A facile synthetic route for the preparation of 4-substituted 6-methyl-2-pyrone derivatives via organozinc reagents

Article abstract of DOI:10.1055/s-0031-1289855

A novel synthetic pathway for the preparation of 4-substituted 2-pyrone derivatives has been developed. It consists of two different methods; the first represents the Negishi coupling reaction utilizing easily accessible organozinc reagents. More signific

Full text of DOI:10.1055/s-0031-1289855

LETTER
2867
A Facile Synthetic Route for the Preparation of 4-Substituted 6-Methyl-2-
pyrone Derivatives via Organozinc Reagents
A
F
acile Syntheti
e
c
R
oute
f
or
u
the Preparat
b
ionof Pyron
e
e
s
n D. Rieke,a Seung-Hoi Kim*b
a
Rieke Metals, Inc., 1001 Kingbird Rd., Lincoln NE 68521, USA
Department of Chemistry, Dankook University, 29 Anseo, Cheonan 330-714, Korea
Fax +82(41)5597860; E-mail: kimsemail@dankook.ac.kr
b
Received 30 August 2011
out using 4-bromo-6-methyl-2-pyrone and easily accessi-
ble organozinc reagents (route A in Scheme 1). And, the
second approach is to make a new organozinc reagent and
utilize it in many subsequent coupling reactions (route B
Abstract: A novel synthetic pathway for the preparation of 4-sub-
stituted 2-pyrone derivatives has been developed. It consists of two
different methods; the first represents the Negishi coupling reaction
utilizing easily accessible organozinc reagents. More significantly,
the other is a new method utilizing a new organozinc reagent, 4-py- in Scheme 1).
ronylzinc bromide, which is easily prepared by highly active zinc
under mild conditions.
route
A
Key words: organozinc, cross-coupling reaction, 4-substituted
pyrone
R
O
Br
RZnX
O
O
O
In our continuing study on the development of organozinc
reagents, we have found a new synthetic method for the
preparation of biologically interesting materials, 2-pyrone
derivatives.
ZnBr
Zn*
RX
route
Due to the particular interest in the 2-pyrone moiety in
natural products,1 studies have focused on the develop-
ment of a versatile synthetic methodology for the prepara-
tion of 2-pyrone derivatives. Among the known
procedures, construction of pyrone ring system from acy-
clic precursors2 and introduction of substituents onto the
preformed pyrone ring are the predominant approaches.3
While these routes provided a variety of 2-pyrone deriva-
tives, major drawbacks to these pathways are multistep
synthesis and ring opening. Thus, in spite of the present
methodologies, there is still a need to explore a versatile
synthetic methodology for the preparation of 2-pyrone
derivatives.
O
O
B
I
Scheme 1 Synthetic pathways for the preparation of 4-substituted
2-pyrones
Since similar approaches with route A have been executed
using organotin and organoborane compounds,3 we car-
ried out only two representative reactions to verify the
utility of organozinc reagent and 4-bromo-6-methyl-2-py-
rone. As summarized in Schemes 2, 2- and 4-substituted
arylzinc halides which were prepared using highly active
zinc5 were coupled with 4-bromo-6-methyl-2-pyrone in
the presence of a catalytic amount of Pd(PPh3)4. The cou-
pling reactions proceeded smoothly under the reaction
conditions shown below and resulted in the coupling
products 1a and 1b (Scheme 2) in good to excellent
yields. Mild reaction conditions (2–4 h at r.t.) were re-
quired to complete the coupling reaction in THF.
We herein would like to report our results of a convenient
synthetic route for the preparation of 2-pyrone deriva-
tives. Interestingly, route B in this study leads to a unique
way of introducing more versatile functional groups on
the 4-position in 2-pyrones.
Prior to the general investigation on the preparation of
2-pyrone derivatives, we have performed the reactions
with 4-bromo-6-methyl-2-pyrone4 because this moiety is
found in a large number of biologically active materials
and also the precursor, 4-hydroxy-6-methyl-2-pyrone,
was readily available.
O
O
O
O
Pd(PPh3)4
THF, r.t.
ZnBr
+
Br
X
X
X = 2-CO2Et
X = 4-Et
1a X = 2-CO2Et (90%)
1b X = 4-Et (75%)
In order to accomplish the goals of this study, we designed
two different approaches, depicted in Scheme 1. First, the
well-known Negishi cross-coupling reaction was carried
Scheme 2 Example of route A
Even though this procedure was satisfactory for the prep-
aration of 4-substituted 2-pyrones, we decided to seek a
more versatile protocol for the preparation of a variety of
4-substituted 2-pyrones utilizing the organozinc proce-
SYNLETT 2011, No. 19, pp 2867–2871
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289855; Art ID: U06411ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2868
R. D. Rieke, S.-H. Kim
LETTER
O
O
O
O
O
E+
THF
Zn*
E
Br
O
+
BrZn
r.t., 30 min
1.0 equiv
1.5 equiv
I
Scheme 3 Schematic diagram of route B
dure. Significantly, it was successfully accomplished via Once again, even though the metal-catalyzed cross-
a new type of organozinc reagent, 4-pyronylzinc bromide coupling reactions of organometallics with halogenated
(I). As shown in Scheme 3, the corresponding organozinc pyrones provided a variety of Csp2–Csp2 and/or Csp2–Csp
reagent was easily prepared by the reaction of highly ac- bonds, there is no report of introducing a carbonyl group
tive zinc with 4-bromo-6-methyl-2-pyrone.6 The oxida- directly attached to the pyrone ring. Therefore, we tried
tive addition of active zinc into C–Br bond was completed somewhat different types of coupling reactions to achieve
at room temperature in THF in 30 minutes. The formation more functionalized pyrone complexes. To accomplish
of the organozinc reagent I and its applicability in organic this goal, the coupling reaction of I with aryl acid chlo-
synthesis were examined by the subsequent cross-cou- rides was carried out first. Table 1 shows the results ob-
pling reactions with a variety of electrophiles in the pres- served from Pd-catalyzed cross-coupling reactions with
ence of an appropriate catalyst.
several acid chlorides.7
Table 1 Coupling Reaction with Aryl Acid Chlorides
COAr
O
Pd(PPh3)4
(1 mol%)
I
ArCOCl
+
THF, r.t.
1.0 equiv
0.8 equiv
O
2a–g
Entry
1
ArCOCl
Time (min)
Product
Yield (%)a
O
O
COCl
30
30
30
30
60
94
O
2a
O
Br
O
Br
COCl
2
3
4
5
80
92
83
75
O
2b
O
O
COCl
O
MeO
MeO
2c
O
O
COCl
Cl
Cl
O
O
2d
O
COCl
O
Cl
N
Cl
N
2e
Synlett 2011, No. 19, 2867–2871 © Thieme Stuttgart · New York

LETTER
A Facile Synthetic Route for the Preparation of Pyrones
2869
Table 1 Coupling Reaction with Aryl Acid Chlorides (continued)
COAr
Pd(PPh3)4
(1 mol%)
I
ArCOCl
+
THF, r.t.
1.0 equiv
0.8 equiv
O
O
2a–g
Entry
6
ArCOCl
Time (min)
Product
Yield (%)a
O
O
COCl
30
30
91
85
O
S
S
2f
O
O
O
7
O
COCl
O
2g
a Isolated yield (based on acid chloride).
The first attempt was carried out with benzoyl chloride in
a standard fashion [1 mol% Pd(PPh3)4]. The coupling
product 2a was achieved in excellent isolated yield (94%,
entry 1, Table 1). To explore the applicability of this
methodology, more benzoyl chlorides containing a func-
tional group were employed in the coupling reaction. Both
electron-withdrawing groups (Br) and electron-donating
groups (MeO) were very cooperative in this reaction sys-
tem giving rise to the corresponding products (2b and 2c,
80% and 92%, respectively). A more reactive functional
group was also tolerant of the organozinc I providing 2d
in 83% isolated yield (entry 4, Table 1). To expand the
scope of this strategy, the coupling reactions with several
heterocyclic acid chlorides were examined under the same
reaction conditions. As shown in Tables 1, 6-chloronico-
tinoyl chloride (entry 5), 3-thionylcarbonyl chloride (en-
try 6), and 2-furfuryl chloride (entry 7) were also
successfully employed in the coupling reaction with I re-
sulting in the formation of unsymmetrical heterocyclic ke-
tones 2e, 2f and 2g in good to excellent yields,
respectively.
Table 2 Coupling Reaction with Alkanoic Acid Chlorides
CuI (10 mol%)
product
I
RCOCl
+
LiCl (20 mol%)
THF, 0 °C
1.0 equiv 0.8 equiv
Entry RCOCl
Time Product
Yield
(%)a
(h)
O
O
1
1
91
82
82
86
87
COCl
O
3a
3b
O
O
COCl
2
1
O
O
O
COCl
3
2
With these preliminary results in hand, we expanded this
methodology to the coupling reactions with several al-
kanoic acid chlorides. Interestingly, the standard Cu-cata-
lyzed reaction conditions were more effective for the
coupling reaction than the Pd-catalyst used in the previous
coupling reactions. Thus, the subsequent coupling reac-
tions were conducted in the presence of 10 mol% of CuI
and 20 mol% of LiCl in THF at 0 °C, and the results are
summarized in Table 2.8 Cyclic alkanoic acid chlorides
were treated with I and the coupling products, 3a and 3b
(Table 2) were obtained in 91% and 82% isolated yields,
respectively. A bulky alkanoic chloride was also coupled
with I in two hours providing the product 3c in 82% iso-
lated yield (entry 3, Table 2). Chlorine-substituted al-
kanoic acid chloride was a good coupling partner to give
the product 3d in 86% yield (entry 4, Table 2). Addition-
O
3c
O
O
Cl
3
4
1
Cl
COCl
O
2
3d
O
O
3
COCl
5
0.5
2
O
3e
a Isolated yield (based on acid chloride).
Synlett 2011, No. 19, 2867–2871 © Thieme Stuttgart · New York

2870
R. D. Rieke, S.-H. Kim
LETTER
ally, an alkanoic acid chloride containing a phenyl ring
underwent the coupling reaction smoothly using the same
conditions to afford the product 3e (87%, entry 5,
Table 2).
Table 3 Coupling Reaction with HetAryl Halides
ArHet
Pd(PPh3)4 (1 mol%)
I
HetArX
+
THF, r.t.
In hopes of increasing the versatility of this strategy, we
next attempted the coupling reaction with some heteroar-
omatic halides. Even though the corresponding products
could be obtained through route A in this study, we at-
tempted to expand the alternative synthetic pathways to
prepare a variety of different types of derivatives using
route B. Several interesting materials were prepared by
this protocol and the results are summarized in Table 3. A
standard fashion of Pd-catalyzed coupling reaction {1
mol% of Pd[(PPh3)4]} was employed to complete the cou-
pling reaction in THF. As expected, the ethoxycarbonyl
group on thiophene ring and furan ring remained intact
during the reaction and the products 4a and 4b (Table 3)
were obtained in 85% and 94% isolated yields, respective-
ly. A selective C–C bond formation occurred in the reac-
tions with 2-bromo-5-chlorothiophene (4 h at r.t.) and 2-
bromo-6-chloropyridine (20 min at r.t.) generating 4c and
4d in 95% and 88% isolated yields, respectively (entries 3
and 4, Table 3). The presence of chlorine atom in the cor-
responding coupling products was easily confirmed by
GC–MS analysis. A slightly longer reaction time was re-
quired to complete the coupling reaction with 2-bromo-
thiazole and an excellent yield was achieved from this
reaction (4e, 89%, Table 3).
1.0 equiv
0.8 equiv
O
O
4a–e
Entry HetArX
Time Product
Yield
(%)a
O
EtO2C
S
1
30 min
85
O
EtO2C
Br
Br
S
4a
O
EtO2C
O
2
30 min
94
O
EtO2C
O
4b
O
Cl
S
3
4 h
95
O
Cl
S
Br
4c
O
Cl
N
4
20 min
88
O
In addition to these results, we attempted to expand the
coupling of I with a partner containing an acidic proton.
Significantly, the coupling products were efficiently
achieved from the Pd-catalyzed coupling reaction with
halogenated anilines and phenol,9 and results are de-
scribed in Scheme 4. For the successful coupling reaction
in this study, 2% Pd(OAc)2/4% SPhos catalytic system
was employed. Even though the reaction conditions were
not optimized in this study, the reaction was carried out at
a refluxing temperature for 24 hours, and the correspond-
ing products 5a and 5b (Scheme 4) from the reactions
with 3-iodoaniline and 4-iodoaniline were obtained in
77% and 58% isolated yields, respectively. Despite the
low yield, 4-iodophenol was successfully coupled with I
under the same conditions affording 5c in 25% isolated
yield. The low yield was attributed to the low conversion
to the product under the conditions used in this study. GC
and GC–MS analyses of the aliquot of the reaction mix-
ture after being reacted for 24 hours showed the presence
of the unreacted starting material (4-iodophenol) in the re-
action mixture.
Cl
N
Br
4d
4e
N
O
N
S
5
24 h
89
O
Br
S
a Isolated yield (based on HetAr).
O
Pd(OAc)2 (2 mol%)
I
+
I
O
SPhos (4 mol%)
THF, reflux
X
X
1.0 equiv
0.8 equiv
X = 3-NH2
X = 4-NH2
X = 4-OH
5a X = 3-NH2 (77%)
5b X = 4-NH2 (58%)
5c X = 4-OH (25%)
P(Cy)2
MeO
OMe
SPhos
In conclusion, an efficient synthetic procedure for the syn-
thesis of a wide range of 4-substituted 6-methyl-2-pyrone
via either Pd- or copper-catalyzed cross-coupling reac-
tions of 4-pyronylzinc bromide with a variety of electro-
philes has been revealed. Of special note are the
introduction of a carbonyl group onto the pyrone ring and
very mild reaction conditions used in this study. Further
applications of this methodology are under investigation.
Scheme 4 Coupling reaction with iodoaniline and iodophenol
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 19, 2867–2871 © Thieme Stuttgart · New York

LETTER
A Facile Synthetic Route for the Preparation of Pyrones
2871
The resulting mixture was stirred at r.t. for 30 min. The
whole mixture was allowed to settle down and then the
supernatant was used for the subsequent coupling reactions.
(7) A Representative Procedure of Pd-Catalyzed Coupling
Reaction: Into a 25-mL round-bottomed flask was added
Pd(PPh3)4 (0.06g, 1 mol%) under an argon atmosphere.
Next, I (0.5 M in THF, 10 mL, 5.0 mmol) was added via a
syringe, and then benzoyl chloride (0.56 g, 4.0 mmol) was
added slowly into the flask at r.t. The resulting mixture was
stirred at r.t. for 30 min. The reaction was quenched with sat.
NH4Cl solution and the mixture was then extracted with
Et2O (3 × 10 mL). It was washed with sat. NaHCO3, Na2S2O3
solution and brine, then dried over anhyd MgSO4.
References and Notes
(1) (a) Chang, J. H.; Kang, H. U.; Jung, I. H.; Cho, C. G.
Org. Lett. 2010, 12, 2016. (b) Barrero, A. E.; Oltra, J. E.;
Herrador, M. M.; Sanchez, J. F.; Quilez, J. F.; Rojas, F. J.;
Reyes, J. F. Tetrahedron 1993, 49, 141. (c) Schlingmann,
G.; Milne, L.; Carter, G. T. Tetrahedron 1998, 54, 13013.
(d) Shi, X.; Leal, W. S.; Liu, Z.; Schrader, E.; Meinwald, J.
Tetrahedron Lett. 1995, 36, 71.
(2) (a) Kim, S. J.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007,
48, 1069. (b) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R.
Tetrahedron 2001, 57, 2857.
(3) (a) Kim, W. S.; Kim, H. J.; Cho, C. G. J. Am. Chem. Soc.
2003, 125, 14288. (b) Lee, J. H.; Kim, W. S.; Lee, Y. Y.;
Cho, C. G. Tetrahedron Lett. 2002, 43, 5779. (c) Lee, J. H.;
Park, J. S.; Cho, C. G. Org. Lett. 2002, 4, 1171. (d) Bellina,
F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron Lett.
2001, 42, 2859. (e) Danieli, B.; Lesma, G.; Martinelli, M.;
Passarella, D.; Peretto, I.; Silvani, A. Tetrahedron 1998, 54,
14081. (f) Cerezo, S.; Moreno-Manas, M.; Pleixats, R.
Tetrahedron 1998, 54, 7813. (g) Liu, Z.; Meinwald, J.
J. Org. Chem. 1996, 61, 6693.
Purification by column chromatography on silica gel (20%
EtOAc–80% heptane) afforded 2a (0.80 g) as a yellow solid
in 94% isolated yield. GC–MS (EI): m/z (%) = 214 (50)
[M+], 186 (62), 105 (100), 77 (99), 43 (75).
(8) A Representative Procedure for Cu-Catalyzed Coupling
Reaction: Into a 25-mL round-bottomed flask were added
CuI (0.09 g, 10 mol%) and LiCl (0.04 g, 20 mol%) under an
argon atmosphere. Next, I (0.5 M in THF, 10 mL, 5.0 mmol)
was added via a syringe, and then cyclopropanecarbonyl
chloride (0.41 g, 4.0 mmol) was added slowly into the flask
at r.t. The resulting mixture was stirred at 0 °C for 60 min.
The reaction was quenched with sat. NH4Cl solution and the
mixture was then extracted with Et2O (3 × 10 mL) and
washed with sat. NaHCO3, 7% NH4OH, sat. Na2S2O3
solution and brine, and then dried over anhyd MgSO4.
Purification by column chromatography on silica gel (20%
EtOAc–80% heptane) afforded 3a (0.65 g) as a yellow solid
in 91% isolated yield. GC–MS (EI): m/z (%) = 178 (25)
[M+], 150 (50), 109 (82), 69 (75), 43 (100).
(4) Marrison, L. R.; Dickinson, J. M.; Ahmed, R.; Fairlamb,
I. J. S. Tetrahedron Lett. 2002, 43, 8853.
(5) For a general application of organozinc reagents using
highly active zinc, see: (a) Rieke, R. D.; Hanson, M. V.
Tetrahedron 1997, 53, 1925. For recent examples of the
cross-coupling reaction of organozinc reagents, see:
(b) Iwai, T.; Naki, T.; Mihara, M.; Ito, T.; Mizuno, T.; Ohno,
T. Synlett 2009, 1091. (c) Mosrin, M.; Knochel, P. Org.
Lett. 2009, 11, 1837. (d) Rieke, R. D.; Kim, S. H.
Tetrahedron Lett. 2011, 52, 3094.
(6) Preparation of 6-Methyl-4-pyronylzinc Bromide (I): Into
an oven-dried 25-mL round-bottomed flask equipped with a
stir bar was added active zinc (Zn*, 1.25 g, 19 mmol). 4-
Bromo-6-methyl-2-pyrone (2.40g, 12.7 mmol) dissolved in
THF (5.0 mL) was then cannulated neat into the flask at r.t.
(9) pKa values; range between 15–20 for phenols, 20–30 for
anilines, source from http://www.chem.wisc.edu/areas/
reich/pkatable/index.htm.
Synlett 2011, No. 19, 2867–2871 © Thieme Stuttgart · New York

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