DABCO-mediated one-pot sequential transformation: Convenient access to fluorinated 1H-pyrazol-5(4H)-ones

Article abstract of DOI:10.1016/j.tetlet.2012.06.110

A Lewis base-mediated one-pot sequential transformation of pyrazolones with Morita-Baylis-Hillman (MBH) carbonates and N-fluoro-N-(phenylsulfonyl) benzenesulfonamide (NFSI) has been developed. By using this process, a series of fluorinated pyrazolone derivatives have been synthesized in 40-83% yields.

Full text of DOI:10.1016/j.tetlet.2012.06.110

Tetrahedron Letters 53 (2012) 4828–4831
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DABCO-mediated one-pot sequential transformation: convenient access
to fluorinated 1H-pyrazol-5(4H)-ones
⇑
Jun-Wei Wu, Feng Li, Yan Zheng, Jing Nie
Department of Chemistry, Tianjin University, Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Lewis base-mediated one-pot sequential transformation of pyrazolones with Morita-Baylis-Hillman
(MBH) carbonates and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI) has been developed. By
using this process, a series of fluorinated pyrazolone derivatives have been synthesized in 40–83% yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 9 May 2012
Revised 14 June 2012
Accepted 26 June 2012
Available online 29 June 2012
Keywords:
Pyrazolones
Allylic alkylation
Electrophilic fluorination
One-pot sequential transformation
Synthesis
The efficient assembly of densely functionalized fluorinated
heterocycles is an appealing subject of investigation due to their
wide application in pharmaceuticals, agrochemicals, and new
materials.1 Among synthetic routes to these compounds, one-pot
multistep transformation appears to be a powerful method for cre-
ating structural diversity by virtue of avoiding the monotonous
purification of intermediate.2 In this aspect, a great deal of efforts
has been devoted to the designing of highly selective and efficient
one-pot multistep transformations in accord with the increasing
need for the continued advancement of the field of organofluorine
chemistry.3 Despite the remarkable achievement made in this area,
the employment of one-pot strategy from readily available
precursors for rapid and efficient construction of fluorinated aza-
heterocyclic compounds is still in great demand.
Pyrazolone, an important class of aza-heterocycles, represents a
prominent structural subunit present in numerous biologically ac-
tive compounds, such as analgesic and antipyretic properties.4
During the past decades, the usefulness of pyrazolones as nucleo-
philes has been explored for construction of a variety of pyrazolone
derivatives.5 However, the use and preparation of monofluorinated
pyrazolones is extremely rare. Only one report by Davis and
co-workers has addressed the electrophilic fluorination of 3-
methyl-1-phenyl-1H-pyrazol-5(4H)-one with N-fluoro-o-benzen-
edisulfonimide, but a mixture of mono- and difluorinated products
was obtained in low yield (Scheme 1a).6 We surmised that a
sequential allylic alkylation/electrophilic fluorination in one-pot
could provide an alternative method for the preparation of mono-
fluorinated pyrazolone derivatives. Moreno-Manas and co-workers
once described an allylation reaction of pyrazolones with acrylic
esters to afford the mixture of C-, N-, and di-allylated products,7a
whereas Grigg and co-workers presented
a Pd(0)-catalyzed
cascade transformation of an iodide and allene with pyrazolin-5-
one to give the di-allylated pyrazolones.7b As a part of our ongoing
interest in developing innovative methodologies for the prepara-
tion of fluorinated compounds,3d-f we recently found that
1,4-diazabicyclo[2.2.2]octane (DABCO) can catalyze the allylic
alkylation of 1H-pyrazol-5(4H)-ones with Morita-Baylis-Hillman
(MBH) carbonates,8 to afford allylated pyrazolones, which could
be further converted into monofluorinated products through one-
pot sequential transformation (Scheme 1b). In this communication,
we report our preliminary results on this subject.
To validate our hypothesis, the model reaction of MBH carbon-
ate 1a and 3-methyl-1-phenylpyrazol-5-one 2a was performed in
the presence of 20 mol % of DABCO in toluene at room tempera-
ture. As indicated in Table 1, the allylation reaction proceeded well,
affording pyrazol-5-ol Int-A in 67% yield. The regioisomer Int-B
was also formed in 21% yield (entry 1). Screening of the Lewis
bases revealed that the use of DABCO allowed for the best regiose-
lectivity of this allylic substitution (entries 1ꢀ4). Further optimiza-
tion on the other reaction conditions (including solvent and base’s
loading) led to the discovery that the regioisomer of Int-A was
formed exclusively in 89% yield when toluene was used as solvent
and base’s loading was increased to 150 mol % (entry 7). Based on
these results, the one-pot procedure was next attempted by
employing NFSI as electrophilic fluorinating reagent for synthesis
⇑
Corresponding author.
E-mail address: niejing@tju.edu.cn (J. Nie).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.110

J.-W. Wu et al. / Tetrahedron Letters 53 (2012) 4828–4831
4829
a) Davis's work
Me
F
Me
Me
F
O
O
F
O
NF
O
CH2Cl2 / H2O
S
S
+
N
N
O
O
N
+
N
Ph
10%
N
Ph
30%
O
N
Ph
b) The present work
R
Ph
N
F
O
O
N
N
N
N
O
O
S
S
OBocO
O
O
(DABCO)
Ph
Ph
F
R
N
+ Ar
OMe
O
N
Allylic alkylation
Fluorination
Ar
OM
e
Ph
40−83%
Scheme 1. Synthesis of fluorinated pyrazolones.
Table 1
Optimization of the conditions for the one-pot synthesis of 3aa
Ph
N
Ph
N
O
Me
N
OBocO
N
OH
O
OMe
OH
O
F-reagent
Solvent, rt
+
Lewis base
Solvent, rt
O
Me
OMe
N
Me
F
O
N
Ph
OMe
OMe
N
Ph
Me
N
1a
2a
3a
Int-B
Int-A
Entry
Lewis base (mol %)
Solvent
F-reagent
Yieldb (%)
Int-B
Int-A
3ad
1
2
3
4
5
6
7
8
9
10
11
12
13c
DABCO (20)
DMAP (20)
DBU (20)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
DCE
—
—
—
—
—
—
—
67
56
51
60
78
85
89
12
55
10
13
20
22
21
24
23
30
8
—
—
—
—
7
—
—
—
—
—
—
—
63
10
55
51
46
41
PPh3 (20)
DABCO (50)
DABCO (100)
DABCO (150)
DABCO (150)
DABCO (150)
DABCO (150)
DABCO (150)
DABCO (150)
DABCO (150)
NFSI
Selectfluor
NFSI
NFSI
NFSI
NFSI
7
5
9
THF
Toluene
a
b
c
1a/2a/Base/F-reagent = 1.5/1/1.5/1.5 in 2 mL of solvents.
Isolated yield.
The reaction was performed at 40 °C.
d
The dr value (50/50ꢀ75/25) was determined by 19F NMR of the crude product.
of fluorinated compound. Gratifyingly, the desired fluorinated
product of 3a was isolated in 63% yield as single regioisomer, albeit
with moderate diastereoselectivity (72/28 dr). Subsequent change
of the electrophilic fluorinating reagent to selectfluor resulted in
the dramatically diminished yield of 3a (entry 9). A sharp decrease
of yield was observed as raising reaction temperature to 40 °C
(entry 13). Overall, the optimized conditions for the fluorination
step were using NFSI as fluorinated reagent in toluene at room
temperature.
entry 7). Moreover, the reactions with 1- and 2-naphthyl pyrazo-
lones were uneventful, and furnished the fluorinated pyrazolones
3j and 3k, respectively (entries 10 and 11). Notably, heteroaro-
matic substrate was also viable substrates, affording the desired
product 3l in 65% yield with 85/15 dr (entry 12). Next, a number
of 3-substituted pyrazolones have also been explored in this one-
pot multistep reaction. 52–64% yields were obtained for pyrazo-
lones bearing electron-neutral or -rich or -deficient aryl groups
(entries 13–16).
Under the optimized experimental conditions, the scope of the
one-pot multistep transformation for synthesis of 3 was examined
with a variety of MBH carbonates 1 and pyrazolones 2, and the
results are summarized in Table 2.9 It was found that when MBH
carbonates with electron-withdrawing or -donating groups on aro-
matic rings were used, the one-pot transformations proceeded
smoothly to give 3a–l in 40–83% yields with acceptable diastere-
oselectivities (from 50/50 to 80/20 dr). However, the relatively
lower yields were observed within the MBH carbonates 1 bearing
functional group at the 2-position of aromatic ring (40% yield,
To test the synthetic potential of the present approach, we ex-
tended this one-pot methodology to electrophilic chlorinating
and brominating reagents. It was found that in the presence of
DABCO, the reaction of MBH carbonates 1a and pyrazol-5-one 2a
with NCS and NBS delivered the corresponding chlorinated and
brominated pyrazolones 4 and 5 in 78% and 61% yields, respec-
tively (Scheme 2).10
On the basis of above experimental results and previous work, a
plausible mechanism accounting for the formation of 3 is illus-
trated in Scheme 3. DABCO attacks from the b0-position of MBH

4830
J.-W. Wu et al. / Tetrahedron Letters 53 (2012) 4828–4831
Table 2
Substrate scope for one-pot synthesis of 3a
Ph
N
R
N
O
O
OBocO
DABCO
NFSI
F
R
N
+
Ar
OMe
O
N
Ph
toluene, rt, 6 h
rt, 24 h
Ar
OMe
1
2
3
Entry
Ar
R
Product 3
Yieldb (%)
Drc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
63
58
53
61
73
80
40
62
83
54
75
65
59
52
61
64
72/28
78/22
80/20
78/22
75/25
71/29
60/40
80/20
67/33
50/50
70/30
85/15
60/40
65/35
70/30
73/27
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
3-MeOC6H4
3,4-Cl2C6H3
1-Naphthyl
2-Naphthyl
2-Furanyl
Ph
Ph
Ph
Ph
4-MeOC6H4
4-ClC6H4
4-BrC6H4
a
b
c
1/2/Base/F-reagent = 1.5/1/1.5/1.5 in 2 mL of toluene.
Isolated yield.
The dr value was determined by 19F NMR of the crude product.
Ph
N
Me
N
O
O
OBocO
NCS or NBS
rt, 24 h
DABCO
X
Me
N
OMe
O
+
N
toluene, rt, 6 h
OMe
Ph
1a
2a
4
: X = Cl, 78%, dr = 50/50
5: X = Br, 61%, dr = 88/12
Scheme 2. One-pot synthesis of 4 and 5.
OBoc
E
N
β
Ar
E
DABCO
CO2
Ar
tBuO
I
β
'
N
Me
1
N
O
N
Ph
Me
N
2
O
DABCO
N
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
Me
E
Base
Me
E
F
HO
Ar
Me
E
O
Me
E
O
O
F
Ar
Ar
Ar
Int-A
II
3
III
Scheme 3. Plausible mechanism for the formation of fluorinated pyrazolones 3.
carbonate to form a quaternary ammonium ion I. The deprotona-
tion of pyrazolone at C-4 by in situ generated tert-butoxide anion
occurs, and is followed by allylation of I to give intermediate II
along with elimination of DABCO. It should be pointed out that
pyrazol-5-ones in this allylations mainly exist as OH-tautomeric
forms Int-A, which have been verified by 1H NMR analysis.11

J.-W. Wu et al. / Tetrahedron Letters 53 (2012) 4828–4831
4831
5. For selected examples, see: (a) Boeckman, R. K., Jr; Reed, J. E.; Ge, P. Org. Lett.
2001, 3, 3651; (b) Abass, M.; Mostafa, B. B. Bioorg. Med. Chem. 2005, 13, 6133;
(c) Chande, M. S.; Barve, P. A.; Suryanarayan, V. J. Heterocycl. Chem. 2007, 44, 49;
(d) Mariappan, G.; Saha, B. P.; Bhuyan, N. R.; Bharti, P. R.; Kumar, D. J. Adv.
Pharm. Technol. Res. 2010, 1, 260; (e) Ma, R.; Zhu, J.; Liu, J.; Chen, L.; Shen, X.;
Jiang, H.; Li, J. Molecules 2010, 15, 3593; (f) Liao, Y.-H.; Chen, W.-B.; Wu, Z.-J.;
Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Adv. Synth. Catal. 2010, 352, 827;
(g) Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009, 50, 2252; (h) Radi, M.;
Bernardo, V.; Bechi, B.; Castagnolo, D.; Pagano, M.; Botta, M. Tetrahedron Lett.
2009, 50, 6572; (i) Gogoi, S.; Zhao, C.-G.; Ding, D. Org. Lett. 2009, 11, 2249; (j)
Yang, Z. G.; Wang, Z.; Bai, S.; Liu, X.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 596; (k)
Alba, A. N.; Zea, A.; Valero, G.; Calbet, T.; Font-Bardía, M.; Mazzanti, A.; Moyano,
A.; Rios, R. Eur. J. Org. Chem. 2011, 1318; (l) Wang, Z.; Yang, Z.; Chen, D.; Liu, X.;
Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2011, 50, 4928.
Finally, the resulting enolate III derived from deprotonation of Int-
A is captured by electrophilic fluorinating reagent to furnish the
corresponding fluorinated compound 3.
In summary, we have developed a one-pot sequential allylic
alkylation/electrophilic fluorination transformation for the facile
synthesis of fluorinated allylic pyrazolones. A series of fluorinated
pyrazolone derivatives were obtained in moderate to good yields.
In the presence of NBS and NCS, further extension of this one-pot
sequential protocol also proved effective. The development of cat-
alytic enantioselective systems, as well as the application of this
process to the synthesis of bioactive fluorinated compounds are
ongoing in our laboratory and will be reported in due course.
6. Davis, F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995, 60, 4730.
7. (a) Moreno-Manas, M.; Pérez, M.; Pleixats, R. Tetrahedron 1994, 50, 515; (b)
Grigg, R.; Sarkar, M. R. A.; Thayaparan, A.; Sridharan, V.; Fishwick, C. W. G.
Tetrahedron 2007, 63, 7213.
Acknowledgment
8. For selected examples about MBH carbonates, see: (a) Basavarath, D.; Rao, P. D.;
Hyma, R. S. Tetrahedron 1996, 52, 8001; (b) Ciganek, E. Org. React. 1997, 51, 201;
For selected examples about MBH carbonates, see: (c) Du, Y.; Han, X.; Lu, X.
Tetrahedron 2004, 45, 4967; (d) Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L. Tetrahedron:
Asymmetry 2007, 18, 1990; (e) van Steenis, D. J. V. C.; Marcelli, T.; Lutz, M.;
Spek, A. L.; van Maarseveen, J. H.; Hiemstra, H. Adv. Synth. Catal. 2007, 349, 281;
(f) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202; (g) Cui, H.-L.;
Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48,
5737; (h) Zhang, S.-J.; Cui, H.-L.; Jiang, K.; Li, R.; Ding, Z.-Y.; Chen, Y.-C. Eur. J.
Org. Chem. 2009, 5804; (i) Cui, H.-L.; Peng, J.; Feng, X.; Du, W.; Jiang, K.; Chen,
Y.-C. Chem. Eur. J. 2009, 15, 1574; (j) Sun, W.; Hong, L.; Liu, C.; Wang, R. Org. Lett.
2010, 12, 3914; (k) Song, W.; Lei, M.; Shen, Y.; Cai, S.; Lu, W.; Lu, P.; Wang, Y.
Adv. Synth. Catal. 2010, 352, 2432; (l) Zhou, R.; Wang, C.; Song, H.; He, Z. Org.
Lett. 2010, 12, 976; (m) Peng, J.; Huang, X.; Lei, H.-C.; Chen, Y.-C. Org. Lett. 2010,
12, 4260; (n) Furukawa, T.; Nishimine, T.; Tokunaga, E.; Hasegawa, K.; Shiro,
M.; Shibata, N. Org. Lett. 2011, 13, 3972; (o) Jiang, L.; Lei, Q.; Huang, X.; Cui, H.-
L.; Zhou, X.; Chen, Y.-C. Chem. Eur. J. 2011, 17, 9489; (p) Pei, C.-K.; Zhang, X.-C.;
Shi, M. Eur. J. Org. Chem. 2011, 4479; (q) Liu, H.; Yan, L.; Huang, K.-W.; Jiang, Z.;
Tan, C.-H. Chem. Eur. J. 2011, 17, 8066.
The financial support from the National Natural Science Foun-
dation of China (NSFC) (No. 20972110 and 21002068) is gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
110.
References and notes
1. For recent reviews, see: (a) Zhu, S. Z.; Wang, Y.; Peng, W.; Song, L. P.; Jin, G. F.
Curr. Org. Chem. 2002, 6, 1057; (b) He, P.; Zhu, S. Z. Mini-Rev. Org. Chem. 2004, 1,
417; (c) Special issue on ‘‘fluorine in the life sciences’’. ChemBioChem 2004, 5,
557.; (d) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Oxford, UK,
2004; (e) Meng, W.-D.; Qing, F.-L. Curr. Top. Med. Chem. 2006, 6, 1499; (f)
Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303; (g) Sandford, G. J.
Fluorine Chem. 2007, 128, 90; (h) Kirk, K. L. Org. Process. Res. Dev. 2008, 12, 305;
(i) Purser, S.; Moore, P. R.; Swallowb, S.; Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320.
2. For recent reviews, see: (a) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem.
Commun. 2003, 551; (b) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004,
248, 9456; (c) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302;
(d) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105,
1001; (e) Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (f)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 354;
(g) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354; (h) Enders, D.;
Grondal, C.; Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (i) Tietze, L. F.;
Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42, 367; (j) Albrecht, Ł.; Jiang, H.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2011, 50, 8492; (k) Climent, M. J.; Corma,
A.; Iborra, S. Chem. Rev. 2011, 111, 1072.
9. General procedure for one-pot synthesis of fluorinated products 3: MBH carbonate
(0.15 mmol), pyrazolin-5-one (0.1 mmol), and DABCO (0.15 mmol), were
added to a 10 mL schlenk equipped with a magneton. The vial was refilled
with Ar for three times. Toluene (2 mL) was added and the resulting mixture
was stirred at room temperature under Ar atmosphere for the appropriate time
(2–6 h) until pyrazolin-5-one was consumed (monitored by TLC). Then NFSI
(0.15 mmol) was added and the mixture was stirred at the same temperature
for 24 h (monitored by TLC). The reaction solution was concentrated in vacuo
and the crude was purified by flash chromatography with ethyl acetate/hexane
(1/20, v/v) to afford the halogenated product 3.
Compound 3a: Yellow oil (23 mg, 63% yield, 72:28 dr). 1H NMR (400 MHz,
CDCl3) d 2.14 (d, J = 1.5 Hz, 3H), 3.73 (s, 3H), 4.92 (d, J = 10.6 Hz, 1H), 6.53 (s,
1H), 6.68 (s, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.32ꢀ7.43 (m, 6H), 7.61 (s,
1H), 7.63 (s, 1H); 13C NMR (100 MHz, CDCl3) d 167.2 (d, 2JCꢀF = 21.2 Hz), 166.7,
156.7 (d, 2JCꢀF = 16.4 Hz), 136.9, 134.7, 133.0, 129.9, 129.4, 128.8, 128.6, 128.5,
1
2
125.7, 119.1, 94.6 (d, JCꢀF = 197.9 Hz), 52.3, 48.4 (d, JCꢀF = 24.6 Hz), 14.0; 19F
NMR (376 MHz, CDCl3) d ꢀ165.59 (d, J = 10.5 Hz); IR (KBr)
m 3064, 2954, 2924,
1728, 1498, 1367, 1253, 1151, 962, 820, 753, 704 cmꢀ1; MS (ESI) found: m/
z = 755.0 [2M+Na]+; HRMS (ESI) found: m/z 389.1271 [M+Na]+, Anal. calcd. for
3. For recent reviews, see: (a) Wilkinson, S. C.; Salmon, R.; Gouverneur, V. Future
Med. Chem. 2009, 1, 847; (b) Zhu, S. Z.; Song, L. P.; Jin, G. F.; Dai, B. F.; Hao, J.
Curr. Org. Chem. 2009, 13, 1015; For selected recent examples, see: (c) Lourie, L.
F.; Serguchev, Y. A.; Shevchenko, G. V.; Ponomarenko, M. V.; Chernega, A. N.;
Rusanov, E. B.; Howard, J. A. K. J. Fluorine Chem. 2006, 127, 377; (d) Cui, H.-F.;
Dong, K.-Y.; Zhang, G.-W.; Wang, L.; Ma, J.-A. Chem. Commun. 2007, 2284; (e)
Nie, J.; Zhu, H.-W.; Cui, H.-F.; Hua, M.-Q.; Ma, J.-A. Org. Lett. 2007, 9, 3053; (f) Li,
F.; Nie, J.; Wu, J.-W.; Zheng, Y.; Ma, J.-A. J. Org. Chem. 2012, 77, 2398; (g) Kishi,
Y.; Nagura, H.; Inagi, S.; Fuchigami, T. Chem. Commun. 2008, 3876; (h) Zhou, C.;
Ma, Z.; Gu, Z.; Fu, C.; Ma, S. J. Org. Chem. 2008, 73, 772; (i) Rudler, H.; Parlier, A.;
Hamon, L.; Herson, P.; Daran, J.-C. Chem. Commun. 2008, 4150; (j) Schuler, M.;
Silva, F.; Bobbio, C.; Tessier, A.; Gouverneur, V. Angew. Chem., Int. Ed. 2008, 47,
7927; (k) Cui, H.; Li, P.; Chai, Z.; Zheng, C.; Zhao, G.; Zhu, S. J. Org. Chem. 2009,
74, 1400; (l) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354; (m) Kishi,
Y.; Inagi, S.; Fuchigami, T. Eur. J. Org. Chem. 2009, 103; (n) Wang, H.-F.; Cui, H.-
F.; Chai, Z.; Li, P.; Zheng, C.-W.; Yang, Y.-Q.; Zhang, G. Chem. Eur. J. 2009, 15,
13299; (o) Wilinson, S. C.; Lozano, O.; Schuler, M.; Pacheco, M. C.; Salmon, R.;
Gouverneur, V. Angew. Chem., Int. Ed. 2009, 48, 7083; (p) Cui, H.-F.; Yang, Y.-Q.;
Chai, Z.; Li, P.; Zhang, C.-W.; Zhu, S.-Z.; Zhao, G. J. Org. Chem. 2010, 75, 117; (q)
Lozano, O.; Blessley, G.; Campo, T. M.; Thompson, A. L.; Giuffredi, G. T.; Bettati,
M.; Walker, M.; Borman, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50,
8105; (r) Lin, R.; Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2011, 13, 4498; (s) Xu, T.; Mu,
X.; Peng, H.; Liu, G. Angew. Chem., Int. Ed. 2011, 50, 8176.
C
21H19FN2O3+Na 389.1277.10.
10. Compound 4: Yellow oil (30 mg, 78% yield, 50:50 dr). 1H NMR (400 MHz,
CDCl3) d 2.27 (s, 3H), 3.72 (s, 3H), 4.88 (s, 1H), 6.77 (s, 1H), 6.91 (s, 1H),
7.36ꢀ7.40 (m, 6H), 7.67 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 6.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 168.8, 166.9, 157.9, 137.3, 135.8, 134.1, 130.7, 129.0, 128.7,
128.4, 128.2, 125.8, 119.1, 66.8, 52.4, 50.2, 13.9; IR (KBr)
m 3064, 2953, 2926,
2849, 1724, 1596, 1498, 1365, 1274, 1148, 970, 825, 755, 703, 643 cmꢀ1; MS
(ESI) found: m/z = 786.2 [2M+Na]+; HRMS (ESI) found: m/z 405.0978 [M+Na]+,
Anal. calcd. for C21H19ClN2O3+Na 405.0982.
Compound 5: Yellow oil (26 mg, 61% yield, 88:12 dr). 1H NMR (400 MHz,
CDCl3) d 2.32 (s, 3H), 3.73 (s, 3H), 4.89 (s, 1H), 6.75 (s, 1H), 6.88 (s, 1H),
7.20ꢀ7.22 (m, 1H), 7.26ꢀ7.28 (m, 2H), 7.36ꢀ7.39 (m, 5H), 7.70 (d, J = 7.9 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 169.2, 166.9, 157.9, 137.2, 136.7, 134.4,
130.6, 129.3, 128.9, 128.7, 128.5, 125.8, 119.5, 58.0, 52.4, 49.8, 14.2; IR (KBr)
m
3063, 2952, 2852, 1719, 1595, 1497, 1364, 1271, 1149, 972, 820, 755, 704,
624 cmꢀ1; MS (ESI) found: m/z = 444.8 [M+NH4]+; HRMS (ESI) found: m/z
449.0469 [M+Na]+, Anal. calcd. for C21H19BrN2O3+Na 449.0477.
11. Spectral data of Int-A: 1H NMR (400 MHz, [D6]-DMSO) d 1.89 (s, 3H), 3.65 (s,
3H), 5.18 (s, 1H) 5.46 (s, 1H), 6.33 (s, 1H), 7.19ꢀ7.25 (m, 4H), 7.29ꢀ7.31 (m,
2H), 7.41ꢀ7.44 (m, 2H), 7.75 (d, J = 7.2 Hz, 2H), 10.88 (s, 1H); 13C NMR
(100 MHz, [D4]-MeOH) d 167.5, 147.6, 141.6, 140.9, 128.8, 128.5, 128.3, 128.0,
127.8, 126.3, 126.0, 125.9, 124.9, 120.7, 51.1, 22.3, 13.0; IR (KBr)
m 3063, 2924,
2853, 1721, 1596, 1498, 1366, 1259, 1149, 965, 756, 703 cmꢀ1; MS (ESI) found:
m/z = 349.6[M+H]+; HRMS (ESI) found: m/z 371.1366 [M+Na]+, Anal. calcd. for
C21H20N2O3+Na 371.1372.
4. For reviews on pyrazolines, see: (a) Lévai, A. J. Heterocycl. Chem. 2002, 39, 1; (b)
Kumar, S.; Bawa, S.; Drahu, S.; Kumar, R.; Gupta, H. Recent Pat. Anticancer Drug
Discov. 2009, 4, 154; (c) Kissane, M.; Maguire, A. R. Chem. Soc. Rev. 2010, 39,
845; (d) Küchenthal, C.-H.; Maison, W. Synthesis 2010, 5, 719.