A divergent approach to the synthesis of 3-substituted-2-pyrazolines: Suzuki cross-coupling of 3-sulfonyloxy-2-pyrazolines

Article abstract of DOI:10.1021/jo9011859

(Chemical Equation Presented) The efficient Suzuki cross-coupling of pyrazoline nonaflates with organoboron reagents was achieved to afford diverse 3-substituted-2-pyrazolines in excellent yield. The nonaflates displayed improved reactivity over the corre

Full text of DOI:10.1021/jo9011859

pubs.acs.org/joc
course of a recent medicinal chemistry program, we required
A Divergent Approach to the Synthesis of
3-Substituted-2-pyrazolines: Suzuki Cross-Coupling
of 3-Sulfonyloxy-2-pyrazolines
access to diverse 3-substituted-2-pyrazolines (1, Scheme 1).
We sought a strategy that would enable rapid exploration of
structure-activity relationships through the late-stage, di-
vergent installation of different C-3 substituents. Several
synthetic methods exist for the preparation of pyrazolines,
such as the condensation of hydrazines with R,β-unsaturated
carbonyl compounds and the dipolar cycloaddition of nitrile
imines with activated olefins.5 The existing routes were not
ideal for our purposes, as they typically fix the pyrazoline
substituents prior to ring formation. Route A (Scheme 1)
illustrates this limitation as it relates to the reaction of
hydrazines with chalcones (4), where the C-3 and C-5
substituents are set in the aldol condensation that precedes
cyclization. We decided to pursue an alternative strategy
(Route B) that is the subject of this Note;the palladium-
catalyzed cross-coupling of 3-sulfonyloxy-2-pyrazolines (6,
from pyrazolidinones 5) with organoboron reagents and
other organometallics.
Jonathan B. Grimm,* Kevin J. Wilson, and David J. Witter
Department of Chemistry, Merck Research Laboratories,
Boston, Massachusetts 02115
jonathan_grimm@merck.com
Received June 4, 2009
SCHEME 1. Strategies for Preparing 3-Substituted-2-pyrazolines
The efficient Suzuki cross-coupling of pyrazoline nona-
flates with organoboron reagents was achieved to afford
diverse 3-substituted-2-pyrazolines in excellent yield. The
nonaflates displayed improved reactivity over the corre-
sponding triflates and smoothly coupled to a variety of
aryl- and heteroarylboronic acids. This process and its
broad scope constitute a rapid, divergent strategy for the
synthesis of elaborated 2-pyrazolines that are not readily
obtained via conventional methods.
Despite the prevalence of transition metal-catalyzed
cross-coupling reactions of alkenyl, aryl, and heteroaryl
(i.e., pyridyl) halides and pseudohalides, those involving
imidoyl halides and pseudohalides are rare. The limited
examples that are known include the cross-coupling of
imidoyl chlorides or triflates with alkynes,6 stannanes,7
Grignard reagents,8 organozinc reagents,9 and boronic
acids.10 A single report exists concerning the Suzuki
cross-coupling of a 3-chloro-2-pyrazoline with boronic
acids; however, the harsh reaction conditions (POCl3)
required to prepare the imidoyl chloride substrate limit
the scope of this method.11 Nonetheless, this suggested that
the previously unexplored pyrazoline sulfonates 6;which
could be prepared through mild, broadly applicable condi-
tions;could function in Suzuki cross-couplings and other
palladium-catalyzed C-C bond formations.
The 2-pyrazoline ring system has attracted significant
interest in organic and medicinal chemistry over the past
several decades. Scaffolds containing the 2-pyrazoline (4,5-
dihydropyrazole) heterocycle have demonstrated a wide
range of biological activity, including anticancer activity
through the inhibition of kinesin spindle protein,1 CB1
receptor antagonism for obesity,2 monoamine oxidase in-
hibition for depression,3 and a host of other antibacterial,
antiviral, and anti-inflammatory activities.4 During the
(1) Coleman, P. J.; Schreier, J. D.; Cox, C. D.; Fraley, M. E.; Garbaccio,
R. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Rickert, K.;
Tao, W.; Diehl, R. E.; South, V. J.; Davide, J. P.; Kohl, N. E.; Yan, Y.; Kuo,
L.; Prueksaritanont, T.; Li, C.; Mahan, E. A.; Fernandez-Metzler, C.; Salata,
J. J.; Hartman, G. D. Bioorg. Med. Chem. Lett. 2007, 17, 5390.
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La Torre, F.; Cardia, M. C.; Distinto, S. J. Med. Chem. 2005, 48, 7113.
(4) Selected examples: (a) Chimenti, F.; Bizzarri, B.; Manna, F.; Bolasco,
A.; Secci, D.; Chimenti, P.; Granese, A.; Rivanera, D.; Lilli, D.; Scaltrito, M.
M.; Brenciaglia, M. I. Bioorg. Med. Chem. Lett. 2005, 15, 603. (b) Goodell, J.
R.; Puig-Basagoiti, F.; Forshey, B. M.; Shi, P.-Y.; Ferguson, D. M. J. Med.
Chem. 2006, 49, 2127. (c) Reddy, M. V. R.; Billa, V. K.; Pallela, V. R.;
Mallireddigari, M. R.; Boominathan, R.; Gabriel, J. L.; Reddy, E. P. Bioorg.
Med. Chem. 2008, 16, 3907. (d) Amir, M.; Kumar, H.; Khan, S. A. Bioorg.
Med. Chem. Lett. 2008, 18, 918.
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(5) (a) Levai, A. J. Heterocycl. Chem. 2002, 39, 1. (b) Huisgen, R. Angew.
Chem., Int. Ed. Engl. 1963, 2, 565.
(6) Lin, S.-Y.; Sheng, H.-Y.; Huang, Y.-Z. Synthesis 1991, 235.
(7) Kobayashi, T.; Sakakura, T.; Tanaka, M. Tetrahedron Lett. 1985, 26,
3463.
(8) Ottesen, L. K.; Ek, F.; Olsson, R. Org. Lett. 2006, 8, 1771.
(9) Yamamoto, S.; Hashiguchi, S.; Miki, S.; Igata, Y.; Watanabe, T.;
Shiraishi, M. Chem. Pharm. Bull. 1996, 44, 734.
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(10) Nadin, A.; Lopez, J. M. S.; Owens, A. P.; Howells, D. M.; Talbot, A.
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Tetrahedron Lett. 2005, 46, 2631.
6390 J. Org. Chem. 2009, 74, 6390–6393
Published on Web 07/17/2009
DOI: 10.1021/jo9011859
r
2009 American Chemical Society

Grimm et al.
JOCNote
SCHEME 2. Preparation of 3-Sulfonyloxy-2-pyrazolines
SCHEME 3. Sonogashira, Stille, and Negishi Cross-Coupling
of 9a
The pyrazoline sulfonates necessary for the exploration of
this methodology were synthesized according to Scheme 2.
Cinnamates 7a-c were condensed with hydrazine in reflux-
ing EtOH; the resulting pyrazolidinones were subsequently
acetylated with acetic anhydride to provide 8a-c.12 The
pendant aryl group and N-acetyl capping group were chosen
due to the preponderance of the 1-acyl-3,5-diarylpyrazoline
core among biologically active pyrazolines.1,3,4 Pyrazolidi-
nones 8a-c were smoothly reacted with the appropriate
sulfonic anhydride (Tf2O or Nf2O)13 to afford triflate 9a
and nonaflates 10a-c via exclusive O-sulfonylation.
Although the primary emphasis of this work was on the
Suzuki cross-coupling of these substrates (vide infra), our
attention initially focused on a brief investigation of the
general cross-coupling scope of pyrazoline sulfonates. As
summarized in Scheme 3, triflate 9a was effective in Sonoga-
shira, Stille, and Negishi cross-couplings. Sonogashira cou-
pling of 9a with phenylacetylene or trimethylsilylacetylene
under standard conditions14 provided 3-alkynylpyrazolines
11a,b in good yield (91%, 76%). Similarly, 3-alkenylpyra-
zolines 12a,b were generated in high yield (81-82%) through
Stille coupling of 9a with the corresponding vinylstan-
nanes.15 Negishi coupling16 of 9a with benzyl zinc halides
under microwave conditions17 allowed for the formation of
3-benzylpyrazolines 13a,b in moderate yield (51-60%).18
Few reports exist concerning the preparation of 3-alkenyl-,
3-alkynyl-, and 3-benzylpyrazolines, and their synthesis by
existing methods is neither general nor trivial.19 The rapid
preparation of these diverse, rare structures from a common
intermediate illustrates the utility of this method. The alky-
nyl and alkenyl groups of 11a,b and 12a,b also provide useful
functional handles for further manipulation.
the reaction of 9a with 3-pyridineboronic acid (14a) was
employed as a model system to optimize the cross-coupling
(Table 1). Initial results were not encouraging, as a variety of
conditions failed to provide appreciable yields of 15a (entries
1-6). These included Suzuki0s initial triflate protocol21 (entry 1),
as well as the versatile conditions of Buchwald22 (entry 4) and
Fu23 (entries 5-6) utilizing electron-rich, hindered phosphines.
Additionally, Dvorak’s conditions for the cross-coupling of
pyrazole triflates (entry 7) afforded only a 20% yield of the
desired product.24 A similar yield of 15a was achieved under more
traditional Suzuki conditions,20 with Pd(PPh3)4 as catalyst,
Na2CO3 as base, and toluene/EtOH/H2O (3:1:1) as solvent
(entry 8, 22%). Performing this reaction in the microwave
afforded no advantage in yield (entry 9), but the reaction time
was dramatically shortened to only 10 min (as determined by the
consumption of 9a).25 In nearly all cases (entries 1-14), the major
species observed was pyrazolidinone 8a, the product of triflate
hydrolysis. Switching to dioxane/H2O as solvent (entry 10) led to
increased hydrolysis, and no conversion (exclusively 9a) was seen
when water was omitted (entry 12). Although the addition of
Bu4NBr had no effect (entry 11), LiCl led to a modest improve-
ment in yield (entry 13, 32%).20a Similar results were seen with an
alternative catalyst, PdCl2(dppf) CH2Cl2 (entry 14).
3
Given that the key side reaction responsible for the low
yields of 15a was triflate hydrolysis, replacement of the
triflate with a nonaflate (10a) was pursued as a mitigation
strategy. Several studies have demonstrated the utility of
alkenyl and aryl nonaflates in various cross-coupling reac-
tions.26 Evidence suggests that nonaflates are more resistant
to O-S hydrolysis27 and display enhanced reactivity in
The Suzuki cross-coupling20 of 3-sulfonyloxy-2-pyrazo-
lines was of particular interest due to the extensive avail-
ability and synthetic accessibility of organoboron reagents.
Such a process would provide rapid access to 3-heteroar-
ylpyrazolines and allow incorporation of heterocycles com-
monly seen in medicinal chemistry. With this in mind,
(12) (a) Godtfredsen, W. O.; Vangedal, S. Acta Chem. Scand. 1955, 9,
1498. (b) Carpino, L. A J. Am. Chem. Soc. 1958, 80, 599.
(13) The routine conditions for nonaflate formation (NfF, base; ref 26)
failed to provide the pyrazoline nonaflates in acceptable yield.
(14) Negishi, E.-i.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(15) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(16) Negishi, E.-i.; Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z. In
Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F.,
Eds.; Wiley-VCH: Weinheim, Germany, 2004; Chapter 15, pp 815-889.
(17) Nearly equivalent results were obtained when the Stille and Negishi
coupling reactions were performed thermally; slightly shorter reaction times
and convenience encouraged use of the microwave.
(21) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201.
(22) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685.
(23) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(24) Dvorak, C. A.; Rudolph, D. A.; Ma, S.; Carruthers, N. I. J. Org.
Chem. 2005, 70, 4188.
(25) The Suzuki reactions were also cleaner, more reproducible, and more
amenable to library generation when performed in the microwave.
€
€
(26) (a) Hogermeier, J.; Reissig, H.-U.; Brudgam, I.; Hartl, H. Adv.
Synth. Catal. 2004, 346, 1868. (b) Minatti, A.; Zheng, X.; Buchwald, S. L.
J. Org. Chem. 2007, 72, 9253. (c) Lyapkalo, I. M.; Vogel, M. A. K. Angew.
€
Chem., Int. Ed. 2006, 45, 4019. (d) Hogermeier, J.; Reissig, H.-U. Tetrahedron
€
2007, 63, 8485. (e) Rottlander, M.; Knochel, P. J. Org. Chem. 1998, 63, 203.
(18) Extensive optimization of Negishi conditions was not pursued.
(19) (a) Botvinnik, E. V.; Blandov, A. N.; Kuznetsov, M. A. Russ. J. Org.
€
(f) Bourrain, S.; Ridgill, M.; Collins, I. Synlett 2004, 795. (g) Hogermeier, J.;
ꢀ
Chem. 2001, 37, 2001. (b) Levai, A.; Jeko, J. J. Heterocycl. Chem. 2006, 43,
Reissig, H.-U. Chem.;Eur. J. 2007, 13, 2410. (h) Denmark, S. E.; Sweis, R.
F. Org. Lett. 2002, 4, 3771.
(27) Neuville, L.; Bigot, A.; Dau, M. E. T. H.; Zhu, J. J. Org. Chem. 1999,
64, 7638.
1303.
(20) Reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
J. Org. Chem. Vol. 74, No. 16, 2009 6391

Grimm et al.
JOCNote
TABLE 1. Optimization of Suzuki Cross-Coupling with Pyrazoline Sulfonates
entry
R
mol % catalyst
base (equiv) additive (equiv)
solvent
T (°C)
85 3 h
timea
yieldb (%)
1
2
3
4
5
6
7
8
9
Tf 5% Pd(PPh3)4
Tf 10% Pd(PtBu3)2
Tf 10% Pd(OAc)2/15% X-Phos
Tf 2% Pd2dba3/8% S-Phos
K3PO4 (3)
K3PO4 (3)
K3PO4 (3)
K3PO4 (2)
dioxane
toluene
THF
<5
<5
<5
<5
0
70 2 h
70 2 h
100 18 h
80 1 h
90 18 h
100 18 h
100 2 h
1-butanol
THF
THF
dioxane
toluene/EtOH/H2O (3:1:1)
toluene/EtOH/H2O (3:1:1) 120 (MW) 10 min
dioxane/H2O(3:1) 120 (MW) 10 min
toluene/EtOH/H2O (3:1:1) 120 (MW) 10 min
toluene 120 (MW) 10 min
toluene/EtOH/H2O (3:1:1) 120 (MW) 10 min
toluene/EtOH/H2O (3:1:1) 120 (MW) 10 min
DMF
toluene/EtOH/H2O (3:1:1) 120 (MW) 10 min
dioxane/H2O(3:1) 120 (MW) 10 min
toluene/EtOH/H2O (3:1:1) 120 (MW) 10 min
toluene/EtOH/H2O (3:1:1) 100 2 h
Tf 10% Pd(OAc)2/12% Cy3PH BF4 KF (3.3)
3
Tf 5% Pd2dba3/10% tBu3PH BF4
KF (3.3)
K3PO4 (3)
0
3
Tf 8% PdCl2(dppf)/4% dppf
Tf 5% Pd(PPh3)4
Tf 5% Pd(PPh3)4
Tf 5% Pd(PPh3)4
Tf 5% Pd(PPh3)4
Tf 5% Pd(PPh3)4
Tf 5% Pd(PPh3)4
20
22
20
6
20
0
32
32
0
87
21
90
84
Na2CO3 (3)
Na2CO3 (3)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (3)
Na2CO3 (3)
K2CO3 (1.5)
Na2CO3 (3)
Na2CO3 (3)
Na2CO3(3)
Na2CO3 (3)
10
11
12
13
14
15
16
17
18
19
a
- -
Bu4NBr (0.1)
Bu4NBr (0.1)
LiCl (3)
Tf 5% PdCl2(dppf) CH2Cl2
3
LiCl (3)
Nf 5% Pd(OAc)2/20% PPh3
Nf 5% Pd(PPh3)4
Nf 5% Pd(PPh3)4
75 18 h
Nf 5% PdCl2(dppf) CH2Cl2
3
Nf 5% PdCl2(dppf) CH2Cl2
3
b
Reactions stirred at indicated temperature until complete (or conversion ceased). Isolated yield of chromatographically pure 15a (yields <5%
determined by LC/MS).
cross-couplings compared to triflates.26e Conditions previously
SCHEME 4. Suzuki Cross-Coupling of Nonaflates 10b-d
reported for nonaflate Suzuki couplings were not suitable for
this reaction, affording none of the desired pyrazoline 15a
(entry 15).26f,g A dramatic improvement in yield was seen when
returning to the Pd(PPh3)4/Na2CO3 conditions previously
applied to the triflate (entry 16), whereby an 87% yield of 15a
was obtained. Importantly, only trace amounts of cleavage pro-
duct 8a were detectable by LC/MS analysis. PdCl2(dppf) CH2Cl2
3
was a slightly superior catalyst and provided the optimum yield of
15a (90%, entry 18). The cross-coupling could also be performed
thermally at the cost of increased reaction time and a slight decrease
in yield (84%, entry 19).
10d28) were efficiently coupled with 14a to provide 3-(3-
pyridyl)pyrazolines 15u-w in excellent yield (90-96%),
further demonstrating the generality of this strategy for the
synthesis of substituted pyrazolines.
The newly optimized Suzuki cross-coupling conditions for
nonaflate 10a were then applied to various boronic acids and
esters (Table 2). The scope was found to be extensive, as a diverse
set of boronic acids and esters uniformly underwent cross-
coupling with 10a in the microwave to afford the desired 3-
substituted pyrazolines 15a-t in excellent to nearly quantitative
yields (78-97%). The cross-coupling conditions were tolerant of
electron-poor (entries 2-4), electron-rich (entries 5-6), and
hindered (entry 7) arylboronic acids, as well as an alkenylboronic
acid (entry 20). Importantly, a wide variety of heteroarylboronic
acids (entries 9-14 and 17-19) and esters (entries 15 and 16)
were effectively coupled to 10a under these conditions, providing
convenient access to pyrazolines with pyridine, pyrimidine, furan,
thiophene, pyrazole, and other heterocyclic substituents at C-3. Of
the boronic acids explored, only 2-pyridineboronic acids;routi-
nely challenging Suzuki substrates;failed in the cross-coupling.
Not surprisingly, modification of the distal (C-5) substi-
tuent of the nonaflate substrate was also well-tolerated in the
cross-coupling (Scheme 4). Nonaflates with functionalized
aryl substituents (10b,c) or an alkyl-linked moiety (benzyl,
To expand the utility of this Suzuki cross-coupling, a
preliminary exploration into the cross-coupling of 10a with
potassium organotrifluoroborates was undertaken. The
advantages of organotrifluoroborates are well-known, as they
are highly stable, display improved reaction stoichiometry,
and often offer functionality not available from boronic acids
and esters (e.g., alkyltrifluoroborates).29 This versatility has
made trifluoroborates compelling substrates for Suzuki-type
coupling reactions.30 Modification of the pyrazoline nona-
flate Suzuki conditions was required to achieve facile cross-
coupling with organotrifluoroborates. The optimal conditions
for the coupling of these species with 10a is shown in Scheme 5.
In concurrence with Molander,30a-c PdCl2(dppf) CH2Cl2
3
(29) Reviews: (a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40,
275. (b) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623.
(c) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
(30) Selected examples: (a) Molander, G. A.; Bernardi, C. R. J. Org.
Chem. 2002, 67, 8424. (b) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003,
68, 4302. (c) Molander, G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B.
J. Org. Chem. 2003, 68, 5534. (d) Molander, G. A.; Gormisky, P. E.;
Sandrock, D. L. J. Org. Chem. 2008, 73, 2052. (e) Molander, G. A.; Canturk,
B. Org. Lett. 2008, 10, 2135.
(28) 10d was prepared according to Scheme 2 (see the Supporting
Information).
6392 J. Org. Chem. Vol. 74, No. 16, 2009

Grimm et al.
JOCNote
SCHEME 5. Cross-Coupling of10a withOrganotrifluoroborates
TABLE 2. Boronic Acid Scope of Suzuki Cross-Coupling
was found to be an efficient catalyst. The use of toluene/H2O as
solvent was essential; no product was seen with toluene/EtOH/
H2O, THF/H2O, or nonaqueous solvent systems. The best
results were obtained with K2CO3 as base, and the addition of
LiCl (3 equiv) consistently enhanced yields. In contrast to the
coupling with boronic acids, thermal conditions (100 °C, 18 h)
generally provided higher conversions and greater yields than the
microwave. Under these conditions, several trifluoroborates
were successfully coupled to 10a in moderate to good yield
(32-87%).31 These included primary alkylborates with pendant
aryl or ester32 groups (13a, 16a,b) and an arylborate (16c). The
cross-coupling of PhCH2BF3K presents a higher yielding alter-
native to the Negishi coupling in Scheme 3. Furthermore, reports
of 3-alkylpyrazolines like 16a,bare rare, and this strategy offers a
convenient route to these novel scaffolds. A number of organo-
trifluoroborates (i.e., MeBF3K, allyl-BF3K) failed to provide
appreciable product with this protocol, and further exploration
of this cross-coupling is ongoing.
In summary, we have developed a convenient and efficient
strategy for the synthesis of 3-substituted-2-pyrazolines.
Exploration of the palladium-catalyzed cross-coupling
chemistry of 3-sulfonyloxy-2-pyrazolines revealed that pyr-
azoline nonaflates are uniquely suited to undergo Suzuki
cross-coupling with a variety of boronic acids and trifluor-
oborates. This strategy allows for the rapid, divergent in-
corporation of aryl, heteroaryl, and alkyl functionality into a
scaffold of considerable synthetic and medicinal interest.
133.7, 129.2, 128.0, 127.7, 125.7, 123.8, 60.2, 42.2, 22.2; HRMS (ESI)
calcd for C16H16N3O [M+H]+ 266.1288, found 266.1248.
General Procedure for Cross-Coupling of 10a with Potassium
Organotrifluoroborates (Scheme 5). The following procedure for
16c is representative. Nonaflate 10a (150 mg, 0.308 mmol), potas-
sium p-tolyltrifluoroborate (73 mg, 0.370 mmol), K2CO3 (128 mg,
Experimental Section
General Procedure for Suzuki Cross-Coupling of Pyrazoline
Nonaflates with Boronic Acids and Esters (Table 2 and Scheme 4).
The following procedure for 15a is representative. Nonaflate
10a (150 mg, 0.308 mmol), 3-pyridineboronic acid (46 mg,
0.925 mmol), LiCl (39 mg, 0.925 mmol), and PdCl2(dppf) CH2Cl2
3
(23 mg, 0.028 mmol) were combined in a vial that was sealed with a
septum and flushed with nitrogen (2ꢀ). Toluene (1.2 mL) and water
(0.40 mL) were added, and the reaction was stirred at 100 °C
overnight. The mixture was cooled to room temperature and
partitioned between water and CH2Cl2 (2ꢀ). The combined organic
extracts were washed with brine, dried (MgSO4), and evaporated.
Silica gel chromatography (0-50% EtOAc/ hexanes) provided 16c
(75 mg, 87%) as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ
7.62 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.26-7.17 (m,
5H), 5.57 (dd, J = 11.8, 4.4 Hz, 1H), 3.71 (dd, J = 17.6, 11.8 Hz,
0.370 mmol), and PdCl2(dppf) CH2Cl2 (13 mg, 0.015 mmol)
3
were combined in a microwave vial that was sealed and flushed
with nitrogen (2ꢀ). Toluene (1.35 mL), EtOH (0.45 mL), and
2 M Na2CO3 (0.45 mL) were added, and the mixture was flushed
again with nitrogen (2ꢀ). The reaction was heated to 120 °C for
10 min in the microwave. The reaction was partitioned between
water and CH2Cl2 (2ꢀ). The combined organic layers were
washed with brine, dried (MgSO4), and evaporated. Silica
gel chromatography (50-100% EtOAc/hexanes) afforded 15a
(74 mg, 90%) as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ
8.87(d,J= 1.9 Hz, 1H), 8.62 (dd, J= 4.8, 1.5 Hz, 1H), 8.06 (dt, J=
8.0, 1.9 Hz, 1H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.30 (t, J = 7.6 Hz,
2H), 7.26-7.14 (m, 3H), 5.59 (dd, J = 11.9, 4.7 Hz, 1H), 3.74 (dd,
J = 17.7, 12.0 Hz, 1H), 3.14 (dd, J = 17.7, 4.8 Hz, 1H), 2.40 (s, 3H);
13C NMR (CDCl3, 151 MHz) δ 169.1, 151.3, 151.2, 148.1, 141.7,
1H), 3.13 (dd, J = 17.6, 4.5 Hz, 1H), 2.41 (s, 3H), 2.38 (s, 3H); 13
C
NMR (CDCl3, 151 MHz) δ 169.0, 154.1, 142.2, 140.9, 129.7, 129.1,
128.9, 127.8, 126.8, 125.8, 60.0, 42.6, 22.2, 21.7; HRMS (ESI) calcd
for C18H19N2O [M+H]+ 279.1492, found 279.1457.
Acknowledgment. We thank Adam Beard for HRMS
analysis of all compounds.
(31) By comparison, coupling of triflate 9a with PhCH2BF3K under the
same conditions afforded only a 45% yield of 13a.
(32) Conditions previously reported for the cross-coupling of potassium
3-trifluoroboratopropionate tert-butyl ester with aryl halides failed when
applied to 10a: Molander, G. A.; Petrillo, D. E. Org. Lett. 2008, 10, 1795.
Supporting Information Available: Experimental proce-
dures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6393