Buchwald-Hartwig reactions of monohaloflavones

Article abstract of DOI:10.1002/ejoc.201403108

The article describes the amination of different monobromo- or monochloroflavones with primary and secondary alkylamines and aniline derivatives by Buchwald-Hartwig reaction. The influence of the phosphine ligands used is described. The use of amino acid derivatives as a nitrogen source is also demonstrated. This latter reaction allows the synthesis of unique flavone-amino-acid conjugates.

Full text of DOI:10.1002/ejoc.201403108

Job/Unit: O43108
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FULL PAPER
DOI: 10.1002/ejoc.201403108
Buchwald–Hartwig Reactions of Monohaloflavones
Krisztina Kónya,[a] Dávid Pajtás,[a] Attila Kiss-Szikszai,[a] and Tamás Patonay*[a]
Keywords: Homogeneous catalysis / Cross-coupling / Amination / Palladium / Amino acids / Oxygen heterocycles
The article describes the amination of different monobromo-
or monochloroflavones with primary and secondary alk-
ylamines and aniline derivatives by Buchwald–Hartwig reac-
tion. The influence of the phosphine ligands used is de-
scribed. The use of amino acid derivatives as a nitrogen
source is also demonstrated. This latter reaction allows the
synthesis of unique flavone–amino-acid conjugates.
one have shown considerable antiproliferative effects
against the MCF-7 breast-cancer cell line.[8] 4Ј-Amino-6- or
7-fluoroisoflavones showed moderate antitumor effects
against MDA-MB-468, MCF-7, HT29, and HCT-116 cell
lines.[9] The aminoflavone-based peptide NSC 710464 (AFP
464)[10] is considered to be an anticancer prodrug. It is in
phase I clinical trials, and it seems to be useful against solid
tumors (Scheme 1).[11]
3-Amino-4Ј-methoxyflavone and 3,3Ј-diamino-4Ј-meth-
oxyflavone showed remarkable cytotoxicity aginst L1210
leukemia cells, and their 3-(diethylaminoethyl)amino ana-
logues showed activities similar to those of the parent 3-
aminoflavones.[12] T-614, a 3-formamidochromone deriva-
tive, showed anti-inflammatory, antiarthritic, and oral anti-
rheumatic effects.[13] 3-(NЈ-Alkylureido)chromone and 3-
(NЈ-alkylureido)-1-thiochromone selectively inhibited the
v-abl tyrosine kinase.[14]
Introduction
Benzopyran derivatives with amino functionalities are a
very important class of oxygen-containing heterocycles, and
many of them have remarkable biological activity. Chrom-
one and flavone alkaloids without a direct link between the
aromatic/heteoaromatic ring and the amine nitrogen are
natural products, and their occurrence and chemistry have
been reviewed.[1] Rohitukine, a chromone alkaloid isolated
from Disoxylum binectifarum and Amoora rohituka, inhibits
cyclin-dependent kinase (CDK).[2] Its semisynthetic ana-
logue, flavopiridol (Alvocidib, HMR 1275, L86–8275, NSC
649890) is an antineoplastic agent, inhibiting CDK1,
CDK2, CDK4, CDK5, CDK6, and CDK9 kinases; it has
been studied alone and in combinations in phase I and II
clinical trials (Scheme 1).[3]
The other important subclass of amine-containing
benzopyran derivatives consists of chromones and flavones
in which the nitrogen is directly attached to an aromatic sp2
carbon. 7-Aminoflavone was found to show antibacterial
effects against, among others, M. tuberculosis strains.[4,5] 6-
Amino-5,7-dihydroxyflavone showed outstanding activity
in the low micromolar range as an α-glucosidase inhibitor.[6]
Many aminoflavones belonging to this second subclass
have shown considerable cytotoxic, kinase inhibitory, or
antiproliferative effects. 4Ј-Aminoflavones with one or more
hydroxy groups in their A-ring have shown tyrosine-kinase
inhibitory effect against p56lck, an enzyme of 56 kDa. The
most active derivative was 4Ј-amino-6-hydroxyflavone.[7a]
However, methods for the synthesis of aminochromones
and flavones suffer from limitations, particularly for those
derivatives with amine substituents in the A-ring. The most
common synthetic methods are based on a Claisen–
Schmidt condensation or
a Baker–Venkataraman re-
arrangement (Scheme 2). In the first case, a base-induced
aldol-type condensation gives a chalcone 2, which, in turn,
can be cyclised into a nitro- or acetamidoflavone 3.[15–21]
The same intermediates (i.e., 3) are accessible by aroylation
followed by Baker–Venkataraman rearrangement under
strongly basic conditions.[7b,8,22–27] The desired aminoflav-
ones (i.e., 4) can be obtained by reduction or hydrolysis.
The latter transformation usually requires harsh conditions
(Scheme 2). The major problem with these methods is the
synthesis of the appropriate acetophenone (i.e., 1), which is
limited by the regioselectivity of the nitration of aceto-
phenone, and by the sensitivity of the R1 substituents under
the harsh conditions.
5,7,4Ј-Triamino-6-hydroxyflavone
selectively
inhibited
p56lck, while 6,4Ј-diamino-7-hydroxyflavone and 5,7,3Ј-tri-
amino-6-hydroxyflavone were more or less active against
EGFr and p60v–src [7b]
5,4Ј-Diaminoflavone, 5-amino-4Ј-di-
.
methylaminoflavone, and 6-amino-4Ј-(dimethylamino)flav-
[a] Department of Organic Chemistry, University of Debrecen,
4032 Debrecen, Egyetem tér 1, Hungary
Alternatively, a previously constructed flavone moiety
can also be nitrated and then submitted to reduction, but
the reactivity and selectivity patterns of the nitration step
are also limiting factors.[7b,28,29] The Wessely–Moser re-
E-mail: patonay.tamas@science.unideb.hu
http://szerves.scienc.unideb.hu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403108.
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K. Kónya, D. Pajtás, A. Kiss-Szikszai, T. Patonay
FULL PAPER
Scheme 1.
Scheme 2.
arrangement is a special route to aminoflavones.[6,28,30] The
synthesis of alkyl/arylamino or disubstituted amino deriva-
tives represents a much greater challenge. Direct alkylation
suffers from a lack of selectivity, which leads to low
yields.[8,15] Alkylation of an acetamido or sulfonylamido
group followed by the cleavage of the protecting group has
been reported.[9,28] Reductive alkylation,[31,32] and direct
aromatic nucleophilic substitution of an aromatic triflyloxy
group under microwave conditions[33] have also been de-
scribed.
The synthesis of 3-aminoflavones 7 can be carried out by
the reduction of 3-nitro 8[12,16,34–37] or 3-oximino derivatives
9, or from 3-azidoflavanones 10 under basic condi-
tions.[38–40] Reduction of the nitro group has been carried
out by catalytic hydrogenation.[12,34,41,42] 3-Oximinoflavan-
Scheme 3.
Sasaki, Miyake, and their coworkers published the syn-
ones 9 gave also 3-aminoflavones 7 upon treatment with thesis of various 3-alkylaminoflavones from 3-bromoflav-
tin(II) chloride (Scheme 3).[43,44] ones,[45a] 3-tosyloxyflavones, or 3-mesyloxyflavones,[45b] but
2
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Buchwald–Hartwig Reactions of Monohaloflavones
the structural assignment of their products proved to be Table 1. Amination of 6-bromoflavone (11).
wrong (vide infra).
Entry
Product R1
R2
Yield [%][a]
In recent decades, Buchwald–Hartwig amination of halo-
substituted aromatic/heteroaromatic systems has become
the method of choice for the synthesis of alkyl- and aryl-
amino substituted arenes.[46] Surprisingly, only sporadic ex-
amples have been published in the field of oxygen hetero-
cycles. There are only two published examples of the prepa-
ration of amino derivatives: the synthesis of 7-amino-5-
hydroxyflavone started from a triflate,[47] while 4Ј-aminoiso-
flavone was prepared from the corresponding bromide.[12]
Caddick and his coworkers reported the Buchwald–Hart-
wig reaction of bromo- or triflyloxy-substituted flavones
under microwave activation, but they only used hexylamine
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
Bu
iBu
sBu
tBu
Bn
cHex
2-Me-C6H4
4-Cl-C6H4
4-MeO-C6H4
Bu
H
H
H
H
H
H
H
H
H
Bu
46[b]
46
38
0[c,d]
59
57
53
48
75
18
40
58
51
9
10
11
12
13
14
–(CH2)4–
–(CH2)5–
–(CH2)2O(CH2)2–
–(CH2)2Me(CH2)2–
Me
73
31
48
as the nitrogen source.[48] This astonishing gap in the amin- 15
Ph
16
1,2,3,4-tetrahydroquinolin-1-yl
ation of oxygen heterocycles prompted us to start a system-
atic investigation of the scope and limitations of this
method. We present our first results in this paper.
[a] Yields refer to pure isolated products. [b] N,N-Bis(flavon-6-yl)-
butylamine (14; 11%) was also isolated. [c] Traces of the expected
product could be detected by TLC. [d] Flavone (13; 7.7%) and β-
diketone 15 (15%) were isolated. These by-products were also de-
tected by TLC in several other reactions.
Results and Discussion
In all cases, flavone (13) was detected or isolated as a by-
product. Competitive reductive elimination and β-hydride
We started our studies using the conditions of Caddick’s elimination from the organopalladium intermediate may
group,[48] but a much wider variety of primary and second- both take place to reform the catalyst, but the latter path-
ary aliphatic and aromatic amines were tested. It turned out way gives a dehalogenated product, i.e., flavone (13), which
that microwave activation has no beneficial effect; reactions results in a decrease of the yield of the aminated product.
using conventional thermal heating show the same effi- In the reaction of substrate 11 with butylamine, an interest-
ciency. Reactions of 6-bromoflavone (11) with various ing bis-arylated product 14 was also obtained in low (11%)
amines in the presence of Pd2(dba)3 (dba = dibenzylidene- yield. Obviously, here the Buchwald–Hartwig product acts
acetone) as a palladium source resulted in the formation of as the amine in a second cross-coupling reaction. Surpris-
the desired 6-aminoflavones (i.e., 12a–12p; Scheme 4, ingly, no similar double Buchwald–Hartwig coupling was
Table 1). The only limiting factor is steric hindrance in the observed with any of the other amines tested. It is note-
reacting amine. Increasing the number of α-branchings worthy that Caddick and his coworkers[48] also mentioned
clearly decreases the yield (Table 1, entries 1–4). A similar the formation of a similar diflavonoid tertiary amine deriva-
effect was also observed in the reactions of 7-bromoflavone tive starting from 4Ј-bromo-2Ј-chloro-6-methylflavone and
(17; vide infra). The lower yield for the reaction with dibut- hexylamine. In some cases, we also observed the formation
ylamine in comparison with the cyclic secondary amines of 5Ј-bromo-2Ј-hydroxydibenzoylmethane (and its tauto-
(Table 1, entry 10 vs. entries 11–14) also supports the role meric form) (15). The appearance of this by-product under
of bulkiness.
the strictly water-free conditions used can be explained by
Scheme 4.
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K. Kónya, D. Pajtás, A. Kiss-Szikszai, T. Patonay
FULL PAPER
Scheme 5.
Scheme 6. Structures of the ligands used.
a concurrent ring-opening of the heterocycle: the tert- Table 2. Efficiency of the amination of 6-bromoflavone (11) in the
presence of different phosphine ligands.[a]
butoxide anion attacks the electrophilic C-2 atom of the
HPLC area [%][b]
flavone moiety, and the intermediate enol ether (i.e., 16)
hydrolyses during aqueous work-up and column chroma-
tography on silica (Scheme 5).
Ligand
BuNH2
cHexNH2
Piperidine
A
B
C
D
E
F
G
H
I
1
3
15
79
61
6
60
28
55
57
24
Next, we investigated the role of the phosphine ligands
and their effect on the yield of the cross-coupling reaction.
6-Bromoflavone (11) was treated with butylamine, cyclohex-
ylamine, or piperidine in the presence of various phosphines
A–I (Scheme 6) keeping all the other reagents the same, but
using microwave activation. The amount of the 6-(di)substi-
tuted aminoflavone product (i.e., 12a, 12f, or 12l) was deter-
mined by HPLC. The results are summarised in Table 2,
and they clearly show that there is no “magic” ligand with
outstanding efficiency for every model amine. The best
yields were achieved using electron-rich monodentate biaryl
ligands, particularly ligands B, C, and E.
45
43
28
41
29
31
38
75
51
35
15
43
30
29
27
43
[a] Reaction conditions: Pd2(dba)3 (5 mol-%), ligand (7.5 mol-%),
NaOtBu (1.4 equiv.), amine (1.2 equiv.), dry toluene, MW (110 °C),
15 min. [b] Product ratios were determined by HPLC; Pinnacle II
C18 column, 150ϫ4.6 mm, MeOH/H2O (gradient).
were either similar to or better than those obtained with 6-
bromoflavone (11). This observation was consistent with
our expectations: the electronic effect of a carbonyl group
in the para position usually speeds up palladium-catalysed
cross-coupling reactions. We can assume that the rate-de-
The average HPLC yields were Ͼ45%, but there were
large deviations. For example, ligand I gave good results
with primary amines, but only a low HPLC yield with the
secondary amine piperidine. We can conclude that many of
these ligands can be used successfully, but a detailed op-
timisation is needed in each case.
We chose 7-bromoflavone (17) as our next substrate to
allow a comparison of the reactivity of the 6- and 7-posi-
tions. We have previously demonstrated the higher reactiv-
ity of the 7-position in Heck–Mizoroki reactions.[49] Brom-
ide 17 was treated with various amines under the same con-
ditions as described above (Scheme 7, Table 3). The reac-
tions were successful with all the tested acyclic and cyclic
aliphatic amines as well as aniline derivatives, and the yields Scheme 7.
4
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Buchwald–Hartwig Reactions of Monohaloflavones
termining step of this amination is the oxidative addition, We can conclude that this method, although it seems to
i.e., the insertion of palladium(0) into the C–Br bond.
work, has only limited synthetic value for the preparation
of mono- or alkylated/arylated 3-aminoflavone derivatives.
Table 3. Amination of 7-bromoflavone (17).
Entry
Product
R1
R2
Yield [%][a]
1
2
3
4
5
6
7
8
18a
18b
18c
18d
18e
18f
18g
18h
18i
Bu
iBu
sBu
tBu
H
H
H
H
H
H
H
Bu
81
79
79
28
89
55
74
16
79
55
74
41
Bn
Scheme 8.
4-Cl-C6H4
4-MeO-C6H4
Bu
Table 5. Synthesis of 3-aminoflavone derivatives 24 by Buchwald–
Hartwig reaction.
9
–(CH2)4–
–(CH2)5–
Entry Product R1
R2
Yield [%][a] Yield of 13 [%][a]
10
11
12
18j
18k
18l
–(CH2)2O(CH2)2–
Me
1
24a
24a
24b
24c
24d
24e
24f
Bu
Bu
Hex
Bn
H
H
H
H
33
27
23
56
13
6
14
n.d.
n.d.
9
17
26
Ph
2[b]
3
[a] Yields refer to pure isolated products.
4
5
6
7
–(CH2)4–
–(CH2)5–
We also compared the reactions of 6- and 7-haloflavones
containing different halogen atoms under our standard con-
ditions. Consistent with our expectations, bromoflavones 11
and 17 gave much higher yields than the corresponding 6-
chloro (21) and 7-chloro (22) derivatives (Table 4). This dif-
ference can be explained on the basis of the higher acti-
vation energy of the oxidative addition step of the shorter
and stronger C–Cl bond, and the electronic effect of the
carbonyl group in the para position.
4-Me-C6H4
H
26
n.d.
[a] Yields refer to pure isolated products; n.d.: not determined.
[b] Reaction carried out under MW irradiation (110 °C, 15 min,
200 W).
Earlier both Caddick’s group[48] and Miyake’s group[45]
reported the synthesis of 3-alkylaminoflavones from 3-
bromo-, 3-tosyloxy-, or 3-mesyloxyflavones. Caddick and
his coworkers[51] treated 3-bromoflavone (23) with hex-
ylamine under microwave irradiation, but in the presence of
Pd(OAc)2 instead of Pd2(dba)3 used previously. However,
Table 4. Isolated yields from the Buchwald–Hartwig reactions of
6/7-bromo- and -chloroflavones 11, 17, 21, and 22 with various
amines.
1
our H and 13C NMR spectroscopic data were completely
different from those reported by them in their Supplemen-
tary Information. The major problem with the assignment
of the right structure is that the heterocyclic product con-
tains only quaternary carbons, which makes the ring size
questionable. Miyake and his coworkers also reported the
synthesis of 3-amino- or 3-(alkylamino)flavones in good or
excellent yields by simply treating 3-bromo-, 3-(tosyloxy)-,
or 3-(mesyloxy)flavones with ammonia or with primary
amines in THF solution at room temperature, but they did
Yield [%][a]
Amine
6-Br (11)
7-Br (17)
6-Cl (21)
7-Cl (22)
BuNH2
BnNH2
Pyrrolidine
4-Cl-C6H4
46
59
40
48
81
89
79
55
7.7
8.8
7.3
6.5
32
41
38
36
[a] Yields refer to pure isolated products.
Next, we tested the amination of 7-bromo-4Ј-meth- not present any m.p. values or spectroscopic data.[45] There-
oxyflavone (19) with some model primary and secondary fore, we tested their reaction conditions by treating 3-
amines (Scheme 7). No significant differences could be ob- bromoflavone (23) with butylamine and hexylamine in THF
served in the yields of the coupled products. The distant without any palladium source. The isolated products had
substituent does not exert any significant electronic effect identical or similar spectral data to “3-hexylaminoflavone”
(see Supporting Information).
reported by Caddick et al. The spectral data indicated the
Next, we studied the possible Buchwald–Hartwig reac- presence of the same groups, thus, our Buchwald–Hartwig
tion of 3-bromoflavone (23) under our previously optimised products and the Caddick/Miyake products should be
conditions, since the number of methods that have been re- structural isomers; one of them is the expected 3-(alk-
ported for the preparation of 3-alkyl/arylaminoflavones or ylamino)flavone, while the other is 2-[α-(alkylamino)benzyl-
related systems is very limited (vide supra). Unfortunately, idene]benzofuran-3(2H)-one, a product of a ring-contrac-
this coupling reaction gave the expected amines (i.e., 24) in tion. Significant differences could be found between the 1H
much lower yields than those obtained with the bromides NMR data of our Caddick/Miyake products and our Buch-
studied earlier (i.e., 11, 17, and 19), particularly with sec- wald–Hartwig products. The Caddick/Miyake products
ondary amines (Scheme 8, Table 5). The use of microwave showed NH signals at δ = 10 ppm, signals of the hydrogen
activation did not change the outcome of the coupling reac- in the peri position to the carbonyl group at δ = 7.84 ppm,
tions (Table 5, entry 2). Typically, reductive elimination and NCH2 signals at δ ≈ 3.22 ppm. The corresponding
leading to flavone (13) took place to a considerable extent. values for our Buchwald–Hartwig products were δ ≈ 4.4,
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K. Kónya, D. Pajtás, A. Kiss-Szikszai, T. Patonay
FULL PAPER
Scheme 9.
8.25, and 2.64 ppm, respectively. The 13C NMR signals dif-
fered less markedly. We carried out 2D NMR spectroscopic
measurements (COSY and HMBC) for both of the butyl-
substituted compounds to assign the signals of the carbon
and hydrogen atoms (see Supporting Information). HMBC
measurements showed a strong cross-peak between the 1ЈЈ-
H (NCH2) and Cα signals in the spectrum of the Caddick/
Miyake product. On the other hand, the cross-peak be-
tween the 1ЈЈ-H (NCH2) and C-3 signals in our Buchwald–
Hartwig product clearly proved that Caddick/Miyake prod-
uct should be 2-[α-(butylamino)benzylidene]benzofuran-
3(2H)-one (25a).
The formation of the ring-contracted products (i.e., 25a
and 25b) can be explained in terms of attack of the amine
nucleophile on the C-2 atom of the oxygen heterocycle
(Scheme 9).
Scheme 10.
been published to date, and neither of them was obtained
To obtain additional and independent proof for the by Buchwald–Hartwig (or Ullmann) type coupling. Korean
structure of 3-(butylamino)flavone (24a) obtained in the authors[53] prepared a conjugate by alkylation of a pre-
Buchwald–Hartwig procedure, and to rule out isomeric formed 6-aminoflavone (28a) with an α-bromo-α-phen-
structure 25a, we alkylated the parent 3-aminoflavone (i.e., ylacetic acid thioester, while Georg et al.[54] coupled 8-
26) with butyl bromide in aqueous solution in the presence amino-4Ј-chloro-5-hydroxyflavone with N-Boc-protected
of potassium carbonate under microwave irradiation using amino acids (Boc = tert-butoxycarbonyl). First, we treated
the protocol developed for 3-(N,N-alkylamino)flavones.[50] 6-bromoflavone (11) with l-phenylalanine methyl ester
The resulting product showed the same spectroscopic data hydrochloride (29a), but the desired coupled product could
as our Buchwald–Hartwig product, thus proving that the not be obtained under the previously used conditions.
structures of Caddick’s and Miyake’s compounds were After extensive optimisation, we found a set of conditions:
erroneously assigned.
Pd2(dba)3 should be replaced by palladium(II) acetate, and
We also investigated the synthesis of N-unsubstituted the original base sodium tert-butoxide should be replaced
aminoflavones. The most frequently used ammonia equiva- by cesium carbonate. However, the expected product (i.e.,
lents in Buchwald–Hartwig cross-coupling are benzophen- 30a) was only obtained in a very low yield (5%), and, in
one imine[51] and lithium silyl amides.[52] Until now, only addition, the regioisomeric 7-{[2-phenyl-1-(methoxycarb-
one example has been published in the field of flavones.[47] onyl)ethyl]amino}flavone (31a) was also isolated in 6%
We successfully prepared both 6-aminoflavone (28a) and 7- yield (Scheme 11). These structures were assigned on the
aminoflavone (28b) via the corresponding imine intermedi- basis of their NMR spectra, and the constitution of com-
ates (i.e., 27a and 27b) in 48 and 38% overall yields, respec- pound 31a was also supported by its independent synthesis
tively (Scheme 10). Unfortunately, the reaction of 3-bromo- (vide infra).
flavone (23) failed to give the desired 3-aminoflavone (27).
A possible explanation for this astonishing observation
Next, we tested the cross-coupling reaction with α-amino may be the so-called “halogen dance”[55] under the strongly
acid methyl esters as the nitrogen source. This reaction basic conditions. According to this suggested mechanism, a
could lead to hitherto almost unknown amino-acid–flavone deprotonation at the 7-position of the starting 6-bromoflav-
hybrids of potential biological importance. To the best of one (11) takes place, followed by a bromine exchange be-
our knowledge, only two examples of such derivatives have tween the resulting carbanion intermediate and a second
6
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Buchwald–Hartwig Reactions of Monohaloflavones
Scheme 11.
molecule of starting material to give 6,7-dibromoflavone.
Another drawback of coupling with amino acid esters, at
The relative ease of this deprotonation may be explained by least at the moment, is racemisation (Table 6). This can be
the higher stability of this carbanion. The 6,7-dibromoflav- attributed to a deprotonation–reprotonation sequence at
one intermediate may react with the above-mentioned carb- the stereogenic centre of the amino acid unit.
anion to yield 7-bromoflavone (17). These hypothetical
steps are consistent with the generally accepted mechanism
of the “halogen dance”. However, it should be emphasised
that the “halogen dance” usually needs more basic condi-
tions [LDA (dithium diisopropylamide), BuLi, NaNH2,
Conclusions
ArNHK, etc.]. In addition, to the best of our knowledge,
In conclusion, we have demonstrated that the Buchwald–
this would be the first example of such a transformation to
Hartwig amination of bromoflavones with halo substituents
be observed in a Buchwald–Hartwig reaction.
on their aromatic rings is a useful tool for the synthesis
of amine derivatives that are hardly available by previously
reported methods. We have pointed out that the previously
published structures of some derivatives obtained from 3-
Applying the same conditions to the reaction of 7-
bromoflavone (17) and various amino acid methyl ester
hydrochlorides 29, the expected products (i.e., 31a–31e)
were obtained (Scheme 11, Table 6), and no 6-substituted
halo- or sulfonyloxyflavones with primary amines were er-
products were obtained or detected. The higher reactivity
roneously assigned, and that in fact, ring-contracted prod-
of 7-bromoflavone (17) caused by electronic effects (vide
ucts were formed. Palladium-catalysed C–N bond forma-
tion also proved to be an efficient tool in the synthesis of
supra) leads to a fast reaction, and so excludes the “halogen
dance”. These results further demonstrate the synthetic util-
flavone–amino-acid hybrids, although the coupling takes
ity of the Buchwald–Hartwig reaction in the field of oxygen
place accompanied by significant racemisation of the ste-
heterocycles. On the other hand, the data summarised in
reogenic centre. Experiments aimed at avoiding this racem-
Table 6 clearly show that the polarity of the amino acid has
isation and extending the number of nitrogen sources are in
a decisive role in the efficiency of the reaction. The coupling
progress, and the results will be published soon.
with l-aspartic acid resulted in a low yield, and no product
was obtained with l-serine or l-tryptophan. The lack of
any reaction may be explained by either the low solubility
of the amino acid derivative in xylene, or by ligation of
Experimental Section
the palladium(0)/palladium(II) ion to the heteroatom of the
reagent.
General Remarks: Column chromatography was carried out on sil-
ica gel (Merck 60, 70–230 mesh). Thin-layer chromatography was
carried out on silica gel plates 60 F254 (Merck, 0.2 mm). In phos-
phine-ligand optimisation studies, product ratios were determined
by HPLC using a Pinnacle II column (C18, 150ϫ4.6 mm, 5 μm;
MeOH/H2O, gradient: from 60 to 90% MeOH in 20 min; flow:
0.9 mL/min, 280 nm). Chiral HPLC was carried out using a Chi-
ralpak IC column (250ϫ4.6 mm) with a Jasco HPLC system: Jasco
PU-980 HPLC pump, Jasco MD-910 multiwavelength detector.
The purity of the compounds was established by GC–MS (Agilent
7890, Agilent 5975 MS detector) with positive EI at 70 eV. NMR
spectra were recorded with a Bruker AM 360 (360.13 MHz for 1H,
90.03 MHz for 13C) spectrometer. Chemical shifts (δ) were cal-
ibrated using the CHCl3 signals (δ = 7.26 ppm) for 1H and (δ =
Table 6. Synthesis of flavone–amino-acid hybrids 31 by Buchwald–
Hartwig reaction.
Entry Amino acid
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
l-Phe
d-Phe
l-Ala
l-Leu
l-Met
l-Asp
l-Ser
31a
31a
31b
31c
31d
31e
31f
31g
64
59
30
56
40
11
0
6
10
n.d.
6
1
2
–
–
l-Trp
0
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43108
/KAP1
Date: 15-12-14 12:48:59
Pages: 13
K. Kónya, D. Pajtás, A. Kiss-Szikszai, T. Patonay
FULL PAPER
77.00 ppm) for 13C spectra. Melting points were determined by
using Büchi B-540 equipment. Elemental analysis (C, H) was con-
ducted with an Elementar Vario MicroCube instrument. IR spectra
were measured as KBr discs with a Jasco FTIR 4100A instrument.
Microwave-assisted reactions were carried out using a CEM-Dis-
cover Focused microwave synthesis system (2450 MHz).
H, 5-H), 7.53 (m, 3 H, 3Ј-H, 5Ј-H, 4Ј-H), 7.48 (d, J = 9.0 Hz, 1 H,
8-H), 7.31 (dd, J = 2.5, 9.7 Hz, 1 H, 7-H), 7.25 (m, 2 H, 3ЈЈ-H, 6ЈЈ-
H), 7.18 (m, 1 H, 5ЈЈ-H), 7.01 (m, 1 H, 4ЈЈ-H), 6.78 (s, 1 H, 3-H),
5.88 (s, 1 H, NH), 2.27 (s, 3 H, 2-CH3) ppm. 13C NMR (CDCl3 +
[D6]DMSO): δ = 177.1 (C-4), 161.9 (C-2), 149.2 (C-8a), 142.9 (C-
1ЈЈ), 140.1 (C-6), 131.3 (C-2ЈЈ), 130.8 (C-3ЈЈ), 130.5 (C-4Ј), 130.3
(C-1Ј), 128.5 (C-3Ј, C-5Ј), 126.1 (C-5ЈЈ), 125.6 (C-2Ј, C-6Ј), 123.9
(C-4a), 122.8 (C-4ЈЈ), 122.6 (C-6ЈЈ), 120.7 (C-7), 118.4 (C-8), 106.9
6-Bromoflavone (11),[56] 7-bromoflavone (17),[56] and amino acid
methyl ester hydrochlorides[57] were synthesised according to litera-
ture procedures.
(C-5), 105.7 (C-3), 17.6 (2ЈЈ-CH ) ppm. IR (KBr): ν = 3317, 3113,
˜
3
3063, 2939, 1641, 1619, 1576, 1534, 1483, 1449, 1365, 1318, 1138,
914, 832, 770, 755, 690 cm–1. MS: m/z = 326 [M]+· (100%), 168.
C22H17NO2 (327.38): calcd. C 80.71, H 5.23, N 4.28; found C
80.69, H 5.20, N 4.26.
Buchwald–Hartwig Cross-Coupling by Thermal Heating: Halo-
flavone (0.66 mmol), NaOtBu (88 mg, 0.92 mmol), BINAP [2,2Ј-
bis(diphenylphosphino)-1,1Ј-binaphthyl; 32 mg, 0.050 mmol], and
amine (0.80 mmol) were mixed in dry toluene (6 mL) in a dried
flask under nitrogen, and Pd2(dba)3 (30 mg, 0.032 mmol) was
added. The reaction mixture was stirred at reflux for 3 h in an oil
bath. The crude reaction mixture was applied directly to a silica
gel column to give the pure cross-coupled product.
6-(Dibutylamino)flavone (12j): Oil, eluent: toluene/ethyl acetate, 8:1;
1
yield 42 mg (18%). H NMR (CDCl3): δ = 7.91 (m, 2 H, 2Ј-H, 6Ј-
H), 7.51 (m, 3 H, 3Ј-H, 5Ј-H, 4Ј-H), 7.43 (d, J = 9.0 Hz, 1 H, 8-
H), 7.29 (d, J = 2.9 Hz, 1 H, 5-H), 7.06 (dd, J = 2.9, 9.0 Hz, 1 H,
7-H), 6.78 (s, 1 H, 3-H), 3.35 (t, J = 7.6 Hz, 4 H, 1ЈЈ-H), 1.60 (m,
4 H, 2ЈЈ-H), 1.38 (m, 4 H, 3ЈЈ-H), 0.97 (t, J = 7.2 Hz, 6 H, 4ЈЈ-H)
ppm. 13C NMR (CDCl3): δ = 178.8 (C-4), 162.5 (C-2), 148.2 (C-
8a), 146.0 (C-6), 132.3 (C-1Ј), 131.1 (C-4Ј), 128.9 (C-3Ј, C-5Ј), 126.1
(C-2Ј, C-6Ј), 124.7 (C-4a), 119.2 (C-7), 118.7 (C-8), 106.4 (C-5),
104.0 (C-3), 50.9 (C-1ЈЈ), 29.3 (C-2ЈЈ), 20.3 (C-3ЈЈ), 14.0 (C-4ЈЈ)
Buchwald–Hartwig Cross-Coupling by Microwave Activation: 6-
Bromoflavone (0.33 mmol), NaOtBu (44 mg, 0.46 mmol), BINAP
(15 mg, 0.025 mmol), and amine (0.80 mmol) were mixed in dry
toluene (3 mL) in a sealed vial under nitrogen, and Pd2(dba)3
(15 mg, 0.016 mmol) was added. The reaction mixture was stirred
for 15 min at 110 °C (200 W). The crude reaction mixture was ap-
plied directly to a silica gel column to give the pure cross-coupled
product.
ppm. IR (KBr): ν = 3060, 2925, 2928, 2870, 1639, 1614, 1566, 1500,
˜
1453, 1363, 911, 771, 689 cm–1. MS: m/z = 349 [M]+·, 306 (100%).
C23H27NO2 (349.47): calcd. C 79.05, H 7.79, N 4.01; found C
79.07, H 7.81, N 4.02.
Only representative examples are given here. Characterisation data
for the vast majority of the products are presented in the Support-
ing Information.
6-(Phenyl-methylamino)flavone (12o): Eluent: hexane/ethyl acetate,
1
4:1; yield 67 mg (31%); m.p. 164.5–165.5 °C. H NMR (CDCl3): δ
= 7.91 (m, 2 H, 2Ј-H, 6Ј-H), 7.67 (d, J = 2.5 Hz, 1 H, 5-H), 7.52
(m, 3 H, 3Ј-H, 5Ј-H, 4Ј-H), 7.36 (m, 3 H, 8-H, 3ЈЈ-H, 5ЈЈ-H), 7.28
(dd, J = 2.9, 9.0 Hz, 1 H, 7-H), 7.10 (m, 3 H, 2ЈЈ-H, 6ЈЈ-H, 4ЈЈ-H),
6.81 (s, 1 H, 3-H), 3.39 (s, 3 H, NCH3) ppm. 13C NMR (CDCl3):
δ = 178.3 (C-4), 162.8 (C-2), 150.7 (C-1ЈЈ), 148.4 (C-8a), 146.5 (C-
6), 131.9 (C-1Ј), 131.3 (C-4Ј), 129.5 (C-3ЈЈ, C-5ЈЈ), 128.9 (C-3Ј, C-
5Ј), 126.1 (C-2Ј, C-6Ј), 125.5 (C-7), 124.6 (C-4a), 123.4 (C-4ЈЈ),
123.0 (C-2ЈЈ, C-6ЈЈ), 118.6 (C-5), 110.6 (C-8), 106.8 (C-3), 40.7
6-(Butylamino)flavone (12a): Eluent: toluene/ethyl acetate, 4:1; yield
88 mg (46%) from 11, 15 mg (7.7%) from 21; m.p. 124.5–126.5 °C.
1H NMR (CDCl3): δ = 7.89 (m, 2 H, 2Ј-H, 6Ј-H), 7.50 (m, 3 H,
3Ј-H, 5Ј-H, 4Ј-H), 7.39 (d, J = 8.6 Hz, 1 H, 8-H), 7.24 (d, J =
2.5 Hz, 1 H, 5-H), 6.98 (dd, J = 2.9, 9.0 Hz, 1 H, 7-H), 6.78 (s, 1
H, 3-H), 3.87 (s, 1 H, NH), 3.19 (t, J = 7.2 Hz, 2 H, 1ЈЈ-H), 1.64
(m, 2 H, 2ЈЈ-H), 1.45 (m, 2 H, 3ЈЈ-H), 0.97 (t, J = 7.6 Hz, 3 H, 4ЈЈ-
H) ppm. 13C NMR (CDCl3): δ = 178.6 (C-4), 162.6 (C-2), 149.3
(C-8a), 146.2 (C-6), 132.2 (C-1Ј), 131.1 (C-4Ј), 128.9 (C-3Ј, C-5Ј),
126.1 (C-2Ј, C-6Ј), 124.8 (C-4a), 121.2 (C-7), 118.8 (C-8), 106.7 (C-
5), 103.5 (C-3), 43.9 (C-1ЈЈ), 31.4 (C-2ЈЈ), 20.2 (C-3ЈЈ), 13.9 (C-4ЈЈ)
(NCH ) ppm. IR (KBr): ν = 3448, 3037, 3002, 2951, 2890, 2815,
˜
3
1620, 1590, 1580, 1566, 1482, 1457, 1450, 1362, 1141, 1134, 1045,
1029, 912, 832, 821, 770, 707 cm–1. MS: m/z = 327 [M]+·, 326
(100%). C22H17NO2 (327.38): calcd. C 80.71, H 5.23, N 4.28; found
C 80.69, H 5.20, N 4.28.
ppm. IR (KBr): ν = 3352, 2949, 2926, 2865, 1624, 1582, 1570, 1490,
˜
1450, 1211, 912, 818, 770 cm–1. MS: m/z = 293 [M]+·, 250 (100%).
C19H19NO2 (293.36): calcd. C 77.79, H 6.53, N 4.77; found C
77.75, H 6.52, N 4.75.
7-(Butylamino)flavone (18a): Eluent: toluene/ethyl acetate, 8:1; yield
157 mg (81%) from 17, 63 mg (32%) from 22; m.p. 163.5–164.5 °C.
1H NMR (CDCl3): δ = 7.96 (d, J = 8.6 Hz, 1 H, 5-H), 7.88 (m, 2
H, 2Ј-H, 6Ј-H), 7.49 (m, 3 H, 3Ј-H, 5Ј-H, 4Ј-H), 6.69 (s, 1 H, 3-H),
6.62 (d, J = 8.6 Hz, 1 H, 6-H), 6.52 (s, 1 H, 8-H), 4.50 (s, 1 H,
NH), 3.21 (q, J = 6.8 Hz, 2 H, 1ЈЈ-H), 1.65 (m, 2 H, 2ЈЈ-H), 1.46
(m, 2 H, 3ЈЈ-H), 0.98 (t, J = 7.6 Hz, 3 H, 4ЈЈ-H) ppm. 13C NMR
(CDCl3): δ = 177.6 (C-4), 162.0 (C-2), 158.8 (C-8a), 153.2 (C-7),
132.1 (C-1Ј), 104.0 (C-4Ј), 128.8 (C-3Ј, C-5Ј), 126.5 (C-5), 125.9 (C-
2Ј, C-6Ј), 114.3 (C-4a), 112.9 (C-6), 107.2 (C-3), 96.2 (C-8), 43.1
N,N-Bis(2-phenyl-4-oxo-4H-chromen-6-yl)butylamine (14): Eluent:
1
toluene/ethyl acetate, 4:1; yield 20 mg (11%); m.p. 218–220 °C. H
NMR (CDCl3): δ = 7.91 (m, 4 H, 4 H), 7.81 (d, J = 2.7 Hz, 2 H),
7.53 (dd, J = 4.8, 1.1 Hz, 5 H), 7.49 (d, J = 9.1 Hz, 3 H), 7.35 (dd,
J = 9.0, 2.8 Hz, 2 H), 6.81 (s, 2 H), 3.91–3.75 (m, 2 H), 1.77–1.61
(m, 2 H), 1.42 (dd, J = 15.0, 7.5 Hz, 2 H), 0.95 (t, J = 7.3 Hz, 3
H) ppm. 13C NMR (CDCl3): δ = 178.1 (C-4), 163.1 (C-2), 151.6
(C-8a), 145.1 (C-6), 131.8 (C-1Ј), 131.4 (C-4Ј), 128.9 (C-3Ј, C-5Ј),
127.9 (C-7), 126.2 (C-2Ј, C-6Ј), 124.9 (C-4a), 12.2 (C-7), 119.3 (C-
8), 115.0 (C-5), 106.9 (C-3), 52.7 (C-1ЈЈ), 29.4 (C-2ЈЈ), 20.2 (C-3ЈЈ),
(C-1ЈЈ), 31.1 (C-2ЈЈ), 20.2 (C-3ЈЈ), 13.8 (C-4ЈЈ) ppm. IR (KBr): ν =
˜
3316, 3139, 3069, 3034, 2948, 2927, 2865, 1632, 1586, 1566, 1503,
1448, 1378, 1248, 1095, 906, 824, 764, 670 cm–1. MS: m/z = 293
[M]+·, 250 (100%). C19H19NO2 (293.36): calcd. C 77.79, H 6.53, N
4.77; found C 77.76, H 6.55, N 4.78.
13.9 (C-4ЈЈ) ppm. IR (KBr): ν = 3446, 3064, 2956, 2925, 2854,
˜
1632, 1566, 1495, 1480, 1451, 1356, 1259, 910, 818, 770 cm–1. MS:
m/z = 326, 213 (100%), 137, 105, 77, 55. C34H27NO4 (513.59):
calcd. C 79.51, H 5.30, N 2.73; found C 79.70, H 5.35, N 2.75.
7-[(4-Chlorophenyl)amino]flavone (18f): Eluent: toluene/ethyl acet-
ate, 4:1; yield 126 mg (55%) from 17, 83 mg (36%) from 22; m.p.
1
6-[(2-Methylphenyl)amino]flavone (12g): Eluent: toluene/ethyl acet-
273.5–276.5 °C. H NMR (CDCl3 + [D6]DMSO): δ = 8.36 (s, 1 H,
ate, 4:1; yield 114 mg (53%); m.p. 220–223 °C. 1H NMR (CDCl3 + NH), 7.99 (d, J = 8.6 Hz, 1 H, 5-H), 7.90 (m, 2 H, 2Ј-H, 6Ј-H),
[D6]DMSO): δ = 7.92 (m, 2 H, 2Ј-H, 6Ј-H), 7.61 (d, J = 2.5 Hz, 1
7.53 (m, 3 H, 3Ј-H, 5Ј-H, 4Ј-H), 7.33 (d, J = 8.6 Hz, 2 H, 3ЈЈ-H,
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43108
/KAP1
Date: 15-12-14 12:48:59
Pages: 13
Buchwald–Hartwig Reactions of Monohaloflavones
5ЈЈ-H), 7.23 (d, J = 8.6 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 7.09 (s, 1 H, 8-H),
= 7.2 Hz, 1 H, 7-H), 7.40–7.51 (m, 4 H, 6-H, 8-H, 3Ј-H, 5Ј-H),
7.02 (d, J = 8.6 Hz, 1 H, 6-H), 6.70 (s, 1 H, 3-H) ppm. 13C NMR 7.36 (m, 1 H, 4Ј-H), 4.41 (s, 1 H, NH), 2.64 (t, J = 6.8 Hz, 2 H,
(CDCl3 + [D6]DMSO): δ = 176.7 (C-4), 161.8 (C-2), 157.6 (C-8a),
1ЈЈ-H), 1.36–1.42 (m, 2 H, 2ЈЈ-H), 1.21–1.29 (m, 2 H, 3ЈЈ-H), 0.79
149.1 (C-7), 139.0 (C-1ЈЈ), 131.3 (C-1Ј), 130.6 (C-4Ј), 128.7 (C-2Ј, (t, J = 7.5 Hz, 3 H, 4ЈЈ-H) ppm. 13C NMR (CDCl3): δ = 175.3 (C-
C-6Ј), 128.3 (C-3ЈЈ, C-5ЈЈ), 126.9 (C-4ЈЈ), 126.0 (C-5), 125.4 (C-2Ј, 4), 155.5 (C-8a), 147.7 (C-2), 133.5 (C-4a), 132.9 (C-7), 131.6 (C-
C-6Ј), 121.3 (C-2ЈЈ, C-6ЈЈ), 115.5 (C-4a), 114.2 (C-6), 106.6 (C-3), 1), 129.6 (C-5), 128.3 (C-2Ј, C-6Ј), 128.1 (C-3Ј, C-5Ј), 125.8 (C-4Ј),
99.2 (C-8) ppm. IR (KBr): ν = 3274, 3188, 3100, 1648, 1627, 1585,
124.0 (C-6), 120.9 (C-3), 117.9 (C-8), 47.0 (C-1ЈЈ), 32.3 (C-2ЈЈ), 19.9
(C-3ЈЈ), 13.8 (C-4ЈЈ) ppm. IR (KBr): ν = 3326, 2957, 2928, 2871,
˜
˜
1534, 1492, 1449, 1438, 1374, 1092, 909, 813, 768, 676 cm–1. MS:
m/z = 347 [M]+· (100%), 319. C21H14ClNO2 (347.80): calcd. C 2358, 1613, 1465, 1195, 757 cm–1. MS: m/z = 293 [M]+·, 250
72.52, H 4.06, Cl 10.19, N 4.03; found C 72.55, H 4.10, Cl 10.21, (100%). C24H19NO2 (353.42): calcd. C 81.56, H 5.42, N 3.96; found
N 4.01.
C 81.60, H 5.45, N 3.93.
7-Morpholinoflavone (18k): Eluent: toluene/ethyl acetate, 4:1; yield
150 mg (74%); m.p. 208–211.5 °C. H NMR (CDCl3): δ = 8.07 (d,
3-N-Pyrrolidinoflavone (24d): Oil, eluent: hexane/ethyl acetate, 3:1;
yield 26 mg (13%). H NMR (CDCl3): δ = 8.22 (d, J = 7.9 Hz, 1
1
1
J = 9.0 Hz, 1 H, 5-H), 7.89 (m, 2 H, 2Ј-H, 6Ј-H), 7.51 (m, 3 H, 3Ј-
H, 5Ј-H, 4Ј-H), 6.96 (dd, J = 2.2, 9.0 Hz, 1 H, 6-H), 6.83 (s, J =
2.2 Hz, 1 H, 8-H), 6.73 (s, 1 H, 3-H), 3.89 (m, 4 H, 3ЈЈ-H, 5ЈЈ-H),
3.36 (m, 4 H, 2ЈЈ-H, 6ЈЈ-H) ppm. 13C NMR (CDCl3): δ = 177.7 (C-
4), 162.6 (C-2), 158.1 (C-8a), 155.0 (C-7), 132.0 (C-1Ј), 131.2 (C-
4Ј), 128.9 (C-3Ј, C-5Ј), 126.6 (C-5), 126.0 (C-2Ј, C-6Ј), 115.9 (C-
4a), 112.9 (C-6), 107.4 (C-3), 100.3 (C-8), 66.4 (C-3ЈЈ, C-5ЈЈ), 47.6
H, 5-H), 8.01 (d, J = 7.2 Hz, 2 H, 2Ј-H, 6Ј-H), 7.64 (m, 1 H, 7-H),
7.47–7.50 (m, 4 H, 6-H, 8-H, 3Ј-H, 5Ј-H), 7.37 (m, 1 H, 4Ј-H), 3.16
(m, 4 H, 2ЈЈ-H, 5ЈЈ-H), 1.94 (m, 4 H, 3ЈЈ-H, 4ЈЈ-H) ppm. 13C NMR
(CDCl3): δ = 177.9 (C-4), 161.9 (C-8a), 155.4 (C-2), 133.1 (C-7),
132.9 (C-1Ј), 130.4 (C-4a), 130.0 (C-5), 128.7 (C-2Ј, C-6Ј), 128.0
(C-3Ј, C-5Ј), 125.6 (C-4Ј), 124.5 (C-6), 124.3 (C-3), 117.9 (C-8),
50.6 (C-2ЈЈ, C-5ЈЈ), 26.3 (C-3ЈЈ, C-4ЈЈ) ppm. IR (KBr): ν = 3437,
˜
2929, 2851, 1615, 1602, 1466, 1376, 1307, 1198, 754, 689 cm–1. MS:
m/z = 291 [M]+· (100 %), 248, 222, 194, 165, 120. C19H17NO2
(291.35): calcd. C 78.33, H 5.88, N 4.81; found C 78.37, H 5.90, N
4.80.
(C-2ЈЈ, C-6ЈЈ) ppm. IR (KBr): ν = 3432, 3060, 2963, 2855, 1632,
˜
1592, 1573, 1511, 1494, 1448, 1383, 1239, 1124, 819, 772 cm–1. MS:
m/z = 307 [M]+· (100%), 249, 222, 147, 91. C19H17NO3 (307.35):
calcd. C 74.25, H 5.58, N 4.56; found C 74.24, H 5.60, N 4.54.
3-Hydroxy-1-(5-bromo-2-hydroxyphenyl)-3-phenylprop-2-en-1-one
(15):
Buchwald–Hartwig Cross-Coupling of 3-Bromoflavone (23) by Mi-
crowave Activation: A mixture of 3-bromoflavone (23; 100 mg,
0.330 mmol), n-butylamine (40 μL, 0.400 mmol), NaOtBu (44 mg,
0.46 mmol), and BINAP (15 mg, 0.025 mmol) in toluene (3 mL) in
a capped vial (10 mL) was irradiated for 15 min (200 W, 110 °C).
Then the mixture was cooled, water was added (10 mL), and the
mixture was extracted with ethyl acetate (2ϫ 25 mL). The com-
bined organic layers were washed with water, and dried (magne-
sium sulfate), and the solvent was evaporated in vacuo. The crude
product was purified by column chromatography (hexane/ethyl
acetate, 4:1) to give 24a (26 mg, 27%) as a yellow oil.
Eluent: toluene/ethyl acetate, 4:1; yield 17 mg (7.7%); m.p. 112–
115 °C. This compound was obtained as a by-product from the
reaction of tert-butylamine and 6-bromoflavone. 1H NMR
(CDCl3): δ = 15.48 (s, 1 H, 2ЈЈ-OH), 12.06 (s, 1 H, 3-OH), 7.96 (d,
J = 7.2 Hz, 2 H, 2Ј-H, 6Ј-H), 7.85 (s, 1 H, 6ЈЈ-H), 7.57 (d, J =
7.2 Hz, 1 H, 4ЈЈ-H), 7.52 (m, 3 H, 3Ј-H, 5Ј-H, 4Ј-H), 6.90 (d, J =
9.0 Hz, 1 H, 3ЈЈ-H), 6.75 (s, 1 H, 2-H) ppm. 13C NMR (CDCl3): δ
= 194.2 (C-1), 178.4 (C-3), 161.3 (C-2ЈЈ), 138.3 (C-4ЈЈ), 133.2 (C-
1Ј), 132.8 (C-6ЈЈ), 130.6 (C-4Ј), 128.8 (C-2Ј, C-6Ј), 127.0 (C-3Ј, C-
5Ј), 120.8 (C-3ЈЈ), 120.3 (C-1ЈЈ), 110.7 (C-5ЈЈ), 92.1 (C-2) ppm. IR
Alkylation of 3-Aminoflavone (26) by Microwave Activation: A
mixture of 3-aminoflavone (26; 474 mg, 2.000 mmol), butyl brom-
ide (603 mg, 4.400 mmol), and potassium carbonate (608 mg,
4.400 mmol) in water (4 mL) was irradiated for 60 min (100 W,
120 °C) in a capped vial (10 mL). Then, the mixture was cooled
and extracted with ethyl acetate (2ϫ 25 mL). The combined or-
ganic layers were washed with water, and dried (magnesium sulf-
ate), and the solvent was evaporated in vacuo. The crude product
was purified by column chromatography (hexane/ethyl acetate, 4:1)
to give 24a (114 mg, 19%) as a yellow oil.
(KBr): ν = 1607, 1567, 1469, 1289, 1190, 913, 744 cm–1.
˜
7-(Butylamino)-4Ј-methoxyflavone (20a): Eluent: toluene/ethyl acet-
ate, 1:1; yield 178 mg (84 %); m.p. 173.5–175.5 °C. 1H NMR
(CDCl3): δ = 7.95 (d, J = 9.0 Hz, 1 H, 5-H), 7.83 (d, J = 8.6 Hz, 2
H, 2Ј-H, 6Ј-H), 6.99 (d, J = 8.6 Hz, 2 H, 3Ј-H, 5Ј-H), 6.59 (m, 2
H, 3-H, 6-H), 6.50 (d, J = 1.8 Hz, 1 H, 8-H), 4.42 (s, 1 H, NH),
3.87 (s, 3 H, 4Ј-OCH3), 3.20 (m, 2 H, 1ЈЈ-H), 1.66 (m, 2 H, 2ЈЈ-H),
1.46 (m, 2 H, 3ЈЈ-H), 0.98 (t, J = 7.6 Hz, 3 H, 4ЈЈ-H) ppm. 13C
NMR (CDCl3): δ = 177.7 (C-4), 162.1 (C-2), 161.9 (C-4Ј), 158.7
(C-8a), 153.0 (C-7), 127.6 (C-2Ј, C-6Ј), 126.5 (C-5), 124.5 (C-1Ј),
114.4 (C-4a), 114.2 (C-3Ј, C-5Ј), 112.7 (C-6), 105.9 (C-3), 96.3 (C-
8), 55.4 (4Ј-OCH3), 43.2 (C-1ЈЈ), 31.2 (C-2ЈЈ), 20.2 (C-3ЈЈ), 13.81
Ring Contraction: A mixture of 3-bromoflavone (100 mg,
0.33 mmol) and amine (0.825 mmol, 2.5 equiv.) in THF was stirred
for 1 d at ambient temperature according to the literature pro-
cedure.[45] Then the solvent was evaporated, and the crude reaction
mixture was submitted directly to a silica gel column to give the
pure product.
2-[α-(Butylamino)benzylidene]benzofuran-3(2H)-one (25a): Yellow
1
oil, eluent: hexane/ethyl acetate, 5:1; yield 71 mg (74%). H NMR
(C-4ЈЈ) ppm. IR (KBr): ν = 3302, 2950, 2929, 2860, 1624, 1608,
˜
(CDCl3): δ = 10.02 (s, 1 H, NH), 7.84 (d, J = 7.6 Hz, 1 H, 5-H),
7.50 (m, 5 H, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), 7.42 (t, J = 7.8 Hz, 1
H, 7-H), 7.13 (m, 2 H, 6-H, 8-H), 3.23 (t, J = 6.8 Hz, 2 H, 1ЈЈ-H),
1.56 (m, 2 H, 2ЈЈ-H), 1.38 (m, 2 H, 3ЈЈ-H), 0.87 (t, J = 7.3 Hz, 3
H, 4ЈЈ-H) ppm. 13C NMR (CDCl3): δ = 177.5, 160.8, 152.2, 132.0,
131.7, 130.2, 129.7, 128.9, 128.6, 124.7, 122.8, 121.6, 112.5, 44.2,
1584, 1566, 1537, 1508, 1423, 1376, 1244, 1176, 1095, 909, 822,
597 cm–1. MS: m/z = 323 [M]+·, 280 (100 %), 148. C20H21NO3
(323.39): calcd. C 74.28, H 6.55, N 4.33; found C 74.25, H 6.58, N
4.35.
3-(Butylamino)flavone (24a): Yellow oil, eluent: hexane/ethyl acet-
ate, 3:1; yield 64 mg (33%). 1H NMR (CDCl3): δ = 8.24 (d, J =
7.9 Hz, 1 H, 5-H), 7.96 (d, J = 7.2 Hz, 2 H, 2Ј-H, 6Ј-H), 7.60 (t, J
32.7, 29.6, 19.7, 13.6 ppm. IR (KBr): ν = 3368, 3065, 2960, 2932,
˜
2873, 1702, 1632, 1603, 1458, 1381, 1250, 755, 713 cm–1. MS: m/z
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O43108
/KAP1
Date: 15-12-14 12:48:59
Pages: 13
K. Kónya, D. Pajtás, A. Kiss-Szikszai, T. Patonay
FULL PAPER
= 293 [M]+·, 250 (100%). C19H19NO2 (293.36): calcd. C 77.79, H
6.53, N 4.77; found C 77.82, H 6.55, N 4.80.
General Procedure for the Synthesis of 6- and 7-(Diphenylmethyl-
eneamino)flavones (27a and 27b): A mixture of 6-bromo- (11) or
7-bromoflavone (17; 1.505 g, 5.00 mmol), BINAP (235 mg,
0.375 mmol), benzophenone imine (2; 1.10 mL, 6.00 mmol), palla-
dium acetate (55 mg, 0.250 mmol, 5 mol-%), and cesium carbonate
(2.120 g, 6.50 mmol) in xylene (30 mL) was stirred at reflux over-
night under a nitrogen atmosphere. The cooled mixture was poured
into water (100 mL), then extracted with ethyl acetate (3ϫ 25 mL).
The combined organic phases were dried with magnesium sulfate,
then the solvents were removed in vacuo. The solid residue was
triturated with a mixture of hexane (20 mL) and acetone (1 mL) to
give pure 27a or 27b as a pale yellow solid.
7-{[2-Phenyl-1-(methoxycarbonyl)ethyl]amino}flavone (31a): Eluent:
toluene/ethyl acetate, 2:1; yield 168 mg (64%); m.p. 171.5–173.5 °C.
1H NMR (CDCl3): δ = 8.00 (d, J = 8.6 Hz, 1 H, 5-H), 7.88 (m, 2
H, 2Ј-H, 6Ј-H), 7.51 (m, 3 H, 3Ј-H, 5-H, 4Ј-H), 7.31 (m, 3 H, 3ЈЈЈ-
H, 5ЈЈЈ-H, 4ЈЈЈ-H), 7.15 (m, 2 H, 2ЈЈЈ-H, 6ЈЈЈ-H), 6.71 (s, 1 H, 3-
H), 6.64 (dd, J = 1.8, 8.6 Hz, 1 H, 6-H), 6.54 (s, 1 H, 8-H), 4.83
(d, J = 7.9 Hz, 1 H, NH), 4.50 (m, 1 H, 1ЈЈ-H), 3.76 (s, 3-H, OCH3),
3.23 (m, 2 H, 2ЈЈ-H) ppm. 13C NMR (CDCl3): δ = 178.2 (C-4),
172.2 (COOMe), 163.2 (C-2), 158.8 (C-8a), 151.4 (C-7), 135.4 (C-
1ЈЈЈ), 131.8 (C-1Ј), 131.5 (C-4Ј), 129.2 (C-3ЈЈЈ, C-5ЈЈЈ), 129.0 (C-
2ЈЈЈ, C-6ЈЈЈ), 128.8 (C-3Ј, C-5Ј), 127.4 (C-5), 127.2 (C-4ЈЈЈ), 126.2
(C-2Ј, C-6Ј), 114.9 (C-4a), 113.6 (C-6), 106.8 (C-3), 97.6 (C-8), 56.8
7-[(Diphenylmethylene)imino]flavone (27b): Yield 73%; m.p. 212–
213 °C. 1H NMR (CDCl3): δ = 7.99 (d, J = 8.6 Hz, 1 H, 5-H), 7.85
(m, 2 H, Ph), 7.77 (m, 2 H, Ph), 7.51 (m, 6 H, Ph), 7.45 (d, J =
8.6 Hz, 1 H, 6-H), 7.29 (m, 3 H, Ph), 7.17 (m, 2 H, Ph), 6.90 (s, 1
H, 8-H), 6.74 (s, 1 H, 3-H) ppm. 13C NMR (CDCl3): δ = 178.0 (C-
4), 169.5 (C=N), 162.9 (C-2), 156.8 (C-8a), 138.6 (C-7), 135.2, 137.5
(C-1ЈЈ), 131.8 (C-1Ј), 132.4, 131.4, 130.0, 129.8, 129.5, 129.1, 128.3
(Ph), 126.1 (C-7), 119.4 (C-4a), 119.0 (C-5), 108.5, 107.5 (C-3, C-
(C-1ЈЈ), 52.6 (OCH ), 38.1 (C-2ЈЈ) ppm. IR (KBr): ν = 3396, 3265,
˜
3
3152, 3065, 3028, 2948, 1726, 1624, 1593, 1538, 1507, 1448, 1436,
1370, 1249, 1191, 1148, 906, 822, 766, 699 cm–1. MS: m/z = 399
[M]+·, 340, 308 (100%), 248, 221, 165, 91. C25H21NO4 (399.45):
calcd. C 75.17, H 5.30, N 3.51; found C 75.21, H 5.33, N 3.54.
8) ppm. IR (KBr): ν = 3455, 3068, 1640, 1617, 1458, 1358, 1289,
˜
1024, 910, 773, 697 cm–1. MS: m/z = 401 [M]+·, 324, 297, 221, 165
(100%), 139, 102, 77. C28H19NO2 (401.46): calcd. C 83.77, H 4.77;
found C 83.80, H 4.75. C28H19NO2 (401.46): calcd. C 83.77, H
4.77, N 3.49; found C 83.80, H 4.75, N 3.54.
This product was also obtained as a by-product from the reaction
of 6-bromoflavone (11) in 6% yield.
7-{[3-Methyl-1-(methoxycarbonyl)butyl]amino}flavone (31c): Eluent:
toluene/ethyl acetate, 2:1; yield 136 mg (56%); m.p. 152–156 °C. 1H
NMR (CDCl3): δ = 8.01 (d, J = 8.6 Hz, 1 H, 5-H), 7.89 (m, 2 H,
2Ј-H, 6Ј-H), 7.50 (m, 3 H, 3Ј-H, 5Ј-H, 4Ј-H), 6.71 (s, 1 H, 3-H),
6.68 (dd, J = 2.1, 8.6 Hz, 1 H, 6-H), 6.56 (d, J = 2.1 Hz, 1 H, 8-
H), 4.80 (d, J = 8.6 Hz, 1 H, NH), 4.21 (m, 1 H, 1ЈЈ-H), 3.77 (s, 3
H, OCH3), 1.78 (m, 3 H, 2ЈЈ-H, 3ЈЈ-H), 1.02 (d, J = 6.5 Hz, 3 H,
4ЈЈ-H), 0.97 (d, J = 6.1 Hz, 3 H, 4ЈЈ-H) ppm. 13C NMR (CDCl3):
δ = 177.7 (C-4), 173.9 (COOMe), 162.4 (C-2), 158.5 (C-8a), 151.8
(C-7), 132.0 (C-1Ј), 131.1 (C-4Ј), 128.9 (C-3Ј, C-5Ј), 127.0 (C-5),
126.1 (C-2Ј, C-6Ј), 115.5 (C-4a), 113.1 (C-6), 107.4 (C-3), 97.5 (C-
8), 54.6 (OCH3), 52.4 (C-1ЈЈ), 41.8 (C-2ЈЈ), 24.9, 22.7 (C-4ЈЈ), 22.1
General Procedure for the Synthesis of 6- and 7-Aminoflavones (28a
and 28b): [(Diphenylmethylene)imino]flavone 27a or 27b (1.466 g,
3.651 mmol) was dissolved in THF (14 mL), and HCl (6 n aq.;
9.2 mL, 18.0 mmol, 5 equiv.) was added. After 10 min, dichloro-
methane (25 mL) and water (50 mL) were added, and then the mix-
ture was stirred at room temperature overnight. Next, dichloro-
methane (10 mL) was added, upon which the reaction mixture be-
came clear. The pH was adjusted to ca. 9–10 by the addition of
saturated sodium hydrogen carbonate solution (vigorous evolution
of gas!). The product was extracted with dichloromethane (3ϫ
50 mL). The combined organic extracts were dried with magnesium
sulfate, and the solvent was evaporated in vacuo. The solid residue
was triturated with a mixture of hexane (20 mL) and acetone
(1 mL) to give pure amine 28a or 28b as a pale yellow solid.
(C-3ЈЈ) ppm. IR (KBr): ν = 3289, 3153, 3087, 2953, 1724, 1620,
˜
1589, 1566, 1534, 1449, 1373, 1250, 1190, 1149, 1000, 9008, 824,
768, 686, 673 cm–1. MS: m/z = 365 [M]+·, 306 (100%), 250, 91.
C22H23NO4 (365.43): calcd. C 72.31, H 6.34, N 3.83; found C
72.35, H 6.38, N 3.85.
7-Aminoflavone (28b): Yield 68%; m.p. 183–185 °C, lit. m.p.[5]
186 °C. 1H NMR (CDCl3): δ = 8.01 (d, J = 9.2 Hz, 1 H, 5-H), 7.87
(m, 2 H, 2Ј-H, 6Ј-H), 7.50 (m, 3 H, 3Ј-H, 5Ј-H, 4Ј-H), 6.69 (m, 3
H, 3-H, 6-H, 8-H), 4.33 (br. s, 2 H, NH2) ppm. 13C NMR (CDCl3):
δ = 177.7 (C-4), 162.4 (C-2), 158.3 (C-7), 151.9 (C-8a), 132.0 (C-
1Ј), 131.2 (C-5), 128.9 (C-3Ј, C-5Ј), 127.2 (C-4Ј), 126.1 (C-2Ј, C-
6Ј), 115.7 (C-4a), 113.7 (C-6), 107.3 (C-3), 100.2 (C-8) ppm. IR
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, physical and spectroscopic data (1H
and 13C NMR, IR, and MS) for the products.
Acknowledgments
(KBr): ν = 3462, 3332, 3194, 1633, 1586, 1569, 1450, 1388, 1370,
˜
1248, 1186, 1026, 909, 832, 768 cm–1. MS: m/z = 237 [M]+·, 209,
180, 152, 135, 107, 79. C15H11NO2 (237.26): calcd. C 75.94, H 4.67,
N 5.90; found C 75.95, H 4.69, N 5.95.
Financial support from the Hungarian Scientific Research Fund
(OTKA) (grant number K75806) and from the New Hungary De-
velopment Plan, cofinanced by the European Social Fund and the
European Regional Development Fund (project number TÁMOP-
4.2.2/B-10/1-2010-0024) is greatly appreciated.
General Method for Coupling 6- and 7-Bromoflavone with Amino
Acid Methyl Ester Hydrochlorides: Bromoflavone 11 or 17
(0.66 mmol), cesium carbonate (557 mg, 1.71 mmol), BINAP
(32 mg, 0.050 mmol), and the amino acid methyl ester hydrochlor-
ide (0.80 mmol) were mixed in dry xylene (6 mL) in an oven-dried
flask under nitrogen, and Pd(OAc)2 (7 mg, 0.032 mmol) was added.
The reaction mixture was stirred at reflux at 135 °C for 24 h in an
oil bath. The crude reaction mixture was applied directly to a silica
gel column to give the pure cross-coupled product.
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O43108
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Date: 15-12-14 12:48:59
Pages: 13
Buchwald–Hartwig Reactions of Monohaloflavones
Amination of Flavones
K. Kónya, D. Pajtás, A. Kiss-Szikszai,
T. Patonay* ..................................... 1–13
Buchwald–Hartwig Reactions of Mono-
haloflavones
Keywords: Homogeneous catalysis / Cross-
coupling / Amination / Palladium / Amino
acids / Oxygen heterocycles
A new and efficient approach to (substi-
tuted) aminoflavones and hybrids of flav-
ones and amino acids using Buchwald–
Hartwig coupling was developed and op-
timised.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13