Unexpected C-N bond formation via Smiles rearrangement: One pot synthesis of N -arylated coumarin/pyran derivatives

Article abstract of DOI:10.1039/c8nj02109k

A conceptually new and one-pot method for the synthesis of N-arylated coumarin/pyran derivatives via Smiles rearrangement. The reaction of 4-bromocoumarin/pyran with 2-amino phenols affords O-arylated coumarin/pyran which subsequently rearranges into N-arylated coumarin/pyran under mild reaction conditions in good yields.

Full text of DOI:10.1039/c8nj02109k

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Journal Name
COMMUNICATION
Unexpected
CꢀN
bond
formation
via
Smiles
rearrangement: one pot synthesis of Nꢀarylated
coumarin/pyran derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
K. Shiva Kumar,* Meesa Siddi Ramulu, N. Praveen Kumar
DOI: 10.1039/x0xx00000x
www.rsc.org/
conditions.
A conceptually new and oneꢀpot method for the synthesis of
Nꢀarylated coumarin/pyran derivatives via smiles
rearrangement. The reaction of 4ꢀbromo coumarin/pyran
reacts with 2ꢀamino phenols to form Oꢀarylated
coumarin/pyran and subsequently rearrange into Nꢀ
arylated coumarin/pyran in mild reaction conditions in
good yields.
The coumarins framework being an integral part of many
bioactive molecules is considered as one of the privileged
structures in drug discovery.9
Previous work
Ref 10 and 11
(a)
Br
NH2
HN
O
i)10 DIEA, DMF, 100 oC, 24 h
+
ii)11 H2O, MW, 15 min, 100 °C or
O
O
The rearrangement of C−O into C−N bond represents an
interesting transformation in organic synthesis and these
valuable transformations can provide access to complex
natural product synthesis, heterocyclic chemistry, and
industrial processes.1 One of the interesting solution for these
valuable transformations referred as Smiles rearrangement. It
is an an intramolecular nucleophilic substitution in which an
aromatic system shifts from one heteroatom to another via a
spirocyclic intermediate.2
Smiles rearrangement are generally applicable to aromatic
compounds bearing electronꢀwithdrawing substituents.3ꢀ5
However, heteroaryl based structures is rather limited.
Funicello et al.6 reported the three step synthesis of 4ꢀ or 5ꢀ
hydroxybenzofuran rearranged to 4ꢀ or 5ꢀaminobenzofuran
under harsh reaction conditions such as NaH in DMF at 150
°C. Synthesis of Nꢀalkyl/arylꢀ6ꢀaminoquinolines three step one
pot method by addition of 6ꢀhydroxyquinoline and Nꢀ
O
Pd(OAc)2, PPh3, K2CO3, 30 min, 80 °C
NH2
Ref 12
(b)
Br
OH
K2CO3, CH3CN
82 oC, 4 h
O
O
+
O
O
O
NH2
(c) T his wor k
X
R
R
Br
R1
OH
Smiles
Rearrangement
X
H
N
N
O
K2CO3
O
O
R1
+
OH
O
HN
O
R1
O-arylation
X
O
O
R
Scheme 1. Synthetic strategies toward the CꢀN bond formation
on coumarin.
Reaction of 4−bromo coumarin readily reacts with anilines to
provide Nꢀarylated coumarins under harsh reaction conditions
with long reaction time or microwave irradiation (Scheme 1a).10ꢀ11
Where as the use of 4ꢀamino phenols react with 4−bromo
coumarin offered only Oꢀarylated coumarins, there is no Nꢀ
arylated coumarins observed (Scheme 1b)12. Despites of these
achievements, we were interested the use of 2−aminophenols due
to a challenging issue to form the either Oꢀselective or Nꢀselective
arylated coumarins. Further, to date there have been no reports on
selective synthesis of Nꢀarylated coumarins and it’s appeared as
alkyl/arylꢀ2ꢀ
chloroacetamides
in
the
presence
of
Cs2CO3/K2CO3 in DMF at 150 oC was demanistrated by Shin
et al.7 Spagnolo et al.8 reported that, the benzothiopheneꢀ4ꢀol
was converted into 4ꢀaminoꢀbenzothiophene via 2ꢀ
methylpropionamide derivative. The rearrangement was
carried out under harsh conditions using sodium hydride in
HMPA or in DMFꢀDMPU at 100 °C. However most of these
reactions are not atom economic and require harsh reaction
difficult or not feasible by using some of these methodologies.
In continuation of our interest in the developing newer and
efficient methodologies for the synthesis of diverse heterocyclic
scaffold,13 we envisaged our preliminary findings on this mild,
singleꢀstep, selective and metal free method for the synthesis of Nꢀ
arylated coumarin/pyran derivatives via smiles rearrangement
(Scheme 1c). The rearrangement of Oꢀarylation into Nꢀarylation of
coumarin/pyran was found to be highly selective and allowed the
straightforward one pot reaction from 4ꢀbromo coumarin/pyran.
†Electronic Supplementary Information (ESI) available: Experimental
procedures, spectral data for all new compounds, and copies of spectra.
CCDC 1555220. For ESI and crystallographic data in CIF and other
electronic format see DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry 20xx
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We first conduct the reaction of 4ꢀbromoꢀ6ꢀmethylꢀ2Hꢀchromenꢀ
2ꢀone (1a) and 2ꢀaminoꢀ4ꢀmethylphenol (2a) in the presence of
K2CO3 in DMF at 80 C, the starting material 1a was consumed
15c
16d
17
18
19
K2CO3 (2.5)
K2CO3 (2.5)
DBU (2.5)
DABCO (2.5)
TEA (2.5)
DMF
DMF
DMF
DMF
DMF
6
5
5
5
5
22
ꢀ
70
ꢀ
48
80
10
76
45
o
after 6 h, To our surprise the reaction proceeded well affording 4ꢀ
((2ꢀhydroxyꢀ5ꢀmethylphenyl)amino)ꢀ6ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone
(4a) was isolated in 85% yield. However, the isolated product
proved not to be the anticipated Oꢀarylated coumarin. Compound
4a was characterized by spectral (NMR, IR and HRMS) data. This
motivated us to potential scope and applicability of this reaction.
We then investigated for the optimization of conditions and the
results were listed in Table 1. Initially, the reaction between 1a
and 2a in the presence of 1 equiv. of K2CO3, in DMF was
provided only O−arylated chromene 3a in good yield (Table 1,
entry 1). When the reaction was carried out 2 equiv. of K2CO3 was
20
aAll the reactions were carried out using 1a (0.84 m.mol), 2a
(0.84 m.mol) and base in a solvent (2 mL) at 80 oC. bIsolated
yield. The reaction was performed at 60 °C. The reaction was
performed at 100 °C
c
d
With the optimization conditions in hand, we decided for
further investigationon the scope and generality of this present
protocol. In this connection, we have conducted the reaction of
a variety of 4ꢀbromocoumarins/pyrans (1) with diffirent 2ꢀ
aminophenols (2) (Table 2). As shown in Table 2, all the
examined substrates provided good to high yields. The effect
of electronꢀdonating (methyl) and electronꢀwithdrawing groups
chloro) on chromen was studied and produced corresponding
products (4a, 4e, 4g−h and 4i−l) in good yields. The
benzo[f]chromen also afforded the desired product with a good
yield (4n and 4o). To our delight, the pyranꢀ2ꢀone furnished
the corresponding products with high yields (4p−s and 4v).
Next, to check the feasibility of 2ꢀaminophenol, electronꢀ
donating (methyl and t-butyl) (4aꢀ4c, 4g, 4jꢀ4k, 4q and 4r) and
electronꢀwithdrawing group (chloro and nitro) (4d, 4h, 4l, 4m,
4o and 4s) on benzene ring, were also studied and in all of the
cases it afforded the corresponding products in good yields.
All the compounds characterized by spectral [IR, NMR (1H
and 13C), and HRMS analysis.
employed,
a mixture of Oꢀarylated (3a, 32%) along with
N−arylated derivative (4a, 55%) was obtained (entry 2) and 2.25
equiv. of K2CO3 was employed significantly improved N−arylated
derivative (4a, 76%) (Table 1, entry 3). Interestingly, on further
incresing the K2CO3 (2.50 equiv.), a dramatic improvement in the
yield of 4a was 85% yield (Table 1, entry 4). The further
increasing the K2CO3 (2.75 equiv.), did not improve the yield of
4a (Table 1, entry 5). Various bases such as Cs2CO3, Na2CO3,
NaOH, NaH, and KOtBu were screened (Table 1, entries 6−10).
Finally, the solvents, such as DMSO, CH3CN, THF or Xylene
(Table 1, entries 11ꢀ14) were also studied but found to be less
effective then DMF (Table 1, entry 4). By lowering the reaction
temperature to 60 °C led to poor substrate conversion (entry 15,
Table 1). Increasing the temperature afforded the product 4a in 80
% yield (Table 1, entry 15). Switching the inorganic base to
organic base such as DBU, DABCO and TEA (Table 1, entries
17ꢀ19) decreased the product yield. Overall, it appeared that the
conditions of entry 4 are optimum for obtaining the desired
product 4a in the best yield.
Table 2: K2CO3 mediated synthesis of Nꢀarylated
coumarin/pyran 4.a,b
Table 1 Optimization of the reaction conditions.a
Yield (%)b
Time
Entry Base (equiv.)
Solvent
(h)
4
8
6
5
3a
85
32
12
‒
4a
‒
1
2
3
4
5
6
7
8
K2CO3 (1.25)
K2CO3 (2.0)
K2CO3 (2.25)
K2CO3(2.5)
K2CO3(2.75)
Cs2CO3 (2.5)
Na2CO3 (2.5)
NaH (2.5)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
CH3CN
THF
55
76
85
82
80
75
66
52
70
80
73
71
78
4a (85%)
4c (83%)
4b (81%)
5
‒
6
‒
8
‒
6
‒
9
NaOH (2.5)
KOtBu (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
6
‒
10
11
12
13
14
4
‒
4f (85%)
4e (82%)
4d (78%)
6
‒
6
‒
6
‒
Xylene
6
‒
2 | J. Name., 2012, 00, 1-3
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Next, we studied our present protocol with secondary Oꢀ
aminophenol. We successfully extended CꢀN bond formation
with secondary amines on coumarins/pyran (4tꢀ4v, Table 2)
with good yields (78ꢀ84%). We further extended the scope of
the present protocol with pyridine derived amino phenol have
also resulted in good yield of the corresponding coumarin
derivative (4w, Table 2).
Further, we reacted 1b with aliphatic aminol such as
ethanolamine (5) under standard conditions and observed that
the formation of Nꢀalkyl coumarin (7), instead of the expected
product 6 (Scheme 2) which was confirmed by its Xꢀray crystal
analysis.14
4i (85%)
4h (75%)
4g (82%)
4j (86%)
4k (80%)
4l (85%)
NO2
HN
O
Scheme 2. Reaction of 1b with 2ꢀaminoethanol (5).
OH
O
In order to access the scalability of this approach, a gram scale
reaction of 1a with 2a under optimized reaction conditions, was
carried out and found yield, 4a in 81% (0.960 g) yield (Scheme 3).
4n (80%)
4o (76%)
4m (81%)
4p (80%)
4q (81%)
4r (86%)
Scheme 3. GramꢀScale preparation of 4a.
Oꢀaryl derivative, 3a was observed to form in 92% yields after
refluxing for 3h of a mixture of 1a, 2a and 1.25 equiv. K2CO3 in
DMF at 60 °C. 3a upon further reaction with 1.25 equiv. K2CO3 in
DMF at 80 oC for 2h, resulted in the formation of Nꢀaryl
derivative, 4a in 88% yield (Scheme 4a). In order to see the
comparison of the reactivity between an intermolecular and an
intermolecular reaction. We carried out the reaction of 4ꢀbromoꢀ
2Hꢀchromenꢀ2ꢀone (1a) (1.0 equiv), 2ꢀaminophenol (2a) (1.1
equiv), and aniline (8) (1.1 equiv) in DMF using 2.5 equiv of
K2CO3 (Scheme 4b). We found that the formation of 4a in 82%
yield and Nꢀaryl derivative of 8 (i.e., 9) was not at all observed.
This clearly shows that an intermolecular reaction (Smiles
rearrangement) is favoured over an intermolecular reaction as
aminophenol (2a) with an attached nucleophile is in close
proximity to attack chromen carbon as compared to aniline
molecule.
4t (84%)
4s (83%)
4u (78%)
4w (78%)
4v (80%)
aAll the reactions were carried out using compound 1a (1.05 m. mol),
o
2a (1.05 m. mol) and 2.63 m. mol. K2CO3 in a DMF (3 mL) at 80 C
for 5 h. bIsolated yield.
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COMMUNICATION
Journal Name
Anelli, M. Brocchetta, E. Cappelletti, A. Ferraris, V.
Vincenzi, Open Org. Chem. J., 2009, 3, 35–41.
2. C. M. Holden, M. F. Greaney Chem. Eur. J., 2017, 23, 8992 –
9008.
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Peet, Tetrahedron, 1997, 53, 6303–6312.
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6. C. Bonini, G. Cristiani, M. Funicello and L. Viggiani,
Synth. Commun., 2006, 36, 1983–1990
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Zuo, Y. J. Yoon, D. S. Shin, Bull. Korean Chem. Soc.,
2013, 34, 3881–3884.
8. C. Bonini, M. Funicello, R. Scialpi, P. Spagnolo,
Tetrahedron, 2003, 59, 7515–7520.
Scheme 4. Competitive study.
Based on the literature precedents15ꢀ16 and our experimental
observations, a plausible mechanism is showed in Scheme 5.
Initially, Oꢀaryl coumarin (3) formed by nucleophilic substitution
participates in cyclization (via azaꢀMichael addition) results in the
formation of spiro intermediate and subsequent cleavage of the
9. (a) R. O’Kennedy, R. Zhorenes, Coumarins: Biology,
Applications, Mode of Action, Wiley, Chichester, 1997;
for reviews, see: (b) J. R. S. Hoult, M. Paya, Gen.
Pharmacol., 1996, 27, 713–722; (c) D. L. Yu, M.
Suzuki, L. Xie, S. L. Morrisꢀ Natschke, K. H. Lee, Med.
Res. Rev., 2003, 23, 322–345; (d) K. C. Fylaktakidou, D.
J. HadjipavlouꢀLitina, K. E. Litines, D. N. Nicolaides,
Curr. Pharm. Des., 2004, 10, 3813–3833; (e) F. Borges,
F. Roleira, N. Mihazes, L. Santana, E. Uriarte, Curr.
Med. Chem., 2005, 12, 887–916; (f ) X. S. Zhang, Z. W.
Li, Z. ꢀJ. Shi, Org. Chem. Front., 2014, 1, 44–49.
10. D. Cao, Y. Liu, W. Yan, C. Wang, P. Bai, T. Wang, M.
Tang, X. Wang, Z. Yang, B. Ma, L. Ma, L. Lei, F.
Wang, B. Xu, Y. Zhou, T. Yang, L. Chen, J. Med.
Chem., 2016, 59, 5721−5739.
weaker C−O forms
a new CꢀN bond give to Nꢀaryl
coumarin/pyran 4.
11. T. Balalas, A. A. Sada, D. J. H. Litina, K. E. Litinas,
Synthesis, 2017, 49, 2575ꢀ2583.
12. (a) M. H. Chen, B. C. Tang, X. Zhang, H. Shu, J.
Heterocyclic Chem., 54, 2017, 1186–1192 (b) M. H.
Chen1, D. W. Lu1, X. Zhang1, Z. Y. Zhou1, X. B.
Wang, H. Shu, Chem. Pap., 2017, 71, 1579–1586.
Scheme 5. Plausible mechanism.
In conclusion, a novel methodology has been developed via
K2CO3 mediated CꢀN bond formation leading to form new
coumarin/pyran derivatives via smiles rearrangement. This
methodology involvesthe reaction of 4ꢀbromo coumarin/pyran
reacts with 2ꢀamino phenols to form Oꢀarylated product and
subsequently rearrange into Nꢀarylated product. The amount of
K2CO3 plays important role to generate the Oꢀ or Nꢀarylated
products.The present methodology is a selective, straightforward
and mild reaction conditions for synthesis of a range of Nꢀarylated
coumarins/pyrans.
13. (a) K. S. Kumar, S. R. Meesa, B. Rajesham, B. Bhasker,
M. A. Ashfaq, A. A. Khan, S. S. Rao, M. Pal, RSC Adv.,
2016, 6, 48324–48328; (b) K. S. Kumar, B. Bhaskar, M.
S. Ramulu, N. P. Kumar, M. A. Ashfaq, M. Pal, Org.
Biomol. Chem., 2017, 15, 82–87; (c) K. S. Kumar, M. S.
Ramulu, B. Rajesham, N. P. Kumar, V. Voora, R. K.
Kancha, Org. Biomol. Chem., 2017, 15, 4468ꢀ4476.
14. Crystal data of (7): CCDC 1825038, Single crystals
suitable for Xꢀray diffraction of 7 DCM: EtOAc (1:1).
Molecular formula = C11 H11 N1 O3, Formula weight =
205.21, Crystal system = Triclinic, space group = P ꢀ1, a
= 8.0084(3) Å, b = 8.1626(3) Å, c = 8.5962(3) Å, V =
465.51(3) Å3, T = 296(2) K, Z = 2, Dc = 1.464 Mg/m3,
7164 Reflections collected, 1801 [R(int) = 0.0751]
independent reflections, Goodness of fit = 1.066.
KSK thanks the University Grants Commission (UGC), New
Delhi, for the award of an Assistant Professorship under FRP and
CSIR, India, for the financial support [02(0234)/15/EMRꢀII].
Conflicts of interest
The authors confirm that this article content has no conflict
of interest.
15. L.
J. Meng, H. Zuo, B.
V.
Notes and references
D. Vijaykumar, D. Gautam, K.
M. Choi, K. Jang, Y.
1. (a) L. E. Overman, Tetrahedron, 2009, 65, 6432–6446;
(b) A. R. Katritzky, A. F. Pozharskii, Handbook of
Heterocyclic Chemistry, 2nd ed.; Pergamon Press:
Oxford, 2000; (c) J. Nowicki, Molecules, 2000, 5, 1033–
1050; (d) A. Commarieu, W. Hoelderich, J. A. Laffitte,
M. ꢀP Dupont, J. Mol. Catal. A: Chem., 2002, 137,
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16. D. Ameen, T. J. Snape, Eur. J. Org. Chem., 2014, 1925–
1934.
4 | J. Name., 2012, 00, 1-3
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GRAPHICAL ABSTRACT
A conceptually new and one-pot method for the synthesis of N-arylated coumarin/pyran
derivatives via smiles rearrangement.