Au(III)-catalyzed regio-and stereoselective tandem synthesis of oxazolo fused naphthyridines and isoquinolines from o-alkynylaldehydes

Article abstract of DOI:10.1016/j.tetlet.2013.11.072

An efficient tandem approach for the regio-and stereoselective synthesis of oxazolo-fused naphthyridines 3a-g, 3i-l and isoquinolines 3h, 3m via the reaction of o-alkynylaldehydes 1a-i with chiral amino alcohols 2a-c under mild reaction conditions is described. The stereochemistry and structures of the products were assigned via NOESY and X-ray crystallographic studies.

Full text of DOI:10.1016/j.tetlet.2013.11.072

Accepted Manuscript
Au (III)-catalyzed regio- and stereoselective tandem synthesis of oxazolo fused
naphthyridines and isoquinolines from o-alkynylaldehydes
Rajeev Ranjan Jha, Abhinandan Kumar Danodia, Sushil Kumar, Akhilesh
Kumar Verma
PII:
S0040-4039(13)02019-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.072
TETL 43867
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 September 2013
14 November 2013
17 November 2013
Please cite this article as: Jha, R.R., Danodia, A.K., Kumar, S., Verma, A.K., Au (III)-catalyzed regio- and
stereoselective tandem synthesis of oxazolo fused naphthyridines and isoquinolines from o-alkynylaldehydes,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.11.072
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Au (III)-catalyzed regio- and stereoselective
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Rajeev Ranjan Jha, Abhinandan Kumar Danodia, Sushil Kumar and Akhilesh Kumar Verma*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Au (III)-catalyzed regio- and stereoselective tandem synthesis of oxazolo fused
naphthyridines and isoquinolines from o-alkynylaldehydes
Rajeev Ranjan Jha, Abhinandan Kumar Danodia, Sushil Kumar and Akhilesh Kumar Verma*
Department of Chemistry, University of Delhi,
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient tandem approach for the regio- and stereoselective synthesis of oxazolo-fused
naphthyridines 3a–g, 3i–l and isoquinolines 3h, 3m via the reaction of o-alkynylaldehydes 1a–i
with chiral amino alcohols 2a–c under mild reaction conditions is described. The
stereochemistry and structures of the products were assigned via NOESY and X-ray
crystallographic studies.
Available online
Keywords:
Tandem Cyclization, Oxazole
Naphthyridines, Stereselective
Gold
2009 Elsevier Ltd. All rights reserved.
Heterocycles are important due to their presence in myriad
natural products, including alkaloids.1 Among these compounds,
oxazoles exhibit potent biological and pharmaceutical activities.2
Similarly, oxazolo-fused naphthyridines3 which are important
members of the nitrogen family of compounds, are present in
many naturally occurring bioactive compounds. The introduction
of new chiral centers into these molecules has increased their use
in asymmetric synthesis as chiral ligands.4 Stereochemically pure
compounds have increasing significance due to the difference in
biological activity between isomers.5 Flunoxaprofen, which is
closely related to naproxen is a chiral non-steroidal anti-
inflammatory drug and has been shown to significantly improve
the symptoms of osteoarthritis and rheumatoid arthritis (Figure 1,
i)6. Very recently pyridine substituted benzoxazoles and
functional groups and exceptional ability to activate the -
system, towards C-C and C-N bond formations.10 In this
direction, tandem methodologies11 and domino reactions12 has
gained considerable attention as these reactions can quickly
synthesize the complex molecules from simple starting materials
in an iterative manner. Predominantly gold-catalyzed13
cyclizations have acquired incredible success due to the
capability to trigger alkynes and alkenes at low-catalyst loading
under mild reaction conditions.
oxazolo[4,5-c]quinolines
have
been
disclosed
as
a
cryptosporidium parvum
inosine
5′-monophosphate
dehydrogenase (CpIMPDH) inhibitor and as TRPV1 antagonists,
respectively (Figure 1, ii–iii).7-8 The importance of these
heterocyclic derivatives justifies the development of new
synthetic strategies towards these molecules.9
Scheme 1. Previous work of our laboratory using o-
alkynylaldehydes.
Recently, o- alkynylaldehydes have been widely explored as
versatile building blocks for the construction of a wide variety of
heterocyclic compounds;14 however, the stereoselective synthesis
of heterocycles from o-alkynylaldehydes remains elusive. Based
on our recent work on the synthesis of heterocycles from o-
alkynylaldehydes, and by applying o-alkynylaldehydes as
building blocks in the synthesis of a variety of heterocyclic
scaffolds (Scheme 1),15 we hypothesized that the reaction of o-
alkynylaldehydes with chiral amino alcohols might offer an
opportunity for the diastereoselective synthesis of oxazolo-fused
heterocycles. Herein, we report our successful regio- and
i. Flunoxaprofen:
Chiral NSAID
Figure 1. Significant examples of biologically active fused-oxazoles
ii. CpIMPDH inhibitor
iii. TRPV1
antagonists
In recent years, transition-metal-catalyzed reactions has gained
considerable interest for the synthesis of heterocyclic,
carbocyclic compounds and natural-product-like scaffolds
because of their high reactivity, tolerance towards several

2
Tetrahedron
AuCl3 afforded the 6-endo-dig cyclized product 3a as a sole
stereoselective synthesis of oxazolo-fused naphthyridines and
product in 80% yield (entry 9). The yield of the product 3a
remained same upon increasing the reaction time (entry 10);
however decrease in reaction time (from 5 to 4 h) adversely
affected the yield of the product (entry 11). Increasing in catalyst
loading from 10 mol % to 15 mol % does not significantly affect
the yield of the product 3a (entry 12); however lowering of the
catalyst loading afforded the product 3a in 59% yield (entry 13).
Lower yield of the product 3a was obtained when reaction was
carried out at 50 °C (entry 14). CuI was found ineffective for the
reaction; however Cu(OTf)2 and InCl3 provided the product 3a in
lower yields (entries 15–17). No product was obtained without
the catalyst (entry 18).
isoquinoline via the reaction of o-alkynylaldehydes with
inexpensive and readily available chiral amino alcohols (Scheme
2).
The use of L-serine methyl ester controlled the chirality of the
product and afforded the 6-endo-dig cyclized products with high
diastereoselectivity. The absolute configurations of the new
stereogenic center at Hb in products 3a were determined by
NOESY experiments.17-18,20 The 1H NMR spectra of 3a show that
Hb appears at 6.19 ppm, as a singlet and that Ha appears at 3.89–
3.86 ppm, respectively, as a multiplet. No distinct NOE effect
was observed between Hb and Ha in compounds 3a. This result
suggests that Hb and Ha are located in the trans orientation. X-ray
crystallographic studies of compounds 3a confirmed the structure
of the products and supported the assigned stereochemistry
(Figure 2).20,21 Optical rotations of the compounds 5a before X-
ray and after X-ray crystallography was found to be same.
Scheme 2. Designed approach for the regio- and stereoselective
synthesis of fused-oxazoles
The starting substrates 1a–i required for the designed reaction
were prepared by the Sonogashira cross-coupling reaction of the
easily accessible o-haloaldehydes with commercially available
terminal alkynes.15,16
Table 1. Optimization of the reaction conditionsa
T oC
Yieldb (%)
Entrya Solvent
Catalyst
(mol %)
Time (h)
2.0
3a
4a
25
40
1
CH2Cl2
AgNO3/10
05
08
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CH2Cl2
CH2Cl2
CHCl3
CHCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
AgNO3/10
AgNO3/15
AgNO3/15
AgOTf /10
AgOTf/10
AgOAc/10
AuCl/10
AuCl3/10
AuCl3/10
AuCl3/10
AuCl3/15
AuCl3/5
AuCl3/10
CuI/10
Cu(OTf)2/10
InCl3/10
-
4.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
8.0
4.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
09
15
17
33
40
23
56
80
80
66
83
59
43
00
51
47
00
12
18
21
55
55
50
10
00
00
00
00
00
00
00
00
00
00
40
60
60
70
70
70
70
70
70
70
70
50
70
70
70
70
(A) NOESY
(B)
Figure 2. (A) NOESY interactions of 3a. (B) ORTEP drawings of
3a.
After optimizing the reaction conditions, we examined the
scope of the reaction by using a variety of alkynes 1a–h (Table
2). The reactions of substrates 1a–d with 2a provided the 6-endo-
dig cyclized products 3a–d in 73–80% yields (entries 1–4).
Alkyne 1e, having no electron-releasing group, provided the
desired product 3e in 69% yield (entry 5). The reaction of the
electron-withdrawing substrate 1f with 2a gave a complex
mixture of inseparable products (entry 6). Reaction of 6-
methoxy substituted o-alkynylaldehydes 1g with 2a afforded the
desired product 3g in 74% yields (entry 7). Interesting results
were obtained with 2-(phenylethynyl)benzaldehyde 1h. The
reaction of alkyne 1h afforded the desired product 3h in only
52% yield (entry 8). The low yield of product 3h was due to the
formation of a byproduct 3-phenylisoquinoline 4 in 40% yield
(Scheme 3). The reaction of L-threonine methyl ester
hydrochloride (2b) with substrates 1a and 1e afforded the
products 3i and 3j in 72 and 68% yields, respectively (entries 9–
10). All of the reactions were highly stereoselective and afforded
products with trans stereochemistry.18 The reaction of substrates
1a and 1e with (S)-phenylglycinol (2c) provided the
diastereoselective products 3k and 3l in 75% and 72% yields,
respectively (entries 11–12). Product 3m was obtained in good
yield by using alkyne 1h (entry 13).
a
Reactions were performed using 0.6 mmol of L-serine methyl ester
hydrochloride 2a, 0.5 mmol of o-alkynylaldehydes 1a and 0.5 mmol of NEt3
in 2.0 mL solvent at 70 °C unless otherwise noted. DCE
= 1,2
dichloroethane.
b Isolated yield.
To identify the optimal conditions for the reaction, a
previously reported catalyst, Ag(I),15a,b,16a for cyclization was
examined in the reaction of o-alkynylaldehyde 1a with L-serine
methyl ester hydrochloride 2a in the presence of 1.1 equiv of
Et3N (Table 1). When 10 mol % of AgNO3 was used as a catalyst
in CH2Cl2 at 25 °C for 2 h, a mixture of oxazolo-fused
naphthyridine 3a (endo product) and pyrroloquinoline 4a (exo
product), was obtained in 5% and 8% yields, respectively (entry
1). Increase in the reaction time, temperature and catalyst loading
does not significantly affect the yield of the product (entry 2–4).
Use of AgOTf and AgOAc as catalyst afforded the mixture of
endo (3a) and exo (4a) products in moderate yields (entries 5–7).
Use of AuCl at 70 °C afforded the product 3a in 56% yield along
with 4a in 10% yield (entry 8). It is interesting to note that use of

3
2c
3k
3l
Table 2. Gold-catalyzed diastereoselective synthesis of 6-endo-dig
oxazolo-fused naphthyridines and isoquinolines 3aa
72% d
Entry
Substrate
Amine
Product
Yield (%)b
12
13
1e
2c
1
78%
72% d
2a
1h
2c
1a
3a
3m
2
3
2a
aReactions were performed using 0.5 mmol of 1, 1.1 equiv of 2, 1.1 equiv of
80%
76%
73%
69%
Et3N, 10 mol % AuCl3 in 2.0 mL of DCE (1,2-dichloroethane) at 70 °C for 6–
8 h.
3b
1b
1c
b Isolated Yield.
c Inseparable complex mixture.
d Using without Et3N.
2a
The byproduct was determined to be 3-
phenylisoquinoline 4 through comparison of its NMR spectrum
with that of an authentic sample. The formation of
phenylisoquinoline 4 (path b) along with that of the desired
product 3g (path a) is explained in Scheme 3.
3c
4
5
6
2a
2a
2a
3d
1d
1e
3e
3f
c
-
1f
Scheme 3. Possible formation of isoquinoline 4.
7
8
2a
2a
Interesting results were observed using cyclohexyl
substituted alkynes 1i. Reaction of alkyne 1i with L-serine methyl
ester hydrochloride 2a and (S)-phenylglycinol (2c) provided the
product 5a and 5b an oxidized form of oxazoline in 65 and 62%
yields respectively (Scheme 4). Possible reason for this auto
oxidation might be due to the lower electron density of alkynes.
74%
3g
1g
52%+
40%
3h
+
1h
4
9
1a
72%
68%
75%d
Scheme 4. Role of cyclohexyl group for the formation of oxidiZed
form of oxazole.
2b
3i
A plausible mechanism for the reaction is shown in Scheme
5. The reaction of alkyne 1 and amino alcohol 2 generates imine
X, which upon activation by Au can form two possible
intermediates P (by the intramolecular attack of the OH on the
imine carbon) and Q (by the intramolecular attack of the imine
on the alkyne). -Complexation between the alkyne, the imine
and Au(III) can lead to the formation of compound 3. Product 3
can also be obtained from the intermediate Q by the attack of the
alcoholic OH group on the iminium ion.
10
11
1e
1a
2b
3j

4
Tetrahedron
7. Gorla, S. K.; Kavitha, M.; Zhang, M.; Chin, J. E. W.; Liu, X.; Striepen, B.;
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Scheme 5. Plausible mechanism
In summary, we have described
a
regio- and
stereoselective synthesis of oxazolo fused naphthyridines and
isoquinolines by the reaction o-alkynylaldehydes with
inexpensive bench-top chiral amino alcohols under mild reaction
conditions. Structure and stereochemistry of the 6-endo-dig
cyclized products were supported by the X-ray crystallography
and NOESY studies. This tandem approach is general and
expand the application of o-alkynylaldehydes for the synthesis of
heterocyclics, which are of importance in medicinal chemistry.
Further investigations of this synthetic protocol are under
progress and will be reported in due course.
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Acknowledgments
We thank DU-DST PURSE Grant and DST for the financial
assistance and USIC University of Delhi for the use of
Instrumentation facility. R.R.J and A.D. is thankful to CSIR and
RGNF for the Fellowship.
Supplementary Material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
125.
References and notes
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18. See the Supporting Information.
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20. General Procedure for the synthesis of benzo[b]oxazolo[2,3-
f][1,6]naphthyridine (3a). An oven-dried Schlenk tube with a Teflon
screw valve was charged with 1.1 equiv of L(-) amino ester hydrochloride
2a–b, DCE (1,2 dichloroethane) (2.0 mL), 1.1 equiv Et3N, 0.5 mmol of
the o-alkanylaldehyde 1a–i, and AuCl3 (10 mol %). The Schlenk tube was
capped with a rubber septum and then evacuated and backfilled with
nitrogen. The septum was then replaced with a Teflon screw valve, and the
Schlenk tube was sealed. The reaction mixture was heated to 70 °C until o-
alkanylaldehyde 1a–j had been completely consumed (as determined by
TLC) and was allowed to cool to room temperature. The reaction mixture
was diluted with ethyl acetate (10 mL) and water (15 mL). Organic layer
was concentrated under reduced pressure. The crude material so obtained
was purified by column chromatography on silica gel. (3S,12bS)-Methyl-5-
(p-tolyl)-3,12b-dihydro-2H-benzo[b]oxazolo[2,3-f][1,6]-naphthyridine-3
6. Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Tetrahedron Lett.
2012, 53, 4121.

5
carboxylate (3a). The product was obtained as
a yellow needles
31
(DCM/Ether), (145.1 mg, 78% yield): mp: 151–152 °C; [α]D = -82.2 (c
0.1, MeOH): 1H NMR (400 MHz, CDCl3) δ: 8.05 (s, 1H), 7.91 (d, J = 8.1
Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.60 (td, J = 8.8 and 1.5 Hz, 1H), 7.40
(d, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.12
(s, 1H), 6.11 (s, 1H), 4.39–4.35 (m, 1H ), 3.84–3.80 (m, 2H), 3.78 (s, 3H),
2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 172.0, 151.4, 150.8, 149.1,
139.7, 135.4, 133.8, 130.3, 129.5, 128.3, 127.8, 127.6, 126.5, 125.1, 120.8,
104.5, 89.2, 64.4, 63.8, 52.7, 21.3. HRMS (ESI) (M)+ Calcd for
C23H20N2O3: 372.1474, found 372.1475.
21. CCDC931655 (3a) contains the supplementary crystallographic data for
this paper and can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www. ccdc.cam.ac.uk/request/cif.

Graphical Abstract
Au (III)-catalyzed regio- and stereoselective tandem synthesis of oxazolo
fused naphthyridines and isoquinolines and from ortho-alkynylaldehydes
Rajeev Ranjan Jha, Abhinandan Kumar Danodia, Sushil Kumar and Akhilesh Kumar Verma*
Synthetic Organic Chemistry Organic Research Laboratory, Department of Chemistry, University of Delhi
An efficient tandem approach for the regio- and stereoselective synthesis of oxazolo-fused naphthyridines
3a–g, 3i–l and isoquinolines 3h, 3m via the reaction of o-alkynylaldehydes 1a–i with chiral amino
alcohols 2a–c under mild reaction conditions is described. The stereochemistry and structures of the
products were assigned via NOESY and X-ray crystallographic studies.