A three-component synthesis of (1,3-oxazol-2-yl)-1,2-dihydro(iso)quinoline and its further structural diversifications

Article abstract of DOI:10.1055/s-2005-862357

A Reissert-type three-component synthesis of 1,3-oxazol-2-yl-1,2- dihydro(iso)quinoline is developed using α-isocyano β-phenyl propionamide as an isonitrile input. The structure of this multicomponent adduct is further diversified taking advantage of the rich chemistry of oxazole. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862357

532
LETTER
A Three-Component Synthesis of (1,3-Oxazol-2-yl)-1,2-dihydro(iso)quinoline
and its further Structural Diversifications
A
T
hree-Compone
i
nt Syn
an
C
-dihydro(iso)quin
e
oline sare Tron,a Jieping Zhu*b
a
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università degli Studi del Piemonte Orientale,
V. Le Ferrucci 33, 28100, Novara, Italy
b
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Received 27 November 2004
dihydro(iso)quinoline by exploiting the unique reactivity
of a-isocyano acetamides.11 Further structural-diversifi-
cation of this adduct is also delineated based on the
chemical reactivity of oxazole.
Abstract: A Reissert-type three-component synthesis of 1,3-ox-
azol-2-yl-1,2-dihydro(iso)quinoline is developed using a-isocyano
b-phenyl propionamide as an isonitrile input. The structure of this
multicomponent adduct is further diversified taking advantage of
the rich chemistry of oxazole.
Key words: aminooxazole, isocyanide, isonitrile, isoquinoline,
multicomponent reaction, Reissert reaction, Ugi reaction
O
+
+
CN
N
O
N
Cl
O
O
Quinoline and isoquinoline derivatives are important
classes of hetertocycles.1 Their ubiquitous occurrence in
nature and their wide spectrum of biological activities
make them the prime targets in medicinal chemistry and
the search of new and efficient synthetic routes has at-
tracted attention of synthetic chemists for years.2 For the
functionalization of quinolines, isoquinolines and related
aromatic azines, the Reissert reaction remained one of the
most powerful tools.3 The reaction can be considered as a
multicomponent reaction (MCR)4 where adducts are
formed from an azine, an acyl chlorides and sodium cya-
nide via a N-acyliminium intermediate.
1
2
3
N
O
CH2Cl2, –40 °C
O
O
N
O
N
molecular sieves, 4 Å
4
Scheme 1
As shown in the Scheme 1, the reaction of isoquinoline
(1), methyl chloroformate (2) and morpholinyl-a-iso-
cyano-b-phenylpropionamide (3) under slightly modified
Lavilla’s conditions (CH2Cl2, –40 °C, 4 Å molecular
sieves)12 provided the expected compound 4 in 76%.13
The reaction turned out to be quite general and com-
pounds prepared by this MCR are listed in Figure 1. As is
seen, both isoquinoline and quinoline participated in this
reaction, although the latter seems to be less reactive
requiring a longer reaction time. A variety of chlorofor-
mates such as ClCOOMe, ClCOOPh, and FmocCl took
part in the reaction to provide the corresponding N-acylat-
ed derivatives. Other acylating agents including acetic an-
hydride, acyl chloride failed to initiate the desired reaction
sequence. We hypothesized that the equilibrium between
isoquinoline and its N-acyl isoquinolinium salt may be
driven to the former species due to the higher electro-
philicity of the carbonyl group and the relatively low nu-
cleophilicity of the isocyanide 3.14 Surprisingly, Boc2O is
also ineffective as an acylating agent although it has been
successfully engaged in Lavilla’s protocol. The presence
of functional groups with different electronic properties
(OH, OMe, Br, NO2) in aromatic ring is tolerated. When
quinoline was used as substrate, two possible regio-
isomers might be expected. However, in agreement with
Lavilla’s observartion, only the C-2 functionalized
The ability of isonitrile to undergo facile a-addition with
a nucleophile and an electrophile under mild conditions
made it a popular reactant for the development of novel
MCRs. The eminent example is the classic Ugi four-com-
ponent reaction which converts an aldehyde, an amine, an
acid and an isonitrile into a-acetamidoamide in one step
with good to excellent yield.5 Recently, Lavilla and co-
workers extended the Ugi-4CR to (iso)quinoline and dem-
onstrated that N-acylated aromatic azine, is susceptible to
nucleophilic attack of isocyanide leading, after hydroly-
sis, to the a-carbamoylated 1,2-dihydroazine.6,7 On the
other hand, Mironov et al. have independently developed
a three-component synthesis of 2,3-dihydro-10H-pyrro-
lo[2,1-a]isoquinoline-1-one by reaction of isoquinoline,
gem-diactivated olefines and isocyanides.8 Earlier, Morel
and his co-workers developed a three-component synthe-
sis of fused imidazolium and dihydropyrimidinium salt by
reaction of methylchlothioimidate, pyridine and iso-
cyanides.9,10 Based on these observations, we report here-
in a three-component synthesis of (1,3-oxazol-2-yl)-1,2-
SYNLETT 2005, No. 3, pp 0532–0534
1
6.
0
2.
2
0
0
5
Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862357; Art ID: G45404ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Three-Component Synthesis of (1,3-Oxazol-2-yl)-1,2-dihydro(iso)quinoline
533
derivative was isolated as evidenced from NMR spectra
studies. Conversely, Ugi has demonstrated earlier that
isocyanides attack preferentially the C-4 position of the
N-alkyl quinolinium salts.7
NCOOMe
TFA
4
HN
O
O
THF/H2O
r.t., 4 h
N
O
13 (91%)
N
O
N
O
O
O
Scheme 2
N
O
N
O
O
N
O
N
Alternatively, heating a toluene solution of 4 and dimeth-
ylacetylene dicarboxylate (DMAD, 14) provided the 1-(2-
furyl)-1,2-dihydroisoquinoline derivative 16 in about
35% yield (reflux, 2 d). Diels–Alder cycloaddition be-
tween 4 and 14 followed by retro-Diels–Alder reaction of
the intermediate cycloadduct 15 might explain the forma-
tion of the observed product (Scheme 3).18–20
5 (46%)
6 (54%)
OR
Br
N
O
N
O
O
O
O
O
O
O
O
toluene
reflux
N
N
O
O
N
+
4
N
14
O
7 (31%)
NO2
8 R = H , OCOMe (38%)
NCOOMe
COOMe
COOMe
N
O
N
O
N
O
O
O
O
O
N
N
O
N
N
O
N
O
15
9 (66%)
10 (51%)
N
O
MeO
O
O
MeOOC
MeOOC
O
N
O
O
N
N
O
N
N
N
O
N
O
O
O
O
16 (35%)
11 (48%)
12 (48%)
Scheme 3
Figure 1
In conclusion we have developed an expeditious synthesis
of (1,3-oxazol-2-yl)-1,2-dihydro(iso)quinolines based on
the unique reactivity of isocyanoacetamide. The reaction
can be realized efficiently in dichloromethane at –40 °C in
the presence of 4 Å molecular sieves. The aminooxazole
attached on the C-1 position of dihydroisoquinoline can
be transformed into the linear amide or other heterocycles
such as furan demonstrating the potential of this MCR for
creating the molecular diversity. Further application in
synthesis of complex natural product such as tropolo-
isoquinolines21 is in progress.
Multicomponent reaction followed by post-functionaliza-
tion constitutes a powerful approach to access rapidly the
structural diversities.15 Taking advantage of the instability
of aminooxazoles under acidic conditions,16,17 the oxazole
4 was readily transformed into the corresponding con-
strained dipeptide as two separable diastereoisomers 13 in
91% yield (trifluoroacetic acid in THF–water 1:1,
Scheme 2). This represents one of the shortest routes to
attach an amino acid residue onto the C-1 position of the
isoquinoline.
Synlett 2005, No. 3, 532–534 © Thieme Stuttgart · New York

534
G. C. Tron, J. Zhu
LETTER
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Acknowledgment
Dr. Gian Cesare Tron is a visiting Professor from Università del
Piemonte Orientale – Facoltà di Farmacia, Novara, Italy. Financial
supports from Università del Piemonte Orientale and CNRS are
gratefully acknowledged.
isocyanoacetamide, see: Fayol, A.; Housseman, C.; Sun, X.;
Janvier, P.; Bienaymé, H.; Zhu, J. Synthesis 2005, 161.
(12) The role of molecular sieve is unknown. It may remove
adventitious water or act as a scavenger of HCl produced in
situ. It is worthy of note that the same reaction did not occur
in the presence of triethylamine.
References
(13) Typical Procedure for the Synthesis of 4.
To a solution of isoquinoline (1, 97.0 mL, 105.7 mg, 0.82
mmol) in dry CH2Cl2 (2.0 mL) at –40 °C were added
powdered molecular sieves (4 Å, 200 mg) and methyl
chloroformate (2, 155.0 mg, 126.7 mL, 1.64 mmol,)
successively. The resulting yellow solution was stirred for 5
min and a solution of a-isocyano b-phenyl propionamide (3,
200.0 mg, 0.82 mmol) in dry CH2Cl2 (3.0 mL) was added
drop-wise. After being stirred for 1.5 h, the reaction was
quenched by addition of sat. aq NaHCO3 solution and
extracted with CH2Cl2. The combined organic extracts were
washed with HCl (2 N), sat. aq NH4Cl solution, dried over
Na2SO4, and the volatile was evaporated under reduced
pressure. The crude product was purified by flash
chromatography (heptane–EtOAc = 6:4) to give 4 as a
yellowish solid (263.0 mg, 76%): mp 110–112 °C. IR: 1713,
1633, 1440, 1347, 1235, 1113, 970 cm–1. 1H NMR (300
MHz, CDCl3): two rotamers, d = 7.27–7.06 (9 H, m), 6.95,
6.91 (1 H, d, J = 7.7 Hz), 6.41, 6.29 (1 H, br s), 5.82 (1 H, d,
J = 7.7), 5.75 (1 H, d, J = 7.7), 3.75, 3.71 (2 H, s), 3.66 (3 H,
s), 3.53 (4 H, m), 2.74 (4 H, m). MS (ESI): m/z (%) = 454
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Synlett 2005, No. 3, 532–534 © Thieme Stuttgart · New York