Palladium-catalyzed synthesis of 8-allyl or 8-prenylcoumarins by using organotin reagents as multicoupling nucleophiles

Article abstract of DOI:10.1002/aoc.2944

In this study, 8-iodocoumarin derivatives underwent a direct Stille cross-coupling reaction with several organotin compounds in the presence of a catalytic amount of Pd(PPh₃)₄ in DMF at 80 °C. The cross-coupling reaction proceeded smoothly under mild conditions and permitted the formation of 8-allyl or 8-prenylcoumarin compounds in good yields. Copyright

Full text of DOI:10.1002/aoc.2944

Full Paper
Received: 24 August 2012
Revised: 9 October 2012
Accepted: 9 October 2012
Published online in Wiley Online Library: 4 December 2012
(wileyonlinelibrary.com) DOI 10.1002/aoc.2944
Palladium-catalyzed synthesis of 8-allyl or
-prenylcoumarins by using organotin reagents
8
as multicoupling nucleophiles
Qiang Yin, Han Yan, Yaqin Zhang, Yige Wang, Guojin Zhang,
Yuxiang He and Weihua Zhang*
In this study, 8-iodocoumarin derivatives underwent a direct Stille cross-coupling reaction with several organotin compounds
ꢀ
in the presence of a catalytic amount of Pd(PPh ) in DMF at 80 C. The cross-coupling reaction proceeded smoothly under
3
4
mild conditions and permitted the formation of 8-allyl or 8-prenylcoumarin compounds in good yields. Copyright © 2012 John
Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: palladium; cross-coupling; organotin; allylcoumarins; prenylcoumarins
8
-iodocoumarins with allyltributyltin to form 8-alkylcoumarin
Introduction
compounds in a very efficient manner.
Coumarins are important structural units that are widespread in
[
1]
many naturally and biologically active compounds. Over the past
decades, the synthesis and screening of coumarin compounds
for drug and material discovery have been subjects of constant
interest in medicinal chemistry and material science because of
their noticeable biological activities, including antimicrobial, anti-
Results and Discussion
The key compounds in the overall synthetic route were identified
to be 7-hydroxycoumarins and 7-hydroxy-4-methylcoumarins.
7-Hydroxycoumarins are known as useful intermediates for many
[
2]
viral and fluorescence activities. This study recently discovered
that 8-allyl and 8-prenylcoumarins have interesting biological
industrial products, and several methods for their preparation have
[3]
[10,11]
properties. For example, osthenol and its analog osthol are two
been reported.
The functionalized 7-hydroxy-8-iodocoumarins
[
4]
8
-prenylcoumarins that show good anti-hepatitis and antibacte-
(1a) were prepared by treating 7-hydroxycoumarin with I /KI/20%
2
[5]
rial activities, respectively.
NH .H O (Scheme 1) and then isolating it in 48% yield after
3
2
[
12]
In contrast to the numerous applications of 8-allyl or 8-prenyl-
coumarin derivatives, few synthetic approaches have been found
to obtain such compounds. Thus this study initiated a program to
develop efficient methods for the synthesis of different coumarin
molecules, with the hope of finding more active hits. The direct
purification.
the coupling reactions were prepared following the literature
Then, the 7-alkoxy-8-iodocoumarins required for
[
13]
procedures (Fig. 1 and Scheme 1).
This study initially adopted the Negishi coupling with allylzinc
bromide and 8-iodocoumarins as substrates. Different solvents,
palladium catalysts and reaction temperatures were used.
However, only the deiodine product was obtained in this study
(Table 1, entries 1 and 2). Thus the protocol in hand is not appropriate
for the coupling of 8-iodocoumarins with allylzinc bromide and
further study is required to find suitable conditions.
[6,7]
replacement under alkaline condition, particularly by the reaction
of hydroxycoumarin with allyl or prenyl halogenated hydrocarbons
under alkaline or Lewis acid conditions, is undoubtedly the most
commonly used method for introducing a variety of allyl or
prenyl substitutions in the 8th position. Although the procedures
above are useful for the preparation of C-allyl or prenyl-substituted
coumarins, their yields and selectivities are unsatisfactory.
We then studied the cross-coupling reactions of 8-iodocoumar-
ins with allyltributyltin and allyltributyltin; results were found to
be excellent, giving the 8-allylcoumarins in satisfactory yields. The
Stille coupling reaction is probably the most widely used among
the transition metal-catalyzed cross-coupling reactions because of
Therefore, the search for high-yield and selective procedures
as well as diversity-oriented reactions, such as Pd-catalyzed
couplings, presents an interesting challenge. However, recent
research focused on the use of palladium-catalyzed C&-C bond
[
14–18]
its great functional group tolerance during transformation.
To the best of our knowledge, no studies on Stille cross-coupling
[
8]
formation to yield 3- or 4-substituted coumarins, and only few
[9]
studies on the use of C&-C substitutions on the benzene ring of
coumarins have been reported. The current study reports a
general and efficient palladium-catalyzed protocol for the facile
synthesis of an array of C-allylcoumarins by using allyltributyltins
as multicoupling nucleophiles. To the best of our knowledge,
this is the first report on the palladium-catalyzed coupling of
*
Correspondence to: Qiang Yin, College of Science, Nanjing Agricultural University,
Nanjing 210095, China. E-mail: wyinqiang@163.com
College of Science, Nanjing Agricultural University, Nanjing 210095, China
Appl. Organometal. Chem. 2013, 27, 85–88
Copyright © 2012 John Wiley & Sons, Ltd.

Q. Yin et al.
Scheme 1. Preparation of 8-iodo derivatives of coumarins.
Table 2. Reaction conditions optimization
R O
O
O
R1O
O
O
4 9 3
Sn(n-C H )
Solvent
Pd]
1
HO
O
O
[
I
I
HO
O
O
I
1
1
1
1
1
a:R =H
1f:R1=CH3
2a
1
1
a
3a
b:R =CH3
1g:R1=C2H5
1h:R1=n-C3H7
1i: R1=n-C4H9
1
c:R =C H
1
2
5
a
b
ꢀ
Entry
Catalyst
Solvent
Temp. ( C)
Yield
d:R =n-C H
7
1
3
e:R =CH CH=CH
1
2
3
1
2
3
4
5
6
Pd(P(Ph)3)4
DMF
Toluene
THF
80
80
80
80
60
100
80
80
70.0%
37.1%
30.3%
51.5%
55.2%
68%
Pd(P(Ph)
Pd(P(Ph)
3
)
)
4
Figure 1. 8-Iodo derivatives of coumarins.
3
4
Pd(OAc)
Pd(P(Ph)
2
DMF
DMF
DMF
DMF
DMF
3
)
4
)
4
)
4
)
4
Pd(P(Ph)
Pd(P(Ph)
Pd(P(Ph)
3
Table 1. The Negishi coupling with allylzinc bromide and 8-iodocoumarins
c
7
3
3
65%
d
8
61%
Solvent
ZnBr
a
Reaction conditions: 8-iodocoumarin 1a (1 mmol), allyltributyltin 2a
1.5mmol), solvent (15 mL), catalyst (0.05mmol), P(Ph) (0.05mmol),
[Pd]
HO
O
O
HO
O
O
(
3
I
LiCl (4.0mmol).
Yields after isolation by column chromatography.
1
a
b
c
3a
Reaction conditions a without LiCl.
d
3
Reaction conditions a without P(Ph) .
a
ꢀ
b
Entry
Catalyst
Solvent
Temp. ( C)
Yield
1
2
Pd(P(Ph)
Pd(OAc)
3
)
4
THF/toluene/ether
THF/toluene/ether
0, 60, 80
0, 60, 80
Trace
Trace
2
influence of different solvents such as THF, DMF and toluene
was examined. We find that the solvent greatly affected the
cross-coupling reaction, and significant increases in yield and rate
were observed when DMF was used as the solvent (Table 1, entries
a
Reaction conditions: 8-iodocoumarin 1a (1 mmol), allylzinc bromide
2 mmol), solvent(15 ml), catalyst(0.05 mmol).
Yields after isolation by column chromatography.
(
b
3
–5). A few control reactions were next carried out to gain the
effective role of the base and ligand. Although the reaction without
LiCl or P(Ph) afforded a moderate yield of the product (Table 2,
entries 7 and 8), we continued our studies with LiCl as base and
P(Ph) as ligand. The impact of other parameters, such as the
reaction using 8-iodocoumarins as substrate in the preparation of
-allylcoumarins have been reported. Our increasing interest in
the palladium-catalyzed Stille cross-coupling reactions of coumarins
prompted us to examine the cross-coupling reaction of 8-iodocou-
marins 1a–i with organotin 2a–b to obtain 8-allyl or prenylcoumar-
ins 3a–n (Table 3).
In this study, initial efforts were devoted to the selection of a
suitable catalyst system for an efficient coupling pathway. In
this method, 7-hydroxy-8-iodocoumarin 1a and allyltributyltin 2a
were used as standard substrates. The optimal conditions for the
palladium-catalyzed coupling of 8-iodocoumarin 1a (0.1mmol)
and allyltributyltin 2a (0.15 mmol) were determined through a
series of experiments in which sequential changes were made to
the catalyst, solvent and temperature used in the reaction (Table 2).
As can be seen in Table 1, catalysts Pd(0) and Pd(II), such as
3
8
3
amount of the organotin compound in the reaction, was also
investigated. The cross-coupling reaction was observed to require
excess amounts of allyltributyltin (1.5 equiv.). Similar yields of
3a were obtained when 1.5 or 2 equiv. of compound 2a was
used. Further, we standardized the temperature conditions, as
the temperature also had an influence on product yields. When
ꢀ
the reaction temperature was increased to 60, 80 and 100 C, the
product yield was 55.2%, 70% and 68%, respectively (Table 2,
entries 1, 5 and 6).
Upon careful analysis of the optimized reactions, optimum
conditions for the cross-coupling were as follows: 7-hydroxy-8-
iodocoumarin 1a (1mmol) and allyltributyltin 2a (1.5 mmol)
Pd(OAc)2 and Pd(PPh ) , were tested, and better results were
catalyzed by Pd(PPh ) (5 mol%) with LiCl (4 mmol) in DMF (15 mL)
3 4
at 80 C. Under these conditions, this study was able to prepare
3 4
ꢀ
obtained when Pd(PPh ) was used, yielding 70% of the desired
3
4
product 3a (Table 2, entry 1). During the preliminary studies, the
7-hydroxy-8-allylcoumarin 3a with 70% yield (Table 2, entry 1).
wileyonlinelibrary.com/journal/aoc
Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 85–88

An efficient protocol for synthesis of 8-allylcoumarins
Upon determination of the optimum reaction conditions, the
coupling of 8-iodocoumarins with organotin was investigated
Table 3. The Stille cross-coupling reaction of 8-iodocoumarin and
organotin
(Table 2). Allyl and prenyl were found able to efficiently transfer
from organotin reagents to coumarins. However, the reaction did
not show sensitivity to the hydroxyl group because the presence
of a phenol hydroxyl substituent at the C-7 position of 8-iodocou-
marins did not alter the course of coupling (Table 3, entry 1). When
7-allyloxy-8-iodocoumarin was used as the substrate, formation of
the desired product was not observed (Table 3, entry 6). The double
bond of allyloxy at the C-7 position likely reacted with the iodo
substituent at C-8 position, resulting in the formation of some kind
of unstable cyclic compounds by using palladium-catalyzed Heck
coupling. In addition, the steric effects on the Stille cross-coupling
reaction were investigated (Table 3, entries 2–14). Experimental
results indicate that the steric effect is insignificant to the reaction
yields. The reactions of allyltributyltin were successfully converted
within 4h (Table 3, entries 1–8). Although a longer reaction time
was needed (6h), the more sterically hindered prenyltributyltin
was observed to work well under the coupling conditions, as
a
b
Entry
8-Iodocoumarins
R = H
Product
3a
Yield (%)
1
70.0
R
R
1
2
= H
= H
2
3
4
5
6
7
8
9
R = H
= CH
= H
R = H
= CH CH
= H
R = H
= CH CH
= H
R = H
= CH
3b
3c
3d
3e
3f
62.3
68.5
67.6
60.9
trace
35.0
46.5
56.2
66.1
69.4
56.7
46.6
42.3
R
1
3
R
2
3i–3n were obtained in a satisfactory yield.
R
1
3
2
R
2
Conclusions
R
1
3
2
CH
2
R
2
In summary, this study investigated the Stille cross-coupling
reaction of 8-iodocoumarin derivatives by using several organotin
compounds in the presence of Pd(PPh ) as the catalyst and LiCl
R
1
3
3
3
4
ꢀ
R2 = CH
as the base in DMF at 80 C. Furthermore, a new route that can
obtain 8-allyl or prenylcoumarin compounds in good to excellent
yield was established. A good reference value was also obtained
for the C-allylation of other natural products. It is known that rear-
ranged products can be obtained in cross-coupling of prenyltribu-
R = H
R
1
= CH
3
CH&dbond;CH
= CH
R = H
2
R
2
3
3g
3h
3i
[
19]
R = CH CH CH CH
tyltin with allyl bromide or in cross-coupling of other substituted
allyltins with aromatic halides or acyl halides; however, non-
rearranged product was observed in the report. The method appear
of a much higher flexibility and, accordingly, will be much more
interesting for the practitioner. The results of analyses of the
1
3
2
2
2
R
2
= CH
3
R = H
= CH CH
= CH
R
1
1
3
2
3
CH
2
2
R
2
1
13
R = CH3
H NMR and C NMR spectra show that all the obtained products
R
= CH
= CH
R = CH
= CH
= H
R = CH3
= CH CH
= H
R = CH
= CH CH
= H
R = CH
3
CH
2
CH
presented data in full agreement with their assigned structures.
R
2
3
1
0
3
3j
R
1
3
Experimental
R
2
General Experimental Methods
11
3k
3l
R
1
3
2
Commercially available reagents(include organotin) and solvents
were used without further purification unless otherwise stated.
Yields refer to isolated and purified products. Reactions were mon-
itored by thin-layer chromatography (TLC), carried out on silica gel
plates (60 F-254) and visualized under UV light. Column chromatog-
raphy was performed on silica gel (100–200 mm). Chemical shifts of
R
2
12
13
14
3
R
1
3
2
CH
2
R
2
3
3m
3n
1
13
R
R
1
2
= CH
= CH
3
3
H NMR and C NMR were reported in ppm (d units). Multiplicity
is given by the following symbols: s (singlet), bs (broad singlet),
d (doublet), t (triplet), q (quadruplet), dd (doublet of doublets),
m (multiplet). Coupling constants are reported in Hz. The proton
signal of residual and non-deuterated solvent 7.26 for deuterated
R = CH
= CH CH
= CH
3
R
1
3
2
R
2
3
chloroform (CDCl ) and 2.50 for deuterated DMSO were used
as an internal reference for H spectra. For C spectra, chemical
a
3
Reaction conditions: 8-iodocoumarin (1 mmol), organotin (1.5 mmol),
1
13
DMF (15 ml), Pd(P(Ph)
(4.0 mmol) at 80 C.
3
)
4
(0.05 mmol), P(Ph)
3
(0.05 mmol), LiCl
ꢀ
shifts are reported relative to the 77.16 resonance of CDCl or
3
b
39.52 resonance of DMSO. IR spectra were recorded with a Bruker
Yields after isolation by column chromatography; average yields.
Tensor-7 FT-IR spectrometer and are reported as wavenumbers
À1
(
cm ). High-resolution mass spectra were recorded on an FT-ICR
mass spectrometer (Ionspec, 7.0T). Reaction times refer to the hold
Appl. Organometal. Chem. 2013, 27, 85–88
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

Q. Yin et al.
M. Mazzorana, G. Zagotto, E. Uriarte, A. Guiotto, L. A. Pinna, F. Meggio,
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time at the desired set temperature. Reaction cooling was
performed by compressed air after the heating period was over.
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General Procedure for the Coupling Reaction (3a–3n)
An oven-dried Schlenk tube under nitrogen was charged with
[
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8
-iodocoumarins (1.0 mmol), organotin (1.5 mmol), Pd(PPh
3 4
)
(5mol%), P(Ph) (0.05 mmol), LiCl (4.0mmol) and dry DMF (15 ml).
3
The mixture was stirred electromagnetically in an oil bath at
ꢀ
80 C, and the reaction time was determined by monitoring the
[
reaction using TLC. After the reaction had completed, the reaction
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2
mixture was cooled to room temperature. Then, CH
COOC H
3 2 5
[
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(20 ml) and 1 M aqueous KF (20 ml) were added, and the resulting
mixture was filtered. The filtrate was extracted with CH
COOC H
3 2 5
[
[
(
3 Â 20 ml). The combined organic phase was washed with saturated
sodium chloride solution. Then, the combined extract was dried
with anhydrous Na SO , and the solvents were evaporated in a
b) M. A. Soussi, D. Audisio, S. Messaoudi, O. Provot, J. D. Brion, M. Alami,
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2
4
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[
Acknowledgment
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of China (21072096, 21272116).
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