide 1 to Alkynyl Imine 2a
atives or cycloaddition reactions.3,4 Recent advances in
cross-coupling chemistry enable the introduction of addi-
Entry
Base additive
pyridine
Base (equiv)
Yield of 2
<10
27
tional substituents to these azaheterocycles.5 We describe
an efficient two-step procedure for the synthesis of a vari-
ety of pyridine and quinoline derivatives from readily
available N-vinyl and N-aryl amides, respectively.6
1
2
3
4
5
6
7
4
4
4
4
4
3
2
2,6-lutidine
Et3N
<4
N-Vinyl and N-aryl amides serve as attractive starting ma-
terials due to their efficient preparation via convergent
synthetic procedures.7 Typical procedures for amide acti-
vation include reagents such as phosphorus pentachloride
and phosphorus oxychloride.8 Trifluoromethanesulfonic
anhydride (Tf2O) has been used in carbonyl activation en-
abling a wide range of valuable synthetic transforma-
tions.9–11
DIPEA
<20
97
2-chloropyridine
2-chloropyridine
2-chloropyridine
92
65
a Reaction conditions: Amide 1 (1 equiv), Tf2O (1.2 equiv), base,
CH2Cl2, –78 → 0 °C; TMSC≡CCu (2.7 equiv), THF, –78 → 0 °C.
We found the use of Tf2O and 2-chloropyridine (2-ClPyr)
in CH2Cl2 to be the optimal reagent combination for acti-
vation of benzamide 1 and its direct conversion to the
alkynyl imine 2 (Scheme 1).6 Other base additives were
found to be less effective in this single-step alkynyl imine
synthesis (Table 1). The results of our mechanistic studies
With an efficient synthesis of a variety of N-vinyl- and N-
arylalkynyl imines at hand, we focused on the develop-
ment of optimal reaction conditions for their conversion to
the corresponding azaheterocycles. The chlorocyclopen-
tadienylbis(triphenylphosphine)ruthenium complex [Cp-
Ru(PPh3)2Cl]12 was identified to be an excellent catalyst
for the desired cycloisomerization following an in situ
protodesilylation of the alkynyl imine substrates
SYNTHESIS 2007, No. 7, pp 1115–1119
x
x
.
x
x
.2
0
0
7
Advanced online publication: 20.02.2007
DOI: 10.1055/s-2007-965940; Art ID: Z24206SS
© Georg Thieme Verlag Stuttgart · New York

1116
M. D. Hill, M. Movassaghi
PRACTICAL SYNTHETIC PROCEDURES
(Scheme 1). The intermediacy of a metal vinylidene inter- amides with electron-withdrawing or electron-donating
mediate enables a 6p-electrocyclization to the desired aza- groups were readily converted to the desired alkynyl
heterocycle. Introduction of 2-dicyclohexylphosphino- imines (Table 2, entries 1–5). Aliphatic amides and a urea
2¢,6¢-dimethoxy-1,1¢-biphenyl (SPhos)13 was found to derivative provided the desired C-silylalkynyl imines
provide for a more robust catalyst system. While the pro- (Table 2, entries 6–8). Unfortunately, N-aryl carbamates
todesilylated derivative of imine 2 could be used as the (e.g., ethyl and phenyl carbamates) did not provide the
substrate for the cycloisomerization reaction to afford corresponding alkynyl imine derivatives (imidates) under
product 3,4c,6 this was found to be non-optimal due to the the standard reaction conditions. Significantly, we were
need for an additional desilylation step and reduced stabil- pleased to find that enamides, including acid sensitive de-
ity of the substrate. Toluene was found to be the optimal rivatives, could be converted to the corresponding imines
solvent and ammonium hexafluorophosphate was an ef- in moderate to excellent yield (Table 2, entries 9–16). For
fective additive allowing in situ protodesilylation of the comparison, the use of existing methods for the synthesis
substrates. These optimal reaction conditions allow the di- of N-2-thienyl and N-dihydropyranyl alkynyl imines
rect conversion of trimethylsilyl alkynyl imines to the cor- (Table 2, entries 13 and 15, respectively) gave none and
responding azaheterocycles.
<10% yield of the desired product, respectively.8 These C-
silylalkynyl imines, except that shown in entry 15 of
Table 2, were found to be stable toward long-term stor-
age. When necessary, the C-silylalkynyl imines could be
efficiently desilylated with potassium carbonate in meth-
Scope and Limitations
A variety of amides were efficiently converted to the cor- anol (Table 2, entries 7 and 16).
responding azadieneyne derivatives (Table 2). N-Aryl
Table 2 Pyridines and Quinolines Prepared
Entry
Amide
Yield (%)a
Yield (%)a
R'
R'
R'
R
N
R"
R
N
R"
R
R"
O
Ph
N
H
Ph
Ph
TMS
1
2
3
4
R = H, R¢ = H, R¢¢ = H (1)
R = H, R¢ = H, R¢¢ = OMe
R = OMe, R¢ = H, R¢¢ = H
R = H, R¢ = CF3, R¢¢ = H
97b (2)
89
91b (3)
92
96
91
73, <10c
89
Ph
N
O
N
S
5
Ph
S
N
S
H
TMS
81
75
Ph
N
O
Ph
N
R
R
N
H
TMS
R
6
7
8
R = c-C6H11
R = t-Bu
85
69
83, 95c
69
62
R = N(CH2CH2)2O
80
Ar
N
O
Ar
N
Ar
Ph
Ph
N
H
Ph
TMS
9
10
11
Ar = Ph
78
86
92
77
83
78
Ar = 1-naphthyl
Ar = 3,4-(MeO)2C6H3
Synthesis 2007, No. 7, 1115–1119 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Substituted Pyridines and Quinolines
Yield (%)a
1117
Table 2 Pyridines and Quinolines Prepared (continued)
Entry
12
Amide
Yield (%)a
O
N
N
Ph
N
H
Ph
Ph
TMS
73
75
S
S
O
S
N
N
13
14
Ph
N
H
Ph
Ph
TMS
99
63d
S
S
O
N
N
S
Ph
N
H
Ph
Ph
TMS
O
97
98
O
N
O
15
16
N
O
Ph
N
H
Ph
Ph
TMS
70
99
NTIPS
NTIPS
O
N
N
NTIPS
Ph
N
H
Ph
Ph
64e
TMS
82, 91c
a Isolated yields: all entries are average of two experiments. Optimum conditions used uniformly.
b Gram-scale experiments.
c Yield of the corresponding desilylated imine.
d Kept at –78 °C.
e 5 mol% of catalyst system was used.
The optimized reaction conditions described above for the In conclusion, we have reported an efficient two-step syn-
conversion of azadienynes to the corresponding azahet- thesis of a wide range of pyridine and quinoline deriva-
erocycles provided a variety of pyridines and quinolines. tives from readily available starting materials. Attractive
Electron-rich and electron-deficient N-aryl derivatives features of this chemistry include the single-step synthesis
gave the desired products in good yield (Table 2, entries of alkynyl imines from N-vinyl and N-aryl amides and the
1–5). The use of aliphatic imines and a urea derivative led direct ruthenium-catalyzed protodesilylation and cyclo-
to the corresponding quinoline derivatives (Table 2, en- isomerization of these products to the corresponding aza-
tries 6–8). We were pleased to find that a variety of N-vi- heterocycles.
nyl/heteroaromatic imines could be used as substrates and
gave the desired pyridine derivatives in moderate to excel-
lent yield (Table 2, entries 9–16). In rare cases where the
rate of the protodesilylation of the C-silylalkynyl imines
Procedures
was prohibitively slow, the use of the corresponding ter- Herein we describe the efficient synthesis of alkynyl
minal alkyne derivatives was beneficial (Table 2, entries imines from N-aryl or N-vinyl amides and the Ru-cata-
7 and 16).
lyzed conversion of these alkynyl imines to the corre-
sponding azaheterocycles.
Synthesis 2007, No. 7, 1115–1119 © Thieme Stuttgart · New York

1118
M. D. Hill, M. Movassaghi
PRACTICAL SYNTHETIC PROCEDURES
4-Trimethylsilyl-N-phenyl-2-phenyl-1-azabut-1-en-3-yne (2);
Typical Procedure
13C NMR (125 MHz, CDCl3): d = 157.5, 148.4, 139.8, 137.0, 129.9,
129.9, 129.5, 129.0, 127.8, 127.7, 127.3, 126.5, 119.2.
A flame-dried flask was charged with anhyd THF (40 mL), cooled
to 0 °C, and vigorously stirred as (trimethylsilyl)acetylene (4.74
mL, 3.36 g, 34.2 mmol, 2.70 equiv) was added in one portion via sy-
ringe. n-BuLi (2.53 M, 13.5 mL, 34.2 mmol, 2.70 equiv) was added
over 10 min and the mixture was kept at 0 °C for an additional 5 min
before warming to r.t. After 40 min, the lithium (trimethylsi-
lyl)acetylide solution was transferred via cannula over 5 min to a
flame dried flask containing CuBr·SMe2 complex (7.03 g, 34.2
mmol, 2.70 equiv) and anhyd THF (20 mL) at –78 °C. The resulting
bright-yellow solution was maintained at –78 °C for 5 min before it
was warmed to 0 °C and maintained at that temperature for an addi-
tional 10 min prior to use. Separately, trifluoromethanesulfonic an-
hydride (2.51 mL, 15.2 mmol, 1.20 equiv) was added via syringe
over 1 min to a well-stirred mixture of amide 1 (2.50 g, 12.7 mmol,
1 equiv), 2-chloropyridine (4.81 mL, 50.7 mmol, 4.00 equiv), and
anhyd CH2Cl2 (25 mL) at –78 °C in a flame-dried and argon-purged
Schlenk (Kjeldahl shape) flask. After 5 min, the mixture was
warmed to 0 °C. After 20 min, the solution was cooled back down
to –78 °C and the freshly prepared solution of copper(I) (trimethyl-
silyl)acetylide described above was added via cannula. The mixture
was kept at –78 °C for 5 min and then warmed to 0 °C. After 10 min,
the mixture was filtered through a column of Celite (2 cm diam × 3
cm length) and the filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel (100% hexanes → 7:93 EtOAc–hexanes) to give the alkynyl
imine 2 as a yellow oil; yield: 3.42 g (97%); Rf = 0.59 (EtOAc–
hexanes, 20:80).
HRMS (EI): m/z [M]+ calcd for C15H11N: 205.0886; found:
205.0885.
Anal. Calcd for C15H11N: C, 87.77; H, 5.40; N, 6.82. Found: C,
87.81; H, 5.36; N, 6.88.
Acknowledgment
M.M. is a Dale F. and Betty Ann Frey Damon Runyon Scholar sup-
ported by the Damon Runyon Cancer Research Foundation (DRS-
39-04). M.M. is a Firmenich Assistant Professor of Chemistry. We
acknowledge financial support by NSF (547905).
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IR (film): 3063 (m), 3030 (w), 2960 (m), 1588 (s), 1565 cm–1 (s).
1H NMR (500 MHz, CDCl3): d = 8.21–8.18 (m, 2 H), 7.51–7.45 (m,
3 H), 7.40–7.36 (m, 2 H), 7.17 (tt, J = 7.5, 1.1 Hz, 1 H), 7.14–7.11
(m, 2 H), 0.14 (s, 9 H).
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128.5, 128.3, 125.0, 120.9, 105.4, 97.5, –0.5.
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278.1365.
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77.97; H, 6.87; N, 5.10.
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An oven-dried pressure vessel containing a magnetic stir bar was
charged with anhyd ammonium hexafluorophosphate (587 mg, 3.60
mmol, 1.00 equiv), CpRuCl(PPh3)2 (262 mg, 0.35 mmol, 0.10
equiv) and SPhos (148 mg, 0.35 mmol, 0.10 equiv) under N2 in a
glove-box and the flask was sealed and brought out of the glove-
box. Imine 2 (1.00 g, 3.60 mmol, 1 equiv) and anhyd toluene (18
mL) were sequentially added via syringe. The flask was flushed
with argon, sealed, the contents were vigorously stirred, and placed
in an oil bath at 105 °C. After 19 h, the reaction vessel was allowed
to cool to r.t. and the mixture was transferred to a recovery flask us-
ing CH2Cl2 (20 mL). This solution was concentrated under reduced
pressure and the residue was purified by flash column chromatogra-
phy on silica gel (3:20 → 1:1 EtOAc–hexanes) to afford the quino-
line 3 as a pale yellow solid; yield: 668 mg (91%); Rf = 0.51
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Synthesis 2007, No. 7, 1115–1119 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Substituted Pyridines and Quinolines
1119
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Synthesis 2007, No. 7, 1115–1119 © Thieme Stuttgart · New York