Zinc enolate/sulfinate prepared from a single-run reaction using zinc dust with O-tosylated 4-hydroxy coumarin and pyrone

Full text of DOI:10.1002/bkcs.10819

Note
DOI: 10.1002/bkcs.10819
BULLETIN OF THE
U. S. Shin et al.
KOREAN CHEMICAL SOCIETY
Zinc Enolate/Sulfinate Prepared from a Single-Run Reaction Using
Zinc Dust with O-Tosylated 4-Hydroxy Coumarin and Pyrone
Ueon Sang Shin,† Seong-Ryu Joo,‡ and Seung-Hoi Kim‡,
*
†Graduate School of Nanobiomedical Science, Dankook University, Cheonan 31116, Republic of Korea
‡Department of Chemistry, Dankook University, Cheonan 31116, Republic of Korea.
*E-mail: kimsemail@dankook.ac.kr
Received March 8, 2016, Accepted April 26, 2016, Published online June 29, 2016
Keywords: Zinc enolate, Zinc sulfinate, Zinc dust, Insertion into oxygen-sulfur bond
Impressive applications of coumarin and pyrone scaffolds
have been established in a wide range of biological areas
such as antioxidants, antifungals, antibiotics, antibacterial
agents, and diverse inhibitors.1 Of these analogs, 4-
substituted coumarin or pyrone moieties have shown very
interesting biological properties. In addition to their increas-
ing significance, more diverse synthetic tools for the prepa-
ration of the 4-functionalized derivatives are required. In
order to achieve the primary goal, a large number of inten-
sive efforts has been devoted to exploring versatile
approaches utilizing transition-metal-catalyzed cross-
coupling reactions as they are recognized to be one of the
most powerful tools for the construction of new carbon–
carbon bond.2
Regarding the synthetic approaches utilizing transition-
metal catalysts, a variety of well-known reactions such as
the Suzuki-Miyaura system with tosylate3 and triflate,4
Rh(I)-catalyzed arylboronic acid,5 Heck coupling,6 Stille
coupling,7 organoindium,8 and triarylbismuth9 have been
accomplished for the synthesis of coumarin and pyrone
analogs. In addition, both tosylate and phosphate substrates
were utilized in the couplings with organozinc reagent.10
Taking account of the easy accessibility of tosylates, we
decided to investigate the possibility of the direct prepara-
tion of the corresponding organomanganese coumarin and
pyrone reagents by the reaction of highly active manganese.
However, contrary to our expectations, the oxidative addi-
tion of the active manganese occurred into the oxygen-
sulfur bond forming enolate and sulfinate anologs.11 With
these results in our hand, we next applied this strategy to
the preparation of zinc complexes utilizing zinc dust. From
the practical point of view, utilizing zinc dust has potential
merits since there is no need for a metal-activation proce-
dure. Herein, we disclose an alternative approach to expand
the scope of zinc complexes for the synthesis of coumarin
and pyrone derivatives. We anticipated that a combination
of zinc dust, LiCl and a catalytic amount of iodine would
be suitable conditions.12
2.0 equiv of zinc dust, 2.0 equiv of LiCl and iodine
(10 mol%) in dimethyl acetamide (DMA). The progress of
the reaction was monitored by GC analysis. After refluxing
for 12 h, GC analysis showed the complete consumption of
compound A. Therefore, we assumed that the oxidative
addition of zinc completed to afford a zinc complex. Next,
the thus-formed zinc complex (I) was employed to the
cross-coupling reaction with acid chlorides in the presence
of a catalytic amounts of Ni(PPh3)2Cl2.13 The coupling
reactions proceeded smoothly in DMA at room tempera-
ture, affording the coupling products. The 13C NMR spec-
trum of the major product clearly showed two carbonyl
carbon peaks in the range 161–163 ppm, corresponding to
the carbonyls of ester. No keto carbonyl carbon peak was
observed. These outcomes coincided exactly with our pre-
vious results.11 These peaks were consistently observed
from the coupling products using zinc complex II which
was prepared from 6-methyl-2-oxo-2H-pyran-4-yl 4-
methylbenzenesulfonate (B). The presence of an extra ester
group in the coupling product was also confirmed by
HRMS. According to the Link’s studies, the O-acylation of
4-hydroxycoumarins and 4-hydroxypyrones is a normal
tendency in the simple reaction with aromatic acid chlor-
ides in the presence of pyridine.14 In addition, a similar
result was reported by Vakhrin et al.15 In their study, zinc
enolate of 3-alkyl-6-aryl-5,5-dimethyl-2,3,5,6-tetrahydro-
pyrone-2,4-diones reacted with acid chlorides to form O-
acylation products. Therefore, it could be concluded that
the zinc complexes used in our study (I and II in Scheme
1) originated from the oxidative addition of zinc dust into
the oxygen-sulfur bond of the tosyl compounds forming
zinc enolate/sulfinate. Accordingly, the subsequent Ni-
catalyzed coupling reactions with acid chlorides provided
the corresponding ester compounds (marked with a in
Scheme 1). All the results are summarized in Tables 1
and 2.
To verify the formation of the zinc complexes (I and II,
Scheme 1), further experiments were conducted using dif-
ferent electrophiles. Since the earlier work15 by Vakhrin
and coworker also showed that a β-ketoester type enolate,
sodium enolate of pyrone derivatives, reacted with benzyl
As in the standard procedure employed for the oxidative
addition of a metal into organic substrates, 2-oxo-2H-chro-
men-4-yl 4-methylbenzenesulfonate (A) was treated with
Bull. Korean Chem. Soc. 2016, Vol. 37, 1144–1147
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library 1144

Note
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
Table 2. Coupling reaction of II with acid chlorides.
Scheme 1. Oxidative addition of zinc dust and the subsequent
coupling reaction with acid chloride.
bromides to give mainly C-alkylation products in low to
moderate yields (9–68%), and, interestingly, no product
was obtained using the corresponding zinc enolate. There-
fore, for the comparative study, we selected benzyl halides
as the next suitable electrophiles.
Entry
ArCOCl
X = H
Product (%)a
1
2
3
4
5
6
12a
13a
14a
15a
16a
17a
56
42
72
40
32
54
X = 4−Br
X = 4−CH3
X = 4−OMe
X = 4−CH2CI
Initial attempt was conducted with 1.2 equiv of benzyl
bromide, giving rise to two major products by TLC.
These two products were successfully isolated using col-
umn chromatography. Spectroscopic analyses (1H and 13C
NMR) of the products provided concrete evidence for the
formation of both C(3)-disubstituted product (marked with
b in Scheme 2) and sulfones (marked with c in Scheme 2)
from a single-run reaction. From this result, we hypothesize
that the thus-formed complexes (I and II) played a double
role as the zinc enolate and zinc sulfinate,16 separately, in
the reaction with benzyl halide. Albeit the zinc enolate
obtained from our protocol revealed a different reactivity
from that of Vakhrin’s,15 however, a further mechanistic
study would be required to understand the double C-
alkylation.
7
8
18a
19a
23
51
9
20a
21a
36
24
10
a
Isolated yield (based on II).
Table 1. Coupling reaction of I with acid chlorides.
Based on this result, excess amount of benzyl halides
(3.3 equiv) were used for the completion of reaction. To
the best of our ability, we could not verify the formation of
pyronyl or coumarinyl ethers delivered from the O-
functionalization of zinc enolate motif.17
A range of benzyl halides was examined and the corre-
sponding products (1b–14b, 1c–7c) are presented in
Table 3. In general, based on the isolated yields, zinc sulfi-
nate appeared to be more nucleophilic than zinc enolate.
Unfortunately, no coupling product was obtained from the
reaction with less reactive benzyl chloride substrates
(entries 5–7, Table 3).
Even though zinc enolate delivered from our protocol
demonstrated a positive reactivity toward benzyl bromide,
slightly lower yields were obtained compared to the corre-
sponding sodium enolate.15 According to several reports,
zinc enolates are poor nucleophiles for subsequent alkyla-
tion reactions especially when the reactions are carried out
in ethereal solvent.18 To improve the performance, solvent
effects were examined using nonethereal solvents such as
OZnTs
OCOAr
2 mol
%
Cl2
Ni(PPh3)2
+
ArCOCl
1.2 eq
h
DMA/rt/4
O
O
O
O
~
1a 11a
I
(1.0 eq)
Entry
ArCOCl
X = H
Product (%)a
1
2
3
4
5
6
7
8
1a
2a
3a
4a
5a
6a
7a
8a
45
42
60
50
40
42
40
70
X = 4−Br
X = 4−CH3
X = 3−Br
X = 4−OMe
X = 4−CH2CI
X = 4−Bu−t
9
9a
50
49
20
10
10a
11a
11
a
Isolated yield (based on I).
Scheme 2. Coupling reaction with benzyl halides.
Bull. Korean Chem. Soc. 2016, Vol. 37, 1144–1147
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1145

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
Table 3. Coupling reactions of I and II with benzyl halides.
afforded a mixture that consisted mainly of two products, C-
alkylation and sulfone, and a number of side products that
could not be identified. Therefore, it could be inferred that
low reactivity of our zinc enolate complex could be caused
by the formation of less-reactive aggregate in DMA.20
In an effort to evaluate the overall feasibility of the zinc
complexes (I and II), slightly different types of electro-
philes (entries 1 and 2, Table 4) were also tested under the
same conditions. As shown in Table 4, the corresponding
sulfones (4a, b) were isolated as a main product in rela-
tively low yields. In these reactions, we were not able to
find any C-alkylation product.
In conclusion, we demonstrated the preparation of new
zinc complexes, 2-oxo-2H-chromen-4-yloxy tosylzinc (I),
and 6-methyl-2-oxo-2H-pyran-4-yloxy tosylzinc (II), by the
oxidative addition of readily available zinc dust into the cor-
responding 4-tosylated coumarin (A) and pyrone (B),
respectively. Of special interest, the thus-obtained zinc com-
plexes showed an electrophile-dependent reactivity. The
subsequent coupling reactions of I and II with a variety of
acid chlorides provided the O-acylation product in moderate
yields. More interestingly, it should be emphasized that the
thus-prepared zinc complexes (I and II) functioned both as
zinc enolate and zinc sulfinate, providing C(3)-disubstituted
product (b) and sulfone (c), respectively, from a single-run
reaction when I or II was treated with benzyl halides. Even
though somewhat low yields were achieved under the non-
optimized conditions, the novel zinc complexes present
another potential application for zinc reagents. Versatile
applications of this discovery are currently underway.
Yield
Yield
[c]a(%)b
Entry
1
FG PhCH2X
FG: H X: Br lb
(8b
[b]a(%)b
26
1c
2c
3c
4c
5c
6c
7c
53
(60)
46
(50)
46
(45)
48
(52)
34
(20)
49
(23)
49
(27)
41)
28
30)
25
38)
21
46)
0
0)
0
0)
0
2
3
4
5
6
7
a
FG: 4-Br
FG: 4-But
FG: 3-CH3
FG: 4-F
X: Br 2b
(9b
X: Br 3b
(10b
X: Br 4b
(11b
X: CI 5b
(12b
FG: 2-CI, 6-F X: CI 6b
(13b
X: CI 7b
(14b
FG: 2,4-C12
0)
Isolated yield (based on I).
b
Numbers in parentheses from using II.
toluene or dichloromethane, and positive outcomes were
achieved.18 Consequently, we applied this conditions to our
system to make zinc complexes. However, unfortunately, no
insertion of zinc dust was took place in toluene even at
refluxing temperature. Along with the solvent effects, role
of catalyst was also tested.19 Among many transition metal
catalysts, Fe- and Pd-catalysts were employed, and the cou-
pling reactions were executed under the same conditions
(room temperature in DMA) using Fe2(CO)9, Pd(PPh3)2Cl2,
or Pd(PPh3)4. None of the catalysts gave a remarkable
improvement in isolated yield for C-alkylation product or
sulfone. For most cases including Ni-catalyst, the reaction
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
References
1. Recent examples:(a) S. Valente, Z. Xu, E. Bana, C. Zwergel,
A. Mai, C. Jacob, P. Meiser, D. Bagrel, A. M. S. Silva,
G. Kirsch, Eur. J. Org. Chem. 2013, 2869; (b) F. Gosselin,
R. A. Britton, I. W. Davies, S. J. Dolman, D. Gauvreau,
R. S. Hoerrner, G. Hughes, J. Janey, S. Lau, C. Molinaro,
C. Nadeau, P. D. O’Shea, M. Palucki, R. Sidler, J. Org.
Chem. 2010, 75, 4154; (c) S. Valente, E. Bana, E. Viry,
D. Bagrel, G. Kirsch, Bioorg. Med. Chem. Lett. 2010, 20,
5827; (d) A. Murakami, G. Gao, M. Omura, M. Yano, C. Ito,
H. Furukawa, D. Takahashi, K. Koshimizu, H. Ohigashi,
Bioorg. Med. Chem. Lett. 2000, 10, 59; (e) J. H. Chang,
H. U. Kang, I. H. Jung, C. G. Cho, Org. Lett. 2010, 12, 2016;
(f ) A. E. Barrero, J. E. Oltra, M. M. Herrador, J. F. Sanchez,
J. F. Quilez, F. J. Rojas, J. F. Reyes, Tetrahedron 1993, 49,
141; (g) G. Schlingmann, L. Milne, G. T. Carter, Tetrahedron
1998, 54, 13013; (h) X. Shi, W. S. Leal, Z. Liu, E. Schrader,
J. Meinwald, Tetrahedron Lett. 1995, 36, 71.
Table 4. Coupling reactions of II.
Entry
1c
Halidea
Product
Yield (%)b
4a
22
2
4b
21
2. A. de Meijere, S. Brase, D. Martin, Metal-Catalyzed Cross-
Coupling Reactions and More, Vol. 3, Wiley-VCH, Wein-
heim, 2014.
3. (a) Y. Luo, J. Wu, Tetrahedron Lett. 2009, 50, 2103;
(b) J. I. Kuroda, K. Inamoto, K. Hiroya, T. Doi, Eur. J. Org.
a
Isolated yield (based on I).
Reacted with 2.2 equiv of II, otherwise mentioned.
3.0 equiv of II used.
b
c
Bull. Korean Chem. Soc. 2016, Vol. 37, 1144–1147
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1146

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
Chem. 2009, 2251; (c) J. Wu, L. Wang, R. Fathi, Z. Yang,
14. (a) H. R. Eisenhauer, K. P. Link, J. Am. Chem. Soc. 1953, 75,
2046; (b) H. R. Eisenhauer, K. P. Link, J. Am. Chem. Soc.
1953, 75, 2044.
Tetrahedron Lett. 2002, 43, 4395; (d) J. Wu, L. Zhang, H. -
G. Xia, Tetrahedron Lett. 2006, 47, 1525; (e) P. Y. Wong,
W. K. Chow, K. H. Chung, C. M. So, C. P. Lau,
F. Y. Kwong, Chem. Commun. 2011, 47, 8328.
15. V. V. Shchepin, Y. K. Sazhneva, N. Y. Russkikh,
M. I. Vakhrin, Russian J. General Chem. 2003, 73, 760.
16. To the best of our knowledge, no report on the preparation of
zinc sulfinate through the present route was released. Other
selective examples for the preparation of sulfones using sulfi-
nates, see:(a) T. Niwa, H. Yorimitsu, K. Oshima, Tetrahedron
2009, 65, 1971; (b) A. Kumar, M. K. Muthyala, Tetrahedron
Lett. 2011, 52, 5368; (c) E. J. Emmett, B. R. Hayter,
M. C. Willis, Angew. Chem. Int. Ed. 2013, 52, 12679;
(d) F. Xiao, S. Chen, Y. Chen, H. Huang, G. J. Deng, Chem.
Commun. 2015, 51, 652; (e) X. J. Pan, J. Gao, G. Q. Yuan,
Tetrahedron 2015, 71, 5525; (f ) J. Chen, J. Mao, Y. Zheng,
D. Liu, G. Rong, H. Yan, C. Zhang, D. Shi, Tetrahedron
2015, 71, 5059; (g) B. N. Rocke, K. B. Hahnck, M. Herr,
S. Lavergne, V. Mascitti, C. Perreault, J. Polivkova,
A. Shavnya, Org. Lett. 2014, 16, 154; (h) N. Margraf,
G. Manolikakes, J. Org. Chem. 2015, 80, 2582.
4. (a) O. Akrawi, G. Z. Nagy, T. Patonay, A. Villinger, P. Langer,
Tetrahedron Lett. 2012, 53, 3206; (b) L. Zhang, T. Meng,
R. Fan, J. Wu, J. Org. Chem. 2007, 72, 7279; (c) M. -L. Yao,
M. -Z. Deng, Heteroatom Chem. 2000, 11, 380.
5. (a) J. Wu, L. Zhang, K. Gao, Eur. J. Org. Chem. 2006, 5260;
(b) J. Wu, L. Zhang, Y. Luo, Tetrahedron Lett. 2006,
47, 6747.
6. (a) S. Valente, G. Kirsch, Tetrahedron Lett. 2011, 52, 3429;
(b) L. A. Hansen, T. Skrydstrup, Org. Lett. 2005, 7, 5585;
(c) Y. Li, Z. Qi, H. Wang, X. Fu, C. Duan, J. Org. Chem.
2012, 77, 2053; (d) M. Khoobi, F. Molaverdi, M. Alipour,
F. Jafarpour, A. Foroumadi, A. Shafiee, Tetrahedron 2013,
69, 11164.
7. L. Schio, F. Chartreaux, M. Klich, Tetrahedron Lett. 2000,
41, 1543.
8. W. Gao, Y. Luo, Q. Ding, Y. Peng, J. Wu, Tetrahedron Lett.
2010, 51, 136.
9. M. L. Rao, V. Venkatesh, D. N. Jadhac, Eur. J. Org. Chem.
2010, 3945.
17. A recent example of O-functionalization of 4-hydroxy-6-
alkyl-2-pyrone, see:M. J. Burns, T. O. Ronson,
R. J. K. Taylor, I. J. S. Fairlamb, Beilstein J. Org. Chem.
2014, 10, 1159, and references cited therein.
10. (a) P. Shah, M. D. Santana, J. Garcia, J. L. Serrano, M. Naik,
S. Pendnekar, A. R. Kapdi, Tetrahedron 2013, 69, 1446;
(b) J. Wu, Z. Yang, J. Org. Chem. 2001, 66, 7875; (c) J. Wu,
Y. Liao, Z. Yang, J. Org. Chem. 2001, 66, 3642; (d) J. Wu,
Z. Yang, J. Org. Chem. 2001, 66, 7875.
18. For the reactivity of zinc enolates, see:(a) X. Rathgeb,
S. March, A. Alexakis, J. Org. Chem. 2006, 71, 5737;
(b) H. C. Guo, J. A. Ma, Angew. Chem. Int. Ed. 2006, 45,
354; (c) G. K. Jarugumilli, C. Zhu, S. P. Cook, Eur. J. Org.
Chem. 2012, 1712.
11. U. S. Shin, S. R. Joo, S. H. Kim, Bull. Korean Chem. Soc.
2016, 37, 950.
19. (a) G. K. Jarugumilli, S. P. Cook, Org. Lett. 2011, 13, 1904;
(b) E. W. Dijk, L. Panella, P. Pinho, R. Naasz, A. Meetsma,
A. J. Minnaard, B. L. Feringa, Tetrahedron 2004, 60, 9687.
20. For the studies on aggregation of enolate, see:
(a) D. B. Collum, A. J. McNeil, A. Ramirez, Angew. Chem.
Int. Ed. 2007, 46, 3002; (b) M. Kitamura, T. Miki,
K. Nakano, R. Royori, Bull. Chem. Soc. Jpn. 2000, 73, 999;
(c) D. B. Collum, Y. Ma, A. C. Hoepker, L. Gupta,
M. F. Faggin, J. Am. Chem. Soc. 2010, 132, 15160.
12. For representative examples of using zinc metal, see:
(a) S. Huo, Org. Lett. 2003, 5, 423; (b) A. Metzger,
M. A. Schade, P. Knochel, Org. Lett. 2008, 10, 1107;
(c) A. Krasovskiy, V. Malakhov, A. Gavryshin, P. Knochel,
Angew. Chem. Int. Ed. 2006, 45, 6040.
13. In the absence of Ni-catalyst, a by-product (an ester from the
reaction of THF with acid chloride) was the major product
along with a mixture of unidentified compounds.
Bull. Korean Chem. Soc. 2016, Vol. 37, 1144–1147
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1147