New access to oxazolopyridines via hydroxyamidine derivatives; application to quinolines

Article abstract of DOI:10.1055/s-2003-41052

Several 2-aryl and 2-heteroaryloxazolo[4,5-b]pyridines were synthesised in high yields from zwitterion or hydroxyamidine derivatives by heating in dimethylacetamide. These intermediates were generated via hetarynic reaction with the complex base NaNH₂-t-BuONa (5:2). The same reactions were possible with quinoline derivatives.

Full text of DOI:10.1055/s-2003-41052

PAPER
2033
New Access to Oxazolopyridines via Hydroxyamidine Derivatives; Application
to Quinolines
New
A
ccess to O
t
xazol
h
opyridines vi
e
a
H
ydroxya
l
midine Deriv
G
atives;
A
pplicatio
a
n
to
Q
uinol
r
ines nier,a Stéphanie Blanchard,a Ivan Rodriguez,a Christian Jarry,b Jean-Michel Léger,b Paul Caubère,*a
Gérald Guillaumet*a
a
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Université d’Orléans, B.P. 6759, 45067 Orléans Cedex 2, France
Fax +33(2)38417078; E-mail: gerald.guillaumet@univ-orleans.fr
b
Pharmacochimie, EA 2962, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France
Received 9 January 2003; revised 3 June 2003
used a transfunctionalisation with esters in the presence of
Abstract: Several 2-aryl and 2-heteroaryloxazolo[4,5-b]pyridines
trimethylaluminium in toluene4 (Method B). Finally, in
were synthesised in high yields from zwitterion or hydroxyamidine
Method C5 the corresponding anhydride was preferred to
acyl chloride for the preparation of 2h.
derivatives by heating in dimethylacetamide. These intermediates
were generated via hetarynic reaction with the complex base
NaNH2–t-BuONa (5:2). The same reactions were possible with
quinoline derivatives.
Table 1 Synthesis of 3 from 1
Key words: cyclizations, heterocycles, zwitterions, pyridines,
quinolines
Compd
R
Reaction 1 Reaction 2 Yield of 3
Methoda
Time (h)
(%) b
(Yield, %)b
2a
2b
t-Bu
A (80)
B (65)
6
80
70
We previously showed that, in the presence of the com-
plex base1 NaNH2–t-BuONa (2:1) (CB), 2-alkylamino-3-
bromopyridines led to dipyridopyrazines2 via intramolec-
ular hetarynic cyclisations. In continuation of this pro-
gram aiming at the hetarynic synthesis of polynuclear
heterocycles, we investigated the behaviour of 2-ami-
nopyridine derivatives 2 under analogous conditions. Cu-
riously, in place of the usual hetarynic cyclisation, 2 led to
an interesting while unexpected reaction, which we report
herein. Moreover, a new synthesis of oxazolopyridines
was also evidenced, as a consequence of this previously
unknown reaction.
18
2c
A (88)
A (81)
4
5
72
81
2d
2e
2f
A (91)
A (89)
B (89)
30
48
15
50
45
65
When non-enolisable amides were submitted to react with
the CB, none of the expected dipyridopyrazines were
detected. Nevertheless, zwitterions or hydroxyamidines
3a–g were isolated in relation to the nature of the substit-
uent R used in the reaction 2 (Scheme 1, Table 1).
2g
2h
2i
Me5
C (98)
A (80)
20
12
degradation
degradation
a Method A: RCOCl (1 equiv), pyridine, 1 h, 10 °C; Method B:
RCOOEt (1 equiv), AlMe3 (1 equiv), toluene, 9 h, reflux; Method C:
Ac2O, reflux, 12 h.
b Yield of pure, isolated products.
Scheme 1
Concerning the formation of 3, we required the usual 2
equivalents of CB to generate the hetarynes,6 and an extra
equivalent for deprotonation of the amides. The structure
of these compounds was established by X-ray diffraction,
when crystals were available (Figures 1, 2 and 3).
To get further insight into this reaction and determine its
scope and limitations, we synthesised various representa-
tive amides 2 by three methods. The first one (Method A)
involved the treatment of 1 with acyl chlorides in pyri-
dine.3 When acyl chlorides were not easily available we
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 22 08 2003.
Art Id.1437-210X,E;2003,0,13,2033,2040,ftx,en;Z00403SS.pdf.
DOI: 10.1055/s-2003-41052
© Georg Thieme Verlag Stuttgart · New York

2034
E. Garnier et al.
PAPER
sp3. Moreover, the two hydrogens H(10A) and H(10B) in
3f are implicated in a chelate with N(6) and in a hydrogen
bond with O(7) of another molecule, respectively. Similar
results were observed for 3g concerning the hybridisation
state of N(8) and the bonding of the two hydrogens H(8A)
and H(8B) (Table 2).
Additional arguments in favour of the proposed structures
were obtained from the study of the pyridyl ring moiety.
No hydrogen was located on O(7) in 3a. Moreover, the
bond length C(6)–O(7) = 1.296(3) Å is shorter than the
corresponding C(2)–O(7) in 3f or C(15)–O(16) in 3g,
which almost comparable to a usual phenolic bond. On the
other hand, in 3a O(7) participates in a chelate O(7)---
H(8)–N(8), with O(7)–H(8) = 2.20 Å and and O(7)–
N(8) = 2.621(2) Å (angle = 109.8°). Conversely, in 3f,
O(7) bound to H(7) established a chelate with N(8) with
Figure 1 ORTEP diagram of compound 3a
O(7)–N(8) = 2.664(4)
Å
and H(7)–N(8) = 2.19
Å
(angle = 116.5°). The same phenomenon was found for
O(16) in 3g: O(16) bound to H(16) established a chelate
with N(9) with O(16)–N(9) = 2.612(2) Å and H(16)–
N(9) = 2.00 Å (angle 127°).
Finally, the three molecules are quite planar. As an exam-
ple, the atoms of the pyridyl ring and of the lateral chain
belong to a single plane. The maximum deviation to pre-
vious plane and the implicated atom are reported in
Table 3.
Table 2 Selected Bond Lengths (Å)
Figure 2 ORTEP diagram of compound 3f
3a
3f
3g
C(9)–N(10)
C(9)–N(8)
C(7)–N(8)
C(7)–N(9)
C(6)–O(7)
C(2)–O(7)
C(15)–O(16)
1.302(2)
1.334(2)
1.337(4)
1.316(4)
1.341(2)
1.304(2)
1.296(3)
1.358(4)
1.360(2)
Figure 3 ORTEP diagram of compound 3g
Table 3 Maximum Deviations to Previous Plane (Å) and Implicated
Atom
Thus, the zwitterionic form was obtained when R was
non-aromatic, whereas only hydroxyamidines were ob-
tained when R was aromatic. These results were enlight-
ened by the determination of X-Ray structures for 3a, 3f
and 3g (Figures 1, 2, 3).
Plane
3a
3f
3g
N(10), C(9), N(8), +0.0248, C(9)
C(1), N(2)
N(10), C(9), N(8),
C(1), N(6)
–0.0456, C(1)
In 3a two hydrogens located on N(10) were assigned from
the study of the difference electron-density maps. The
first one H(10A) is also bound to N(2), generating a pseu-
N(8), C(7), N(9),
+0.0012, C(7)
do cycle [H(10A)–N(2) is 2.01(2) Å] whereas H(10B) is C(10), N(11)
bound to the O(7) of another molecule [H(10BI)–O(7II) is
1.80(2) Å]. Moreover, as depicted in Table 2, the two
Interestingly, it appeared that zwitterions possessed a
large and strong absorption band between 3500–2200
cm–1 while with hydroxyamidines a broad sharp absorp-
tion between 3500–3000 cm–1 was observed. A more de-
bond lengths C(9)–N(10) and C(9)–N(8) illustrate the sp2
character of N(10) in 3a. For 3f (Figure 2), the corre-
sponding bond lengths (Table 2) indicate that the hybrid-
isation state of N(10) was intermediate between sp2 and
Synthesis 2003, No. 13, 2033–2040 © Thieme Stuttgart · New York

PAPER
New Access to Oxazolopyridines via Hydroxyamidine Derivatives; Application to Quinolines
2035
tailed IR study was made with diluted solutions of these for microwave irradiations. The main interest of the latter
different compounds: thus, an increasingly diluted solu- is to greatly shorten the reaction time.
tion of 3a showed a decreasing of the 3400 cm–1 bond (in-
termolecular association) with simultaneous increasing of
the 2961 cm–1 bond (intramolecular chelation), according
to that which is expected for zwitterions. In contrast, with
3f and 3g, increasing dilution gave a decrease of the
3500–3300 cm–1 bond (intermolecular association) with
Scheme 3
simultaneous appearance of a narrow bond at 3590 cm–1
(free hydroxyl group).
Table 4 Synthesis of 4 from 3 by Warming or Microwave Irradia-
As a consequence, when crystals could not be obtained (in
spite of the fact that these compounds were solid) we used
IR spectra to establish the structures.
tion
Compd Time (Yield, %)a Mp (°C)d Molecular MS (IS)
(h)
formular
Finally it appeared that such reactions were limited to
non-enolisable amides: the presence of acidic protons on
the R group, such as methyl and even cyclopropyl
(Table 1, entry 2h and 2i), which is generally unfavour-
able to enolisation, only led to degradation and tars.
We have previously shown6 that under the conditions
presently used, dihydropyridines were formed. So the
mechanism reported in Scheme 2 is suggested to account
for the observed reactions. The protonation of the anionic
intermediate formed during the cyclisation step must be
due, as usual, to proton abstraction from the solvent and/
or from the formed NH3. This latter, as previously shown,7
substantially remains in solution.
Classi- Micro-
calb
wavec
4a
4b
4c
4d
4e
4f
5 (88) 0.5 (88)
12 (88) 3 (85)
6 (83) 3 (85)
10 (85) 3 (74)
15 (70) 7 (70)
12 (70) 4 (68)
10 (55) 3 (65)
72–73
82–83
C10H12N2O 177.0 (M + 1)
C10H12N2O 175.0 (M + 1)
126–127e C12H8N2O 197.0 (M + 1)
139–140 C15H14N2O4 287.0 (M + 1)
oil
142–143 C10H6N2OS 203.0 (M + 1)
oil C11H7N3O 198.0 (M + 1)
C10H6N2O2 187.0 (M + 1)
4g
a Yield of pure isolated products.
b Warming: dimethylacetamide, 170 °C in an oil bath.
c Microwave irradiations dimethylacetamide, 165 °C under 150 W
with a quartz reactor.
d Uncorrected.
e Lit.8a mp 127–127.5°C
Scheme 2
As an extension of the reactions described above, we
briefly studied the behaviour of two quinoline derivatives
(Scheme 4).
At first we thought that oxazolopyridines such as 4 (vide
infra) could be an intermediate in these reactions. Howev-
er, when 4 were submitted to the action of the CB under
the reaction conditions used to obtain 3, these latter com-
pounds were never formed. Thus we suggest that amide
anion attacks 2 before the hetaryne formation.
Finally, we reasoned that it ought to be possible to prepare
oxazolopyridines 4 (Scheme 3) from 3 by intramolecular
cyclisation and NH3 elimination. This methodology is a
new access to oxazolopyridine derivatives.8 We guessed
that such reactions could be performed by classical warm-
ing or with the help of microwave irradiation.9 According
to our hypothesis, compounds 4 were obtained in very
good yields as reported in Table 4. The cyclisations were
performed in dimethylacetamide, a solvent usually used
Scheme 4
We chose tert-butyl and phenyl groups as examples of al-
iphatic and aromatic substituents, respectively. The com-
pounds 7 were obtained from 5 under the same conditions
as described before (Table 5).
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2036
E. Garnier et al.
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Table 5 Synthesis of 7 from 5
with a Finnigan MAT 95Q, BEQQ by the Institut de recherches
Servier (Suresnes). TLC was performed with plates coated with
Kieselgel G (Merck). The silica gel used for flash chromatography
was Kieselgel of 0.04–0.063 mm particle size. Focused microwave
irradiations were carried out with a SynthewaveTM S402 Prolabo®
microwave reactor (monomode system, 2450 MHz, 300 W) which
has variable-speed rotation, visual control, irradiation monitored by
PC computer, IR measurement and continuous feedback tempera-
ture control by PC.
Compd
R
Reaction 1a
Yield of 6 (%) Time (h)
Reaction 2
Yield of 7
(%)
6a
6b
t-Bu
81b
24
24
87d
53e
c
–
Sodium amide powder was commercially available (Merck). Re-
agent-grade THF was first distilled from potassium hydroxide, then
from sodium benzophenone ketyl and stored over sodium until
used. Petroleum ether refers to the fraction with bp 40–60 ºC.
a Acyl chloride (1 equiv), pyridine, 1 h, 10 °C.
b Yield of pure, isolated product 6a based on 5.
c Partially soluble, sufficiantly pure to be directly used in the next re-
action.
d Yield of pure, isolated product 7a based on 6a.
e Yield of pure, isolated product 7b based on 5.
The 2-amino-3-bromopyridine (1) was prepared as described in the
literature.1c
Amides 2a–g and 6a,b; General Procedure
Method A
Furthermore, as with pyridine derivatives, by classical
heating or with microwave irradiation, the intramolecular
cyclisation can be observed, and some oxazoles 8 have
been isolated in good yields, as shown in Table 6.
Acyl chlorides (8.7 mmol) were added dropwise to a solution of 2-
amino-3-bromopyridine (1) (1.5 g, 8.7 mmol) in pyridine (9 mL) at
10 °C. After 1 h at 10 °C, the reaction was poured into EtOAc (20
mL) and washed several times with H2O (20 mL). The organic layer
was dried (MgSO4), filtered and concentrated in vacuo. The expect-
ed compounds were isolated after purification by chromatography
(silica gel; EtOAc–hexane, 1:6 for pyridines; EtOAc–petroleum
ether, 1:1 for quinolines).
Table 6 Synthesis of 8 from 7 by Warming or Microwave Irradia-
tion
Compd Time (h) (Yield, %)d Mp (°C)c Molecular MS (IS)
formula
Method B
Classical a Micro-
wave b
Under argon, at r.t., a solution of AlMe3 in toluene (2.0 M; 2.9 mL,
5.8 mmol) was added dropwise to a solution of 2-amino-3-bro-
mopyridine (1) (1.0 g, 5.8 mmol) in toluene (30 mL). After 1 h at
r.t., esters (5.8 mmol) were added to the previous mixture which
was refluxed for 9 h. After cooling at 0 °C, the mixture was hydrol-
ysed and filtered on Celite. The filtrate was extracted several times
with CH2Cl2 and the combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo. The expected compounds were
isolated after purification by chromatography (silica gel; EtOAc–
hexane, 1:6 for pyridines; EtOAc–petroleum ether, 1:1 for quino-
lines).
8a
8b
5 (90)
5 (96)
1 h (94) 134–135 C14H14N2O 227.0 (M + 1)
1 h (85) 220–222 C16H10N2O 247.0 (M + 1)
a Warming: dimethylacetamide, 170 °C in an oil bath.
b Microwave irradiations: dimethylacetamide, 165 °C under 150 W
with a quartz reactor.
c Uncorrrected.
d Yields of pure, isolated product 8.
N-(3-Bromopyridin-2-yl)-2,2-dimethylpropanamide (2a)
Again under microwave irradiations the reaction times
were significantly reduced without significantly affecting
the yields.
Mp (Kofler) 136–137 °C (Lit.10 mp 140–141 °C).
1H NMR (CDCl3): d = 1.36 (s, 9 H, CH3), 6.98 (dd, 1 H, J = 7.9, 4.9
Hz, H5), 7.87 (dd, 1 H, J = 7.9 Hz, J = 1.5 Hz, H4), 8.04 (br s, 1 H,
NH), 8.44 (dd, 1 H, J = 4.9, 1.5 Hz, H6).
In this work, non-enolisable amides were submitted to re-
action in the presence of the complex base NaNH2–t-
BuONa, leading either to zwitterions or to hydroxya-
midines. Furthermore, we have shown that zwitterions or
hydroxyamidines 3 and 6 were good starting materials to
generate corresponding oxazolo derivatives. Moreover,
we have underlined the interest of using microwave irra-
diation to reduce reaction time and degradation.
N-(3-Bromopyridin-2-yl)-1-methylcyclopropanacarboxamide
(2b)
Mp (Tottoli) 71–72 °C.
IR (KBr): 1664, 3222–3015 cm–1.
1H NMR (CDCl3): d = 0.71–0.75 (m, 2 H, CH2), 1.37–1.41 (m, 2 H,
CH2), 1.53 (s, 3 H, CH3), 6.98 (dd, 1 H, J = 7.9, 4.7 Hz, H5), 7.88
(dd, 1 H, J = 7.9, 1.2 Hz, H4), 8.24 (br s, 1 H, NH), 8.43 (dd, 1 H,
J = 4.7, 1.2 Hz, H6).
Mps were determined on a Tottoli or a Kofler melting point appara-
tus and are uncorrected. 1H and 13C NMR spectra were recorded in
CDCl3 with a Bruker AM 400 or a Bruker 250 MHz spectrometer
(Attached Proton Test Method, APT) or a Bruker instrument
Avance DPX 250 at 250.131 and 62.9 MHz, respectively. Chemical
Shifts (d values) were reported in parts per million and coupling
constants (J values) in Hz. TMS was the internal standard. Infrared
spectra were recorded using NaCl films or KBr pellets techniques
on a Perkin–Elmer 841 instrument. Elemental analyses were per-
formed by CNRS laboratory (Vernaison). Mass spectra (MS) were
recorded on a Perkin–Elmer mass spectrometer SCIEX API 300 by
ion spray (IS). Mass HR spectra were recorded by ‘peak matching’
13C NMR (CDCl3): d = 17.2 (2 CH2), 19.4 (CH3), 20.3 (Cq), 111.8
(C3), 121.0 (C5), 141.1 (C4), 147.4 (C6), 148.4 (C2), 172.5 (C=O).
MS (IS): m/z = 255 (M + 1, 79Br), 257 (M + 1, 81Br).
Anal: Calcd for C10H11N2BrO: C, 47.08; H, 4.35; N,10.98. Found:
C, 47.46; H, 4.67; N, 11.20.
N-(3-Bromopyridin-2-yl)-2-benzamide (2c)
Mp (Tottoli) 89–90 °C.
IR (KBr): 1671, 3219 cm–1.
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New Access to Oxazolopyridines via Hydroxyamidine Derivatives; Application to Quinolines
2037
1H NMR (CDCl3): d = 7.03 (dd, 1 H, J = 7.9, 4.8 Hz, H5), 7.46–7.61
(m, 3 H, Harom), 7.92 (dd, 1 H, J = 7.9, 1.5 Hz, H4), 7.93–7.97 (m, 2
H, Harom), 8.46 (dd, 1 H, J = 4.8,1.5 Hz, H6), 8.63 (br s, 1 H, NH).
13C NMR (CDCl3): d = 114.7 (C3), 122.3 (C5), 123.3 (Cpyr), 129.7
(Cq), 135.6 (Cq), 141.7 (C4), 147.1 (Cpyr), 148,4 (Cpyr), 152.3 (C6),
155,8 (C2), 164.0 (C=O).
13C NMR (CDCl3): d = 112.6 (C3), 121.5 (C5), 127.4 (2 Carom),
128.8 (2 Carom), 132.3 (Carom), 134.1 (Cq), 141.4 (C4), 147.4 (C6),
148.7 (C2), 164.8 (C=O).
MS (IS): m/z = 278 (M + 1, 79Br), 280 (M + 1, 81Br).
Anal: Calcd for C11H8N3BrO: C, 47.51; H, 2.90; N, 15.11. Found:
C, 47.72; H, 3.18; N, 14.71.
MS (IS): m/z = 277 (M + 1, 79Br), 279 (M + 1, 81Br).
N-(3-Bromopyridin-2-yl)cyclopropanecarboxamide (2i)
Mp (Tottoli) 136–137 °C.
IR (KBr): 1664, 3227 cm–1.
Anal: Calcd for C12H9N2BrO: C, 52.01; H, 3.27; N, 10.11. Found:
C, 52.10; H, 3.32; N, 9.85.
N-(3-Bromopyridin-2-yl)-3,4,5-trimethoxybenzamide (2d)
Mp (Tottoli) 154–155 °C.
IR (KBr): 1651, 3186 cm–1.
1H NMR (CDCl3): d = 3.92 (s, 6 H, 2 CH3), 3.93 (s, 3 H, CH3), 7.05
(dd, 1 H, J = 7.9 Hz, J = 4.6 Hz, H5), 7.17 (br s, 2 H, Harom), 7.94
(dd, 1 H, J = 7.9, 1.5 Hz, H4), 8.45–8.47 (m, 2 H, H6, NH).
1H NMR (CDCl3): d = 0.88–0.96 (m, 2 H, CH2), 1.15–1.21 (m, 2 H,
CH2), 2.15–2.25 (m, 1 H, CH), 6.96 (dd, 1 H, J = 7.9, 4.7 Hz, H5),
7.87 (dd, 1 H, J = 7.9, 1.5 Hz, H4), 8.08 (br s, 1 H, NH), 8.36 (dd, 1
H, J = 4.7, 1.5 Hz, H6).
13C NMR (CDCl3): d = 9.1 (2 CH2), 14.7 (CH), 110.9 (C3), 120.7
(C5), 141.3 (C4), 147.0 (C6), 148.6 (C2), 173.0 (C=O).
13C NMR (CDCl3): d = 56.3 (2 CH3), 60.9 (CH3), 104.9 (2 Carom),
121.6 (C5), 129.4 (Cq), 141.5, 141.7, (C3, C4), 147.5 (C6), 148.7
(C2), 153.3 (2 Cq), 164.7 (C=O).
MS (IS): m/z = 241 (M + 1, 79Br), 243 (M + 1, 81Br).
Anal: Calcd for C9H9N2BrO: C, 44.84; H, 3.76; N, 11.62. Found: C,
45.10; H, 3.68; N, 11.60.
MS (IS): m/z = 367 (M + 1, 79Br), 369 (M + 1, 81Br).
N-(3-Bromo-2-quinolyl)-2,2-dimethylpropanamide (6a)
Mp (Tottoli) 133–135 °C.
IR (KBr): 1657, 3464 cm–1.
Anal: Calcd for C15H15N2BrO4: C, 49.06; H, 4.12; N, 7.63. Found:
C, 49.18; H, 4.12; N, 7.61.
N-(3-Bromopyridin-2-yl)-2-furamide (2e)
Mp, gum.
IR (KBr): 1733, 3250 cm–1.
1H NMR (CDCl3): d = 6.58 (dd, 1 H, J = 1.5, 3.3 Hz, =CH), 7.07
(dd, 1 H, J = 7.9, 4.8 Hz, H5), 7.28 (dd, 1 H, J = 3.3, 0.9 Hz, =CH),
7.56 (m, 1 H, =CH), 7.96 (dd, 1 H, J = 7.9, 1.5 Hz, H4), 8.47 (dd, 1
H, J = 4.8, 1.5 Hz, H6), 8.85 (br s, 1 H, NH).
1H NMR (CDCl3): d = 1.41 (9 H, s, 3 CH3), 7.48 (1 H, ddd, J = 6.9,
1.1, 7.5 Hz, H6), 7.67 (1 H, dd, J = 7.5, 1.2 Hz, H5), 7.69 (1 H, ddd,
J = 6.9, 1.2, 8.0 Hz, H7), 8.04 (1 H, dd, J = 1.1, 8.0 Hz, H8), 8.35
(1 H, s, H4), 8.41 (1 H, br s, NH).
13C NMR (CDCl3): d = 27.7 (3 CH3), 40.6 (Cq), 110.9 (C3), 126.5
(C6), 126.6 (C4¢), 127.1 (C8), 128.9 (C5), 130.4 (C4), 140.5 (C7),
146.0 (C8¢), 146.7 (C2), 176.1 (C=O).
13C NMR (CDCl3): d = 111.6 (C3), 112.6 (=CH), 116.2 (=CH),
121.2 (C5), 141.2 (C4), 144.6 (=CH), 147.2 (Cq), 147.3 (C6), 147.9
(C2), 154.8 (C=O).
MS (IS): m/z = 307.0 (M + 1, 79Br), 309.0 (M + 1, 81Br).
Anal: Calcd for C15H15N2BrO: C, 54.74; H, 4.92; N, 9.12. Found: C,
54.44; H, 5.02; N, 9.39.
MS (IS): m/z = 267 (M + 1, 79Br), 269 (M + 1, 81Br).
N-(3-Bromo-2-quinolinyl)benzamide (6b)
An analytical sample was obtained by purification on column chro-
matography, in order to obtain physical and spectroscopic data.
Anal: Calcd for C10H7N2BrO2: C, 44.97; H, 2.64; N, 10.49. Found:
C, 44.88; H, 2.66; N, 10.32.
N-(3-Bromopyridin-2-yl)-2-thienamide (2f)
Mp (Tottoli) 100–101 °C.
IR (KBr): 1662, 3258 cm–1.
1H NMR (CDCl3): d = 7.03 (dd, 1 H, J = 8.2, 4.7 Hz, H5), 7.14 (dd,
1 H, J = 5.0, 3.8 Hz, =CH), 7.59 (dd, 1 H, J = 5.0, 1.1 Hz, =CH),
7.72 (dd, 1 H, J = 3.8, 1.1 Hz, =CH), 7.92 (dd, 1 H, J = 8.2, 1.3 Hz,
H4), 8.44 (dd, 1 H, J = 4.7, 1.3 Hz, H6), 8.53 (br s, 1 H, NH).
13C NMR (CDCl3): d = 112.5 (C3), 121.5 (C5), 127.9 (=CH), 129.5
(=CH), 131.7 (=CH), 138.5 (Cq), 141.5 (C4), 147.4 (C6), 156,7
(C2), 157.8 (C=O).
Mp (Tottoli) 173–174 °C.
IR (KBr): 1659, 3206 cm–1.
1H NMR (CDCl3): d = 7.49–7.63 (5 H, m, Harom), 7.69–7.74 (2 H,
m, H6, H7), 7.99–8.07 (2 H, m, H8, H5), 8.41 (1 H, s, H4), 8.79 (1
H, br s, NH).
13C NMR (CDCl3): d = 101.4 (C3), 123.5 (C6), 16.9 (C4¢), 127.3 (2
Carom.), 128.9 (2 Carom), 129.1 (C8), 130.7 (Carom), 131.6 (C5), 132.4
(Cq), 133.5 (C4), 136.4 (C7), 144.4 (C8¢), 155.1 (C2), 175.8 (C=O).
MS (IS): m/z = 327.0 (M + 1, 79Br), 329.0 (M + 1, 81Br).
Anal: Calcd for C16H11N2BrO: C, 52.01; H, 3.27; N, 10.11. Found:
C, 52.10; H, 3.32; N, 9.85.
MS (IS): m/z = 283 (M + 1, 79Br), 285 (M + 1, 81Br).
Anal: Calcd for C10H7N2BrOS: C, 42.42; H, 2.49; N, 9.89. Found:
C, 42.56; H, 2.54; N, 9.75.
Formation of Zwitterions or Hydroxyamidines 3a–g and 7a,b;
General Procedure
N-(3-Bromopyridin-2-yl)nicotinamide (2g)
Preparation of the Complex Base
Mp, gum.
IR (KBr): 1681, 3232 cm–1.
1H NMR (CDCl3): d = 7.07 (dd, 1 H, J = 8.2, 4.8 Hz, H5), 7.43 (m,
1 H, Hpyr), 7.95 (dd, 1 H, J = 8.2, 1.8 Hz, H4), 8.26 (ddd, 1 H,
J = 7.9, 1.8, 1.5 Hz, Hpyr), 8.42–8.43 (m, 1 H, Hpyr), 8.78 (dd, 1 H,
J = 4.8, 1.8 Hz, H6), 8.99 (br s, 1 H, NH), 9.16 (d, 1 H, J = 1.5 Hz,
Hpyr).
Under argon, to a suspension of sodium amide (529 mg, 13.6 mmol)
in THF (2 mL) was added fresh distilled t-BuOH (0.37 mL, 3.88
mmol) in THF (0.5 mL). The mixture was warmed to 45 °C over 2
h, then cooled to 0 °C with a vigorous stream of argon.
Reaction with The Complex Base
Under argon, a solution of the desired amides 2 or 6 (500 mg, 1.94
mmol) in THF (10 mL) was added dropwise on the complex base.
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E. Garnier et al.
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The mixture was stirred at r.t. and stopped when the starting mate-
rial disappeared (TLC). The mixture was hydrolysed at 0 °C and ex-
tracted with EtOAc. The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. After purification by
chromatography (silica gel; EtOAc–hexane, 1:1), the expected
compounds 3 or 7 were isolated.
Anal: Calcd for C15H17N3O4: C, 59.40; H, 5.65; N, 13.85. Found: C,
59.05; H, 5.57; N, 13.79.
N¢-(3-Hydroxypyridin-2-yl)furan-2-carboximidamide (3e)
Mp (Tottoli) 108–109 °C.
IR (KBr): 1599, 2900–3500 cm–1.
1H NMR (CDCl3): d = 5.30–6.30 (m, 2 H, NH2), 6.54 (dd, 1 H,
J = 3.3, 1.5 Hz, =CH), 6.85 (dd, 1 H, J = 7.9, 5.2 Hz, H5), 7.13–7.16
(m, 2 H, Harom), 7.51–7.52 (m, 1 H, Harom), 7.81 (dd, 1 H, J = 5.2, 1.2
Hz, H6), 10.58 (br s, 1 H, OH).
13C NMR (CDCl3): d = 111.9, 112.4, 118.6, 136.5, 143.9 (CHarom),
147.3 (C3), 149.2 (C2), 149.7 (C=N), 141.2 (C4), 151.2 (Carom).
2-[(1-Iminio-2,2-dimethylpropyl)amino]pyridin-3-olate (3a)
Mp (Tottoli) 113–114 °C.
IR (KBr): 1645, 2400–3400 cm–1.
1H NMR (CDCl3): d = 1.32 (s, 9 H, 3 CH3), 5.69 (sl, 2 H, NH2), 6.81
(dd, 1 H, J = 7.9, 5.2 Hz, H5), 7.11 (dd, 1 H, J = 7.9, 1.5 Hz, H4),
7.75 (dd, 1 H, J = 5.2, 1.5 Hz, H6), 10.65 (br s, 1 H, NH).
13C NMR (CDCl3): d = 28.4 (3 CH3), 37.9 (Cq), 118.1 (C5), 118.4
(C6), 135.8 (C4), 147.4 (C3), 151.2 (C2), 169.8 (C=N).
MS (IS): m/z = 204 (M + 1).
Anal: Calcd for C10H9N3O2: C, 59.11; H, 4.96; N, 20.68. Found: C,
59.27; H, 4.46; N, 20.25.
MS (IS): m/z = 194 (M + 1).
Anal: Calcd for C10H15N3O: C, 62.15; H, 7.82; N, 21.74. Found: C,
62.20; H, 7.77; N, 21.71.
N¢-(3-Hydroxypyridin-2-yl)thienyl-2-carboximidamide (3f)
Mp (Tottoli) 142–143 °C.
IR (KBr): 1618, 3300–3500 cm–1.
2-{[Iminio-(1-methylcyclopropyl)methyl]amino}pyridin-3-
olate (3b)
Mp (Tottoli) 113–114 °C.
IR (KBr): 1624, 2250–3250 cm–1.
1H NMR (CDCl3): d = 0.75 (q, 2 H, J = 3.8 Hz, CH2), 1.28 (q, 2 H,
J = 3.8 Hz, CH2), 1.41 (s, 3 H, CH3), 5.77 (br s, 2 H, NH2), 6.78 (dd,
1 H, J = 7.9, 5.2 Hz, H5), 7.08 (dd, 1 H, J = 7.9, 1.5 Hz, H4), 7.73
(dd, 1 H, J = 5.2, 1.5 Hz, H6), 10.70 (br s, 1 H, OH).
13C NMR (CDCl3): d = 17.1 (2 CH2), 19.6 (Cq), 20.3 (CH3), 117.9,
118.0 (C5, C6), 135.9 (C4), 146.9 (C3), 151.2 (C2), 166.8 (C=N).
1H NMR (CDCl3): d = 5.90–6.70 (m, 2 H, NH2), 6.86 (dd, 1 H,
J = 7.8, 5.0 Hz, H5), 7.08 (dd, 1 H, J = 5.0, 3.8 Hz, =CH), 7.16 (dd,
1 H, J = 7.8, 1.6 Hz, H4), 7.44–7.46 (m, 2 H, =CH), 7.81 (dd, 1 H,
J = 5.0, 1.6 Hz, H6), 10.63 (br s, 1 H, OH).
13C NMR (CDCl3): d = 118.8, 119.1 (C5, =CH), 126.0, 127.6, 129.7
(C4, C6, =CH), 136.5 (=CH), 141.1 (Cq), 147.5 (C3), 150.7 (C2),
153.0 (C=N).
MS (IS): m/z = 220 (M + 1).
Anal: Calcd for C10H9N3OS: C, 54.78; H, 4.14; N, 19.16. Found: C,
54.55; H, 4.13; N, 18.84.
MS (IS): m/z = 192 (M + 1).
Anal: Calcd for C10H13N3O: C, 62.81; H, 6.85; N, 21.97. Found: C,
62.53; H, 6.79; N, 21.84.
N¢-(3-Hydroxypyridin-2-yl)pyridin-3-carboximidamide (3g)
Mp (Tottoli): 134–135 °C.
IR (KBr): 1643, 3000–3400 cm–1.
N¢-(3-Hydroxypyridin-2-yl)benzenecarboximidamide (3c)
1H NMR (CDCl3): d = 6.15 (sl, 2 H, NH2), 6.92 (dd, 1 H, J = 7.8,
5.0 Hz, H5), 7.20 (dd, 1 H, J = 7.8, 1.5 Hz, H4), 7.41 (ddd, 1 H,
J = 0.6, 7.8, 4.7 Hz, Hpyr), 7.86 (dd, 1 H, J = 4.7, 1.6 Hz, Hpyr), 8.20
(ddd, 1 H, J = 1.8, 7.8, 1.6 Hz, Hpyr), 8.73 (dd, 1 H, J = 5.0, 1.5 Hz,
H6), 9.13 (d, 1 H, J = 1.8 Hz, Hpyr), 10.92 (br s, 1 H, OH).
13C NMR (CDCl3): d = 119.2, 119.7 (C5, C6), 123.3 (C9), 132.2
(C11), 134.4 (C4), 136.4 (C10), 147.8 (C2), 148.0 (C12), 150.6
(C3), 151.6 (C8), 156.2 (C=N).
Mp (Tottoli) 149–150 °C.
IR (KBr): 1642, 2700–3150 cm–1.
1H NMR (CDCl3): d = 5.55–6.00 (m, 2 H, NH2), 6.87 (dd, 1 H,
J = 7.9, 5.0 Hz, H5), 7.19 (dd, 1 H, J = 7.9, 1.5 Hz, H4), 7.33–7.51
(m, 3 H, Harom), 7.73 (dd, 1 H, J = 5.0, 1.5 Hz, H6), 7.82–8.07 (m, 2
H, Harom.), 8.69 (br s, 1 H, OH).
13C NMR (CDCl3): d = 119.3, 119.5 (C4, C5), 126.7 (2 Carom), 128.7
(2 Carom), 131.2 (Carom), 135.6 (Cq), 136.0 (C6), 147.7 (C3), 150.1
(C2), 158.7 (CNH2).
MS (IS): m/z = 215 (M + 1).
Anal: Calcd for C11H10N4O: C, 61.67; H, 4.25; N, 26.28. Found: C,
61.94; H, 4.21; N, 26.30.
MS (IS): m/z = 214 (M + 1).
Anal: Calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C,
67.29; H, 5.34; N, 19.86.
2-[(1-Iminio-2,2-dimethylpropyl)amino]quinolin-3-olate (7a)
Mp (Tottoli) 139–140 °C.
N¢-(3-Hydroxypyridin-2-yl)-3,4,5-trimethoxybenzenecarbox-
imidamide (3d)
Mp (Tottoli) 135–136 °C.
IR (KBr): 1648, 2500–3200 cm–1.
1H NMR (CDCl3): d = 3.92 (s, 6 H, 2 CH3), 3.93 (s, 3 H, CH3), 5.99
(sl, 2 H, NH2), 7.05 (dd, 1 H, J = 7.9, 4.6 Hz, H5), 7.17 (br s, 2 H,
IR (KBr): 1654, 2750–3300 cm–1.
1H NMR (CDCl3): d = 1.37 (9 H, s, 3 CH3), 6.08 (2 H, br s, NH2),
7.32 (1 H, ddd, J = 7.9 Hz, J = 7.0, 1.2 Hz, H6), 7.35 (1 H, s, H4),
7.40 1 H, ddd, J = 1.5, 7.9, 7.0 Hz, H7), 7.59 (1 H, dd, J = 7.9, 1.5
Hz, H5), 7.71 (1 H, dd, J = 7.9, 1.2 Hz, H8), 11.61 (1 H, br s, NH).
13C NMR (CDCl3): d = 28.6 (CH3), 38.4 (Cq), 112.3 (C4), 124.8
(C4¢), 125.8 (C5), 126.2 (C6), 126.9 (C8), 127.2 (C7), 140.6 (C3),
145.5 (C8¢), 151.7 (C2), 157.2 (C=N).
Harom), 7.94 (dd, 1 H, J = 7.9,1.5 Hz, H4), 8.45–8.47 (m, 2 H, H6,
OH).
13C NMR (CDCl3): d = 56.3 (2 CH3), 60.9 (CH3), 104.1 (2 Carom),
104.9 (C5), 129.4 (Cq), 141.5 (C4), 141.6 (Cq), 147.5 (C6), 148.7
(C2), 153.3 (2 Cq), 164.7 (C=N).
MS (IS): m/z = 244.0 (M + 1).
Anal: Calcd for C15H17N2O: C, 69.11; H, 7.04; N, 17.27. Found: C,
68.87; H, 7.17; N, 17.00.
MS (IS): m/z = 304 (M + 1).
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New Access to Oxazolopyridines via Hydroxyamidine Derivatives; Application to Quinolines
2039
N¢-(3-Hydroxyquinolyn-2-yl)benzenecarboximidamide (7b)
13C NMR (CDCl3): d = 112.6 (=CH), 116.2 (=CH), 118.1 (C7),
120.1 (C6), 141.9, 142.4 (2 Cq), 146.6, 146.9 (C5, =CH), 155.8,
157.5 (2 Cq).
Mp (Tottoli) 159–162 °C.
IR (KBr): 1659, 3000–3350 cm–1.
Anal: Calcd for C10H6N2O2: C, 64.52; H, 3.25; N, 15.05. Found: C,
64.56; H, 3.32; N, 14.94.
1H NMR (CDCl3): d = 6.38 (2 H, br s, NH2), 7.33–7.64 (8 H, m, 5
Harom, H4, H6, H7), 7.80 (1 H, d, J = 7.9 Hz, H5), 7.95 (1 H, d,
J = 8.1 Hz, H8), 11.77 (1 H, br s, OH).
13C NMR (CDCl3): d = 113.0 (C5), 125.1 (C4¢), 126.0 (Cq), 126.3
(C4), 127.0 (2 Carom), 127.1 (C6), 127.5 (C8), 128.9 (2 Carom), 129.2
(Carom.), 131.6 (C3), 136.1 (C2), 140.7 (C7), 146.7 (C8¢), 153.6
(C=N).
2-(2-Thienyl)[1,3]oxazolo[4,5-b]pyridine (4f)
1H NMR (CDCl3): d = 7.22 (dd, 1 H, J = 5.0, 3.8 Hz, =CH), 7.28
(dd, 1 H, J = 8., 5.0 Hz, H6), 7.65 (dd, 1 H, J = 5.0, 1.3 Hz, =CH),
7.82 (dd, 1 H, J = 8.0, 1.2 Hz, H7), 8.02 (dd, 1 H, J = 3.8, 1.3
Hz, =CH), 8.56 (dd, 1 H, J = 5.0, 1.2 Hz, H5).
13C NMR (CDCl3): d = 117.8 (=CH), 119.9 (C7), 128.4 (C6), 128.9
(Cq), 131.2, 131.8 (2 =CH), 142.7 (Cq), 146.7 (C5), 156.3 (C3a),
161.5 (C2).
MS (IS): m/z = 264.0 (M + 1).
Anal: Calcd for C16H13N2O: C, 72.99; H, 4.98; N, 15.96. Found: C,
72.81; H, 5.01; N, 15.93.
Anal: Calcd for C10H6N2OS: C, 59.39; H, 2.99; N, 13.85. Found: C,
58.43; H, 2.91; N, 13.50.
Oxazolopyridines 4a–g and 8a,b; General Procedure
The zwitterions or hydroxyamidines 3 or 7 were diluted in dimeth-
ylacetamide (2 mL) and the mixture was heated either by classical
means to 170 °C in an oil bath (for 200 mg of starting material) or
by microwaves in a quartz reactor (for 50 mg). When the reaction
was finished, the mixture was co-evaporated with toluene in vacuo
and the oil was purified by chromatography (silica gel; EtOAc–hex-
ane, 1:6 for pyridines; EtOAc–petroleum ether 1:9 for quinolines).
2-Pyridin-3-yl[1,3]oxazolo[4,5-b]pyridine (4g)
1H NMR (CDCl3): d = 7.36 (dd, 1 H, J = 8.0, 4.9 Hz, H6), 7.51 (dd,
1 H, J = 8.2, 5.0 Hz, H10), 7.93 (dd, 1 H, J = 8.0, 1.3 Hz, H7), 8.26
(dt, 1 H, J = 7.9, 1.8 Hz, H11), 8.63 (dd, 1 H, J = 5.0, 1.5 Hz, H9),
8.82 (dd, 1 H, J = 4.9, 1.3 Hz, H5), 9.53 (d, 1 H, J = 1.5, H13).
13C NMR (CDCl3): d = 118.5 (C7), 120.6 (C6), 123.8 (C10), 135.3
(C11), 143.1 (Cq), 147.1 (C9), 149.0 (C13), 155.8 (C5), 155.9 (Cq),
163.4 (Cq).
2-(tert-Butyl)[1,3]oxazolo[4,5-b]pyridine (4a)
IR (KBr): 1670, 3182 cm–1.
Anal: Calcd for C11H7N3O: C, 67.00; H, 3.58; N, 21.31. Found: C,
67.23; H, 3.44; N, 21.20.
1H NMR (CDCl3): d = 1.52 (s, 9 H, CH3), 7.24 (dd, 1 H, J = 8.2, 4.9
Hz, H6), 7.77 (dd, 1 H, J = 8.2, 1.2 Hz, H7), 7.52 (dd, 1 H, J = 4.9,
1.2 Hz, H5).
13C NMR (CDCl3): d = 28.2 (3 CH3), 34.5 [C(CH3)], 117.7 (C5),
119.4 (C3), 142.9 (C4), 145.9 (C6), 155.9 (C2), 176.5 (C=O).
2-(tert-Butyl)[1,3]oxazolo[4,5-b]quinoline (8a)
1H NMR (CDCl3): d = 1.56 (9 H, s, CH3), 7.55 (1 H, ddd,
J = 8.2, 6.9, 1.3 Hz, H6), 7.71 (1 H, ddd, J = 1.4, 6.9, 8.5 Hz, H7),
7.93 (1 H, dd, J = 8.2, 1.4 Hz, H5), 8.11 (1 H, s, H4), 8.23 (1 H, dd,
J = 1.3, 8.5 Hz, H8).
Anal: Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C,
68.27; H, 6.70; N, 15.54.
13C NMR (CDCl3): d = 28.3 (3 CH3), 38.0 (Cq), 114.5 (C4), 125.9
(C4¢), 126.6 (C6), 128.0 (C5), 128.4 (C8), 129.7 (C7), 141.7 (C3),
146.6 (C8¢), 157.5 (C2), 180.5 (C=N).
2-(1-Methylcyclopropyl)[1,3]oxazolo[4,5-b]pyridine (4b)
1H NMR (CDCl3): d = 1.04 (q, 2 H, J = 4.3 Hz, CH2), 1.54 (q, 2 H,
J = 4.3 Hz, CH2), 1.65 (s, 3 H, CH3), 7.18 (dd, 1 H, J = 7.9, 4.8 Hz,
H6), 7.69 (dd, 1 H, J = 7.9, 1.2 Hz, H7), 8.47 (dd, 1 H, J = 4.8, 1.2
Hz, H5).
Anal: Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C,
74.12; H, 6.38; N, 12.47.
13C NMR (CDCl3): d = 15.5 (Cq), 18.1 (2 CH2), 20.0 (CH3), 117.2,
2-Phenyl[1,3]oxazolo[4,5-b]quinoline (8b)
1H NMR (CDCl3): d = 7.54–7.68 (5 H, m, Harom), 7.74 (1 H, ddd,
J = 8.0, 7.2, 1.2 Hz, H6), 8.22 (1 H, ddd, J = 1.2, 7.2, 8.2 Hz, H7),
8.40–8.44 (2 H, m, H5, H8).
118.9 (C6, C7), 142.7 (Cq), 145.8 (C5), 156.4, 173.9 (2 Cq).
Anal: Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C,
68.91; H, 5.81; N, 16.04.
13C NMR (CDCl3): d = 102.2 (C4), 125.6 (C4¢), 126.1 (Carom), 126.3
(C6), 126.9 (C5), 128.1 (C8), 129.2 (Carom), 130.0 (Carom), 133.3
(C7), 137.4 (=CH), 142.1 (C3), 149.4 (C8¢), 162.0 (C2), 176.8
(C=N).
2-Phenyl[1,3]oxazolo[4,5-b]pyridine (4c)
1H NMR (CDCl3): d = 7.29 (dd, 1 H, J = 8.2, 4.9 Hz, H6), 7.50–7.59
(m, 3 H, Harom), 7.86 (dd, 1 H, J = 8.2, 1.6 Hz, H7), 8.30–8.34 (m, 2
H, Harom), 8.58 (dd, 1 H, J = 4.9, 1.6 Hz, H5).
Anal: Calcd for C16H10N2O: C, 78.03; H, 4.09; N, 11.38. Found: C,
77.99; H, 4.01; N, 11.29.
2-(3,4,5-Trimethoxyphenyl)[1,3]oxazolo[4,5-b]pyridine (4d)
1H NMR (CDCl3): d = 3.95 (s, 3 H, OCH3), 3.99 (s, 6 H, 2 OCH3),
7.29 (dd, 1 H, J = 8.2, 4.8, H6), 7.57 (s, 2 H, Harom), 7.86 (dd, 1 H,
J = 8.2, 1.3 Hz, H7), 8.58 (dd, 1 H, J = 4.9, 1.3 Hz, H5).
Crystal Structure Analysis of 3a
The crystal structure of compound 3a has been determined by sin-
gle-crystal X-ray diffraction techniques and refined by full-matrix
least-squares procedures, to give a final R value of 0.04. The crys-
tals are monoclinic, space group P 21/n, with a = 7.699(1) Å,
b = 11.326(2) Å, c = 12.300(1) Å, b = 91.96(1)°, and Z = 4. A crys-
tal 0.25 × 0.40 × 0.50 mm was chosen.
13C NMR (CDCl3): d = 118.1 (C7), 120.0 (C6), 126.4 (Cq), 128.0 (2
Carom), 128.9 (2 Carom), 132.4 (Carom), 143.0 (C7a), 146.6 (C5), 156.3
(C3a), 165.5 (C2).
Anal: Calcd for C12H8N2O: C, 62.93; H, 4.93; N, 9.78. Found: C,
62.76; H, 5.16; N, 9.75.
The data were collected on a CAD4 Enraf–Nonius diffractometer
with graphite monochromatized CuKa radiation. The cell parame-
ters were determined by least-squares from the setting angles for 25
reflexions.
2-(2-Furyl)[1,3]oxazolo[4,5-b]pyridine (4e)
1H NMR (CDCl3): d = 6.66 (dd, 1 H, J = 3.3, 1.3 Hz, =CH), 7.30
(dd, 1 H, J = 8.2, 4.9 Hz, H6), 7.42 (d, 1 H, J = 3.3 Hz, =CH), 7.73
(d, 1 H, J = 1.3 Hz, =CH), 7.85 (dd, 1 H, J = 8.2, J = 1.5 Hz, H7),
8.59 (dd, 1 H, J = 4.9, 1.5 Hz, H5).
In the collection of intensities the q/20 scan method was used, and
1815 independent reflexions were collected in the region q < 65°.
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2040
E. Garnier et al.
PAPER
Correction was made for Lorentz and polarisation effects. 1582 re-
flexions with I > 2s (I) were considered observed and were used in
the subsequent calculations. Semi-empirical method of absorption
correction was applied. Full crystallographic results have been de-
posited at the Cambridge Crystallographic Data Centre (CCDC),
UK, as Supplementary Materials.11 The position of non-H atoms
were determined by the program SHELXS12 and the position of the
H atoms were deduced from coordinates of the non-H atoms and
confirmed by Fourier Synthesis. H atoms were included for struc-
ture factor calculations but not refined.
Full crystallographic results have been deposited at the Cambridge
Crystallographic Data Centre (CCDC), UK, as Supplementary
Marerials.11
Acknowledgment
We gratefully acknowledge A.D.I.R. Company (Servier, Courbe-
voie, France) for financial support.
References
Crystal Structure Analysis of 3f
(1) Caubère, P. Chem. Rev. 1993, 93, 2317; and references cited
therein.
The crystal and molecular structure of 3f has been determined by X-
ray diffraction methods (CuKa) and refined to an R value of 0.032.
A crystal 0.05 × 0.15 × 0.37 mm was chosen. The crystal is orthor-
hombic, space group Pna21, with a = 10.690(1) Å, b = 16.646(1) Å,
c = 5.686(1) Å, Z = 4.
(2) (a) Rodriguez, I.; Kuehm-Caubère, C.; Vinter-Pasquier, K.;
Renard, P.; Pfeiffer, B.; Caubère, P. Tetrahedron Lett. 1998,
39, 7283. (b) Blanchard, S.; Guillaumet, G.; Caubère, P.
Tetrahedron Lett. 2001, 42, 7037. (c) Blanchard, S.;
Rodriguez, I.; Kuehm-Caubère, C.; Renard, P.; Pfeiffer, B.;
Guillaumet, G.; Caubère, P. Tetrahedron 2002, 58, 3513.
(3) Flouzat, C.; Guillaumet, G. Synthesis 1990, 64.
(4) Clark, R. D.; Miller, A. B.; Berger, J.; Repke, D. B.;
Weinhard, K. K.; Kowalczyk, B. A.; Eglen, R. M.; Bonhaus,
D. W.; Lee, C. H.; Michel, A. D.; Smith, W. L.; Wong, E. H.
F. J. Med. Chem. 1993, 36, 2645.
The cell parameters were determined by least-squares from the set-
tings angles for 25 reflexions. An empirical absorption correction
was applied. The data were also corrected for Lorentz and polariza-
tion effect. In the collection of intensities the q/20 scan method was
used, and 958 independent reflexions were collected in the region q
< 65°. The positions of non-H atoms were determined by the pro-
gram SHELXS 8612 and the position oh the H atoms were deduced
from coordinates of the non-H atoms and confirmed by Fourier
Synthesis. H atoms were included for structure factor calculations
but not refined.
(5) Malm, J.; Rehn, B.; Hörnfeldt, A. B.; Gronowitz, S. J.
Heterocycl. Chem. 1994, 31, 11.
(6) Vinter-Pasquier, K.; Jamart-Grégoire, B.; Caubère, P.
Heterocycles 1997, 45, 2113.
Full crystallographic results have been deposited at the Cambridge
Ctystallographic Data Centre (CCDC), UK, as Supplementary Ma-
terials.11
(7) (a) See references cited in: Caubère, P. Acc. Chem. Res.
1974, 7, 30. (b) Caubère, P. Top. Curr. Chem. 1978, 73, 50.
(8) (a) Fraser, J.; Tittensor, E. J. Chem. Soc. 1957, 4625.
(b) Clark, R. L.; Pessolano, A. A.; Witzel, B.; Lanza, T.;
Shen, T. Y. J. Med. Chem. 1978, 21, 1158. (c) Flouzat, C.;
Guillaumet, G. J. Heterocycl. Chem. 1991, 28, 899.
(d) Savarino, P.; Viscardi, G.; Carpignano, R.; Barni, E. J.
Heterocycl. Chem. 1989, 26, 77. (e) Rüfenacht, K.;
Kristinson, H.; Mattern, G. Helv. Chim. Acta 1976, 59, 1593.
(9) (a) Besson, T.; Guillard, J.; Rees, C. W. Tetrahedron Lett.
2000, 41, 1027. (b) Guillard, J.; Besson, T. Tetrahedron
1999, 55, 5139. (c) Besson, T.; Dozias, M. J.; Guillard, J.;
Jacquault, P.; Legoy, M. D.; Rees, C. W. Tetrahedron 1998,
54, 6475.
(10) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1999, 1505.
(11) Supplementary X-ray crystallographic data: Cambridge
Crystallographic Data Centre, University Chemical Lab,
Lensfield Road, Cambridge CB2 1EW, UK; e-mail: http/
www.deposit@chemcrys.cam.ac.uk.
Crystal Structure Analysis of 3g
The compound 3g crystallizes in the monoclinic group P 21/c with
8 molecules in a unit cell of dimension a = 13.567(1) Å,
b = 13.150(2) Å, c = 12.656(6) Å, b = 116.44(2)° (two independent
molecules). The intensities of the reflexions with q < 65° were mea-
sured in in the w/20 scan mode with a variable scan rate. 3430 inde-
pendent reflexions were measured and 3180 of these with I > 2s (I)
were used in the structure analysis. The reflexions were corrected
for Lorentz and polarization factors and for absorption. The struc-
ture was solved by the program SHELXS 8612 and refined by full-
matrix least-squares procedures, to give a final R value of 0.036 for
3180 reflexions with reasonable intensities collected on a four-cir-
cle diffractometer. The position of the H atoms were deduced from
coordinates of the non-H atoms and confirmed by Fourier Synthe-
sis. H atoms were included for structure factor calculations but not
refined.
There are two independent molecules A and B. The major differ-
ence between the two molecules are found in the dihedral angles
concerning the cycles plans I (C1…C6), and II (C10…C15): 19.0(1)
for the A molecule; 26.9(1) for the B molecule.
(12) Sheldrick, G. M. In Crystallographic Computing 3;
Sheldrick, G. M.; Kröger, C.; Goddard, R., Eds.; Oxford
University Press: Oxford, 1985, 175.
Synthesis 2003, No. 13, 2033–2040 © Thieme Stuttgart · New York