A new synthetic approach to biaryls of the rhazinilam type. Application to synthesis of three novel phenylpyridine-carbamate analogues

Article abstract of DOI:10.1039/b613173e

The synthesis of three novel racemic phenylpyridine-carbamate analogues of rhazinilam and their biological evaluation as inhibitors of microtubule assembly and disassembly by interaction with tubulin are described. The sterically hindered ortho-disubstituted biaryl unit as the challenging key structural element is first obtained by a sequential regiocontrolled nucleophilic addition of a lithium ortho-lithiohomobenzylic alkoxide species to 3-bromo-5-oxazolyl pyridine as the electrophile and a subsequent oxidation step. The incorporation of the amino group by replacement of the bromide has been achieved using a Buchwald-Hartwig amination coupling. Ultimate deprotection steps furnished free-amino and free-hydroxyl appendages which were connected by phosgenation to furnish the nine-membered median carbamate ring. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b613173e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A new synthetic approach to biaryls of the rhazinilam type. Application to
synthesis of three novel phenylpyridine-carbamate analogues
Anne-Laure Bonneau,a Nicolas Robert,a Christophe Hoarau,a Olivier Baudoinb and Francis Marsais*a
Received 15th September 2006, Accepted 18th October 2006
First published as an Advance Article on the web 23rd November 2006
DOI: 10.1039/b613173e
The synthesis of three novel racemic phenylpyridine-carbamate analogues of rhazinilam and their
biological evaluation as inhibitors of microtubule assembly and disassembly by interaction with tubulin
are described. The sterically hindered ortho-disubstituted biaryl unit as the challenging key structural
element is first obtained by a sequential regiocontrolled nucleophilic addition of a lithium
ortho-lithiohomobenzylic alkoxide species to 3-bromo-5-oxazolyl pyridine as the electrophile and a
subsequent oxidation step. The incorporation of the amino group by replacement of the bromide has
been achieved using a Buchwald–Hartwig amination coupling. Ultimate deprotection steps furnished
free-amino and free-hydroxyl appendages which were connected by phosgenation to furnish the
nine-membered median carbamate ring.
We expected thus to evaluate the effect of the charge distribution
Introduction
on the aniline moiety of (−)-rhazinilam (ring A) on the antitubulin
(−)-Rhazinilam 1 is a tetracyclic phenyl-pyrrole alkaloid isolated
activity. Here we wish to report the synthesis of three novel racemic
from various Apocynaceae.1 It was found both to induce in
phenylpyridine-carbamate analogues of rhazinilam 4a, 4b and 4c
(Fig. 1) and their biological evaluation.
vitro spiralization of microtubules (vinblastin effect) and to
inhibit the cold-induced disassembly of microtubules1 (paclitaxel
effect). As a consequence of these unique antitubulin properties,
(−)-rhazinilam showed significant in vitro cytotoxicity towards
various cancer cell lines but no activity was found in vivo.1 Thus
structure–activity relationships on rhazinilam analogues are of
considerable interest.1 Recently three-dimensional quantitative
structure–activity relationships (3D-QSAR) from all available
analogues were investigated.2 The biphenyl carbamate analogue
(−)-2 mimicking the structure of (−)-rhazinilam developed by
Gue´ritte et al.3 is currently the most active analogue with a 2-fold
activity on microtubule disassembly compared to 1 and a similar
cytotoxicity. The synthesis of several biphenyl analogues allowed
the establishment of the main structural elements for maximum
antitubulin activity which are the presence of the biaryl unit
bridged by a nine-membered carbamate ring (ring B) as well as
a quaternary center mimicking the stereogenic center of 1. Our
laboratory proposed in 2001 the first phenylpyridine analogues
of rhazinilam4 and their biological evaluation confirmed that the
Fig. 1 Analogues of rhazinilam 4a, 4b and 4c.
replacement of the lactam by a carbamate function enhances the
antitubulin activity. The best biological result was obtained with
rac-3 which is however six times less active on the inhibition of
Results ans discussion
microtubule disassembly than (−)-rhazinilam. In continuation of
this study, we embarked on a program aimed at the synthesis of new
phenylpyridine analogues derived from biphenyl analogue 2 by
replacing the aniline moiety (ring A) by an aminopyridine system
and keeping the nine-membered carbamate ring and a quaternary
center as essential structural elements for the antitubulin activity.
Our planned approach to phenylpyridine-carbamates 4 bearing
the nitrogen atom on the aniline moiety (ring A) is shown in
Scheme 1. The nine-membered carbamate ring could be installed
by ring-closure of the aminoalcohol 5 (route a). The final ring-
closure could also be achieved by an intramolecular palladium
catalyzed Buchwald–Hartwig amidation of bromocarbamate 7
obtained by carbamoylation of the bromoalcohol 6 (route b). The
two ortho-substituted biaryl precursors 5, 6 could be obtained a
priori using cross-coupling protocols but Gue´ritte and Baudoin
have pointed out the sensitivity of cross-couplings toward steric
hindrance in biphenyl series due in particular to the presence
aLaboratoire de Chimie Organique Fine et He´te´rocyclique UMR 6014,
Universite´ et INSA de Rouen, Place E. Blondel, 76131, Mont Saint Aignan,
France. E-mail: francis.marsais@insa-rouen.fr; Fax: +33 0235522962;
Tel: +33 0235522475
bInstitut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse,
91198, Gif sur Yvette, France
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Scheme 2 Reagents and conditions: (i) LDA (4 equiv.), THF, −78 ◦C; (ii)
EtI (5 equiv.); (iii) LiAlH4, THF, r.t., 2 h; (iv) sec-BuLi (3 equiv), hexane,
70 ◦C, 6 h; (v) D2O (see Table 1) then hydrolysis; (vi) 1,2-dibromotetra-
chloroethane; (vii) B(OMe)3 then aq. HCl.
technique (Table 1). We first applied Meyer and Seebach’s
conditions reported for the lithiation of a,a’-methylbenzylic
alcohol,5 similar to homobenzylalcohol 10 (Table 1-entry 1). After
quenching with D2O, a mixture of 10 and 13 was obtained in a
4 : 1 ratio. We turned to stronger bases, sec-BuLi and tert-BuLi.
The lithiation was carried out on a broad range of temperatures
and using different equivalents of base. After several experiments
summarized in Table 1 (entries 2–7), the best result was obtained
with the treatment of 10 with 3 equiv. of sec-BuLi in hexane
at 70 ◦C for 6 h, which provided a 1 : 9 mixture of 10–13
in 60% yield after chromatography (entry 6). The ortho-bromo
a,a’-ethylhomobenzylic alcohols 14 could be prepared in modest
46% yields using 1,2-dibromo-tetrachloroethane as a halogenating
agent. The borylation of the lithium ortho-lithioarylalkoxide salt
9 could also be performed with trimethylborate as an electrophile
followed by hydrolysis with HCl to give the first prepared six-
membered ring oxaborine 15 in 20% yield over two steps.
The 3-bromo-5-oxazolyl pyridine scaffold 8 was prepared on
a multigram-scale from commercially available 3-bromo-5-cyano
pyridine 16 by treatment with 2-amino-2-methyl propanol 17
in the presence of ZnCl2 as a catalyst6 (Scheme 3). Although
Ottow and co-workers have previously reported the nucleophilic
addition of 3-anisylmagnesium bromide to 5-bromo-3-pyridine
carboxamide7 similar to our scaffold 8, no previous report has
given sound support to the nucleophilic addition of aryllithium
species to protected 3-bromo-5-carboxypyridine derivatives. Such
a nucleophilic addition was explored by reacting 3-bromo-5-
oxazolyl pyridine 8 with phenyllithium at room temperature in
THF for 1 h as a typical experiment.8 Subsequent oxidative
Scheme 1
of the highly hindered quaternary center.3c Thus, in order to
prepare phenylpyridine analogue rac-3,4 Rocca et al. opted for
a post-alkylation of the picolinic site to install the quaternary
carbon after formation of the biaryl unit. However this elegant
approach cannot be applied to the preparation of the two biaryl
precursors 5 and 6 due to the much lower acidity of the benzylic
site compared to the picolinic one. In this paper we envisage the
formation of the pivotal ortho-substituted biaryl unit using a key
nucleophilic addition of the lithium ortho-lithioarylalkoxide salt
9 to an adequate activated bromopyridine scaffold 8, followed by
an oxidative step to regenerate the pyridine nucleus.
We initially investigated the unreported ortho-lithiation of the
a,a’-ethylhomobenzylic alcohol 10 ready prepared from methyl 2-
phenyl acetate 12 in 82% yield using a double ethylation and reduc-
tion sequence depicted in Scheme 2. The a,a’-ethylhomobenzylic
alcohol 10 was subjected to a series of strong bases. The lithiation
yield was determined by measuring the ratios of starting material
and deuterated product (10 : 13) after an external D2O quench
Table 1 Lithiation–D2O trapping of 10
Entry
Base
Equiv.
t/◦C
Time/h
Ratio 10–13 x–ya(%)b
1
2
3
4
5
6
7
n-BuLi–TMEDA
sec-BuLi
2
2
3
5
3
3
3
70
70
r.t.
r.t.
40
70
r.t.
12
6
4 : 1 (—)
7 : 3 (—)
6 : 4 (—)
7 : 3 (—)
3 : 7 (50)
1 : 9 (60)
3 : 7 (55)
sec-BuLi
24
24
32
6
sec-BuLi
sec-BuLi
sec-BuLi
tert-BuLi
32
a NMR conversion to deuterated compound. b Isolated yield obtained using the optimal metallation conditions.
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addition of aryllithium species to 3-oxazolylpyridine may occur
indifferently at C2, C4 and C6 sites depending mainly on three
factors: polarity of the solvent, addition temperature and steric
hindrance of the nucleophilic reagent.8 Unfortunately we were
not able to direct the nucleophilic addition of lithio anion 9 at
another position whatever the solvent (Et2O and toluene were
used), the temperature or the use of TMEDA. Construction
of the nine-membered cyclic carbamate from bromoalcohol 6a
was next investigated. To this purpose carbamate 7a was first
prepared in 70% yield via carbamoylation of 6a in the presence
of trichloroacetylisocyanate9 (Scheme 5) before cyclisation of the
N-metallated derivative of 7a. Thus, 7a was N-metallated by
treatment with sodium hydride in DMF at room temperature10
(Table 2-entry 1). However the expected annelated product 4a
was not formed, but instead the seven-membered-ring biaryl-
ether 19 was exclusively obtained in excellent 90% yield. We
could hypothesize that the competitive elimination of isocyanic
acid11 from the N-metallated carbamate produced in situ the
lithium oxanion which then substituted the bromine atom in
an intramolecular way. We then turned to the transition metal-
catalyzed carbamatation. Ring-closure via Buchwald’s amidation
by using Cu(I) and a diamine ligand as catalyst12 (Table 2-
entry 2) led to the cleavage of the carbamoyl function affording
bromoalcohol 6a in 70% yield. The Pd(0)-catalyzed intramolecular
Scheme 3 Reagents and conditions: (i) 2-amino-2-methylpropan-1-ol 17,
ZnCl2 (10%mol), PhCl, D, 2 days; (ii) PhLi (1 equiv.), THF, r.t., 1 h then
NH4Cl; (iii) chloranil, toluene, D, 2 h.
treatment of the crude reaction mixture with chloranil in refluxing
toluene for 2 h afforded the expected phenylpyridine 18 in good
87% isolated yield (Scheme 3). The latter showed two characteristic
singlets corresponding to the H2 and H6 protons in the 1H
NMR spectrum indicating that the phenyl group was exclusively
introduced to the C4 site of the pyridine nucleus in agreement with
Ottow’s observations.7 We next investigated the addition of lithium
ortho-lithioarylalkoxide salt 9 to 3-bromo-5-oxazolyl pyridine 8.
After generation from 10 as previously described, 9 was added to
3-bromo-5-oxazolyl pyridine 8 in THF at room temperature for
1 h.
Treatment of the crude reaction with chloranil in refluxing
toluene for 2 h provided a biaryl compound in 26% overall
yield. Careful analysis surprisingly revealed the introduction of
the phenyl moiety at the C2 site of the pyridine nucleus leading to
bromoalcohol 6a (Scheme 4).
carbamatation was then tested using two specific ligands, P(tBu)3
13
and Xantphos14 (Table 2-entries 3 and 4). In both cases no
expected annelated compound rac-4a could be obtained. Similar
to previous observations, decarbamoylation occurred, especially
when using Xantphos as a ligand (Table 2-entry 4), and the
Meyers, Hauck, Knaus and Bourguignon et al. previously
demonstrated that the regiochemical outcome of the nucleophilic
Scheme 4 Reagents and conditions: (i) sec-BuLi (6 equiv.), hexane, 70 ◦C,
6 h; (ii) 8 (1 equiv.), THF, r.t., 1 h then NH4Cl; (iii) chloranil, toluene, D,
Scheme 5 Reagents and conditions: (i) trichloroacetylisocyanate, CH2Cl2,
r.t., 30 min; (ii) K2CO3, MeOH, r.t., 3 h; (iii) see conditions and results in
Table 2.
2 h.
Table 2 Assays of nine-membered ring-closing of 7a
Entry
Conditions
%-4aa
%-6aa
%-7aa
%-19a
1
2
3
4
NaH, DMF, r.t., 12 h
None
None
None
None
0
70
16
60
0
30
60
20
90b
0
24
20
CuI, (MeNHCH2)2, K2CO3, toluene, D, 16 h
Pd(dba)2, P(tBu)3HBF4, NaOPh, toluene, D,16 h
Pd2(dba)3, Xantphos, Cs2CO3, dioxane, 16 h
a NMR conversion except for entry 1. b Yield of isolated product.
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resulting bromoalcohol 6a was then partially converted in low
yields to the seven membered-ring biaryl-ether 19.
corresponding ethyl ester rac-4b and carboxylic acid rac-4c were
obtained via H2SO4-induced cleavage21 of the oxazolyl group in
EtOH or in H2O respectively but in low 20 and 15% yields due
to the undesired hydrolysis of the carbamate group (Scheme 7).
Milder methods for oxazoline hydrolysis involving the prior
formation of oxazolinium salts22 and subsequent treatment with
NaOH couldn’t be applied as the treatment of rac-4a with CH3I
exclusively afforded the N-methylpyridinium salt 24. Treatment of
rac-4a with NaOCl also remained unsuccessful leading only to the
N-chlorocarbamate analogue 25 (Scheme 7).
At this stage it appeared necessary to protect the free-
alcohol function of 6a before performing the substitution of
the bromine by an amino group. The TBS-alcohol protection
of 6a was effected using a standard procedure15 to give 21 in
67% yield. As Akiba and co-workers have previously shown that
N-silyldihydropyridine could be readily reoxidized to pyridine
through treatment with chloranil,16 the TBS-alcohol protection
was directly performed after the nucleophilic addition of lithium
ortho-lithioarylalkoxide salt 9 to scaffold 8 via subsequent addition
of tert-butyldimethylsilylchloride (TBSCl). Without isolation,
protected N-silyldihydropyridine intermediate 20 (Scheme 6) was
then subjected to oxidative treatment with chloranil giving rise
to 21 in 21% yield through a one-pot four step synthesis. A
classical palladium-catalyzed Buchwald–Hartwig amination17 of
21 provided then the bis-protected biarylic aminoalcohol 22 in
excellent 83% yield (Scheme 6). Next, both N-PMB and O-TBS
deprotections were carried out with TFA18 and the resulting crude
free-amino ester 23 thus obtained was immediately hydrolyzed
by simple basic treatment with K2CO3 in a mixture of MeOH–
H2O to give biarylic aminoalcohol 5a in 78% yield over two steps
(Scheme 6). The final internal carbamatation was first attempted
by treating 5a with triphosgene.4 Surprisingly this process failed
due probably to the poor nucleophilicity of the amino group in
the presence of the electron-withdrawing oxazolyl group on the
pyridine nucleus. Nucleophilic activation of both free-amino and
free-alcohol groups remained unsuccessful after metallation of
5a with 2.5 equivalents of n-BuLi and treatment of the resulting
N,O-dilithio anions with diethylcarbonate19 at room temperature
for 16 h. Finally, the direct phosgenation of 5a in the presence
Scheme 7 Reagents and conditions: (i) H2SO4–EtOH or H2O (1 : 9), D,
5 h; (ii) CH3I, CH3CN, r.t., 12 h; (iii) NaOCl, Bu4NHSO4, AcOEt, r.t., 4 h.
The cytotoxicity and the antitubulin activity of the new
phenylpyridine analogues 4a, 4b and 4c were evaluated and
compared to those of (−)-1 (Table 3). The seven-membered-ring
20
of NEt3 was achieved providing the desired phenylpyridine
carbamate rac-4a in an excellent 84% yield (Scheme 6). The
Scheme 6 Reagents and conditions: (i) sec-BuLi (6 equiv.), THF, 70 ◦C, 6 h; (ii) 8 (1 equiv.), THF, r.t., 1 h; (iii) TBSCl, r.t., 16 h; (iv) chloranil, toluene,
t
D, 2 h; (v) p-methoxybenzylamine (1.2 equiv.), Pd2dba3, BINAP, BuONa, toluene, D, 16 h; (vi) TFA, r.t., 16 h; (vii) K2CO3, MeOH–H2O, r.t., 1 h;
(viii) phosgene (1 equiv.), NEt3, THF, 0 ◦C to 25 ◦C, 1 h.
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Table 3 Cytotoxicity and antitubulin activity of (−)-rhazinilam, rac-4a–c and 19
Cytotox. KB cell line
Cytotox. MCF7 cell line
Inhibition of microtubule
Inhibition of microtubule
Compound
IC50/lMa
IC50/lMa
disassembly IC50/lMb
assembly IC50/lMb
1
0.6
in
in
in
in
4.0
in
in
in
in
3.7
6.7
4a
4b
4c
19
1%c
12%c
in
32%c
18%c
in
190
110
a IC50 is the concentration of compound corresponding to 50% growth inhibition after 72 h incubation. b IC50 is the concentration of compound required
to inhibit 50% of the rate of microtubule assembly or disassembly (in = inactive). c Percentage of inhibition of assembly or disassembly at 10 mg L−1 (IC50
could not be measured).
bridged biaryl-ether 19 was also submitted to the same test as
the ring structure analogue of the antimitotic (−)-colchicine.
Phenylpyridine analogues 4a, 4b and 4c were weakly active in
the polymerization and depolymerization of microtubules. In
addition, no cytotoxicity was found on KB cancer cells as well
as on human breast adeno-carcinoma MCF7. It was previously
demonstrated that the addition of sterically hindered substituents
on the aniline moiety (ring A) of (−)-2a lowers the interaction with
tubulin.1 This suggests that the inactivity of rac-4a, rac-4b and rac-
4c is imputable to the substitution of the pyridine nucleus rather
than to its electron-deficient character. The biological evaluation
of the unsubstituted pyridine analogue would be necessary to
verify this assumption. The seven-membered-ring biaryl-ether 19
was respectively 15 and 50 times less active than (−)-1 in tubulin
polymerization and depolymerization and no cytotoxicity towards
adeno-carcinoma MCF7 as well as KB cancer cells was observed.
benzophenone–Na. Silica gel (Geduran Si 60, 0.063–0.200 mm)
was purchased from Merck. The compounds 12 and 17, the
solutions of n-BuLi, sec-BuLi and tert-BuLi and the ligands
P(tBu3)HBF4, Xantphos were used as received.
2-Ethyl-2-phenylbutan-1-ol (10). A solution of n-BuLi (48 ml
of 2.5 M solution in hexane, 120 mmol) was slowly added,
◦
at −78 C under N2, to a stirred solution of 2,2ꢀ-bipyridyl
(4 mg, 0.02 mmol) and N-diisopropylamine (DIPEA) (16.8 ml,
120 mmol) in THF (120 ml). The mixture was stirred for 15 min
◦
at −78 C and a solution of methyl 2-phenylacetate 12 (4.31 ml,
30 mmol) in THF (50 ml) was added. After an additional 30 min
stirring period, EtI (12 ml, 150 mmol) was added. The mixture was
allowed to warm to r.t. for 3 h and H2O (100 ml) was added. The
product was extracted with CH2Cl2 (3 × 70 ml) and the combined
organic extracts were dried (MgSO4), filtered and concentrated
under vacuo. The residue was dissolved in THF (50 ml) and
the above deprotonation–ethylation sequence was repeated (LDA
(60 mmol) in THF (60 ml) and EtI (6 ml, 75 mmol)). The residue
was purified by flash chromatography (Cy–EA 98 : 2) to give 2-
methyl-2-ethylphenylbutanoate (5.7 g, 92%) as a pale yellow oil. To
a solution of 2-methyl-2-ethylphenylbutanoate (500 mg, 2.4 mmol)
in THF (10 ml) was slowly added a solution of LiAlH4 (91 mg,
2.4 mmol) in THF (5 ml) at 0 ◦C. The mixture was stirred at 25 ◦C
Conclusion
The hindered rhazinilam-like phenylpyridine carbamates were
prepared for the first time by using a one-pot three step sequence
with the generation of the lithium ortho-lithioarylalkoxide salt
9 by ortho-lithiation, subsequent nucleophilic addition to the
3-bromo-5-oxazolyl pyridine scaffold 8 at the C2 position and
a final oxidative step. The method was directly applied to the
preparation of three novel phenyl-3-carboxypyridyl-carbamate
analogues 4a, 4b and 4c of rhazinilam as racemic mixtures in
11, 2.2 and 1.6% overall yields respectively. These new analogues
proved to be inactive in the inhibition of the polymerization
and depolymerization of tubulin. Other substituted as well as
unsubstituted phenylpyridine carbamates will be synthesized by
extension of the nucleophilic addition of the lithium ortho-
lithioarylalkoxide salt 9 to other activated pyridine scaffolds.
◦
for 2 h under N2 and cooled at 0 C before H2O (91 ll), NaOH
(2 M, 91 ll) and H2O (270 ll) were successively added. After
filtration though a short pad of celite, the product was extracted
with AcOEt (3 × 10 ml). The combined organic extract was dried
(MgSO4), filtered and concentrated under vacuo. The residue was
purified by distillation (112 ◦C, 2 mbar) to give 10 (384 mg, 90%)
as a colorless oil (Found: C, 80.79; H, 10.23. Calc. for C12H18O:
1
C, 80.85; H, 10.18%); IR mmax/cm−1 3307 (OH), 2969; H NMR
dH (300 MHz, CDCl3): 0.75 (6 H, t, J 7.2, 2 × CH2CH3), 1.07
(1 H, s, OH), 1.74 (4 H, m, 2 × CH2CH3), 3.74 (2 H, d, J 6.0,
1
CH2OH), 7.22 (1 H, m, 4-H), 7.33 (4 H, m, Ph); H NMR dH
Experimental
(300 MHz, DMSO): 0.59 (6 H, t, J 7.1, 2 × CH2CH3), 1.64 (4 H,
m, 2 × CH2CH3), 3.61 (2 H, d, J 4.9, CH2OH), 4.48 (1 H, t,
J 4.9, OH), 7.12 (1 H, m, 4-H), 7.26 (4 H, m, Ph); 13C NMR dC
(75 MHz, CDCl3): 7.9 (2 × CH3), 26.0 (2 × CH2), 46.0 (C(Et)2),
67.1 (CH2OH), 125.9 (CHar), 126.9 (2 × CHar), 128.3 (2 × CHar),
144.4 (CAr).
General
Melting points were measured on a Kofler apparatus. NMR
spectra were recorded on a Bruker AM 300 spectrometer with
residual protic solvent as the internal reference. Chemical shifts
are quoted in ppm and coupling constants in Hz. IR spectra
were recorded using KBr cells on a Perkin-Elmer FT IR 205
spectrometer. Elemental analyses were performed on a Carlo
Erba 1106 apparatus. High-resolution mass spectra (HRMS) were
recorded by the department service. THF was distilled from
2-(2-Deuteriophenyl)-2-ethyl-butan-1-ol (13). A solution of
sec-BuLi (2.6 ml of 1.3 M solution in cyclohexane–hexane 98 :
2, 3.36 mmol) was slowly added, at r.t. under N2, to a stirred
solution of 2-ethyl-2-phenylbutan-1-ol (10, 200 mg, 1.12 mmol) in
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hexane (2 ml). The mixture was refluxed for 6 h and cooled to 0 ◦C
before D2O (0.6 ml, 30 mmol) was added. The temperature was
slowly allowed to warm to r.t. and water (2 ml) was added. The
product was extracted with AcOEt (3 × 5 ml) and the combined
organic extract was washed with brine, dried (MgSO4), filtered
and concentrated under vacuo. The residue was purified by flash
chromatography (Cy–EA 8 : 2) to give 13 (125 mg, 60%) as a
colorless oil. 1H NMR dH (300 MHz, DMSO): 0.59 (6 H, t, J 7.1,
2 × CH2CH3), 1.64 (4 H, m, 2 × CH2CH3), 3.61 (2 H, d, J 4.9,
CH2OH), 4.48 (1 H, t, J 4.9, OH), 7.12 (1 H, m, 4-H), 7.26 (3 H,
m, Ph).
5-bromonicotinonitrile (5 g, 27.3 mmol) and 2-amino-2-
methylpropan-1-ol (17, 2.74 mL, 28.6 mmol). The resulting
mixture was refluxed for 48 h and solvent was removed under
vacuo. The residue was dissolved in CH2Cl2 (30 mL) and the
resulting organic phase was washed with H2O (30 mL). The
separated aqueous phase was extracted with CH2Cl2 (3 × 10 mL)
and the combined organic extract was dried (MgSO4), filtered
and concentrated under vacuo. The residue was purified by flash
chromatography (EA) to give 8 (6.61 g, 95%) as white powder; mp
91 ◦C (Found: C, 47.14; H, 4.33; N, 10.83. Calc for C10H11BrN2O:
C, 47.08; H, 4.35; N, 10.98%); IR mmax/cm−1 3033, 2870, 1935,
1
1651; H NMR dH (300 MHz, CDCl3): 1.39 (6 H, s, 2 × CH3),
2-(2-Bromophenyl)-2-ethyl-butan-1-ol (14). A solution of sec-
BuLi (2.6 ml of 1.3 M solution in cyclohexane–hexane 98 : 2,
3.36 mmol) was slowly added, at r.t. under N2, to a stirred solution
of 2-ethyl-2-phenylbutan-1-ol (10, 200 mg, 1.12 mmol) in hexane
(2 ml). The mixture was refluxed for 6 h and cooled to 0 ◦C before
a solution of 1,2-dibromotetrachloroethane (1.82 g, 5.6 mmol) in
THF (3 ml) was added. The temperature was allowed to warm
4.15 (2 H, s, CH2), 8.38 (1 H, dd, J 1.9 and 2.2, 4-H), 8.74 (1 H, d,
J 2.2, 2-H), 9.02 (1 H, d, 1H, J 1.9, 6-H); 13C NMR dC (75 MHz,
CDCl3): 28.7 (2 × CH3), 69.0 (C(Me)2), 80.1 (CH2), 120.5 (Car),
125.8 (Car), 138.1 (CHar), 147.5 (CHar), 152.0 (CHar), 159.1 (CN).
3-Bromo-5-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-4-phenylpyri-
dine (18). PhLi (0.39 ml of 2 M solution in Bu2O, 0.78 mmol)
was slowly added, at r.t. under N2, to a solution of 3-bromo-5-(4,5-
dihydro-4,4-dimethyloxazol-2-yl)pyridine 8 (200 mg, 0.78 mmol)
in THF (6 ml). The solution was stirred at r.t. for 1 h. Saturated
NH4Cl (10 ml) was added and the mixture was extracted with
CH2Cl2 (3 × 10 ml). The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. The crude residue
was then dissolved in toluene (30 ml) and subsequently treated
with chloranil (193 mg, 0.78 mmol). The mixture was refluxed for
an additional 2 h and washed successively with aqueous NaOH
(12%, 3 × 30 ml) and water (30 ml). The separated organic layer
was dried (MgSO4), filtered and concentrated under vacuo. The
crude residue was purified by flash chromatography (P–EA 3 : 7)
to give 18 (224 mg, 87%) as a yellow oil (Found: C, 58.29; H, 8.07;
N, 4.62. Calc. for C16H15BrN2O: C, 58.02; H, 8.46; N, 4.56%);
◦
to 25 C and the mixture was stirred for 16 h. Water (2 ml) was
added and the product was extracted with AcOEt (3 × 5 ml). The
combined organic extract was washed with brine, dried (MgSO4),
filtered and concentrated under vacuo. The residue was purified by
flash chromatography (Cy–EA 8 : 2) to give 14 (134 mg, 46%) as
a colorless oil (Found: C, 56.34; H, 6.65. Calc. for C12H17BrO: C,
56.04; H, 6.66%); IR mmax/cm−1 3380, 2965; 1H NMR dH (300 MHz,
CDCl3): 0.71 (6 H, t, J 7.2, 2 × CH2CH3), 1.20 (1 H, t, J 6.0, OH),
1.98 (2 H, m, CH2CH3), 2.10 (2 H, m, CH2CH3), 4.08 (2 H, d,
J 6.0, CH2OH), 7.05 (1 H, t, J 6.8, 4-H), 7.26 (2 H, m, 5-H, 6-H),
7.60 (1 H, d, J 7.5, 3-H); 13C NMR dC (75 MHz, CDCl3): 8.9 (2 ×
CH3), 25.3 (2 × CH2), 48.5 (C(Et)2), 64.7 (CH2OH), 122.8 (Car),
127.5 (CHar), 128.2 (CHar), 131.4 (CHar), 136.4 (CHar), 142.1 (Car).
1
IR mmax/cm−1 2964, 1651; H NMR dH (300 MHz, CDCl3): 1.03
3,4-Dihydro-1-hydroxy-4,4-diethyl-(2,1)-benzoxaborine
(15).
A solution of sec-BuLi (2.6 ml of 1.3 M solution in cyclohexane–
hexane 98 : 2, 3.36 mmol) was slowly added, at r.t. under N2,
to a stirred solution of 2-ethyl-2-phenylbutan-1-ol (10, 200 mg,
1.12 mmol) in hexane (2 ml). The mixture was refluxed for 6 h and
(6 H, s, 2 × CH3), 3.56 (2 H, s, CH2), 7.13 (2 H, m, Ph), 7.27 (3 H,
m, Ph), 8.64 (1 H, s, Py), 8.72 (1 H, s, Py); 13C NMR dC (75 MHz,
CDCl3): 28.3 (2 × CH3), 68.3 (C(Me)2), 79.9 (CH2), 122.6 (CAr),
127.1 (CAr), 128.6 (CHAr), 128.8 (CHAr), 129.0 (CAr), 137.2 (CHAr),
149.0 (CHAr), 149.7 (CAr), 153.9 (CHAr), 160.4 (CN).
◦
cooled to −78 C before trimethyl borate (1.35 ml, 12.00 mmol)
was added. The solution was allowed to warm to 25 ◦C and the
mixture was continued for 16 h. Saturated NH4Cl (15 ml) was
added. The separated aqueous extract was then acidified with
HCl (3 M) to pH = 1, extracted with AcOEt (3 × 10 ml) and
the combined organic extract was washed with NaOH (2 N, 3 ×
10 ml). The aqueous extract was acidified with HCl (3 M) to pH =
5 and extracted with AcOEt (3 × 15 ml). The combined organic
extract was dried (MgSO4), filtered and concentrated under
vacuo to give 15 (46 mg, 20%) as a white solid without further
purification; mp 145 ◦C (Found: C, 70.47; H, 8.52. Calc. for
C12H17BO2: C, 70.63; H, 8.40%); IR mmax/cm−1 3215 (OH), 1459,
2-(2-(3-Bromo-5-(4,5-dihydro-4,4-dimethyloxazol-2-yl)pyridin-
2-yl)phenyl)-2-ethylbutan-1-ol (6a).
A solution of sec-BuLi
(7.75 ml of 1.3 M solution in cyclohexane–hexane 98 : 2,
10.11 mmol) was added dropwise, at r.t. under N2, to a stirred
solution of 2-ethyl-2-phenylbutan-1-ol (10, 600 mg, 3.37 mmol) in
hexane (6 ml). The mixture was refluxed for 6 h, cooled to 25 ◦C
and a solution of 3-bromo-5-(4,5-dihydro-4,4-dimethyloxazol-2-
yl)pyridine (8, 430 mg, 1.69 mmol) in THF (6 ml) was added. The
resulting mixture was stirred at 25 ◦C for 1 h before saturated
NH4Cl (10 ml) was added. The product was extracted with AcOEt
(3 × 10 ml) and the combined organic extract was dried (MgSO4),
filtered and concentrated in vacuo. The residue was dissolved in
toluene (34 ml) and chloranil (416 mg, 1.69 mmol) was added. The
mixture was refluxed for an additional 2 h. The cooled solution
was washed with NaOH (12%, 3 × 30 ml) and water (30 ml)
and the separated organic phase was dried (MgSO4), filtered
and concentrated under vacuo. The residue was purified by flash
chromatography (DCM–Ac 9 : 1) to give 6a (190 mg, 26%) as a
brown solid; mp 46 ◦C (Found: C, 61.27; H, 6.61; N, 6.10. Calc. for
C22H27BrN2O2: C, 61.26; H, 6.31; N, 6.49%); IR mmax/cm−1 3364
1
805 (B–C); H NMR dH (300 MHz, DMSO): 0.71 (6 H, t, J 7.5,
2 × CH2CH3), 1.55–1.66 (4 H, m, 2 × CH2CH3), 3.90 (2 H, s,
CH2OB), 7.22 (2 H, m, Ph), 7.43 (1 H, t, J 7.2, Ph), 7.69 (1 H,
d, J 7.5, Ph), 8.42 (1 H, s, OH); 13C NMR dC (75 MHz, CDCl3):
8.6 (2 × CH3), 29.0 (2 × CH2), 43.0 (C(Et)2), 71.5 (CH2O), 125.1
(CHar), 125.8 (CHar), 131.2 (CHar), 133.6 (CHar), 151.3 (Car).
3-Bromo-5-(4,5-dihydro-4,4-dimethyloxazol-2-yl)pyridine
(8).
To suspension of zinc chloride (371 mg, 2.73 mmol)
a
in chlorobenzene (55 mL) was added, at r.t. under N2,
180 | Org. Biomol. Chem., 2007, 5, 175–183
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(OH), 1651; 1H NMR dH (300 MHz, CDCl3): 0.64 (3 H, t, J 7.5,
CH2CH3), 0.88 (3 H, t, J 7.2, CH2CH3), 1.25 (2 H, m, CH2CH3),
1.42 (6 H, s, 2 × CH3), 1.74 (1 H, m, CH2CH3), 1.83 (1 H, m,
CH2CH3), 3.16 (1 H, d, J 10.9, CH2OH), 3.31 (1 H, s, OH), 3.46
(1 H, d, J 10.9, CH2OH), 4.18 (2 H, s, CH2), 6.99 (1 H, d, J 7.5,
6-H), 7.28 (1 H, t, J 7.5, 5-H), 7.43 (1 H, t, J 8.3, 4-H), 7.55 (1 H, d,
(Car), 155.1 (Car), 160.3 (CN); HRMS (IC+, tert-butane) calcd. for
C22H27N2O2 [(M + H)+] 351.2072, found 351.2065.
3-Bromo-5-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-2-(2-(3-(((1,1-
dimethylethyl)dimethylsilyloxy)methyl)pentan-3-
yl)phenyl)pyridine (21).
Method A (from compound 6a). Tert-butylchlorodimethyl-
silane (82 mg, 0.55 mmol) was added to a stirred solution of
compound 6a (214 mg, 0.50 mmol) and 1H-imidazole (54 mg,
0.80 mmol) in DMF (1 ml). The resulting mixture was stirred at
25 ◦C under N2 for 2 h and water (10 ml) was added. The product
was extracted with CH2Cl2 (3 × 15 ml) and the combined organic
extract was dried (MgSO4), filtered and concentrated under vacuo.
The residue was purified by flash chromatography (DCM–Ac 9.5 :
0.5) to give 21 (183 mg, 67%) as an orange oil. IR mmax/cm−1 2961,
1653, 1085; 1H NMR dH (300 MHz, CDCl3): −0.14 (3 H, s, MeSi),
−0.12 (3 H, s, MeSi), 0.64–0.70 (6 H, m, 2 × CH2CH3), 0.80 (9 H, s,
(CH3)3Si), 1.42 (6 H, s, 2 × CH3), 1.45–1.71 (4 H, m, 2 × CH2CH3),
3.36 (1 H, d, J 9.2, CH2OSi), 3.44 (1 H, d, J 9.2, CH2OSi), 4.17
(2 H, s, CH2), 6.99 (1 H, dd, J 7.5 and 1.3, 3ꢀ-H), 7.22 (1 H, td, J 8.3
and 1.3, 4ꢀ-H), 7.35–7.44 (2 H, m, 5ꢀ-H, 6ꢀ-H), 8.51 (1 H, d, J 1.9,
4-H), 9.03 (1 H, d, J 1.9, 6-H); 13C NMR dC (75 MHz, CDCl3):
−5.4 (MeSi), −5.3 (MeSi), 9.2 (CH3), 9.3 (CH3), 18.5 (CMe3), 26.1
(3 × CH3), 28.7 (2 × CH3), 29.1 (CH2), 30.1 (CH2), 49.4 (C(Et)2),
64.1 (CH2OSi), 68.4 (C(Me)2), 79.8 (CH2), 122.0 (Car), 124.4 (Car),
125.6 (CHar), 128.5 (CHar), 129.6 (CHar), 131.2 (CHar), 139.8 (Car),
139.9 (CHar), 142.4 (Car), 146.3 (CHar), 159.3 (CN), 165.1 (Car);
HRMS (DIC+, tert-butane) calcd. for C28H42N2O2SiBr [(M + H)+]
545.2199–547.2183, found 545.2206–547.2174.
J 8.3, 3-H), 8.57 (1 H, d, J 1.7, 4ꢀ-H), 8.99 (1 H, d, J 1.7, 6ꢀ-H); 13
C
NMR dC (75 MHz, CDCl3): 8.8 (2 × CH3), 27.3 (CH2), 27.6 (CH2),
28.7 (2 × CH3), 48.9 (C(Et)2), 67.7 (CH2OH), 68.4 (C(Me)2), 79.8
(CH2), 121.9 (Car), 124.8 (Car), 126.0 (CHar), 129.0 (CHar), 130.2
(CHar), 131.7 (CHar), 139.4 (Car), 140.7 (CHar), 141.9 (Car), 146.3
(CHar), 159.1 (CN), 164.6 (Car).
2-(2-(3-Bromo-5-(4,5-dihydro-4,4-dimethyloxazol-2-yl)pyridin-
2-yl)phenyl)-2-ethylbutyl carbamate (7a). Trichloroacetyl iso-
cyanate (101 ll, 0.85 mmol) was slowly added, at 0 ◦C under N2, to
a stirred solution of compound 6a (280 mg, 0.65 mmol) in freshly
dry CH2Cl2 (6 ml). The mixture was allowed to warm to room
temperature and stirred for an additional 30 min. After removal of
the solvent under vacuo, the crude product obtained was dissolved
in methanol (6 ml) and the resulting solution was treated with
potassium carbonate (196 mg, 1.42 mmol). The mixture was stirred
for 3 h and water (10 ml) was then added. The mixture was
extracted with ethyl acetate (3 × 15 ml) and the combined organic
layers were dried (MgSO4), filtered and concentrated under vacuo.
The crude material was purified by flash chromatography (DCM–
◦
Ac 9 : 1) to give 7a (216 mg, 70%) as an orange solid; mp 70 C
(Found: C, 58.16; H, 6.02; N, 8.93. Calc. for C23H28BrN3O3: C,
1
58.23; H, 5.95; N, 8.86%); IR mmax/cm−1 3338 (NH2), 1725; H
Method B (one-pot procedure from compound 10). A solution
of sec-BuLi (1.25 ml of 1.3 M solution in cyclohexane–hexane
98 : 2, 1.68 mmol) was slowly added, at r.t. under N2, to a stirred
solution of 2-ethyl-2-phenylbutan-1-ol (10, 200 mg, 0.56 mmol) in
hexane (1 ml). The mixture was refluxed for 6 h, cooled to 25 ◦C
and a solution of 3-bromo-5-(4,5-dihydro-4,4-dimethyloxazol-2-
yl)pyridine (8, 72 mg, 0.28 mmol) in THF (1 ml) was added. The
resulting mixture was stirred at r.t. for 1 h before a solution of tert-
butylchlorodimethylsilane (253 mg, 1.68 mmol) in THF (1 ml) was
added. The mixture was stirred for 16 h, water (2 ml) was added and
the product was extracted with AcOEt (3 × 5 ml). The combined
organic extract was dried (MgSO4), filtered and concentrated in
vacuo. The residue was dissolved in toluene (7 ml) and chloranil
(69 mg, 0.28 mmol) was added. The mixture was refluxed for an
additional 2 h and the cooled solution was washed with NaOH
(12%, 3 × 5 ml) and water (5 ml). The separated organic phase
was dried (MgSO4), filtered and concentrated under vacuo. The
residue was purified by flash chromatography (DCM–Ac 9.5 :
0.5) to afford 21 (30 mg, 21%) as an orange oil with the same
characteristic analysis as above.
NMR dH (300 MHz, CDCl3): 0.72 (6 H, m, 2 × CH2CH3), 1.42
(6 H, s, 2 × CH3), 1.53 (4 H, m, 2 × CH2CH3), 4.03 (1 H, d, J 10.9,
CH2OCO), 4.15 (1 H, d, J 10.9, CH2OCO), 4.17 (2 H, s, CH2),
4.56 (2 H, s, NH2), 7.01 (1 H, dd, J 7.5 and 1.5, 6-H), 7.28 (1 H,
t, J 7.5, 5-H), 7.37–7.47 (2 H, m, 3-H, 4-H), 8.52 (1 H, d, J 1.9,
4ꢀ-H), 9.03 (1 H, d, J 1.9, 6ꢀ-H); 13C NMR dC (75 MHz, CDCl3):
8.9 (CH3), 9.0 (CH3), 28.0 (CH2), 28.4 (CH2), 28.7 (2 × CH3), 47.2
(C(Et)2), 68.1 (CH2OCO), 68.4 (C(Me)2), 79.8 (CH2), 122.0 (Car),
124.5 (Car), 126.1 (CHar), 128.7 (CHar), 129.3 (CHar), 131.8 (CHar),
139.7 (Car), 140.2 (CHar), 141.7 (Car), 146.5 (CHar), 157.2 (CO),
159.3 (CN), 164.7 (Car).
7,7-Diethyl-6,7-dihydro-4,5-dihydro-3-(4,4-dimethyloxazol-2-
yl)benzoxepino[1,2,b]pyridine (19). To a stirred solution of com-
pound 7a (70 mg, 0.15 mmol) in DMF (1 ml) were added small
portions of NaH (13 mg of 60% in mineral oil, 0.32 mmol). The
resulting mixture was allowed to warm to 100 ◦C for 16 h and
saturated NH4Cl (2 ml) was added. The product was extracted
with AcOEt (3 × 5 ml). The combined organic extract was
dried (MgSO4), filtered and concentrated under vacuo. The crude
material was purified by flash chromatography (DCM–Ac 9 : 1) to
give 19 (46 mg, 90%) as a yellow oil. IR mmax/cm−1 2968, 1652; 1H
NMR dH (300 MHz, CDCl3): 0.76 (6 H, m, 2 × CH2CH3), 1.40
(6 H, s, 2 × CH3), 1.67 (2 H, m, CH2CH3), 1.89 (2 H, m, CH2CH3),
4.13 (2 H, s, CH2), 4.26 (2 H, s, CH2OAr), 7.38 (3 H, m, Ph), 7.80
(1 H, d, J 1.9, 4-H), 8.59 (1 H, m, Ph), 8.91 (1 H, d, J 1.9, 6-H);
13C NMR dC (75 MHz, CDCl3): 9.0 (2 × CH3), 28.8 (2 × CH3),
31.9 (2 × CH2), 48.3 (C(Et)2), 68.2 (C(Me)2), 79.6 (CH2OAr), 79.7
(CH2), 123.7 (Car), 126.9 (CHar), 127.2 (CHar), 128.4 (CHar), 129.0
(CHar), 132.4 (CHar), 136.3 (Car), 143.2 (CHar), 145.1 (Car), 149.0
N-(4-Methoxybenzyl)-5-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-
2-(2-(3-(((1,1-dimethylethyl)dimethylsilyloxy)methyl)pentan-3-yl)-
phenyl)pyridin-3-amine (22). To a stirred solution of compound
21 (300 mg, 0.55 mmol) in dry toluene pre-degassed by argon
bubbling for 30 min (3 ml) were added 4-methoxybenzylamine
(87 ll, 0.66 mmol), sodium tert-butoxide (73 mg, 0.76 mmol),
BINAP (14 mg, 0.02 mmol) and Pd2dba3 (8 mg, 0.008 mmol).
The resulting mixture was refluxed for 16 h under N2. After
filtration through a short pad of celite, the solvents were removed
under vacuo and the residue was purified by flash chromatography
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(DCM–Ac 9 : 1) to give 22 (274 mg, 83%) as a yellow oil. IR
mmax/cm−1 3416 (NH), 1651, 1084; 1H NMR dH (300 MHz, CDCl3):
−0.11 (6 H, s, 2 × MeSi), 0.57–0.67 (6 H, m, 2 × CH2CH3), 0.80
(9 H, s, (CH3)3Si), 1.40 (6 H, s, 2 × CH3), 1.47–1.61 (2 H, m,
CH2CH3), 1.69–1.74 (2 H, m, CH2CH3), 3.45 (2 H, s, CH2OSi),
3.71 (1H, m, NH), 3.77 (3 H, s, OMe), 4.12 (2 H, s, CH2), 4.16–4.32
(2 H, m, CH2N), 6.82 (2 H, d, J 8.6, H-PhOMe), 7.03 (1 H, dd,
J 7.3 and 1.3, 3ꢀ-H), 7.14 (2 H, d, J 8.6, 2 × H-PhOMe), 7.24 (1 H,
t, J 7.1, 4ꢀ-H), 7.34 (1 H, td, J 7.1 and 1.7, 5ꢀ-H), 7.40–7.45 (2 H,
m, 4-H, 6ꢀ-H), 8.51 (1 H, d, J 1.7, 6-H); 13C NMR dC (75 MHz,
CDCl3): −5.3 (2 × MeSi), 9.1 (CH3), 9.2 (CH3), 18.5 (CMe3), 26.1
(3 × CH3), 28.7 (2 × CH3), 29.1 (CH2), 29.6 (CH2), 47.5 (CH2N),
49.4 (C(Et)2), 55.5 (OCH3), 63.6 (CH2OSi), 68.0 (C(Me)2), 79.4
(CH2), 114.3 (CHar), 115.3 (CHar), 124.0 (Car), 126.6 (CHar), 128.6
(CHar), 129.0 (CHar), 130.2 (CHar), 130.4 (Car), 131.2 (CHar), 136.6
(CHar), 137.2 (Car), 142.0 (Car), 144.0 (Car), 152.0 (Car), 159.2 (Car),
161.2 (CN); HRMS (DIC+, tert-butane) calcd. for C36H52N3O3Si
[(M + H)+] 602.3778, found 602.3780.
124.3 (Car), 126.8 (CHar), 129.0 (CHar), 131.0 (CHar), 131.2 (CHar),
136.7 (Car), 138.2 (CHar), 140.4 (Car), 143.6 (Car), 151.4 (Car), 160.9
(CN); HRMS (DIC+, tert-butane) calcd. for C22H30N3O2 [(M +
H)+] 367.2260, found 367.2256.
9,9-Diethyl-8,9-dihydro-3-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-
benzo[f ]pyrido[3,2,d]oxazonin-6(5H)-one (rac-4a). Et3N (162 ll,
1.16 mmol) was added to a stirred solution of compound 5a
(170 mg, 0.46 mmol) in THF (8◦.5 ml) at r.t. under N2. The
solution was allowed to cool to 0 C and phosgene (251 ll of a
20% solution in toluene, 0.47 mmol) was added dropwise. The
mixture was stirred at 25 ◦C for 1 h and saturated NaHCO3 (8 ml)
and EtOAc (10 ml) were added. The product was extracted with
EtOAc (3 × 10 ml) and the combined organic extract was dried
(MgSO4), filtered and concentrated under vacuo. The residue was
purified by flash chromatography (DCM–Ac 8 : 2) to give rac-4a
(152 mg, 84%) as a pale yellow solid; mp-(decomposition). IR
mmax/cm−1 3311, 1743, 1651; 1H NMR dH (300 MHz, CDCl3): 0.70
(3 H, t, J 7.2, CH2CH3), 0.92 (3 H, t, J 7.4, CH2CH3), 1.39 (6 H, s,
2 × CH3), 1.40 (2 H, m, CH2CH3), 1.76 (1 H, m, CH2CH3), 1.90
(1 H, m, CH2CH3), 3.80 (1 H, d, J 10.7, CH2OCO), 4.16 (2 H, s,
CH2), 4.21 (1 H, d, J 10.7, CH2OCO), 6.60 (1 H, s, NH), 6.80
(1 H, dd, J 7.5 and 1.7, 3ꢀ-H), 7.24 (1 H, t, J 7.4, 4ꢀ-H), 7.40 (1 H,
td, J 7.4 and 1.7, 5ꢀ-H), 7.50 (1 H, d, J 8.1, 6ꢀ-H), 7.97 (1 H, d,
J 1.9, 4-H), 8.95 (1 H, d, J 1.9, 6-H); 13C NMR dC (75 MHz,
CDCl3): 8.3 (CH3), 8.4 (CH3), 24.7 (CH2), 24.8 (CH2), 28.7 (2 ×
CH3), 48.5 (C(Et)2), 68.3 (C(Me)2), 73.6 (CH2OCO), 79.8 (CH2),
124.0 (Car), 127.0 (CHar), 128.4 (CHar), 129.7 (CHar), 131.3 (CHar),
132.4 (CHar), 133.7 (Car), 139.1 (Car), 141.7 (Car), 145.5 (CHar),
156.4 (Car), 160.1 (CN), 165.4 (CO); HRMS (IC+, tert-butane)
calcd. for C23H28N3O3 [(M + H)+] 394.2131, found 394.2134.
2-(2-(3-Amino-5-(4,5-dihydro-4,4-dimethyloxazol-2-yl)pyridin-
2-yl)phenyl)-2-ethylbutyl 2,2,2-trifluoroacetate (23). A solution
of compound 22 (150 mg, 0.25 mmol) in TFA (1.5 ml) was stirred
for 16 h at 25 ◦C. TFA was removed under vacuo and the residue
was dissolved in CH2Cl2 (5 ml). Saturated NaHCO3 (5 ml) was
added and the separated aqueous phase was extracted with CH2Cl2
(3 × 15 ml). The combined organic extract was dried (MgSO4),
filtered and concentrated under vacuo. The residue was purified by
flash chromatography (DCM–Ac 9 : 1) to give 23 (93 mg, 80%) as
a yellow solid; mp-(degradation). 1H NMR dH (300 MHz, CDCl3):
0.72 (6 H, t, J 7.4, 2 × CH2CH3), 1.41 (6 H, s, 2 × CH3), 1.58–1.78
(4 H, m, 2 × CH2CH3), 3.59 (2 H, s, NH2), 4.15 (2 H, s, CH2),
4.30 (1 H, d, J 11.0, CH2OCO), 4.38 (1 H, d, J 11.0, CH2OCO),
7.08 (1 H, dd, J 7.5 and 1.3, 6-H), 7.33 (1 H, td, J 7.5 and 1.7,
5-H), 7.39–7.46 (2 H, m, 3-H, 4-H), 7.60 (1 H, d, J 1.8, 4ꢀ-H), 8.55
(1 H, d, J 1.8, 6ꢀ-H); 13C NMR dC (75 MHz, CDCl3): 8.6 (CH3),
8.7 (CH3), 27.6 (CH2), 28.1 (CH2), 28.7 (2 × CH3), 46.9 (C(Et)2),
67.9 (C(Me)2), 70.7 (CH2OCO), 79.7 (CH2), 118.0 (q, JC–F 285,
CF3), 121.4 (CHar), 124.1 (Car), 127.5 (CHar), 129.0 (CHar), 129.8
(CHar), 131.7 (CHar), 137.2 (Car), 138.4 (CHar), 140.5 (Car), 141.5
(Car), 150.7 (Car), 159.0 (d, JC–F 41, CO), 161.1 (CN); 19F NMR
dF (138 MHz, CDCl3): −75.5 (CF3); m/z (ESI, acetonitrile) 464.1
[(M + H)+].
9,9-Diethyl-8,9-dihydro-3-(ethoxycarboxy)benzo[f ]pyrido[3,2,d]-
oxazonin-6(5H)-one (rac-4b). A solution of compound rac-4a
(26 mg, 0.07 mmol) in EtOH–conc◦. H2SO4 (9 : 1, 2 ml) was
refluxed for 5 h. After cooling at 25 C, saturated NaHCO3 was
added to pH = 8–9 and the product was extracted with CH2Cl2
(3 × 5 ml). The combined organic extract was dried (MgSO4),
filtered and concentrated under vacuo. The residue was purified
by flash chromatography (DCM–Ac 9.5 : 0.5) to give rac-4b
1
(5 mg, 20%) as a pale yellow oil. IR mmax/cm−1 3274, 1727; H
NMR dH (300 MHz, CDCl3): 0.71 (3 H, t, J 7.3, CH2CH3), 0.94
(3 H, t, J 7.3, CH2CH3), 1.44 (5 H, m, CH2CH3, COOCH2CH3),
1.75 (1 H, m, CH2CH3), 1.90 (1 H, m, CH2CH3), 3.82 (1 H, d,
J 10.9, CH2OCO), 4.25 (1 H, d, J 10.9, CH2OCO), 4.45 (2 H, q,
J 7.1, COOCH2CH3), 6.08 (1 H, s, NH), 6.80 (1 H, dd, J 7.5 and
1.5, 3ꢀ-H), 7.26 (1 H, m, 4ꢀ-H), 7.43 (1 H, td, J 7.0 and 1.5, 5ꢀ-H),
7.54 (1 H, d, J 7.7, 6ꢀ-H), 8.05 (1 H, d, J 1.9, 4-H), 9.07 (1 H, d,
J 1.9, 6-H); 13C NMR dC (75 MHz, CDCl3): 8.4 (CH3), 8.5 (CH3),
14.7 (CH3Et), 24.9 (2 × CH2), 48.6 (C(Et)2), 62.1 (CH2Et), 73.8
(CH2OCO), 126.0 (Car), 127.1 (CHar), 128.5 (CHar), 129.8 (CHar),
131.1 (CHar), 133.7 (CHar), 133.8 (Car), 139.0 (Car), 141.6 (Car),
147.2 (CHar), 156.1 (Car), 165.2 (CO), 167.2 (CO); HRMS (IC+,
tert-butane) calcd. for C21H25N2O4 [(M + H)+] 369.1814, found
369.1794.
2-(2-(3-Amino-5-(4,5-dihydro-4,4-dimethyloxazol-2-yl)pyridin-
2-yl)phenyl)-2-ethylbutan-1-ol (5a). To a solution of compound
23 (90 mg, 0.2 mmol) in H2O–CH3OH (1 : 2, 3.5 ml) was added
K2CO3 (124 mg, 0.9 mmol). The mixture was stirred at 25 ◦C
for 1 h and the solvents were removed under vacuo. The residue
was purified by flash chromatography (DCM–Ac 8 : 2) to give
◦
5a (71 mg, 97%) as a pale yellow solid; mp 65 C. IR mmax/cm−1
1
3316–3202, 1649; H NMR dH (300 MHz, CDCl3): 0.63 (3 H, t,
J 7.3, CH2CH3), 0.87 (3 H, t, J 7.3, CH2CH3), 1.28–1.38 (2 H, m,
CH2CH3), 1.40 (6 H, s, 2 × CH3), 1.65–1.85 (2 H, m, CH2CH3),
3.16 (1 H, d, J 12.2, CH2OH), 3.40 (1 H, d, J 12.2, CH2OH), 3.60
(2 H, s, NH2), 4.14 (2 H, s, CH2), 7.04 (1 H, dd, J 7.5 and 1.7,
6-H), 7.29 (1 H, td, J 7.5 and 1.1, 5-H), 7.41 (1 H, td, J 7.5 and
1.7, 4-H), 7.58 (1 H, dd, J 7.5 and 1.1, 3-H), 7.62 (1 H, d, J 1.8,
4ꢀ-H), 8.50 (1 H, d, J 1.8, 6ꢀ-H); 13C NMR dC (75 MHz, CDCl3):
8.7 (CH3), 8.8 (CH3), 27.5 (CH2), 27.7 (CH2), 28.7 (2 × CH3), 48.8
(C(Et)2), 67.7 (CH2OH), 67.8 (C(Me)2), 79.7 (CH2), 121.6 (CHar),
3-Carboxy-9,9-diethyl-8,9-dihydrobenzo[f ]pyrido[3,2,d]oxazonin-
6(5H)-one (rac-4c). A stirred solution of compound rac-4a
(15 mg, 0.04 mmol) in H2SO4 (1.8 N, 2 ml) was refluxed for 5 h.
The mixture was allowed to cool to r.t. and saturated NaHCO3
182 | Org. Biomol. Chem., 2007, 5, 175–183
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was added to pH = 8–9. The aqueous phase was washed with (1 ×
5 ml) and HCl (4 N) was added to pH 4. The separated aqueous
phase was extracted with CH2Cl2 (3 × 5 ml) and the combined
organic extract was dried (MgSO4), filtered and concentrated
under vacuo to give rac-4c (2 mg, 15%) as a pale yellow solid;
mp-(decomposition). IR mmax/cm−1 3500–3000, 1722, 1599; 1H
NMR dH (300 MHz, CDCl3): 0.72 (3 H, t, J 7.3, CH2CH3), 0.95
(3 H, t, J 7.3, CH2CH3), 1.45 (2 H, m, CH2CH3), 1.77 (1H,
m, CH2CH3), 1.93 (1 H, m, CH2CH3), 3.84 (1 H, d, J 10.9,
CH2OCO), 4.27 (1 H, d, J 10.8, CH2OCO), 6.80 (2 H, m, NH,
3ꢀH), 7.26 (1 H, m, Ph), 7.44 (1 H, t, J 7.3, Ph), 7.54 (1 H, d,
J 8.0, 6ꢀ-H), 8.08 (1 H, s, 4-H), 9.09 (1 H, s, 6-H); 13C NMR dC
(75 MHz, CD3CD2OD): 8.3 (CH3), 8.5 (CH3), 24.9 (CH2), 25.2
(CH2), 49.2 (C(Et)2), 73.6 (CH2OCO), 127.2 (CHar), 128.8 (CHar),
130.1 (CHar), 132.2 (CHar), 134.3 (CHar), 135.8 (Car), 140.1 (Car),
142.7 (2 × Car), 146.4 (CHar), 157.2 (Car), 165.9 (CN), 169.4
(CO); HRMS (IC−, tert-butane) calcd. for C19H19N2O4 [(M–H)+]
339.1345, found 339.1355.
7 (a) Ottow has reported the unique example of C4 addition of
aryl magnesium bromide to the 5-bromo-3-pyridinecarboxamide: W.
Schlecker, A. Huth and E. Ottow, Tetrahedron, 1995, 51, 9531–
9542; (b) For general examples of the addition of organometallics
to pyridinecarboxamides and nicotinates: E. Piers and M. Soucy,
Can. J. Chem., 1974, 52, 3563–3564; K. Akiba, Y. Iseki and M. Wada,
Bull. Chem. Soc. Jpn., 1984, 57, 1994–1999; H. Hans, F. Hoffmann-
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Pat., 1103546, 2001; M.-L. Bennasar, C. Juan and J. Bosch, Tetrahedron
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Juan, Tetrahedron, 2002, 58, 8099–8106; M.-L. Bennasar, T. Roca and
M. Monerris, J. Org. Chem., 2004, 69, 752–756.
8 For examples of regiochemical control outcomes of nucleophilic
addition of aryllithium to 3-oxazoyl pyridine see: A. I. Meyers and
N. R. Natale, Heterocycles, 1982, 18, 13–19; S. H. Rosenberg and H.
Rapoport, J. Org. Chem., 1984, 49, 56–62; A. E. Hauck and C. S.
Giam, J. Chem. Soc., Perkin Trans. 1, 1984, 2227–2231; S. K. Dubey
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E. E. Knaus, Heterocycles, 1986, 24, 125–134; P. Binay, G. Dupas, J.
Bourguignon and G. Que´guiner, Can. J. Chem., 1987, 65, 648–655.
9 D. Dube´, D. Descheˆnes, J. Tweddell, H. Gagnon and R. Carlini,
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10 D. Montebugnoli, P. Bravo, E. Corradi, G. Dettori, C. Mioskowski, A.
Volonterio, A. Wagner and M. Zanda, Tetrahedron, 2002, 58, 2147–
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Acknowledgements
11 For previous reports of the elimination of isocyanic acid from N-
metallated carbamate see: T. Kaneko, H. Wong and T. W. Doyle,
Tetrahedron Lett., 1985, 26, 3923–3926; H. Al-Rawi and A. Williams,
J. Am. Chem. Soc., 1977, 99, 2671–2678.
The authors are grateful to Dr F. Gue´ritte for the support of this
work, S. Thoret for tubulin assays and G. Aubert for cytotoxicity
assays.
12 A. Klapars, X. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2002,
124, 7421–7428.
13 J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy and
L. M. Alcazar-Roman, J. Org. Chem., 1999, 64, 5575–5580.
14 B. H. Yang and S. L. Buchwald, Org. Lett., 1999, 1, 35–37; J. Yin and
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Johnson and J. G. Kettle, Tetrahedron Lett., 2004, 45, 3733–3735.
15 6a was treated with tert-butyldimethylsilylchloride (TBSCl) and imida-
zole at r.t. for 2 h.
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