A novel organozinc reagent 4-coumarinylzinc bromide; Preparation and application in the synthesis of 4-substituted coumarin derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.03.151

A novel organozinc reagent, 4-coumarinylzinc bromide, was prepared by the direct oxidative addition of active zinc to 4-bromocoumarin. The resulting organozinc bromide underwent the palladium-catalyzed cross-coupling reactions with a variety of aryl halid

Full text of DOI:10.1016/j.tetlet.2011.03.151

Tetrahedron Letters 52 (2011) 3094–3096
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Tetrahedron Letters
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A novel organozinc reagent 4-coumarinylzinc bromide; preparation and
application in the synthesis of 4-substituted coumarin derivatives
Reuben D. Rieke a, Seung-Hoi Kim b,
⇑
a Rieke Metals, Inc., 1001 Kingbird Rd. Lincoln, NE 68521, USA
b Department of Chemistry, Dankook University, 29 Anseo, Cheonan 330-714, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel organozinc reagent, 4-coumarinylzinc bromide, was prepared by the direct oxidative addition of
active zinc to 4-bromocoumarin. The resulting organozinc bromide underwent the palladium-catalyzed
cross-coupling reactions with a variety of aryl halides and acid chlorides affording the corresponding
coupling products in good yields under mild conditions.
Received 12 February 2011
Revised 28 March 2011
Accepted 31 March 2011
Available online 7 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Due to the particular interest in the coumarin moiety in natural
products1 as well as in material chemistry,2 numerous studies
have focused on the development of a versatile synthetic methodol-
ogy for the preparation of coumarin derivatives. Among the
well-known procedures, palladium-catalyzed cross-coupling
reactions of organometallic reagents with coumarin derivatives
are one of the predominant approaches, especially for the prepara-
tion of 4-substituted coumarins (route A in Scheme 1). Scheme 1
illustrates the schematic diagram of the convenient synthetic routes
utilizing organometallic reagents for the 4-substituted coumarin
derivatives.
Y
MX
O
R
O
B
A
R-X
O
O
R-MX
O
O
Scheme 1. Synthetic routes for 4-substituted coumarin.
Table 1
Coupling reaction with benzoyl chloride
O
R
Although various methods were reported for the synthesis
of 4-substituted coumarin, inconvenient reaction conditions were
utilized in most of the previously reported reactions.3 As mentioned
before, route A in Scheme 1 is the most widely used in the
synthesis of the title compound. For example, Yang described the
preparation of 4-substituted coumarin using palladium-catalyzed
cross-coupling reaction of 4-tosylcoumarins4a and nickel-catalyzed
cross-coupling reaction of 4-diethylphosphonooxycoumarins with
ZnBr
1 % Pd(PPh3)4
THF/ rt/ 30 min
benzoyl
chloride
+
O
O
O
O
I
(1.0 eq)
0.8 eq
1a - 1f
Entry
Acid chloride
Producta (%)
COCl
O
organozinc.4b
A similar approach using palladium-catalyzed
O
X
X
cross-coupling reaction of 4-trifluoromethylsulfonyloxycoumarins
or 4-toluenesulfonyloxycoumarins with organostannes was also
reported by Wattanasin and Schio, respectively.5 The Suzuki-type
coupling reaction with 4-halocoumarin was employed to generate
the 4-substituted coumarins.6
Even though the route A could provide a variety of 4-substituted
coumarins, a drawback to this procedure is that some of the
organometallic reagents are not readily available. Therefore, in
spite of the present methodologies, there is still a need to explore
a versatile synthetic methodology for the construction of a chem-
ical library of 4-substituted coumarin derivatives. We considered
the alternative route to the synthesis of 4-substituted coumarins,
O
1
2
3
4
5
6
X = H (1a)
(90)
(86)
(88)
(91)
(92)
(79)
X = 3-Br (1b)
X = 4-F (1c)
X = 4-CF3 (1d)
X = 4-OMe (1e)
X = 3-CH2Cl (1f)
a
Isolated yield (based on acid chloride).
depicted route B in Scheme 1. We assumed that this route could
provide a versatile way of introducing a variety of different substit-
uents at the 4-position of coumarin. The direct preparation and
application of 4-coumarinylzinc bromide represents a novel and
versatile approach to many new substituted coumarins.
⇑
Corresponding author.
E-mail address: kimsemail@dankook.ac.kr (S.-H. Kim).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.151

R. D. Rieke, S.-H. Kim / Tetrahedron Letters 52 (2011) 3094–3096
3095
I
Br
ZnBr
Table 2
I2
1.2 eq Zn*
THF/rt/1 h
Coupling reaction with heteroaryl acid chloride
THF
O
O
O
O
O
I
O
1 % Pd(PPh3)4
THF/ rt/ 30 min
product
> 97 % by GC
I
+
Acid chloride
0.8 eq
2a - 2e
1.0 eq
Scheme 2. Preparation of 4-coumarinylzinc bromide (I).
Entry
1
Acid chloride
Producta (%)
Yielda (%)
In our continuing effort to develop a new class of organozinc re-
agents, we found that 4-coumarinylzinc bromide (1) was easily
prepared by the direct insertion of active zinc to 4-bromocoumarin
under mild conditions.7 Herein, we would like to report our
preliminary results obtained from the cross-coupling reaction of
the 4-coumarinylzinc bromide with a wide range of electrophiles
(Scheme 2).
Br
COCl
O
O
2a
N
75
O
N
COCl
O
O
Cl
N
2b
Prior to the study of this reagent in the coupling reactions, an
aliquot of the solution was treated with iodine and analyzed by
GC and GC–MS to confirm the formation of the corresponding
organozinc reagent. Both analyses clearly showed the formation
of 4-iodocoumarin. In addition, 1H NMR spectroscopic investiga-
tion was completed with the isolated product of the reaction ali-
quot after acidic quenching.8 From these results, it could be
concluded that the corresponding organozinc reagent (1) was suc-
cessfully obtained.
2
3
4
70
85
79
O
Cl
N
COCl
O
O
2c
S
O
S
O
O
COCl
O
O
O
As described in aforementioned reports,4–6 introducing aryl and
alkyl substituents directly to the C4-position of coumarin has been
primarily carried out via palladium-catalyzed cross-coupling reac-
tions with the corresponding organometallic reagents (route A in
Scheme 1). We have taken a different approach which allows the
introduction of a carbonyl group in the C4-position. Table 1 shows
the results observed from Pd-catalyzed cross-coupling reactions
with a variety of aryl acid chlorides. These reactions yields a car-
bonyl group directly bonded to C4-position of coumarin. All of
the coupling reactions were completed in 30 min at room temper-
2d
O
COCl
O
O
5
81
2e
a
Isolated yield (based on acid chloride).
Table 3
Coupling reaction with arylhalide
1 % Pd(PPh3)4
product
I
+
aryl halide
0.7 eq
THF/rt/6 h
3a - 3h
1.0 eq
Entry
1
Halide
Product
Yielda (%)
Entry
5
Halide
Product
Yielda (%)
I
Br
S
S
O
83
75
77
76
81
O
O
O
O
S
3eb
3ab
Br
Br
Br
CO2Et
CO2Et
2
3
4
6
7
8
84
88
79
O
O
O
O
F
CO2Et
CO2Et
S
3bb
F
3f
Br
O
O
Me
O
O
O
3cb
Me
Br
3g
N
Br
N
O
O
OMe
O
O
3db
3hb
OMe
a
Isolated yield (based on aryl halide).
All the spectroscopic data are consistent with literature value (Ref. 4).
b

3096
R. D. Rieke, S.-H. Kim / Tetrahedron Letters 52 (2011) 3094–3096
0.8 eq
1.2 eq
Br
I
NH2
2 % Pd(OAc)2
4 % SPhos
THF/reflux/4 h
70 %
I
O
O
O
O
NH2
1 % Pd (PPh3)4
1.0 eq
THF/ reflux/ 3h
83 %
s2
s1
Scheme 3. Expansion of coupling reaction.
ature in THF in the presence of 1 mol % Pd(PPh3)4. Not only a
simple acid chloride but halogenated benzoyl chlorides were suc-
cessfully coupled with I under very mild conditions affording the
corresponding products (1a, 1b, and 1c, Table 1) in excellent yields.
Both coupling reactions with benzoyl chlorides possessing elec-
tron-withdrawing group (CF3) and electron-donating group
(OCH3) gave rise to the products (1d and 1e, Table 1) in 91% and
92% isolated yield, respectively. A benzoyl chloride possessing a
benzylic halide reacted under the conditions used in this study to
give the product 1f in good yields (entry 6, Table 1). Unfortunately,
the desired coupling product was not obtained from the coupling
reactions with alkyl carbonyl chlorides under the same reaction
conditions.
refluxing temperature affording 4-(40-aminophenyl)coumarin (s2)
in moderate yield.9
In conclusion, a novel synthetic route for the preparation of 4-
substituted coumarin derivatives has been demonstrated. It has
been accomplished by utilizing a simple coupling reaction of a
readily available 4-coumarinylzinc bromide (I), which was pre-
pared via the direct insertion of active zinc to 4-bromocoumarin.
The subsequent coupling reactions with a variety of different elec-
trophiles have been carried out under mild conditions providing a
new class of 4-substituted coumarins. Development of the ana-
logues of our organozinc reagent and their applications are cur-
rently under way.
Since the heterocyclic moiety found in many natural com-
pounds plays a critical role for biological activity, our next attempt
was to couple I with several heteroaryl acid chlorides. Table 2
illustrates the reaction conditions and the results. Once again, it
should be emphasized that all the coupling reactions were car-
ried out under mild conditions. 5-Bromonicotinoyl chloride and
6-chloronicotinoyl chloride were efficiently employed for the
coupling reaction giving rise to the products (2a and 2b) in moderate
yields (entries 1 and 2, Table 2). 3-Thiophenecarbonyl chloride
and 2-furoyl chloride were also coupled with I under the same
conditions and the coupling products (2c and 2d, Table 2) were
obtained in 85% and 79% yields, respectively.
In an effort to evaluate the overall feasibility of the organozinc I,
coupling reactions with arylhalides were performed. The afore-
mentioned route A can also provide the 4-aryl-substituted couma-
rins. However, as illustrated in Scheme 1, our strategy (route B) is
to use a totally new organometallic reagent instead of known orga-
nometallic reagents. Palladium-catalyzed coupling reaction of I
with iodobenzene (entry 1, Table 3) and bromobenzenes (entries
2, 3, and 4, Table 3) proceeded smoothly resulting in the formation
of 4-arylsubstituted coumarins (3a, 3b, 3c, and 3d, Table 3) in good
yields. Heteroaryl halides also proceeded smoothly to yield
4-heteroaryl-substituted coumarins in good yields. Interestingly,
the reaction conditions used before worked well for the coupling
reaction with heteroaryl compounds. 2-Bromothiophene reacted
with I to afford 3e in 85% yield (entry 1, Table 3). Good results were
obtained from the coupling reactions using bromothiophene and
bromofuran bearing a functional group (entries 6 and 7, Table 3).
The coupling reaction with 2-bromopyridine also proceeded well
to generate 3h in good yield (entry 8, Table 3).
References and notes
1. (a) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.; Furukawa, H.; Takahashi,
D.; Koshimizu, K.; Ohigashi, H. Bioorg. Med. Chem. Lett. 2000, 10, 59; (b) Maier,
W.; Schmidt, J.; Nimtz, M.; Wray, V.; Strack, G. Phytochemistry 2000, 54, 473; (c)
Garcia-Argaez, A. N.; Ramirez Apan, T. O.; Delgado, H. P.; Velazquez, G.;
Martinez-Vazquez, M. Planta Med. 2000, 66, 279; (d) Zhou, P.; Takaishi, Y.; Duan,
H.; Chen, B.; Honda, G.; Itoh, M.; Takeda, Y.; Kodzhimatov, O. K.; Lee, K.-H.
Phytochemistry 2000, 53, 689.
2. (a) Jones, G., II; Jackson, W. R.; Choi, C. J. Phys. Chem. 1985, 89, 294; (b) Jones, G.,
II; Ann, J.; Jimenez, A. C. Tetrahedron Lett. 1999, 40, 8551; (c) Raboin, J.-C.; Beley,
M.; Kirsch, G. Tetrahedron Lett. 2000, 41, 1175.
3. (a) De la Hoz, A.; Moreno, A.; Vazquez, E. Synlett 1999, 608; (b) Arcadi, A.; Cacchi,
S.; Fabrizi, G.; Marinelli, F.; Pace, P. Synlett 1996, 568; (c) Donnely, D. M. X.;
Finet, J.-P.; Guiry, P. J.; Hutchinson, R. M. J. Chem. Soc., Perkin Trans 1 1990, 2851;
(d) Britto, N.; Gore, V. G.; Mali, R. S.; Ranade, A. C. Synth. Commun. 1989, 19,
1899; (e) Sato, K.; Inour, S.; Ozawa, K.; Kobayashi, T.; Ota, T.; Tazaki, M. J. Chem.
Soc., Perkin Trans 1 1987, 1753; (f) Awasthi, A. K.; Tewari, R. S. Synthesis 1986,
1061.
4. (a) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642; (b) Wu, J.; Yang, Z. J. Org.
Chem. 2001, 66, 7875.
5. (a) Wattanasin, S. Synth. Commun. 1988, 18, 1919; (b) Schio, L.; Chatreaux, F.;
Klich, M. Tetrahedron Lett. 2000, 41, 1543.
6. (a) Boland, G. M.; Donnelly, D. M. X.; Finet, J.-P.; Rea, M. D. J. Chem. Soc., Perkin
Trans 1 1996, 2591; (b) Yao, M.-L.; Deng, M.-Z. Heteroat. Chem. 2000, 11, 380.
7. Representative procedures: (a) Preparation of 4-coumarinylzinc bromide (I); In an
oven-dried 50 mL round-bottomed flask equipped with a stir bar was added
1.40 g of active zinc (Zn⁄, 22.0 mmol). 4-Bromocoumarin (4.50 g, 20.0 mmol)
dissolved in 20 mL of THF was then cannulated neat into the flask at room
temperature. The resulting mixture was stirred for 1 h at room temperature. The
whole mixture was settled down and then the supernatant was used for the
subsequent coupling reactions; (b) Representative Pd-catalyzed cross-coupling
reaction procedure; into a 25 mL round-bottomed flask were added Pd(PPh3)4
(0.025 g, 1 mol %) and 4.0 mL of 4-coumarinylzinc bromide (I) (0.5 M in THF,
2.0 mmol) was added into the flask under an argon atmosphere. Next, 4-
methoxybenzoyl chloride (0.27 g, 1.60 mmol) was slowly added via a syringe
while being stirred at room temperature. The resulting mixture was stirred at
room temperature for 30 min. Quenched with 3 M HCl solution, it was then
extracted with ethyl ether (10 mL ꢀ 3). Washed with saturated NaHCO3,
Na2S2O3 solution and brine, it was then dried over anhydrous MgSO4.
Purification by column chromatography on silica gel (20% ethyl acetate/80%
heptane) afforded 0.39 g of 1e in 92% isolated yield as white solid (mp 107–
108 °C). MS (EI) m/z (relative intensity): 280 (M+, 80), 252 (25), 135 (100).
8. All chemical shifts of the reduced product (coumarin) were consistent with the
literature values; The Aldrich Library of 13C and 1H FT NMR Spectra.
9. Recent examples of using Pd(OAc)2/SPhos-system for the Negishi-type coupling
reaction with haloaromatic amine; see, (a) Kim, S. H.; Rieke, R. D. Tetrahedron
2010, 66, 3135; (b) Manolikakes, G.; Schade, M. A.; Hernandez, C. M.; Mayr, H.;
Knochel, P. Org. Lett. 2008, 10, 2765.
In order to demonstrate the exceptional versatility of this reac-
tion, two other very different types of halides were reacted with an
excellent reagent. A SN20-type reaction was performed with allyl
bromide resulting in the formation of 4-allylcoumarine (s1) in
83% yield (Scheme 3). Consequently, we then investigated the
coupling reaction with a haloaromatic amine. As illustrated in
Scheme 3, the coupling reaction was easily accomplished with 4-
iodoaniline using 2 mol % Pd(OAc)2 and 4 mol % SPhos in THF at