Thulium Triflate Catalyzed Hydration of 2-Substituted 4-Alkynones

Article abstract of DOI:10.1055/s-0035-1561652

We report on a facile synthetic route for the preparation of substituted 1,4-diketones by thulium triflate mediated hydration of substituted 4-alkynones in MeNO₂ at 25 °C for five hours. The products were obtained in moderate to high yields.

Full text of DOI:10.1055/s-0035-1561652

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
M.-Y. Chang, Y.-C. Cheng
Letter
Synlett
Thulium Triflate Catalyzed Hydration of 2-Substituted 4-Alkynones
M.-Y. Chang*
Y.-C. Cheng
O
O
2
R
R
Ar
Ar
37 examples
Tm(OTf)3
MeNO2
O
Y
4
50–88% yield
Department of Medicinal and Applied Chemistry, and General
Research Centers of R&D Office, Kaohsiung Medical University,
Kaohsiung 807, Taiwan
Y
ychang@kmu.edu.tw
Ar = Ph, 4-FC6H4, 4-MeOC6H4, 4-MeC6H4, 4-F3CC6H4, 4-PhC6H4, 2-naphthyl,
2-thienyl, 3,4-(MeO)2C6H3, 2,3,4-(MeO)3C6H2
R = TolSO2, PhSO2, MeSO2, 3-MeC6H4SO2, 4-t-BuC6H4SO2, 4-MeOC6H4SO2,
4-FC6H4SO2; Ph, 4-MeC6H4, 4-MeOC6H4, 4-FC6H4, 4-F3CC6H4, 3,5-F2C6H3,
4-PhC6H4, 2-naphthyl
Y = H, Me, Et, Ph
Received: 18.03.2016
Accepted after revision: 08.05.2016
Published online: 01.06.2016
tion, oxidative or radical coupling, nucleophilic substitu-
tion, and the umpolung process.21,22
DOI: 10.1055/s-0035-1561652; Art ID: st-2016-w0188-l
Y
O
O
S
Br
O
O
S
Abstract We report on a facile synthetic route for the preparation of
substituted 1,4-diketones by thulium triflate mediated hydration of
substituted 4-alkynones in MeNO2 at 25 °C for five hours. The products
were obtained in moderate to high yields.
R1
2
Ar
O
Ar
R1
K2CO3, acetone
O
Y
1
3
Key words diketones, thulium triflate, hydration, alkynone, pyri-
dazine
O
O
S
Ar
R1
Ln(OTf)3
MeNO2
O
3
O
The transition metal complex mediated chemoselective
hydration of terminal alkynes to obtain methyl ketones is
one of the most straightforward functional-group transfor-
mations.1,2 The Markovnikov-type hydration of alkynes
promoted by mercuric salts is a classic procedure.3 Because
traditional mercury(II) catalysts are environmentally haz-
ardous, alternative metal catalysts have been developed, in-
cluding gold(I),4 silver(I),5 silver(I)/silver(III),6 rutheni-
um(II),7 rhodium(III),8 platinum(II),9 osmium(II),10 iridi-
Y
4
Scheme 1 Synthesis of 1,4-Diketones
After perusing literature on the synthesis of substituted
1,4-diketones and our previous studies on metal triflate
promoted reactions, 13 commercially available lanthanide
triflates were examined for the
um(III),11
palladium(II),12
iron(III),13
copper(II),14
Ln(OTf)3-promoted hydration of substrate 3a in MeNO2
at room temperature for three hours. However, no obvious
yield changes occurred with the isolation of 4a using 5
mol% of La(OTf)3, Ce(OTf)3, Pr(OTf)3, Nd(OTf)3, Sm(OTf)3,
Eu(OTf)3, Gd(OTf)3, Tb(OTf)3, Dy(OTf)3, Ho(OTf)3, Er(OTf)3,
or Yb(OTf)3. Only Gd(OTf)3, Ho(OTf)3, and Tm(OTf)3provid-
ed 4a in 10%, 14% and 31% yields, respectively. On the basis
of the results, Tm(OTf)3 was used as a catalyst to screen the
optimal reaction conditions, as shown in Table 1. Further
variations in the reaction parameters such as the catalyst
loading were examined as follows. In Table 1, entry 1, in-
creasing the catalytic amount of Tm(OTf)3 (5 mol% to 10
mol%) increased the yield of 4a (31% to 46%) and 43% of 3a
were recovered. In Table 1, entry 2, the catalytic ability of
20 mol% Tm(OTf)3 was similar to 10 mol%. With an elongat-
indium(III),15 and zinc(II).16 Notably, some cases have been
reported of metal triflate mediated hydration of alkynes us-
ing Hg(OTf)2,3 AgOTf,5 Cu(OTf)2,14 In(OTf)3,15 and Zn(OTf)2.16
To the best of our knowledge, no examples have been per-
formed where Ln(OTf)3 (lanthanide triflates) promote the
formation of carbonyl compounds.17 In continuation of our
investigation on metal triflates and α-substituted β-keto-
sulfones,18,19 a facile synthesis of sulfonyl 1,4-diketones
through Ln(OTf)3-mediated hydration of α-propargyl β-ke-
tosulfones18c was developed (Scheme 1). 1,4-Diketones are
versatile building blocks in the synthesis of substituted fu-
rans, thiophenes, and pyrroles.20A number of articles have
highlighted fascinating developments in the synthesis of
functionalized 1,4-diketones, including conjugated addi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
M.-Y. Chang, Y.-C. Cheng
Letter
Synlett
Table 1 Optimal Conditionsa,b
4), we further explored the conversion of other substrate
scopes, with the results shown in Table 2. For three substit-
uents of 3a–aj (Ar, R, and Y), the Ar ring [Ph, 4-FC6H4, 4-
MeOC6H4, 4-MeC6H4, 4-F3CC6H4, 4-PhC6H4, 2-naphthyl, 2-
thienyl, 3,4-(MeO)2C6H3, 2,3,4-(MeO)3C6H2] with diversified
electron-neutral, electron-donating, or electron-withdraw-
ing groups was well tolerated. The R group included sulfo-
nyl groups (TolSO2, PhSO2, MeSO2, 3-MeC6H4SO2, 4-t-
BuC6H4SO2, 4-MeOC6H4SO2, 4-FC6H4SO2) and aryl groups
(Ph, 4-MeC6H4, 4-MeOC6H4, 4-FC6H4, 4-F3CC6H4, 3,5-F2C6H3,
4-PhC6H4, 2-naphthyl). Y can be a hydrogen (H), methyl
(Me), ethyl (Et), or phenyl (Ph) group. By the Tm(OTf)3-me-
diated hydration reaction of 4-alkynones 3a–aj, 1,4-dike-
tones 4a–aj were provided in moderate to good yields (73–
88%, entries 1–36).25 In all entries, no obvious yield changes
for 4 were observed when different substituents of 3 were
involved. However, 50% of 4ak was isolated along with 18%
of a complex mixture when H2O was involved on the ben-
zylic position of 3ak (Table 2, entry 37).
O
O
S
O
O
O
S
Tol
S
Tol
Tm(OTf)3
conditions
Ph
Tol
Ph
O
O
O
O
Ph
Me
O
Me
3a
4a
5
Entry
Tm(OTf)3
(mol%)
Solvent
Temp
Time (h) Yield of 4a
(%)c
1
2
10
20
10
10
10
10
10
10
10
10
10
MeNO2
MeNO2
MeNO2
MeNO2
toluene
toluene
CH2Cl2
CH2Cl2
EtOAc
25 °C
25 °C
25 °C
3
3
46 (43)d
48 (33)d
51 (38)d
88
3
20
3
4
reflux
25 °C
25 °C
reflux
reflux
reflux
reflux
reflux
e
5
3
–
e
6
20
3
–
e
7
–
e
8
20
3
–
9
15e
46f
36g
Table 2 Synthesis of 4a–aka
10
11
DMF
3
O
O
S
O
O
MeNO2
20
R
R
Tm(OTf)3
MeNO2
a Reaction was run using 3a (1.0 mmol) and solvent (97%, 5 mL, containing
at least 2–3% of H2O).
Ph
Tol
Ph
Ar
Ar
O
O
Y
b All solvents were obtained from commercial sources and used without fur-
ther purification.
Y
c Isolated yield.
O
d Isolated yield of 3a.
4ak
3
4
e 3a was recovered (for entry 5, 82%; for entry 6, 70%; for entry 7, 74%; for
entry 8, 70%; for entry 9, 49%).
Entry
3 Ar =, R =, Y =
Yield of 4 (%)b
f A complex mixture (27%) was isolated.
g 30% of 3-sulfonyl furan 5 was observed.
1
2
3a Ph, TolSO2, H
4a 88
4b 86
4c 84c
4d 85
4e 87
4f 86
4g 84
4h 82
4i 84
3b 4-FC6H4, TolSO2, H
ed reaction time (3 h to 20 h), a higher yield (51%) was ob-
served (Table 1, entry 3). After elevating the temperature
(room temperature to reflux), 4a was isolated in 88% yield
(Table 1, entry 4). After changing the reaction solvent from
MeNO2 to toluene and CH2Cl2, only 3a was recovered (Table
1, entries 5–8) and no hydrated products could be detected
at room temperature and under reflux conditions, respec-
tively. In refluxing EtOAc (Table 1, entry 9), 4a was isolated
in low yield (15%) and 3a was recovered (49%). Entry 10
showed that in refluxing DMF, 4a was obtained
in 46% yield of along with 27% of complex mixture.
However, treatment of 3a with refluxing MeNO2 for 20
hours afforded 4a in low yield (36%) due to the formation of
the skeleton of 3-sulfonyl furan 5 (Table 1, entry 11). On the
basis of a higher yield, we believe that 10 mol% Tm(OTf)3,
MeNO2, reflux for three hours should be the optimal reac-
tion conditions for the formation of 4a.
3
3c 4-MeOC6H4, TolSO2, H
3d 4-MeC6H4, TolSO2, H
3e 4-F3CC6H4, TolSO2, H
3f 4-PhC6H4, TolSO2, H
3g 2-naphthyl, TolSO2, H
3h 4-FC6H4, PhSO2, H
3i 4-MeOC6H4, PhSO2, H
3j 4-PhC6H4, PhSO2, H
3k 4-MeC6H4, MeSO2, H
3l 4-PhC6H4, MeSO2, H
3m Ph, 3-MeC6H4SO2, H
3n Ph, 4-t-BuC6H4SO2, H
3o Ph, 4-MeOC6H4SO2, H
3p Ph, 4-FC6H4SO2, H
3q 2-thienyl, TolSO2, H
3r Ph, TolSO2, Me
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4j 80
4k 80
4l 82
4m 84
4n 85
4o 80
4p 80
4q 82
4r 78
4s 76
4t 79
4u 82
On the other hand, Tm(OTf)3 has been reported as a cat-
alyst for Ferrier rearrangements23a and Diels–Alder cycload-
ditions.23b Remarkably, only a few examples of thulium(III)
salt mediated reactions have been performed in compari-
son with other commercially available metal triflates.24
With the facile reaction conditions in hand (Table 1, entry
3s Ph, TolSO2, Et
3t Ph, Ph, H
3u 4-MeOC6H4, Ph, H
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
M.-Y. Chang, Y.-C. Cheng
Letter
Synlett
Table 2 (continued)
lium complex was generated (green arrow) such that in situ
formed triflate anion mediated the reversed pathway may
be occurred. Following the proton exchange of oxonium
cation and triflate anion on B2 (having the γ addition of
H2O), tautomerization of C, and then triflic acid promoted
dethuliumation of D, the removal of Tm(OTf)3 afforded 4r
and 4s.
Entry
3 Ar =, R =, Y =
Yield of 4 (%)b
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
3v 4-MeOC6H4, 4-MeC6H4, H
3w 4-MeOC6H4, 4-MeOC6H4, H
3x 4-MeOC6H4, 4-FC6H4, H
4v 78
4w 78
4x 80
3y 4-MeOC6H4, 4-F3CC6H4, H
3z 4-MeOC6H4, 3,5-F2C6H3, H
3aa 4-MeOC6H4, 4-PhC6H4, H
3ab 4-MeOC6H4, 2-naphthyl, H
3ac 3,4-(MeO)2C6H3, Ph, H
4y 76
4z 74
O
O
S
4aa 73
4ab 76
4ac 75
4ad 74
4ae 74
4af 76
4ag 76
4ah 77
4ai 76
4aj 78
4ak 50c
N
Me
N2H4
Ar
Tol
O
N
O
dioxane
Ar
Me
4a, Ar = Ph
4b, Ar = 4-FC6H4
4c, Ar = 4-MeOC6H4
3ad 3,4-(MeO)2C6H3, 4-MeC6H4, H
3ae 3,4-(MeO)2C6H3, 4-MeOC6H4, H
3af 3,4-(MeO)2C6H3, 4-FC6H4, H
3ag 3,4-(MeO)2C6H3, 4-PhC6H4, H
3ah 3,4-(MeO)2C6H3, 3,5-F2C6H3, H
3ai 3,4,5-(MeO)3C6H2, Ph, H
3aj 3,4,5-(MeO)3C6H2, 4-FC6H4, H
3ak Ph, TolSO2, Ph
6a (92%)
6b (94%)
6c (92%)
Scheme 3 Synthesis of pyridazines 6a–c
In an extension of this method, we were able to perform
a synthesis of pyridazine, as shown in Scheme 3. 2-Arylpyr-
idazine is a versatile scaffold for useful synthetic intermedi-
ates.26 It also exhibits versatile biological activities.27 Many
articles have highlighted fascinating developments based
on two carbon–nitrogen bond formations.28 Furthermore,
condensation of sulfonyl 1,4-diketones 4a–c with 80% hy-
drazine in dioxane for four hours at 25 °C provided 2-
arylpyridazines 6a–c in high yields (92%, 94%, and 92%)
during the desulfonylative aromatization process. As shown
in Scheme 4,Tm(OTf)3-mediated reactions of α-propargyl
β-ketoesters 7a,b and α-propargyl β-diketone 7c in MeNO2
at reflux for three hours were examined next. In particular,
2-arylfurans 8a–c provided as the sole isomer in 53–68%
yields via the cycloisomerization process under the above
conditions.
a The synthesis of 6 was run on a 1.0 mmol scale with 3, Tm(OTf)3 (10
mol%), MeNO2 (5 mL), 3 h, reflux.
b Isolated yield.
c Complex mixture (18%) was isolated.
Based on the results, a possible reaction mechanism is
shown in Scheme 2. How were regioisomers 4r and 4s pro-
duced? The mechanism should be initiated to form A by
complexation of an α-alkynyl motif of 3r and 3s with
Tm(OTf)3, and participation of H2O (from MeNO2) could
lead to the B1 and B2 via the intermolecular anti addition of
H2O on the δ position (blue) and γ position (red) of A. For
the configuration of B1 (having the δ addition of H2O), a
stronger repulsion between the benzoyl group and the thu-
O
O
O
Tm(OTf)3
MeNO2
EtO
Ar
OEt
O
O
S
O
O
S
Ar
Me
O
Tm(OTf)3
MeNO2
Tm(OTf)3
Ph
Tol
Ph
Tol
O
7a, Ar = Ph
7b, Ar = 4-MeOC6H4
8a (53%)
8b (60%)
O
O
O
O
S
Y
O
O
O
Ph
Tol
3r, Y = Me
3s, Y = Et
4r, Y = Me
4s, Y = Et
Y
O
Tm(OTf)3
MeNO2
Ph
Ph
Ph
Tm(OTf)2
OTf
O
O
S
O
Ph
Me
O
Y
H
Ph
Tol
more
O
7c
8c (68%)
repulsion
D
O
O
S
δ
OH2
α
Scheme 4 Tm(OTf)3-mediated cycloisomerization of 7a–c
O
O
Ph
Tol
(TfO)2Tm
O
Y
S
Tm(OTf)3
B1
Ph
Tol
TfO
O
Furthermore, changing 1,3-diacrbonyls synthons 7 with
the propargyl group to arylacetylenes 9, substituted ace-
tophenones 10a–c afforded in 49–81% yields as shown in
Scheme 5. In Scheme 5, eq. 1, 9a was easily converted into
10a in 81% yield. However, the Boc-protective group on 9b
could be removed by Tm(OTf)3 and 10b was isolated in 49%
yield under the refluxing MeNO2 conditions (Scheme 5, eq.
2). In Scheme 5, eq. 3, 4-alkenone 10c afforded in 74% yield
O
O
Y
Tm(OTf)2
S
H2O
Ph
Tol
HO
TfOH
A
O
Y
γ
C
Tm(OTf)2
TfO
H2O
Y
B2
Scheme 2 Plausible mechanism of 4r,s
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
M.-Y. Chang, Y.-C. Cheng
Letter
Synlett
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O
Tm(OTf)3
Ph
H
Ph
(1)
(2)
MeNO2
Me
10a (81%)
9a
H
O
N
H
Tm(OTf)3
MeNO2
O
H2N
O
Me
tBu
9b
10b (49%)
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Ph
Ph
Tm(OTf)3
MeNO2
(3)
O
OMe
OMe
(6) For Ag+/Au3+, see: (a) Arcadi, A.; Alfonsi, M.; Chiarini, M.;
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9c
10c (74%)
Scheme 5 Tm(OTf)3-mediated of hydration of 9a–c
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via Tm(OTf)3-mediated hydration of enyne 9c having the
olefin group. The olefinic motif did not be affected under
the acid-sensitive conditions.
In summary, we have developed a mild and facile syn-
thesis of substituted 1,4-diketones 4 in good yields through
a 10 mol% Tm(OTf)3-mediated hydration reaction of substi-
tuted 4-alkynones 3 in MeNO2 at reflux for three hours. The
control of reaction parameters such as the lanthanide tri-
flate catalyst loading, the reaction temperature, the solvent,
and reaction time, had to be finely tuned in order to explore
optimal reaction conditions. Furthermore, 2-arylpyri-
dazines 6a–c were synthesized from a concentration reac-
tion of sulfonyl 1,4-diketones 4a–c with hydrazine. Further
investigation regarding synthetic applications of lanthanide
triflates will be conducted and published in due course.
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Acknowledgment
The authors would like to thank the Ministry of Science and Technol-
ogy of the Republic of China for its financial support (MOST 104-
2113-M-037-012). This study is supported partially by Kaohsiung
Medical University ‘Aim for the Top Universities Grant, grant No.
KMU-TP104PR15’.
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Supporting Information
Supporting information (experimental procedures and scanned pho-
tocopies of NMR (CDCl3) spectral data) for this article is available on-
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line at http://dx.doi.org/10.1055/s-0035-1561652.
S
u
p
p
ortiInfogrmoaitn
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u
p
p
o
nrtIo
g
f
rmoaitn
References and Notes
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(1) For reviews on hydration of alkynes, see: (a) Hintermann, L.;
Labonne, A. Synthesis 2007, 1121. (b) Alonso, F.; Beleskaya, I. P.;
Yus, M. Chem. Rev. 2004, 104, 3079. (c) Corma, A.; Leyva-Perez,
A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657.
(2) (a) Larock, R. C.; Leong, W. W. In Comprehensive Organic Synthe-
sis; Trost, B. M.; Fleming, I.; Semmelhack, M. F., Eds.; Pergamon
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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M.-Y. Chang, Y.-C. Cheng
Letter
Synlett
(d) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2015, 17, 3142.
(e) Chang, M.-Y.; Cheng, Y.-C. Org. Lett. 2015, 17, 5702. For
In(OTf)3, see: (f) Chang, M.-Y.; Lu, Y.-J.; Cheng, Y.-C. Tetrahedron
2015, 71, 6840.
(24) Recent Tm(III) salts mediated reactions, see: (a) Shie, J.-J.;
Workman, P. S.; Evans, W. J.; Fang, J.-M. Tetrahedron Lett. 2004,
45, 2703. (b) Taydakov, I. V.; Nelyubina, T. V. Tetrahedron Lett.
2013, 54, 1704. (c) Szostak, R.; Aube, J.; Szoztak, M. J. Org. Chem.
2015, 80, 7905.
(19) Synthetic applications on α-substituted β-ketosulfones by
authors, for styrylsulfones, see: (a) Chang, M.-Y.; Chen, Y.-C.;
Chan, C.-K. Synlett 2014, 25, 1739. For vinylcyclopropanes, see:
(b) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Tetrahedron 2014, 70,
8908. For 2,5-diaryltetrahydrofurans, see: (c) Chang, M.-Y.;
Cheng, Y.-C. Synlett 2016, 27, 854. For 2,6-diaryltetrahydropy-
rans, see: (d) Chang, M.-Y.; Lu, Y.-J.; Cheng, Y.-C. Tetrahedron
2015, 71, 1192. For 2-arylpyrroles, see: (e) Chang, M.-Y.; Cheng,
Y.-C.; Lu, Y.-J. Org. Lett. 2014, 16, 6252. For 2-vinylfurans, see:
(f) Chan, C.-K.; Lu, Y.-J.; Chang, M.-Y. Tetrahedron 2015, 71,
9544. For tetralins and benzosuberans, see: (g) Chang, M.-Y.;
Cheng, Y.-C. Org. Lett. 2016, 18, 608. For 1-aryltetralins, see:
(h) Chang, M.-Y.; Cheng, Y.-C. Org. Lett. 2016, 18, 1682. For 1-
arylnaphthalenes, see: (i) Chang, M.-Y.; Huang, Y.-H.; Wang, H.-
S. Tetrahedron 2016, 72, 1888. For phenanthrenes, see:
(j) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Tetrahedron 2015, 71,
782. For phenanthrofurans, see: (k) Chan, C.-K.; Chen, Y.-C.;
Chen, Y.-L.; Chang, M.-Y. Tetrahedron 2015, 71, 9187.
(20) For review articles, see: (a) Bhardwaj, V.; Gumber, D.; Abbot, V.;
Dhiman, S.; Sharma, P. RSC Adv. 2015, 5, 15233.
(b) Khaghaninejad, S.; Heravi, M. M. Adv. Heterocycl. Chem.
2014, 111, 95. (c) Donohoe, T. J.; Pullin, R. D. C. Chem. Commun.
2012, 48, 11924. (d) Schmuck, C.; Rupprecht, D. Synthesis 2007,
3095.
(21) (a) Eymur, S.; Gollu, M.; Tanyeli, C. Turkish J. Chem. 2013, 37,
586. (b) Yetra, S. R.; Patra, A.; Biju, A. T. Synthesis 2015, 47, 1357.
(c) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis,
T. Chem. Rev. 2015, 115, 9307. (d) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606. (e) Nair, V.; Deepthi, A.
Chem. Rev. 2007, 107, 1862.
(22) (a) Ragno, D.; Bortolini, O.; Fantin, G.; Fogagnolo, M.;
Giovannini, P. P.; Massi, A. J. Org. Chem. 2015, 80, 1937.
(b) Huang, S.; Kotzner, L.; De, C. K.; List, B. J. Am. Chem. Soc.
2015, 137, 3446. (c) Peralta-Hernández, E.; Blé-Gonzáles, E. A.;
Garcia-Medrano-Bravo, V. A.; Cordero-Vargas, A. Tetrahedron
2015, 71, 2234. (d) Zhang, F.; Du, P.; Chen, J.; Wang, H.; Luo, Q.;
Wang, X. Org. Lett. 2014, 16, 1932. (e) Bar, G.; Parsons, A. F.;
Thomas, C. B. Org. Biomol. Chem. 2003, 1, 373. (f) Bar, G.;
Parsons, A. F.; Thomas, C. B. Synlett 2002, 1069. (g) Schweitzer-
Chaput, B.; Demaerel, J.; Engler, H.; Klussmann, M. Angew.
Chem. Int. Ed. 2014, 53, 8737. (h) Schweitzer-Chaput, B.; Kurten,
T.; Klussmann, M. Angew. Chem. Int. Ed. 2015, 54, 11848.
(i) Christoffers, J.; Werner, T.; Frey, W.; Baro, A. Eur. J. Org. Chem.
2003, 4879. (j) Rossle, M.; Werner, T.; Frey, W.; Christoffers, J.
Eur. J. Org. Chem. 2005, 5031.
(25) Representative Synthetic Procedure of Skeleton 4
Tm(OTf)3 (62 mg, 0.1 mmol) was added to a solution of 3 (1.0
mmol) in MeNO2 (5 mL) at r.t. The reaction mixture was stirred
at reflux for 3 h. The reaction mixture was cooled to r.t. The
solvent of reaction mixture was concentrated and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with brine, dried, filtered, and evaporated to afford the
crude product under reduced pressure. Purification on silica gel
(hexanes–EtOAc = 8:1 to 3:1) afforded 4.
Compound 4a: Rf = 0.3 (hexanes–EtOAc = 8:1); yield 88% (290
mg); colorless oil. ESI-HRMS: m/z calcd for C18H19O4S [M+ + 1]:
331.1004; found: 331.1010. 1H NMR (400 MHz, CDCl3): δ = 7.91
(d, J= 8.8 Hz, 2 H), 7.58–7.54 (m, 3 H), 7.43–7.39 (m, 2 H), 7.24
(d, J = 8.4 Hz, 2 H), 5.51 (dd, J = 2.8, 10.8 Hz, 1 H), 3.49 (dd, J =
10.8, 18.0 Hz, 1 H), 3.29 (dd, J = 2.8, 18.0 Hz, 1 H), 2.40 (s, 3 H),
2.16 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 203.79, 191.59,
145.60, 136.58, 133.68, 133.54, 129.68 (2×), 129.36 (2×), 129.17
(2×), 128.49 (2×), 65.55, 41.87, 29.55, 21.64.
Compound 4b: Rf = 0.3 (hexanes–EtOAc = 8:1); yield 86% (299
mg); colorless oil. ESI-HRMS: m/z calcd for C18H18FO4S [M+ + 1]:
349.0910; found: 349.0918. 1H NMR (400 MHz, CDCl3): δ =
7.99–7.94 (m, 2 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.8 Hz, 2
H), 7.13–7.07 (m, 2 H), 5.43 (dd, J = 2.8, 10.8 Hz, 1 H), 3.47 (dd, J
= 10.8, 18.0 Hz, 1 H), 3.27 (dd, J = 2.8, 18.0 Hz, 1 H), 2.42 (s, 3 H),
2.15 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 203.81, 190.02,
166.13 (d, J = 255.5 Hz), 145.77, 133.36, 133.03 (d, J = 3.0 Hz),
132.97 (d, J = 9.1 Hz, 2×), 130.53, 129.74, 129.35, 128.84, 115.71
(d, J = 21.9 Hz, 2×), 65.58, 41.99, 29.49, 21.65.
(26) For recent reviews on synthesis of pyridazines, see:
(a) Bourguignon, J. J.; Oumouch, S.; Schmitt, M. Curr. Org. Chem.
2006, 10, 277. (b) Elnagdi, M. H.; Al-Awadi, N. A.; Abdelhamid, I.
A. Adv. Heterocycl. Chem. 2009, 97, 1. (c) Haider, N.; Holzer, W.
Sci. Synth. 2004, 16, 125.
(27) For the potential biological activities of pyridazines, see:
(a) Gyoten, M.; Nagaya, H.; Fukuda, S.; Ashida, Y.; Kawano, Y.
Chem. Pharm. Bull. 2003, 51, 122. (b) Tamayo, N.; Liao, L.;
Goldberg, M.; Powers, D.; Tudor, Y. Y.; Yu, V.; Wong, L. M.;
Henkle, B.; Middleton, S.; Syed, R.; Harvey, T.; Jang, G.; Hungate,
R.; Dominguez, C. Bioorg. Med. Chem. Lett. 2005, 15, 2409.
(c) Emmerich, J.; Hu, Q.; Hanke, N.; Hartmann, R. W. J. Med.
Chem. 2013, 56, 6022.
(28) For recent examples on the synthesis of pyridazines, see:
(a) Gao, Q.; Zhu, Y.; Lian, M.; Liu, M.; Yuan, J.; Wu, A.; Yin, G.
J. Org. Chem. 2012, 77, 9865. (b) Petiot, P.; Gagnon, A. Eur. J. Org.
Chem. 2013, 24, 5282. (c) Mboyi, C. D.; Duhayon, C.; Canac, Y.;
Chauvin, R. Tetrahedron 2014, 70, 4957.
(23) Tm(OTf)3-mediated reactions, for the Ferrier rearrangement,
see: (a) Chen, P.; Bi, B. Tetrahedron Lett. 2015, 56, 4895. For
Diels–Alder cycloadditions, see: (b) Yoshida, K.; Morikawa, T.;
Yokozuka, N.; Harada, S.; Nishida, A. Tetrahedron Lett. 2014, 55,
6907.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E