Copper-catalyzed C(sp3)-C(sp2) cross-coupling: Synthesis of 4-aryl-2-alkylamino-3-nitro-4h-chromenes

Article abstract of DOI:10.1002/ejoc.201402003

Inexpensive copper(II) acetate effectively catalyzes cross-coupling of electron-deficient as well as electron-rich arylboronic acids with 4-methylsulfanyl-2-alkylamino-3-nitro-4H-chromenes under near neutral conditions at room temp. to furnish a range of 4-aryl-4H-chromenes. This new strategy enabled substitution of the C(4)SMe group present on a sp³ hybridized carbon of the 4H-chromenes with aryl/heteroaryl groups. Mechanistic probing revealed that the Cu^I-Cu^III cycle is involved in catalysis. One-pot sequential substitution of C(4)SMe followed by C(6)Br with aryl groups has been achieved through Cu(OAc)₂ and Pd ₂(dba)₃ (Suzuki coupling) catalysis. Copyright

Full text of DOI:10.1002/ejoc.201402003

Job/Unit: O42003
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Date: 23-04-14 17:46:05
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201402003
Copper-Catalyzed C(sp3)–C(sp2) Cross-Coupling: Synthesis of 4-Aryl-2-
alkylamino-3-nitro-4H-chromenes
H. Surya Prakash Rao*[a] and A. Veera Bhadra Rao[a]
Keywords: C–C coupling / Copper / Cross-coupling / Medicinal chemistry / Drug discovery
Inexpensive copper(II) acetate effectively catalyzes cross-
coupling of electron-deficient as well as electron-rich aryl-
boronic acids with 4-methylsulfanyl-2-alkylamino-3-nitro-
4H-chromenes under near neutral conditions at room temp.
to furnish a range of 4-aryl-4H-chromenes. This new strategy
enabled substitution of the C(4)SMe group present on a sp3
hybridized carbon of the 4H-chromenes with aryl/heteroaryl
groups. Mechanistic probing revealed that the CuI–CuIII cy-
cle is involved in catalysis. One-pot sequential substitution
of C(4)SMe followed by C(6)Br with aryl groups has been
achieved through Cu(OAc)2 and Pd2(dba)3 (Suzuki coupling)
catalysis.
genic, anticoagulant, antianaphylactic, spasmolytic and di-
uretic activities.[6] Furthermore, 4H-chromene derivatives
have been employed for the treatment of Alzheimer’s dis-
ease and schizophrenia disorder.[7] In cancer chemotherapy,
4H-chromene 1 (Figure 1) was marked for drug develop-
ment because it effectively binds to cancer-implicated Bcl-2
proteins and induced programmed cell death (apoptosis) in
selected cancer cell lines.[8] The 4-aryl-4H-chromenes, the
target structures of the present study, represented by 2 (Fig-
ure 1), exhibit highly useful proapoptotic properties for the
treatment of a wide range of cancer ailments including
breast, lung and colo-rectal cancers.[9] In certain cases these
compounds act on cancer cells that are resistant to common
anticancer drugs such as paclitaxel and vinblastine. Apart
from applications in cancer chemotherapy, 4-aryl-4H-
chromenes for example 3 have found application in the en-
hancement of cognitive functions such as memory, and are
thus useful in the treatment of dementia.[10] Overall, synthe-
sis and biological evaluation of structurally diverse 4-aryl-
4H-chromenes is of high importance. For diversity oriented
synthesis, 4-aryl-4H-chromenes of type 2 provide opportu-
nities in three regions of the molecule, namely, the aromatic
ring of the benzopyran, substitution at the C2-amine, and
the aryl group at the C4 position.
Introduction
Among the fundamental requirements of de novo discov-
ery of lead molecules for medicinal use are the possibilities
of (i) quick, high yielding, experimentally facile and envi-
ronmentally benign combinatorial assembly, (ii) lack or
minimal number of stereogenic (chiral) centers, (iii) rigid
heterocyclic ring systems, (iv) structural diversity in terms
of well-defined functional group disposition that can be fi-
nely tuned for target recognition and (v) absence of labile
functional groups.[1] The parent molecular entities that can
incorporate such guiding concepts are referred to as “privi-
leged medicinal scaffolds”.[2] In the quest for the develop-
ment of lead molecules for specific targets there is a need
to unearth high yielding and catalytic methods that are tol-
erant to a variety of functional groups. These concepts
underlie the focal themes of research in modern medicinal
chemistry and drug discovery.[3] Reflecting the above con-
cepts, in recent years, 2H-chromene (2H-1-benzopyran) and
its close relative 4H-chromene (4H-1-benzopyran) have
emerged as privileged scaffolds because their derivatives
have found applications as drug candidates.[4] Whereas 2H-
chromene is surprisingly well-represented as a structural
element in biologically active and naturally occurring com-
pounds such as tocopherols, flavonoids, anthocyanins and
some alkaloids, there are very few natural products with
4H-chromene structure.[5] The derivatives of 4H-chromene,
however, exhibit a plethora of favorable medicinal proper-
ties including antifungal, antioxidant, antileishmanial,
hypotensive, antiproliferation, local anesthetic, antialler-
[a] Department of Chemistry, Pondicherry University,
Pondicherry 605014, India
E-mail: hspr.che@pondiuni.edu.in
http://www.pondiuni.edu.in/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402003.
Figure 1. Structure of anticancer agents 1 and 2, and an agent for
the treatment of cognitive dysfunction 3.
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H. S. P. Rao, A. V. B. Rao
FULL PAPER
We have recently described a facile, high yielding, atom- action of 6 with phenylmagnesium bromide, but the reac-
economic synthesis of 4-methylsulfanyl-4H-chromenes 6 tion did not provide any tangible product (Scheme 2). By
from readily available 2-hydroxybenzaldehydes (salicylalde- screening various options, we found that the substitution of
hydes) 4 and nitroketene-N,S-acetals 5 (Scheme 1).[11] The C(4)SMe in 6 with an aryl group could be achieved through
4H-chromenes 6 have a highly labile C(4)SMe group that is its cross-coupling with arylboronic acids 11 under cop-
open for substitution with nucleophiles through the inter- per(II) acetate catalysis (Scheme 2), details of which are pre-
mediary of benzopyrylium cations. As an example, the reac- sented here. Although there have been several reports on
tions of 6 with phenols 7, lead to exclusive substitution at copper-catalyzed substitution of the SMe group present on
the ortho position in phenols to provide 4-aryl-4H- sp2 carbon atoms, particularly under aerobic conditions
chromenes 8 (Scheme 1).[12] Whereas this aromatic electro- (Chan–Lam reaction),[14] to the best of our knowledge, the
philic substitution in phenols is high yielding and regio- present reaction constitutes the first report on cross-cou-
chemically defined, the reaction is, however, limited to pling involving an SMe group present on a sp3 hybridized
phenols. In addition, the reaction is also limited to products carbon.
formed from the reaction of phenols at their ortho position.
Despite the fact that copper-mediated coupling reactions
The C(4)SMe group in 6a, however, can be replaced with as a means of carbon–carbon bond formation were discov-
highly electron-rich aromatic compounds such as indole 9 ered several decades earlier than the palladium-catalyzed
to generate 4-aryl-4H-chromenes of type 10.[13] Once again, reactions,[15] due to the requirement for harsh reaction con-
the substitution is limited to electron-rich aromatic com- ditions and high catalytic loading, they have been largely
pounds. In our quest to develop a generic method for sub- excluded from synthetic planning. Nevertheless, in recent
stitution of C(4)SMe with a range of aromatic rings to pro- years there has been a huge resurgence of cross-coupling
duce 4-aryl-4H-chromenes 12, initially, we attempted the re- reactions involving organocopper intermediates due to the
Scheme 1. Synthesis of 4-methylsulfanyl-4H-chromene 6 and its further transformations into 4-aryl-4H-chromenes 8, 10, and 12.
Scheme 2. Reactions of 4H-chromene 6a with different reagent systems.
2
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Copper-Catalyzed C(sp3)–C(sp2) Cross-Coupling
discovery of milder reaction conditions and because of the mediated cross-coupling reactions.[18] Among the copper(II)
advantages of copper catalysts over the use of more expens- catalysts screened [Cu(OAc)2, Cu(OCOCF3)2, Cu(OTf)2,
ive and toxic palladium catalysts.[16] As a result, there is CuSO4, CuCl2, CuBr2, CuO, Cu(acac)2] it was found that
now a paradigm shift in the conduct of cross-coupling reac- 10 mol-% Cu(OAc)2 provided 4H-chromene 12a in the best
tions with palladium catalysis to copper catalysis. Like the yield (Table 1, entry 2). Although the difference in yield of
Pd0–PdII redox cycle in palladium-mediated cross-coupling 12a was not high, the rate of the reaction was at least half
reactions, copper exhibits facile CuI–CuIII or occasionally when 5 mol-% Cu(OAc)2 was used (entry 1). On the other
Cu0–CuII redox cycles, and involves oxidative addition, hand, the addition of larger quantities of Cu(OAc)2 did not
transmetallation, and reductive disintegration steps to facil- improve either the rate or the yield (entries 3 and 4). Cop-
itate cross-coupling.[17] One additional advantage of em- per(I) catalysts such as CuBr, CuI, CuCl, and Cu2O were
ploying copper reagents in cross-coupling is that, unlike not as efficient as Cu(OAc)2 (Table 1, entries 12–15). Sur-
those of its close neighbors palladium and nickel, the prisingly, coupling was not observed when organic solvent
copper salts or complexes tolerate functional groups with soluble but air-sensitive copper(I) catalysts such as CuIBr-
sulfur, a facet that we demonstrate in the present work.
SMe2 (entry 15) or Cu(PPh3)3Br (entry 16) were employed.
Similarly, there was no reaction with air-stable copper(I)
complexes such as copper(I)-thiophene-2-carboxylate
(CuTC)[19] (entry 18) or CuI-3-methylsalicylate (CuMeSal)
Results and Discussion
[20]
(entry 19). Notably, there was no reaction when well-
For screening of catalysts and development of optimal
reaction conditions, the cross-coupling reaction of 4H-
chromene 6a with phenylboronic acid 11a to form the par-
ent 4-phenyl-4H-chromene 12a was selected (Scheme 2,
Table 1). The reactions were conducted at room temp. on a
0.4 mmol scale with catalyst and in solvents that have been
extensively employed previously for promoting Cu or Pd
known palladium(II) catalyst Pd(OAc)2 (entry 20) or palla-
dium(0) catalyst Pd2(dba)3 (entry 21) were employed. How-
ever, when two equivalents of the base Na2CO3[21] was pres-
ent in the reaction medium, Pd(OAc)2 or Pd2(dba)3 cata-
lyzed the reaction to provide the target cross-coupled prod-
uct in moderate yield (entries 22 and 23). No reaction was
observed when common nickel(0) catalysts such as Ni(cod)2
(entry 24) or Ni[P(OEt)3]4 (entry 25) were employed, poss-
ibly due to the presence of the sulfur functional group.
Based on the above experiments, we concluded that 10 mol-
% Cu(OAc)2 is the best catalyst for the preparation of a
series of 4-aryl-4H-chromenes 12.
Table 1. Optimization of reaction conditions for cross-coupling
using different catalysts.
We then screened solvents for optimization of the reac-
tion conditions (Table 2). Of the solvents investigated such
as dimethyl sulfoxide (DMSO; polar aprotic, entry 1), N,N-
dimethylformamide (DMF; polar aprotic, entry 2), aceto-
nitrile (polar aprotic, entry 6), EtOH (polar protic, entry 7),
and dioxane (nonpolar, entry 8), DMF worked well when
Entry
Catalyst
Time [h] mol-% Yield [%][a]
1
2
3
4
5
6
7
8
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(CF3COO)2·H2O
Cu(OTf)2
CuSO4·5H2O
CuCl2·2H2O
CuBr2
Cu(acac)2
CuO
CuBr
CuI
6
3
3
3
6
6
4
4
4
4
4
5
5
6
4
6
6
4
5
6
12
6
14
1
1
5
82
86
85
81
61
n.r.
51
n.r.
25
67
51
10
20
30
5
Table 2. Optimization of reaction conditions for cross-coupling
using different solvents.
5
10
10
10
10
10
10
10
10
10
10
10
10
10
5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
57
35
72
Entry Solvent
Ligand/Base
Atmosphere Time [h] Yield [%]
CuCl
Cu2O
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
48
1
2
3
4
5
6
7
8
DMSO
DMF
DMF
DMF
NMP
MeCN
EtOH
dioxane
DMF
DMF
DMF
DMF
–
–
–
–
–
–
–
–
N2
N2
Air
O2
N2
N2
N2
N2
N2
N2
N2
N2
4
3
4
4
6
4
4
4
4
4
4
3
26
86
62
24
15
nr
nr
16
34
46
72
78
CuIBrSMe2
Cu(PPh3)3Br
CuTC
CuMeSal
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2, Na2CO3 (2 equiv.)
Pd2(dba)3, Na2CO3 (2 equiv.)
Ni(cod)2
5
5
5
10
10
38
n.r.
n.r.
9
PPh3
10
11
12
phenanthroline
Na2CO3
K2CO3
Ni[P(OEt)3]4
[a] n.r.: no reaction.
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H. S. P. Rao, A. V. B. Rao
FULL PAPER
conducted under an atmosphere of nitrogen.[22] Reaction
under aerobic conditions (entry 3) or in an oxygen atmo-
sphere (entry 4) provided lower yields, indicating that the
reaction does not go through oxygen-mediated oxidation
for catalyst regeneration. The use of ligands such as PPh3
(entry 9) or phenanthroline (entry 10), which could complex
with reactive copper species, in fact led to a decrease in
yield. The inclusion of acid-scavenging bases such as
Na2CO3 (entry 11) or K2CO3 (entry 12) did not improve
the yield of the product. The reaction with Cu(OAc)2 in
DMF worked well at room temp. (25–30 °C); although it
was faster at elevated temperature (60 °C), the reaction pro-
vided a mixture of the cross-coupled product 12a (34%)
and the hydrolysis product 13 (28%) (Scheme 2).
The nature of leaving group in 4H-chromene 6 was evalu-
ated for its influence in the cross-coupling reaction
(Table 3). Of the three substrates 6a (R = Me, entry 1), 6b
(R = nBu, entry 2), and 6c (R = Ph, entry 3) studied, the
reaction worked best with C(4)SMe (6a), indicating that a
smaller (Me vs. nBu) electron-donating (Me vs. Ph) group
is better suited for the cross-coupling.
Scheme 3. Reaction of 4H-chromene 6a with PhMgBr under reac-
tion conditions for substitution.
standing of the reaction is sketchy owing to the occurrence
of multiple oxidation states of copper (0, +1, +2, +3) in the
reaction medium and weak C–Cu bond energy
(200Ϯ30 kJmol–1).[24] Additionally, reactive copper species
could occur in clusters with Cu–Cu bonds. Based on the
experimental results discussed above, a possible mechanism
of Cu(OAc)2-mediated cross-coupling of 4H-chromene 6a
with phenylboronic acid (11a) is depicted in Scheme 4. In
the first cycle, phenylboronic acid reacts with Cu(OAc)2 to
form a CuIPh species.[25] Newly generated CuIPh 14 reacts
with 6a to form transmetallated CuIII species 15. Cross-cou-
pling leads to generation of the product 12a and CuISMe.
Newly formed CuISMe reacts with 11a to generate PhCuIII
-
Table 3. Effect of different thio-ether leaving groups in cross-cou-
pling.
(SMe)B(OH)2 16. Decomposition of this CuIII intermediate
furnishes stable B(OH)2SMe and reactive CuIPh 14, which
enters into the catalytic cycle again. Although the Cu0–CuII
redox cycle could be invoked as the driving force for the
coupling process, we believe that in view of the high stan-
dard reduction potential[26] (+0.34 volts for Cu2+ to Cu0)
this is unlikely. To rule out involvement of Cu0 as the active
catalyst for the transformation, a Hg0-poisoning experiment
was carried out. As shown in Scheme 5, the inclusion of
a 30-fold excess of Hg0 did not exhibit any effect on the
reaction.[27] If Cu0 was generated in the reaction, it was
expected to become rapidly poisoned by Hg0 by amal-
gamation, thereby suppressing the catalytic cycle.[28]
Entry
Substrate
Time [h]
Yield [%]
1
2
3
6a: R = Me
6b: R = nBu
6c: R = Ph
3
4
14
86
76
41
Two experiments were conducted to evaluate the effect
of the sequence of addition of the two reactants, namely,
phenylboronic acid (11a) and 4H-chromene 6a. The yield
of the product 12a was higher in the former experiment
(86%) in which 11a was stirred with Cu(OAc)2 before the
addition of 6a. In an analogous experiment in which 6a was
stirred with Cu(OAc)2 before the addition of 11a, the yield
was less than half (37%). In the absence of Cu(OAc)2, for-
mation of 12a was not observed, even when the reaction
was conducted at elevated temperatures. These experiments
showed that the first step in the catalytic cycle is the reac-
tion of Cu(OAc)2 with 11a. To evaluate whether the trans-
formation of 6a into 12a proceeded through an SN1 or SN2
pathway, instead of going through cross-coupling, 6a was
treated with phenylmagnesium bromide in the presence of
a catalytic amount of CuI (Scheme 3) under classical CuI-
mediated substitution reaction conditions.[23] This reaction
Scheme 4. A plausible mechanism for Cu(OAc)2-catalyzed cross-
coupling of arylboronic acids with 4H-chromenes 6a.
The 4-phenyl-4H-chromene 12a was characterized by
provided 12a in only 8% yield, indicating that simple nu- spectral (IR, 1H NMR, 13C NMR and DEPT-135) and ana-
1
cleophilic substitution was not the major route for the lytical data. A singlet for C(4)H at δ = 5.3 ppm in the H
transformation.
NMR spectrum is a diagnostic signal for 4-phenyl-4H-
Although several reliable copper-mediated coupling reac- chromene 12a. To demonstrate the scope of the cross-cou-
tions have been well-documented, a mechanistic under- pling reaction, a range of arylboronic acids 11b–o were
4
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Copper-Catalyzed C(sp3)–C(sp2) Cross-Coupling
To demonstrate the possibilities of diversity in the aryl
ring of the 4H-chromene moiety, three C(4)-methanesulf-
anyl 4H-chromenes 6d–f were subjected to Cu(OAc)2-cata-
lyzed cross-coupling with 11a to realize 4-phenyl-4H-
chromenes 12p–r (Table 5). Similarly, possibilities of diver-
sity in nitrogen substitution was demonstrated by subjecting
4H-chromene with N-butyl substitution 6g to coupling with
11a to furnish the corresponding cross-coupled product 12s.
We then targeted cross-coupling of 6a with heteroaryl-
boronic acids because several such heterocyclic motifs are
important structural elements within bioactive molecules.
The Cu(OAc)2-mediated reaction of 6a with furan-2-
boronic acid smoothly provided 12t (Scheme 6). However,
no reaction was observed with pyridine-2-boronic acid at
room temp. On mild heating, the reaction provided dimeric
product 17 (24%) together with hydrolysis product 13
(31%) instead of the anticipated cross-coupled product
(Scheme 6). Likely, radical intermediates that are generated
from 6a dimerize to form 17. The reaction with thiophene-
2-boronic acid also did not yield the desired cross-coupled
product when the reaction was conducted at room temp. At
higher temperature (45 °C) both dimeric product 17 (15%)
and hydrolysis product 13 (37%) were isolated. Although it
is not clear, we presume that both pyridine-2-boronic acid
and thiophene-2-boronic acid are less reactive in copper-
Scheme 5. Cu-catalyzed cross-coupling in the presence of Hg0.
treated with 4H-chromene 6a under the optimized reaction
conditions to realize fourteen 4-aryl-4H-chromenes 12b–o
(Table 4). These arylboronic acids were selected with a view
to their structural diversity and their potential binding to
biological targets and thus for their potential as medicinally
important compounds. High efficiency of cross-coupling
was observed regardless of the presence of strongly elec-
tron-withdrawing [C(4)CF3 11b, C(3) and C(5)CF3 11c,
C(3) and C(5)F 11d], mildly electron-withdrawing [C(4)F
11e, C(4)Cl 11f, C(4)Br 11g, C(3)Cl 11h and C(3)OMe 11i],
strongly electron-donating [C(4)OMe 11j, C(4)OEt 11k and
C(4)OBn 11l] or mildly electron-donating [C(4)Et 11m]
nature of the substituents in arylboronic acids employed.
Notably, the cross-coupling reaction worked well even with
ortho-substituted boronic acids [C(2) and C(3)-OMe 11n
and C(2) and C(5)OMe 11o], indicating that the cross-cou-
pling is not highly sensitive to steric bulk on the aryl ring.
Table 4. Scope of Cu-catalyzed cross-coupling of arylboronic acids with 4H-chromene 6a.
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H. S. P. Rao, A. V. B. Rao
FULL PAPER
Table 5. Exploring the scope of diversity in 4H-chromenes for coupling with 11a.
Scheme 6. Cu(OAc)2-catalyzed cross-coupling reactions of 6a with heteroarylboronic acids.
mediated cross-coupling reactions owing to their ability to catalyst for the second Suzuki coupling step because when
act as Cu coordinating ligands and in the process do not Pd(OAc)2 or PdCl2 were employed 4H-chromene 18 was
allow efficient copper insertion into the aryl–boron bond.
Among four 4-methylsulfanyl-4H-chromenes 6d–g that
were subjected to cross-coupling with arylboronic acids,
4H-chromene 6e is the most interesting because of the
presence of C(6)Br. The molecule is open for sequential
coupling reactions with arylboronic acids first under
Cu(OAc)2 catalysis to substitute C(4)SMe, followed by Pd0
catalysis to substitute C(6)Br. The one-pot sequential sub-
stitution was demonstrated on 6e by initial coupling
with phenylboronic acid under Cu(OAc)2 catalysis, followed
by coupling with 4-methoxyphenylboronic acid under
[Pd2(dba)3] catalysis to provide bis-aryl-4H-chromene 18 in
good yield (Scheme 7). Heating the reaction mixture to at
least 60 °C was required to induce the second step to take
place. 4-Methoxyphenylboronic acid was employed in the
isolated in low yield of 11 or 13%, respectively.
Conclusion
We have shown that Cu(OAc)2 efficiently catalyzes cross-
coupling of N-methyl-4-(methylthio)-3-nitro-4H-chromen-
2-amines 6 with arylboronic acids 11 in DMF under anaer-
obic conditions to provide N-methyl-3-nitro-4-aryl-4H-
chromen-2-amines 12. A combinatorial library of 4-aryl-
4H-chromenes could be synthesized by varying the substi-
tution in the arylboronic acid, aryl ring of the chromone,
and C(2)-amino group. The cross coupling works well with
furan-2-boronic acid but not with less reactive thiophene-
2-boronic acid or pyridine-2-boronic acid. Sequential one-
pot Cu(OAc)2 coupling followed by Suzuki coupling could
be achieved on 4H-chromene 6e. Thus, we have demon-
strated the first example of a copper-catalyzed coupling re-
action on a substrate having a SMe functional group on a
carbon with sp3 hybridization.
1
second step to follow the reaction by using H NMR spec-
troscopy. The [Pd2(dba)3] appeared to be a more suitable
Experimental Section
General Experimental Methods: Progress of all the reactions was
monitored by TLC using hexanes (60–80 °C boiling mixture)/ethyl
acetate mixture as eluent. Column chromatography was performed
on silica gel (100–200 mesh SRL Chemicals) using increasing per-
Scheme 7. Sequential Cu(OAc)2- and Pd-catalyzed cross-coupling
reactions of 6c with arylboronic acids.
6
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Copper-Catalyzed C(sp3)–C(sp2) Cross-Coupling
1
centage of ethyl acetate in hexanes. H NMR spectra (400 MHz),
(t, J = 7.8 Hz, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 5.46 (s, 1 H), 3.20
13C NMR (100 MHz) and DEPT-135 spectra were recorded for (d, J = 5.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2
CDCl3 or [D6]DMSO solutions with a Bruker Avance 400 spec- (C), 147.6 (C), 146.2 (C), 131.8 (q, J = 66.1 Hz, C), 129.8 (CH),
trometer with TMS as internal standard. Coupling constants J are
given in Hz. IR spectra were recorded as KBr pellets with a Nico-
let-6700 FTIR spectrometer. Melting points were recorded using
open-ended capillary tubes with a VEEGO VMP-DS instrument
and are uncorrected. High-resolution mass spectra were recorded
with a Micromass Q-TOF micro mass spectrometer using electro-
spray ionization mode. X-ray diffraction measurements were car-
ried out at 298 K with an Oxford CrysAlis CCD area detector sys-
tem equipped with a graphite monochromator and a Mo-Kα fine-
focus sealed tube (λ = 0.71073 Å). Organic solvents were dried by
standard methods. Commercially obtained reagents were used after
purification. Arylboronic acid were purchased from Sigma-Aldrich
and copper salts from MERCK and were used as received. The
catalyst [Pd2(dba)3] and the starting compounds N-methyl-4-(meth-
ylthio)-3-nitro-4H-chromen-2-amines were prepared according to
reported procedures.[29]
129.2 (CH), 128.2 (CH), 126.5 (CH), 124.6 (C), 123.0 (C), 121.9
(C), 121.2 (t, J = 3.7 Hz, CH), 116.7 (CH), 107.9 (C), 41.9 (CH),
28.1 (CH3) ppm. HRMS (ESI): m/z calcd. for C18H12F6N2O3Na
[M + Na] 441.0650; found 441.0655.
4-(3,5-Difluorophenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12d):
Yield 108 mg (85%); light-yellow crystals; m.p. 228 °C. IR (KBr):
ν = 3174, 3092, 2925, 2859, 1642, 1463, 1363, 1216, 1160, 1114,
˜
1058, 992, 908, 848, 774, 696, 660 cm–1. 1H NMR (400 MHz, [D6]-
DMSO): δ = 10.34 (br. s, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.21–7.19
(m, 1 H), 7.13–7.09 (m, 1 H), 6.89–6.85 (m, 2 H), 6.76–6.71 (m, 1
H), 5.40 (s, 1 H), 3.22 (d, J = 5.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 163.7 (d, J = 12 Hz, C), 161.2 (d, J =
13 Hz, C), 158.5 (C), 148.6 (t, J = 8 Hz, C), 147.1 (C), 129.2 (CH),
128.4 (CH), 125.5 (CH), 123.5 (C), 116.2 (CH), 110.2 (q, J = 18 Hz,
CH), 106.7 (C), 101.9 (t, J = 25 Hz, CH), 41.0 (CH), 27.9
(CH3) ppm. HRMS (ESI): m/z calcd. for C16H12F2N2O3Na [M +
Na] 341.0714; found 341.0717.
Synthesis of 4-Aryl-2-alkylamino-3-nitro-4H-chromenes. General
Procedure:
A solution of arylboronic acid 11 (0.48 mmol,
4-(4-Fluorophenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12e):
1.2 equiv.) and Cu(OAc)2·H2O (0.1 equiv.) in anhydrous DMF
(0.3 mL) in an atmosphere of nitrogen was stirred for 10 min, by
which time copper salt dissolved and the reaction mixture became
light-green. To this, 4H-chromen 6 (0.4 mmol, 1 equiv.) in anhy-
drous DMF (0.2 mL) was added and the mixture was stirred at
room temp. until TLC showed the disappearance of 4H-chromene.
The reaction mixture was then diluted with ice-cold water (10 mL)
and the organic layer was extracted with CH2Cl2 (2ϫ 20 mL). The
organic layer was washed with water (2ϫ 20 mL), brine (1ϫ
10 mL) and CH2Cl2 was removed under reduced pressure. The
crude product was subjected to column chromatography (silica gel;
gradient elution with increasing volume of EtOAc in hexanes) to
give 4-aryl-2-alkylamino-3-nitro-4H-chromenes 12. An analytical
sample was obtained by recrystallization from a 9:1 mixture of hex-
anes and EtOAc.
Yield 106 mg (89%); white plates; m.p. 169 °C. IR (KBr): ν = 1642,
˜
1
1609, 1506, 1473, 1401, 1367, 1215, 1170, 1065, 828, 760 cm–1. H
NMR (400 MHz, CDCl3): δ = 10.35 (br. s, 1 H), 7.18–7.04 (m, 6
H), 6.86–6.81 (m, 2 H), 5.33 (s, 1 H), 3.17 (d, J = 5.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 162.9 (C), 160.4 (C), 159.3 (C),
147.9 (C), 139.4 (C), 129.6 (CH), 129.3 (d, J = 8 Hz, CH), 128.3
(CH), 126.0 (CH), 124.8 (C), 116.1 (CH), 115.3 (d, J = 21 Hz, CH),
108.9 (C), 41.0 (CH), 27.9 (CH3) ppm. HRMS (ESI): m/z calcd. for
C16H13FN2O3Na [M + Na] 323.0808; found 323.0809.
4-(4-Chlorophenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12f):
Yield 67.7 mg (69%); white solid; m.p. 162 °C. IR (KBr): ν = 3174,
˜
2925, 1650, 1605, 1462, 1372, 1213, 1172, 1066, 816, 763, 706 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.42 (br. s, 1 H), 7.27–7.09 (m,
8 H), 5.39 (s, 1 H), 3.25 (d, J = 5.6 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.4 (C), 147.6 (C), 142.2 (C), 132.7 (C),
129.7 (CH), 129.2 (CH), 128.7 (CH), 128.5 (CH), 126.1 (CH), 124.5
(C), 116.3 (CH), 108.7 (C), 41.3 (CH), 28.0 (CH3) ppm. HRMS
(ESI): m/z calcd. for C16H13ClN2O3Na [M + Na] 339.0512; found
339.0514.
N-Methyl-3-nitro-4-phenyl-4H-chromen-2-amine (12a): Yield 96 mg
(86%); white solid; m.p. 183 °C. IR (KBr): ν = 1642, 1607, 1467,
˜
1
1401, 1369, 1209, 1168, 1065, 754, 698 cm–1. H NMR (400 MHz,
CDCl3): δ = 10.33 (br. s, 1 H), 7.14–6.98 (m, 9 H), 5.31 (s, 1 H),
3.11 (d, J = 5.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
159.5 (C), 147.6 (C), 143.7 (C), 129.7 (CH), 128.5 (CH), 128.2
(CH), 127.7 (CH), 126.9 (CH), 125.9 (CH), 125.0 (C), 116.1 (CH),
109.0 (C), 41.8 (CH), 27.9 (CH3) ppm. HRMS (ESI): m/z calcd. for
C16H14N2O3Na [M + Na] 305.0902; found 305.0900.
4-(4-Bromophenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12g):
Yield 107 mg (74%); white solid; m.p. 209 °C. IR (KBr): ν = 1644,
˜
1612, 1487, 1474, 1459, 1435, 1403, 1367, 1253, 1238, 1211, 1170,
1066, 756 cm–1. 1H NMR (400 MHz, CDCl3): δ = 10.32 (br. s, 1
H), 7.27 (d, J = 8.3 Hz, 2 H), 7.17–7.15 (m, 1 H), 7.09–7.03 (m, 5
H), 5.29 (s, 1 H), 3.16 (d, J = 5.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.4 (C), 147.6 (C), 142.8 (C), 131.6 (CH),
129.7 (CH), 129.6 (CH), 128.5 (CH), 126.1 (CH), 124.4 (C), 120.9
(C), 116.3 (CH), 108.7 (C), 41.4 (CH), 28.0 (CH3) ppm. HRMS
(ESI): m/z calcd. for C16H13BrN2O3Na [M + Na] 383.0007; found
383.0010.
N-Methyl-3-nitro-4-[4-(trifluoromethyl)phenyl]-4H-chromen-2-
amine (12b): Yield 101 mg (79 %); white solid; m.p. 219 °C. IR
(KBr): ν = 3202, 1644, 1470, 1363, 1248, 1213, 1163, 1117, 1062,
˜
1
826, 757, 416 cm–1. H NMR (400 MHz, CDCl3): δ = 10.34 (br. s,
1 H), 7.41 (d, J = 8.1 Hz, 2 H), 7.28 (d, J = 8.0 Hz, 2 H), 7.20–
7.16 (m, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 7.04–7.03 (m, 2 H), 5.38
(s, 1 H), 3.16 (d, J = 5.3 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.4 (C), 147.6 (C), 129.7 (CH), 129.3 (C), 129.0 (C),
128.7 (CH), 128.2 (CH), 126.2 (CH), 125.6 (q, J = 7.3 Hz, CH),
124.0 (C), 122.8 (C), 116.4 (CH), 108.4 (C), 41.8 (CH), 28.0
(CH3) ppm. HRMS (ESI): m/z calcd. for C17H13N2O3F3Na [M +
Na] 373.0776; found 373.0779.
4-(3-Chlorophenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12h):
Yield 108 mg (86%); white solid; m.p. 194 °C. IR (KBr): ν = 1639,
˜
1608, 1472, 1429, 1403, 1354, 1211, 1235, 1168, 1112, 1036, 769,
1
723, 690, 665 cm–1. H NMR (400 MHz, CDCl3): δ = 10.34 (br. s,
1 H), 7.20–7.02 (m, 8 H), 5.31 (s, 1 H), 3.18 (d, J = 5.2 Hz, 3
4-[3,5-Bis(trifluoromethyl)phenyl]-N-methyl-3-nitro-4H-chromen-2-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.4 (C), 147.6 (C),
amine (12c): Yield 136 mg (82 %); white solid; m.p. 191 °C. IR 145.6 (C), 134.4 (C), 129.8 (CH), 129.7 (CH), 128.6 (CH), 127.8
(KBr): ν = 1645, 1613, 1476, 1404, 1370, 1279, 1213, 1168, 1132, (CH), 127.2 (CH), 126.2 (CH), 126.1 (CH), 124.3 (C), 116.3 (CH),
˜
1069, 761cm–1. 1H NMR (400 MHz, CDCl3): δ = 10.32 (br. s, 1
H), 7.59 (s, 3 H), 7.24–7.20 (m, 1 H), 7.14 (t, J = 7.3 Hz, 1 H), 7.06
108.5 (C), 41.7 (CH), 28.0 (CH3) ppm. HRMS (ESI): m/z calcd. for
C16H13ClN2O3Na [M + Na] 339.0512; found 339.0512.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42003
/KAP1
Date: 23-04-14 17:46:05
Pages: 11
H. S. P. Rao, A. V. B. Rao
FULL PAPER
4-(3-Methoxyphenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12i):
(d, J = 8.1 Hz, 1 H), 7.05 (td, J = 7.5, 1.2 Hz, 1 H), 6.93 (t, J =
7.8 Hz, 1 H), 6.86 (dd, J = 7.8, 1.6 Hz, 1 H), 6.74 (dd, J = 8.0,
1.6 Hz, 1 H), 3.79 (s, 3 H), 3.70 (s, 3 H), 3.25 (d, J = 5.2 Hz, 3
Yield 106 mg (86%); white solid; m.p. 177 °C. IR (KBr): ν = 3176,
˜
2944, 1645, 1609, 1489, 1457, 1403, 1364, 1277, 1255, 1209, 1144,
1
1067, 1047, 778, 754, 698 cm–1. H NMR (400 MHz, CDCl3): δ = H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.0 (C), 153.0 (C),
10.43 (br. s, 1 H), 7.26–7.07 (m, 5 H), 6.84–6.81 (m, 2 H), 6.71–
6.68 (m, 1 H), 5.39 (s, 1 H), 3.74 (s, 3 H), 3.22 (d, J = 5.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.7 (C), 159.5 (C),
147.6 (C), 145.3 (C), 129.6 (CH), 129.5 (CH), 128.2 (CH), 125.9
147.4 (C), 146.5 (C), 137.2 (C), 129.8 (CH), 127.9 (CH), 125.7
(CH), 124.8 (C), 123.8 (CH), 121.3 (CH), 115.8 (CH), 111.3 (CH),
108.4 (C), 60.2 (CH3), 55.7 (CH3), 37.7 (CH), 27.9 (CH3) ppm.
HRMS (ESI): m/z calcd. for C18H18N2O5Na [M + Na] 365.1113;
(CH), 124.9 (C), 120.1 (CH), 116.1 (CH), 114.1 (CH), 111.7 (CH), found 365.1110.
108.9 (C), 55.2 (CH3), 41.8 (CH), 27.9 (CH3) ppm. HRMS (ESI):
4-(2,3-Dimethoxyphenyl)-N-methyl-3-nitro-4H-chromen-2-amine
m/z calcd. for C17H16N2O4Na [M + Na] 335.1008; found 335.1009.
(12o): Yield 98 mg (72%); white solid; m.p. 206 °C. IR (KBr): ν =
˜
4-(4-Methoxyphenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12j):
1648, 1608, 1500, 1457, 1402, 1374, 1245, 1220, 1175, 1057, 1025,
Yield 96 mg (78%); white solid; m.p. 146 °C. IR (KBr): ν = 1645,
763 cm–1. 1H NMR (400 MHz, CDCl3): δ = 10.55 (br. s, 1 H), 7.18–
˜
1509, 1466, 1367, 1249, 1170, 1066, 823, 757 cm–1 1H NMR 7.17 (m, 1 H), 7.10–7.08 (m, 1 H), 7.02–6.95 (m, 2 H), 6.80 (d, J
.
(400 MHz, CDCl3): δ = 10.37 (br. s, 1 H), 7.18–7.03 (m, 6 H), 6.70–
6.68 (m, 2 H), 5.30 (s, 1 H), 3.65 (s, 3 H), 3.16 (d, J = 5.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.6 (C), 158.5 (C),
147.7 (C), 136.0 (C), 129.8 (CH), 128.8 (CH), 128.1 (CH), 126.0
(CH), 125.5 (C), 116.1 (CH), 113.9 (CH), 109.3 (C), 55.3 (CH3),
= 3.0 Hz, 1 H), 6.64 (d, J = 8.8 Hz, 1 H), 6.61–6.58 (m, 1 H), 5.51
(s, 1 H), 3.66 (s, 3 H), 3.58 (s, 3 H), 3.17 (d, J = 5.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 160.2 (C), 153.7 (C), 151.4 (C),
147.8 (C), 133.0 (C), 129.4 (CH), 127.9 (CH), 125.5 (CH), 124.5
(C), 116.3 (CH), 115.6 (CH), 113.0 (CH), 112.2 (CH), 108.1 (C),
41.0 (CH), 28.0 (CH3) ppm. HRMS (ESI): m/z calcd. for 56.5 (CH3), 55.7 (CH3), 38.0 (CH), 27.9 (CH3) ppm. HRMS (ESI):
C17H16N2O4Na [M + Na] 335.1008; found 335.1017.
m/z calcd. for C18H18N2O5Na [M + Na] 365.1113; found 365.1111.
4-(4-Ethoxyphenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12k):
6-Ethyl-N-methyl-3-nitro-4-phenyl-4H-chromen-2-amine (12p):
Yield 103 mg (79%); white solid; m.p. 174 °C. IR (KBr): ν = 1639, Yield 96 mg (78%); light-yellow solid; m.p. 198 °C. IR (KBr): ν =
˜
˜
1610, 1513, 1477, 1456, 1436, 1398, 1357, 1245, 1208, 1173, 1116,
3176, 3047, 2954, 1640, 1474, 1399, 1353, 1211, 1169, 1061, 827,
1
1
1061, 827, 800, 753 cm–1. H NMR (400 MHz, CDCl3): δ = 10.36 776, 702, 634 cm–1. H NMR (400 MHz, CDCl3): δ = 10.36 (br. s,
(br. s, 1 H), 7.18–7.13 (m, 1 H), 7.10–7.02 (m, 5 H), 6.68 (d, J =
6.8 Hz, 2 H), 5.29 (s, 1 H), 3.89–3.84 (m, 2 H), 3.15 (d, J = 5.2 Hz,
3 H), 1.27 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.6 (C), 157.9 (C), 147.7 (C), 135.8 (C), 129.8 (CH), 128.8
1 H), 7.18–6.89 (m, 8 H), 5.31 (s, 1 H), 3.12 (d, J = 5.2 Hz, 3 H),
2.45 (m, 2 H), 1.06 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.7 (C), 145.8 (C), 143.7 (C), 142.0 (C), 128.6 (CH),
128.4 (CH), 127.7 (CH), 127.6 (CH), 126.8 (CH), 124.7 (C), 115.9
(CH), 128.1 (CH), 126.0 (CH), 125.5 (C), 116.1 (CH), 114.5 (CH), (CH), 109.2 (C), 41.9 (CH), 28.1 (CH2), 27.8 (CH3), 15.4
109.4 (C), 63.4 (CH2), 41.0 (CH), 28.0 (CH3), 14.9 (CH3) ppm. (CH3) ppm. HRMS (ESI): m/z calcd. for C18H18N2O3Na [M + Na]
HRMS (ESI): m/z calcd. for C18H18N2O4Na [M + Na] 349.1164; 333.1215; found 333.1210.
found 349.1161.
6-Bromo-N-methyl-3-nitro-4-phenyl-4H-chromen-2-amine (12q):
4-[4-(Benzyloxy)phenyl]-N-methyl-3-nitro-4H-chromen-2-amine
Yield 116 mg (81%); white solid; m.p. 232 °C. IR (KBr): ν = 3054,
˜
(12l): Yield 126 mg (82%); white solid; m.p. 214 °C. IR (KBr): ν =
3025, 2879, 1637, 1602, 1461, 1399, 1360, 1252, 1212, 1161, 1063,
1017, 920, 824, 740, 699 cm–1. 1H NMR (400 MHz, CDCl3): δ =
10.35 (br. s, 1 H), 7.36–7.33 (m, 1 H), 7.29–7.18 (m, 6 H), 7.05 (d,
˜
3446, 1759, 1642, 1608, 1508, 1474, 1457, 1401, 1358, 1237, 1214,
1168, 1135, 1112, 1056, 767, 743, 695 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 10.36 (br. s, 1 H), 7.29–7.21 (m, 4 H), 7.17–7.13 (m, 1 J = 8.4 Hz, 1 H), 5.36 (s, 1 H), 3.23 (d, J = 5.2 Hz, 3 H) ppm. 13C
H), 7.10–7.09 (m, 1 H), 7.08–7.03 (m, 5 H), 6.76 (d, J = 6.8 Hz, 2 NMR (100 MHz, CDCl3): δ = 159.2 (C), 146.8 (C), 143.0 (C), 132.5
H), 5.30 (s, 1 H), 4.90 (s, 2 H), 3.15 (d, J = 5.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.6 (C), 157.8 (C), 147.7 (C), 137.1
(CH), 131.4 (CH), 128.8 (CH), 127.8 (CH), 127.4 (CH), 127.3 (C),
118.6 (CH), 118.0 (C), 108.6 (C), 41.8 (CH), 28.0 (CH3) ppm.
(C), 136.2 (C), 129.8 (CH), 128.9 (CH), 128.6 (CH), 128.2 (CH), HRMS (ESI): m/z calcd. for C16H14BrN2O3Na [M + Na] 383.0007;
128.0 (CH), 127.5 (CH), 126.1 (CH), 125.5 (C), 116.1 (CH), 114.9
(CH), 109.4 (C), 70.1 (CH2), 41.0 (CH), 28.0 (CH3) ppm. HRMS
(ESI): m/z calcd. for C23H20N2O4Na [M + Na] 411.1324; found
411.1315.
found 383.0006.
6-Chloro-N-methyl-3-nitro-4-phenyl-4H-chromen-2-amine (12r):
Yield 93 mg (73%); white solid; m.p. 218 °C. IR (KBr): ν = 2945,
˜
2193, 1641, 1606, 1471, 1362, 1254, 1219, 1169, 1061, 1018, 916,
816, 768, 741, 703 cm–1. 1H NMR (400 MHz, CDCl3): δ = 10.39
(br. s, 1 H), 7.27–7.10 (m, 8 H), 5.37 (s, 1 H), 3.25 (d, J = 5.2 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2 (C), 146.2 (C),
143.0 (C), 131.1 (C), 129.5 (CH), 128.8 (CH), 128.5 (CH), 127.8
(CH), 127.4 (CH), 126.9 (C), 117.7 (CH), 108.6 (C), 41.9 (CH),
4-(4-Ethylphenyl)-N-methyl-3-nitro-4H-chromen-2-amine (12m):
Yield 109 mg (88%); white solid; m.p. 169 °C. IR (KBr): ν = 1646,
˜
1610, 1463, 1401, 1372, 1212, 1169, 1067, 828, 753, 698 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 10.31 (br. s, 1 H), 7.14–7.04 (m, 5
H), 6.97–6.95 (m, 3 H), 5.29 (s, 1 H), 3.07 (d, J = 5.2 Hz, 3 H),
2.48–2.42 (m, 2 H), 1.06 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR 28.1 (CH3) ppm. HRMS (ESI): m/z calcd. for C16H14ClN2O3 [M +
(100 MHz, CDCl3): δ = 159.5 (C), 147.6 (C), 142.7 (C), 140.9 (C),
129.6 (CH), 128.0 (CH), 127.9 (CH), 127.6 (CH), 125.9 (CH), 125.3
(C), 116.0 (CH), 109.1 (C), 41.4 (CH), 28.3 (CH2), 27.8 (CH3), 15.4
(CH3) ppm. HRMS (ESI): m/z calcd. for C18H18N2O3Na [M + Na]
333.1215; found 333.1218.
H] 317.0693; found 317.0688.
N-Butyl-3-nitro-4-phenyl-4H-chromen-2-amine (12s): Yield 98 mg
(76%); white solid; m.p. 137 °C. IR (KBr): ν = 3047, 2963, 2933,
˜
1638, 1604, 1445, 1360, 1310, 1259, 1236, 1174, 1065, 778, 752,
699 cm–1. 1H NMR (400 MHz, CDCl3): δ = 10.54 (br. s, 1 H), 7.25–
7.21 (m, 5 H), 7.18–7.10 (m, 4 H), 5.43 (s, 1 H), 3.67–3.60 (m, 2
H), 1.76–1.67 (m, 2 H), 1.52–143 (m, 2 H), 1.0 (t, J = 7.3 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.1 (C), 147.7 (C),
143.7 (C), 129.8 (CH), 128.6 (CH), 128.2 (CH), 127.7 (CH), 127.0
(CH), 126.0 (CH), 125.3 (C), 116.1 (CH), 108.9 (C), 41.9 (CH),
4-(2,5-Dimethoxyphenyl)-N-methyl-3-nitro-4H-chromen-2-amine
(12n): Yield 113 mg (83%); white solid; m.p. 222 °C. IR (KBr): ν
˜
= 3202, 2934, 2831, 1639, 1609, 1475, 1394, 1357, 1250, 1215, 1177,
1
1062, 1004, 756 cm–1. H NMR (400 MHz, CDCl3): δ = 10.62 (br.
s, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.29 (d, J = 6.9 Hz, 1 H), 7.10
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42003
/KAP1
Date: 23-04-14 17:46:05
Pages: 11
Copper-Catalyzed C(sp3)–C(sp2) Cross-Coupling
41.3 (CH2), 31.8 (CH2), 20.0 (CH2), 13.7 (CH3) ppm. HRMS (ESI): give 4H-chromenes 18. An analytical sample was obtained by
m/z calcd. for C19H21N2O3 [M + H] 325.1552; found 325.1548.
recrystallization from 9:1 mixture of hexanes and CH2Cl2 to give
a white solid, yield 124 mg (78%); m.p. 197 °C. IR (KBr): ν = 3059,
˜
4-(Furan-2-yl)-N-methyl-3-nitro-4H-chromen-2-amine (12t): Yield
3029, 2938, 2836, 1640, 1604, 1472, 1402, 1367, 1244, 1174, 1119,
1067, 821, 755, 725, 697 cm–1. 1H NMR (400 MHz, CDCl3): δ =
10.44 (br. s, 1 H), 7.42–7.37 (m, 3 H), 7.31–7.15 (m, 7 H), 6.92 (d,
J = 8.2 Hz, 2 H), 5.48 (s, 1 H), 3.82 (s, 3 H), 3.27 (d, J = 5.2 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.7 (C), 159.5 (C),
146.9 (C), 143.7 (C), 139.0 (C), 132.2 (C), 128.7 (CH), 128.1 (CH),
127.87 (CH), 127.83 (CH), 127.1 (CH), 126.6 (CH), 125.5 (C),
116.5 (CH), 114.4 (CH), 109.2 (C), 55.5 (CH3), 42.1 (CH), 28.0
(CH3) ppm. HRMS (ESI): m/z calcd. for C23H20N2O4Na [M + Na]
411.1321; found 411.1320.
82 mg (76%); m.p. 162 °C. IR (KBr): ν = 3200, 2946, 1734, 1643,
˜
1609, 1475, 1403, 1365, 1246, 1215, 1175, 1144, 1067, 929,
1
755 cm–1. H NMR (400 MHz, CDCl3): δ = 10.41 (br. s, 1 H), 7–
32–7.25 (m, 2 H), 7.20–7.13 (m, 3 H), 6.22–6.21 (m, 1 H), 6.18 (d,
J = 3.2 Hz, 1 H), 5.60 (s, 1 H), 3.24 (d, J = 5.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.9 (C), 154.1 (C), 148.1 (C), 141.9
(CH), 129.5 (CH), 128.7 (CH), 125.9 (CH), 122.4 (C), 116.2 (CH),
110.4 (CH), 106.2 (C), 106.0 (CH), 35.7 (CH), 28.0 (CH3) ppm.
HRMS (ESI): m/z calcd. for C14H12N2O4Na [M + Na] 295.0695;
found 295.0697.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra, HRMS data for the com-
pounds 12a–t and 18, and the ORTEP plot of the X-ray structure
of 12d along with crystal data.
Experimental Procedure for Hg0 Poisoning Experiment: A solution
of phenylboronic acid 11b (0.48 mmol, 1.2 equiv.) and Cu-
(OAc)2·H2O (0.1 equiv.) in anhydrous DMF (0.3 mL) under an at-
mosphere of nitrogen was stirred for 10 min, by which time copper
salt dissolved and the reaction mixture became light-green. To this
solution N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine 6a
(0.4 mmol, 1 equiv.) in anhydrous DMF (0.2 mL) and Hg0
(12 mmol, 30 equiv.) was added and the mixture was stirred at
room temp. until TLC showed the consumption of 4H-chromene
(3 h). The reaction mixture was then diluted with ice-cold water
(10 mL) and the organic layer was extracted with CH2Cl2 (2ϫ
20 mL). The organic layer was washed with water (2ϫ 20 mL) and
brine (10 mL) and CH2Cl2 was removed under reduced pressure.
The crude product was subjected to column chromatography (silica
gel; gradient elution with increasing volume of EtOAc in hexanes)
to yield N-methyl-3-nitro-4-phenyl-4H-chromen-2-amine (12a)
(101 mg, 82%) as a white solid.
Acknowledgments
H. S. P. R thanks the University Grants Commission (UGC), New
Delhi, the University Grants Commission – Special Assistance Pro-
gram (UGC-SAP), the Council of Scientific and Industrial Re-
search (CSIR), New Delhi and the Department of Science and
Technology – Fund for Improvement of Science and Technology
Infrastructure (DST-FIST) for financial assistance. A. V. R thanks
CSIR for a fellowship. The authors thank the Central Instrumen-
tation Facility (CIF), Pondicherry University, and the Indian Insti-
tute of Science (IISc), Banglore for recording spectra.
[1] J. Poupaert, P. Carato, E. Colacino, Curr. Med. Chem. 2005,
12, 877–885.
[2] a) Q. Ren, W.-Y. Du, Z. Siau, K. Zhang, J. Wang, Chem. Eur.
J. 2011, 17, 7781–7785; b) G. W. Bemis, M. A. Murcko, J. Med.
Chem. 1996, 39, 2887–2893.
[3] L. A. Thompson, Curr. Opin. Chem. Biol. 2000, 4, 324–337.
[4] a) B. W. Fravel, Comprehensive Heterocyclic Chemistry III 2008,
7, 701–726; b) G. R. Green, J. M. Evans, A. K. Vong, Compre-
hensive Heterocyclic Chem. II 1995, 5, 469–500; c) J. D. Hep-
worth, Comprehensive Heterocyclic Chem. I 1984, 2, 737–883.
[5] a) I. M. Lockhart, in: Chromenes, Chromanones and Chromones
(Ed.: Ellis G. P.), John Wiley & Sons, London, 1977, p. 207–
428; b) The Flavanoids: Advances in Research (Ed.: J. B. Har-
borne), Chapman and Hall, London, 1994.
3-Nitro-2H-chromen-2-one (13): A stirred solution of phenylboronic
acid (0.48 mmol, 1.2 equiv.) and Cu(OAc)2·H2O (0.1 equiv.) in an-
hydrous DMF (0.3 mL) was stirred under an atmosphere of nitro-
gen for 10 min, by which time copper salt dissolved and reaction
mixture became light-green. To this solution, N-methyl-4-(meth-
ylthio)-3-nitro-4H-chromen-2-amine (0.4 mmol, 1 equiv.) in anhy-
drous DMF (0.2 mL) was added and the reaction mixture was
heated at 60 °C until TLC showed the consumption of 4H-
chromene (2 h). The reaction mixture was then diluted with ice-
cold water (10 mL) and the organic layer extracted with CH2Cl2
(2ϫ 20 mL). The organic layer was washed with water (2ϫ 20 mL)
and brine (10 mL), and CH2Cl2 was removed under reduced pres-
sure. The crude product was subjected to column chromatography
(silica gel; gradient elution with increasing volume of EtOAc in
hexanes) to yield 13 (21 mg, 28%).
[6] a) N. M. Sabry, H. M. Mohamed, E. S. A. E. H. Khattab, S. S.
Motlaq, A. M. El-Agrody, Eur. J. Med. Chem. 2011, 46, 765–
772, and references cited therein.
[7] a) C. Bruhlmann, F. Ooms, P. Carrupt, B. Testa, M. Catto, F.
Leonetti, C. Altomare, A. Cartti, J. Med. Chem. 2001, 44,
3195–3198; b) S. R. Kesten, T. G. Heffner, S. J. Johnson, T. A.
Pugsley, J. L. Wright, D. L. Wise, J. Med. Chem. 1999, 42,
3718–3725.
[8] J. L. Wang, D. Liu, Z. Zhang, S. Shan, X. Han, S. M. Srinivas-
ula, C. M. Croce, E. S. Alnemri, Z. Huang, Proc. Natl. Acad.
Sci. USA 2000, 97, 7124–7129.
[9] a) M. Mahdavi, J. Davoodi, M. R. Zali, A. Foroumadi, Bio-
med. Pharmacother. 2011, 65, 175–182; b) W. Kemnitzer, J.
Drewe, S. Jiang, H. Zhang, C. Crogan-Grundy, D. Labreque,
M. Bubenick, G. Attardo, R. Denis, S. Lamothe, H. Gourdeau,
B. Tseng, S. Kasibhatla, S. X. Cai, J. Med. Chem. 2008, 51,
417–423; c) S. X. Cai, Recent Pat. Anti-Cancer Drug Discovery
2007, 2, 79–101; d) W. Kemnitzer, J. Drewe, S. Jiang, H. Zhang,
C. Crogan-Grundy, D. Labreque, M. Bubenick, G. Attardo, R.
Denis, S. Lamothe, H. Gourdeau, B. Tseng, S. Kasibhatla,
S. X. Cai, J. Med. Chem. 2008, 51, 417–423; e) H. Aryapour,
G. Riazi, S. Ahmadian, A. Foroumadi, M. Mahdavi, S. Em-
6-(4-Methoxyphenyl)-N-methyl-3-nitro-4-phenyl-4H-chromen-2-
amine (18): A solution of phenylboronic acid 11 (0.48 mmol
1.2 equiv.) and Cu(OAc)2·H2O (0.1 equiv.) in anhydrous DMF
(0.3 mL) was stirred under an atmosphere of nitrogen for 10 min
by which time copper salt dissolved and reaction mixture became
light-green. To this solution, 4H-chromen 6c (0.4 mmol, 1 equiv.)
in anhydrous DMF (0.2 mL) was added and the mixture was stirred
at room temp. until TLC showed the consumption of 4H-
chromene. To the mixture, [Pd2(dba)3] (2 mol-%), NaHCO3
(0.8 mmol, 2 equiv.), and 4-methoxyphenylboronic acid (0.4 mmol,
1 equiv.) were added and the mixture was heated at 60 °C for 3 h.
The reaction mixture was then diluted with ice-cold water (10 mL)
and the organic layer was extracted with CH2Cl2 (2ϫ 20 mL). The
organic layer was washed with water (2 ϫ 20 mL) and brine
(10 mL) and CH2Cl2 was removed under reduced pressure. The
crude product was subjected column chromatography (silica gel;
gradient elution with increasing volume of EtOAc in hexanes) to
Eur. J. Org. Chem. 0000, 0–0
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Date: 23-04-14 17:46:05
Pages: 11
H. S. P. Rao, A. V. B. Rao
FULL PAPER
ami, Pharm. Biol. 2012, 50, 1551–1560; f) J. Drewe, S. X. Cai, [17] P. I. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248,
Expert Opin. Drug Discovery 2010, 5, 583–596.
2337–2364.
[18] B. H. Lipshutz, in: Organometallics in Synthesis: A Manual
(Ed.: M. Schlosser), 2nd ed., John Wiley & Sons, West Sussex,
2002, p. 665–816.
[10]
a) A. L. Albiston, S. Diwakarla, R. N. Fernando, S. J. Mount-
ford, H. R. Yeatman, B. Morgan, V. Pham, J. H. Holien, M. W.
Parker, P. E. Thompson, S. Y. Chai, J. Pharmacol. 2011, 164,
37–47; b) A. L. Albiston, C. J. Morton, H. L. Ng, V. Pham,
H. R. Yeatman, S. Ye, R. N. Fernando, D. De Bundel, D. B.
Ascher, F. A. Mendelsohn, M. W. Parker, S. Y. Chai, FASEB J.
2008, 22, 4209–4217.
[19] H. Prokopcová, C. O. Kappe, J. Org. Chem. 2007, 72, 4440–
4448.
[20] C. Savarin, J. Srogl, L. S. Liebeskind, Org. Lett. 2001, 3, 91–
93.
[21] L. Liu, Y. Zhang, Y. Wang, J. Org. Chem. 2005, 70, 6122–6125.
[22] C. Reichardt, Solvents and Solvent Effects in Chemistry, 2nd
ed., VCH Verlagsgesellschaft, 1988, Weinheim, Germany.
[23] C.-T. Yang, Z.-Q. Zhang, J. Liang, J.-H. Liu, X.-Y. Lu, H.-H.
Chen, L. Liu, J. Am. Chem. Soc. 2012, 134, 11124–11127.
[24] J. F. Liebman, S. W. Slayden, in: The Chemistry of Organocop-
per Compounds (Eds.: Z. Rappoport, I. Marek), John Wiley &
Sons, Chichester, UK, 2009, p. 156.
[25] a) S. K. Gurung, S. Thapa, D. A. Dickie, R. Giri, Org. Lett.
2014, 16, 1264–1267; b) T. Uemura, N. Chatani, J. Org. Chem.
2005, 70, 8631–8634; c) A. S. Demir, O. Reis, M. Emrullahoglu,
J. Org. Chem. 2003, 68, 10130–10134; d) D. A. Evans, J. L.
Katz, T. R. West, Tetrahedron Lett. 1998, 39, 2937–2940.
[26] S. G. Bratsch, J. Phys. Chem. Ref. Data 1989, 18, 1–21.
[27] C. He, G. Zhang, J. Ke, H. Zhang, J. T. Miller, A. J. Kropf, A.
Lei, J. Am. Chem. Soc. 2013, 135, 488–493.
[11]
[12]
a) H. S. P. Rao, K. Geetha, Tetrahedron Lett. 2009, 50, 3836–
3839; b) D. Gayathri, D. Velmurugan, K. Ravikumar, K. Gee-
tha, H. S. P. Rao, Acta Crystallogr., Sect. E: Struct. Rep. Online
2006, 62, o1961–o1963.
H. S. P. Rao, K. Geetha, M. Kamalraj, Tetrahedron 2011, 67,
8146–8154.
[13] H. S. P. Rao, K. Geetha, M. Kamalraj, RSC Adv. 2011, 1,
1050–1059.
[14] a) W. Jin, W. Du, Q. Yang, H. Yu, J. Chen, Z. Yu, Org. Lett.
2011, 13, 4272–4275; b) J. X. Qiao, P. Y. S. Lam, Synthesis
2011, 829–856; c) Y. Dong, M. Wang, J. Liu, W. Ma, Q. Liu,
Chem. Commun. 2011, 47, 7380–7382.
[15] a) F. Ullmann, J. Bielecki, Ber. Dtsch. Chem. Ges. 1901, 34,
2174–2185; b) I. Goldberg, Ber. Dtsch. Chem. Ges. 1906, 39,
1691–1692.
[16] a) F. Monnier, M. Taillefer, Angew. Chem. Int. Ed. 2009, 48,
6954–6971; Angew. Chem. 2009, 121, 7088; b) G. Evano, N.
Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054–3131; c)
J. T. B. H. Jastrzebski, G. van Koten, in: Modern Organocopper
Chemistry (Ed.: N. Krause), Wiley-VCH, Weinheim, Germany,
2002, p. 1–40.
[28] J. A. Widegren, M. A. Bennett, R. G. Finke, J. Am. Chem. Soc.
2003, 125, 10301–10310.
[29] Y. Takahashi, T. Ito, S. Sakai, Y. Ishii, J. Chem. Soc. D 1970,
1065–1066.
Received: February 3, 2014
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42003
/KAP1
Date: 23-04-14 17:46:05
Pages: 11
Copper-Catalyzed C(sp3)–C(sp2) Cross-Coupling
Cross-Coupling with Copper
H. S. P. Rao,* A. V. B. Rao ............. 1–11
Copper-Catalyzed C(sp3)–C(sp2) Cross-
Coupling: Synthesis of 4-Aryl-2-alkyl-
amino-3-nitro-4H-chromenes
Copper(II) acetate efficiently catalyzes C–
C bond formation between 4-methylsulf-
anyl-2-alkylamino-3-nitro-4H-chromenes
and arylboronic acids to provide a library
of 4-aryl/heteroaryl-4H-chromenes via sp3–
sp2 cross-coupling. The reaction also al-
lows one-pot sequential substitution of
C(4)SMe and C(6)Br with aryl groups
through Cu(OAc)2 and Pd2(dba)3 (Suzuki
coupling) catalysis.
Keywords: C–C coupling / Copper / Cross-
coupling / Medicinal chemistry / Drug dis-
covery
Eur. J. Org. Chem. 0000, 0–0
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11