Magnesium-Catalyzed N 2-Regioselective Alkylation of 3-Substituted Pyrazoles

Article abstract of DOI:10.1055/s-0039-1690160

A highly regioselective Mg-catalyzed alkylation of 3-substituted pyrazoles has been developed to provide N 2-alkylated regioisomers. Using α-bromoacetates and acetamides as alkylating agents, this new method was applied to a variety of 3-substituted and 3,4-disubstituted pyrazoles to produce the N 2-alkylated products with high regioselectivities ranging from 76:24 to 99:1 and 44-90percent yields.

Full text of DOI:10.1055/s-0039-1690160

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
cluster
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D. Xu et al.
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Magnesium-Catalyzed N2-Regioselective Alkylation of 3-Substi-
tuted Pyrazoles
Di Xu*a
0
0
0
0-
0
0
0
2-8
2
2
3-3
3
3
9
R2
Lena Franka
Tina Nguyenb
R1
cat. Mg2+, base
2
1
N
N
yield up to 90%
Andreas Stumpfa
David Russellb
Remy Angelauda
Francis Gosselina
O
R2
R3
O
N2/N1 up to 98:2
13 examples
R1
+
Br
R3
1
2
N
NH
R2
a Department of Small Molecule Process Chemistry, Genentech
Inc., 1 DNA Way, South San Francisco, CA 94080, USA
xud19@gene.com
b Department of Small Molecule Analytical Chemistry, Genen-
tech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
R1
base
yield up to 70%
1
2
N
N
O
R3
Published as part of the ISySyCat2019 Special Issue
N1/N2 up to 99:1
15 examples
Received: 18.06.2019
Accepted after revision: 26.07.2019
Published online: 09.08.2019
kylated isomer 2-N2 was produced preferentially in an
89:11 ratio (N2/N1; Scheme 1). Although the effects of Mg
on the N-alkylation regioselectivity of imidazoles had al-
ready been described,6 similar effects on pyrazoles have, to
the best of our knowledge, not been reported in the literature.
DOI: 10.1055/s-0039-1690160; Art ID: st-2019-b0316-c
Abstract A highly regioselective Mg-catalyzed alkylation of 3-substi-
tuted pyrazoles has been developed to provide N2-alkylated regioiso-
mers. Using -bromoacetates and acetamides as alkylating agents, this
new method was applied to a variety of 3-substituted and 3,4-disubsti-
tuted pyrazoles to produce the N2-alkylated products with high regio-
selectivities ranging from 76:24 to 99:1 and 44–90% yields.
Ph
Mg(OEt)2 (130 mol%)
THF/MeOH (3 mL)
1
2
N
N
25 °C, 84% yield
O
N
Key words pyrazole, alkylation, magnesium, catalysis, regioselectivity
O
Ph
2-N2
N2/N1 = 89:11
Br
+
1
2
N
N
NH
N-Substituted pyrazoles are important motifs in a vari-
ety of anticancer1 and anti-inflammatory2 drugs. The syn-
thesis of these important molecules has been well docu-
mented.3 As part of a drug development program, we need-
ed to synthesize analogues of N2-acetamide-3-phenyl
pyrazoles. Direct N2-alkylation of 3-phenyl pyrazole is one
of the simplest and most direct approaches to synthesize
these analogues. However, N-alkylation of 3-substituted
pyrazoles under basic conditions proceeds preferentially at
the N1 position due to electronic and steric preferences.4 It
is therefore challenging to form selectively the N2-alkylated
regioisomers. Wright and coworkers5 circumvented this
problem by first installing a removable bulky triphenylsilyl
at the C5-position to direct the desired alkylation to the N2-
nitrogen. Although this method provides satisfactory yields
and regioselectivities, it is time consuming and has poor
atom economy. The direct N2-alkylation would be pre-
ferred.
Ph
1
1
K2CO3 (130 mol%)
DMSO (3 mL)
2
100 mol%
120 mol%
N
N
25 °C, 70% yield
O
N
2-N1
N2/N1 = 3:97
Scheme 1 N-Alkylation of 3-phenyl-1H-pyrazole with 2-bromo-acet-
amide
In order to better understand the scope of this new
methodology, we evaluated a series of Lewis acid catalysts7
in THF using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as
base (Table 1). In the absence of Lewis acid, the alkylation
highly favors the N1 position (2-N2/2-N1 = 3:97, Table 1,
entry 1). While the addition of a catalytic amount of Lewis
acid improved the N2 regioisomer ratio (Table 1, entries 2–
6), use of MgCl2 (50 mol%) completely reversed the regio-
selectivity (2-N2/2-N1 = 98:2, Table 1, entry 5). It is also
noteworthy that in the presence of MgCl2, the conversion
increased from 60% to 95% (Table 1, entries 1 and 5).
During development of the N-alkylation of 3-phenyl
pyrazole (1) with 2-bromo-N,N-dimethylacetamide, the
N1-alkylated isomer 2-N1 was selectively formed as ex-
pected in a 3:97 ratio (N2/N1) under basic conditions (DM-
SO and K2CO3) in 70% yield. However, we discovered that
when using Mg(OEt)2 (130 mol%) as the base, the N2-al-
Following our promising lead with MgCl2, subsequent
screens were run with MgBr2 to optimize reaction condi-
tions. First, we screened a variety of bases in the reaction of
8
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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D. Xu et al.
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Table 1 Catalyst Screen for N2-Alkylationa
Table 3 Solvent Screen for N2-Alkylation of 3-Phenyl-1H-pyrazole with
2-Bromo-N,N-Dimethylacetamidea
catalyst (50 mol%)
DBU (210 mol%), THF
O
Ph
MgBr2 (20 mol%)
O
+
2-N2 + 2-N1
Br
1
i-Pr2NEt (210 mol%), solvent
Ph
2
N
NH
Me2N
25 °C, overnight
+
2-N2 + 2-N1
1
Br
2
1
N
NH
25 °C, overnight
Me2N
1
Entry
Catalyst
Conversion (%)b
2-N2/2-N1b
Entry
Solvent
2-N2/2-N1b
Assay yield (2-N2%)c
1
2
3
4
5
6
N/A
60
60
60
67
95
99
3:97
1
2
3
4
5
6
7
8
9
10
1,4-dioxane
EtOAc
96:4
95:5
96:4
95:5
93:7
98:2
96:4
90:10
10:90
61:39
86
84
84
85
82
90
86
55
3
MnCl2
NiCl2
CuCl2
MgCl2
CaCl2
71:29
30:70
82:18
98:2
DCM
toluene
MeCN
73:27
THF
a Reaction conditions: 3-phenyl-1H-pyrazole (200 mg, 100 mol%), 2-bro-
mo-N,N-dimethylacetamide (200 mol%), THF (3 mL).
b Determined by HPLC peak area percent analysis of the crude reaction
mixture.
2-MeTHF
MTBE
DMSO
MeOH
28
1 and 2-bromo-N,N-dimethylacetamide (Table 2). All the
bases screened provided 2-N2 with good yields (>78%) and
high regioselectivities (>95:5). i-Pr2NEt was selected for fur-
ther experiments due to fact that it provided the highest
yield and selectivity (Table 2, entry 3).10 After the base
screen, different solvents were assessed using the above
conditions (Table 3). Except DMSO and MeOH, all solvents
tried proved to be effective; their dielectric properties seem
to have low or no impact on either selectivity or yield. For
example, 1,4-dioxane and toluene gave similar N-alkylated
ratios and yields (>95:5 and ca. 85%, Table 3, entries 1 and
4). MeCN and MTBE gave the lowest N2/N1 ratio, 93:7 and
90:10, respectively (Table 3, entries 5 and 8). MTBE also led
to the lowest assay yield (55%, Table 3, entry 8). Overall, THF
provided the best selectivity and yield (98:2 and 90%; Table
2, entry 6). Finally, MgBr2 loadings were evaluated (5–40
mol%) in THF with i-Pr2NEt (see Supporting Information,
Table S2), and it was found that 20 mol% provided the best
yield (90%) without erosion of regioselectivity (98:2).
a Reaction conditions: 3-phenyl-1H-pyrazole (200 mg, 100 mol%), 2-bro-
mo-N,N-dimethylacetamide (200 mol%), solvent (3 mL), 25 °C.
b Determined by HPLC peak area percent analysis of the crude reaction
mixture.
c Determined by HPLC analysis with external standard.
With optimized reaction conditions in hand (conditions
A),11 N2-alkylation was evaluated on a variety of 3-substi-
tuted pyrazoles, using 2-bromo-N,N-dimethylacetamide.
The corresponding products were successfully synthesized
in 44–90% yields with N2/N1 selectivity ranging from 76:24
to >99:1 (Table 4). Pyrazoles with electron-withdrawing
groups at the 3-position (3a–e) provided the corresponding
alkylated pyrazoles 3a–e-N2 with excellent regioselectivity
(>95:5, Table 4, entries 1–5) with the exception of 3-cyano-
1H-pyrazole (3c, Table 4, entry 3).12 Lower regioselectivities
were observed with substrates bearing electron-donating
groups at the 3-position (3f and 3g), which afforded 3f-N2
and 3g-N2 in regioselectivities of 85:15 and 86:14, respec-
tively (Table 4, entries 6 and 7). These substrates also re-
quired higher catalyst loading (40 mol%).13 This method was
successfully extended to 3,4-disubstituted pyrazoles (3h
and 3i), and selectivities of 96:4 and 92:8 were achieved for
3h-N2 and 3i-N2, respectively (Table 4, entries 8 and 9). In
addition, chromenopyrazole 3j, which has a fused ring sys-
tem, also furnished 3j-N2 in high regioselectivity (94:6)
and yield (Table 4, entry 10). It is worth pointing out that
under the conventional reaction conditions, substrates 3a–j
were preferably alkylated at the N1-positions to afford 3a–
j-N1 in high regioselectivities (15:85 to 1:99) and good
yields (44–90%, Table 3, conditions B), thus making our new
N2-selective protocol complementary..
Table 2 Base Optimization for N2-Alkylation of 3-Phenyl-1H-pyrazole
with 2-Bromo-N,N-Dimethylacetamidea
MgBr2 (20 mol%)
O
base (210 mol%), THF
25 °C, overnight
Ph
+
2-N2 + 2-N1
Br
1
2
N
NH
Me2N
1
Entry
Base
2-N2/2-N1b
Assay yield (2-N2%)c
1
2
3
DBU
Et3N
95:5
97:3
98:2
78
84
90
i-Pr2NEt
a Reaction conditions: 3-phenyl-1H-pyrazole (200 mg, 100 mol%), 2-bro-
mo-N,N-dimethylacetamide (200 mol%), THF (3 mL), 25 °C.
b Determined by HPLC peak area percent analysis of the crude reaction mix-
ture.
To expand the scope of this methodology, a variety of -
bromo methyl electrophiles were selected to probe the ef-
fectiveness of the catalytic system (Table 5). High regio-
selectivities were achieved with morpholinopiperidinyl -
c Determined by HPLC analysis with external standard.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

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Table 4 N2-Alkylation of 3-Substituted Pyrazoles with 2-Bromo-N,N-Dimethylacetamide
R2
R2
R1
R1
R2
O
conditions A or B
1
1
2
2
R1
+
+
N
N
N N
Br
Me2N
1
2
N
NH
O
O
Me2N
NMe2
3x
3x-N2
3x-N1
Entry
Pyrazole
Conditions Aa
Conditions Bb
Isolated yield (N2%)
N2/N1l
Isolated yield (N1%)
N2/N1l
O2N
1
2
3
4
5
6
70c,e
90c,e
60c,e
44c,f
62c,e
67d,f
97:3
70g,i
1:99
5:95
11:89
7:93
14:86
9:91
N
NH
3a
F3C
>99:1
76:24
96:4
62g,j
54g,j
90g,i
44g,k
70h,i
N
NH
3b
NC
N
NH
3c
MeO2C
N
NH
3d
Br
95:5
N
NH
3e
BnO
85:15
N
NH
3f
7
8
63d,f
86:14
96:4
47h,i
15:85
10:90
N
NH
3g
3h
3i
Br
70c,e
49g,j
N
NH
CHO
NH
9b
62c,f
92:8
94:6
68g,j
11:89
6:94
N
O
10
77c,f
75g,j
N
NH
3j
a Reaction conditions A: pyrazole (200 mg, 100 mol%), 2-bromo-N,N-dimethylacetamide (200 mol%), MgBr2 (20–40 mol%), i-Pr2NEt (210 mol%), THF (3 mL).
b Reaction conditions B: pyrazole (200 mg, 100 mol%), 2-bromo-N,N-dimethylacetamide (120 mol%), K2CO3 (130 mol%), solvent (3 mL), 25 °C.
c MgBr2 (20 mol%).
d MgBr2 (40 mol%).
e 0 °C.
f 25 °C.
g Base: K2CO3 (130 mol%).
h Base: Cs2CO3 (130 mol%).
i Solvent: DMSO.
j Solvent: MeCN.
k Solvent: THF/water (9:1).
l Determined by HPLC peak area percent analysis of the crude reaction mixture.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

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Table 5 N2-Alkylation of 3-Phenyl-1H-Pyrazole with -Bromomethyl Electrophiles
Ph
Ph
conditions A or B
Ph
1
1
2
2
R3
Br
N
N
N N
+
+
1
2
N
NH
R3
R3
1
4x
4x-N2
4x-N1
Entry
Alkylating agent
Conditions Aa
Conditions Bb
Isolated yield (N2%)
N2/N1i
Isolated yield (N1%)
N2/N1i
O
Br
N
1
49c,f
97:3
90
1:99
HBr
N
O
4a
O
Br
2
3
86d,g
84:16
> 99:1
98
86
1:99
5:95
(MeO)MeN
4b
O
80e,h
Br
i-PrO
4c
BnBr
4d
4
5
3c,h j
< 1:99
67j
74
6:94
MeOCH2Br
4e
74c,h
< 5:95k
10:90k
a Reaction conditions A: 3-phenyl-1H-pyrazole (200 mg, 100 mol%), -bromomethyl electrophiles (150–200 mol%), MgBr2 (20 mol%), i-Pr2NEt (210–410 mol%),
THF (3 mL), 25 °C.
b Reaction conditions B: 3-phenyl-1H-pyrazole (200 mg, 100 mol%), -bromomethyl electrophiles (120 mol%), K2CO3 (130 mol%), MeCN (3 mL), 25 °C.
c -Bromomethyl electrophiles (200 mol%).
d N-Methoxy-N-methyl-2-bromoacetamide (220 mol%).
e Isopropyl bromoacetate (150 mol%).
f i-Pr2NEt (410 mol%).
g i-Pr2NEt (230 mol%).
h i-Pr2NEt (210 mol%).
i Determined by HPLC peak area percent analysis of the crude reaction mixture.
j Conversion; product was not isolated.
k Determined by 1 H NMR spectroscopic analysis.
R2
4
bromoacetamide 4a (97:3), -bromoacetamide 4b (84:16),
and -bromo ester 4c (>99:1). Again, in the absence of the
Mg catalyst, the corresponding N1 products were obtained
with high selectivities (Table 5, conditions B). Both benzyl
bromide (4d) and bromomethyl methyl ether (4e) failed to
provide the N2-alkylated product under conditions A. In-
stead, the N1-alkylated products formed (<1:99 and <5:95,
Table 5, entries 4 and 5). This suggests that the MgBr2-cata-
lyzed alkylation requires coordination between Mg and the
amide or ester in the electrophile to obtain high N2 regiose-
lectivity.
The chemical structure assignments of the N2/N1-al-
kylated pyrazole regioisomers were determined unambigu-
ously by heteronuclear multiple-bond correlation (HMBC)
NMR spectroscopy. For N2-alkylated regioisomers, HMBC
H–C coupling was observed between the -carbonyl pro-
tons and the C3-carbon in the pyrazole ring, while for N1-
alkylated regioisomers, H–C coupling of the -carbonyl pro-
tons and the C5-carbon were detected (Figure 1).
R2
4
R1
3
3 bonds
3 bonds
R1
3
5
2
5
N
N
1
2
N
1
N
H
H
O
O
R3
R3
Figure 1 Structure elucidation of regioisomers by NMR spectroscopy
In conclusion, we have developed a Mg-catalyzed N2-re-
gioselective alkylation of 3-substituted pyrazoles with vari-
ous -bromo acetate and acetamide electrophiles that
grants facile access to a series of 2,3-disubstitued pyrazoles.
High yields and regioselectivities were achieved using this
operationally simple protocol. A variety of functional
groups are tolerated in this procedure. The regioselectivity
and functional group tolerance of the method makes it
highly synthetically useful. It complements the existing N1-
alkylation protocol well and enables both pyrazole regioiso-
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

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mers to be synthesized selectively from the same electro-
phile. Mechanistic studies are underway, and the results
will be disclosed in due course.
(8) The impact of the Mg counterions on regioselectivity and yield
were also tested (see Supporting Information, Table S1).
Although the N2 isomer was formed selectively in all cases, cat-
alysts with less dissociating counterions9 provided superior
regioselectivity. MgBr2 provided the best compromise between
yield and regioselectivity and was thus selected as the catalyst
of choice.
Acknowledgment
(9) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, W. J. Am. Chem.
Soc. 2002, 124, 392.
(10) Alkylation side products of DBU and Et3N with 2-bromo-N,N-
dimethylacetamide were observed by LC-MS.
We thank Kyle Clagg and Dr. Haiming Zhang for helpful discussions;
Tristan Maschmeyer, Dr. Kenji Kurita, and Dr. Chris Crittenden for
HRMS analysis; and Dr. Derek Dalton for helpful suggestions on this
manuscript.
(11) Representative Procedure (Conditions A)
In a glovebox filled with N2 (≤0.1 ppm O2, ≤0.1 ppm H2O) were
charged 3-phenyl-1H-pyrazole (200 mg, 1.39 mmol, 100 mol%)
and MgBr2 (51.0 mg, 0.277 mmol, 20 mol%) into a vial equipped
with a magnetic stir bar. THF (3.00 mL) and 2-bromo-N,N-
dimethylacetamide (461 mg, 2.77 mmol, 200 mol%) were then
added. i-Pr2NEt (377 mg, 2.91 mmol, 210 mol%) was added to
the solution dropwise at 25 °C. The resulting mixture was
stirred at 25 °C for 2 h. The reaction was quenched with satu-
rated NH4Cl in MeOH (2 mL), and the resulting solution was
concentrated to dryness. Water (1 mL) was then added to the
residue which was extracted with i-PrOAc (4 × 1 mL). The crude
product was loaded on to silica gel column and eluted with hep-
tane/i-PrOAc to give compound 2-N2 (239 mg, 75% yield as a
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690160.
S
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p
p
orti
n
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p
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orit
n
gInformati
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n
References and Notes
(1) (a) Lin, Q.; Meloni, D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard, S.; Li,
M.; Galya, L.; Metcalf, B.; Yue, T-Y.; Liu, P.; Zhou, J. Org. Lett.
2009, 11, 1999. (b) Cui, J. J.; Tran-Dube, M.; Shen, H.; Nambu,
M.; Kung, P.-P.; Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.;
McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.; Alton, G.;
Timofeevski, S.; Yamazaki, S.; Li, Q.; Zhou, H.; Christensen, J.;
Mroczkowski, B.; Bender, S.; Kania, R. S.; Edwards, M. P. J. Med.
Chem. 2011, 54, 6342.
(2) (a) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Weenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347. (b) Raulf, M.; Koenig,
W. Immunopharmacology 1990, 19, 103.
(3) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Hetero-
cycles, 3rd ed; Wiley-VCH: Weinheim, 2013.
(4) Huang, A.; Wo, K.; Lee, S. Y. C.; Kneitschel, N.; Chang, J.; Zhu, K.;
Mello, T.; Bancroft, L.; Norman, N. J.; Zheng, S.-L. J. Org. Chem.
2017, 82, 8864.
(5) Wright, S. W.; Arnold, E. P.; Yang, X. Tetrahedron Lett. 2018, 59,
402.
(6) Chen, S.; Graceffa, R. F.; Boezio, A. A. Org. Lett. 2016, 18, 16.
(7) Anhydrous Lewis acid catalysts were used. No conversion was
observed with addition of 100 mol% water.
1
white solid. H NMR (400 MHz, CDCl3):  = 7.59 (s, 1 H), 7.51–
7.34 (m, 5 H), 6.34 (s, 1 H), 4.93 (s, 2 H), 2.98 (d, J = 8.0 Hz, 7 H).
13C NMR (101 MHz, CDCl3):  = 167.03, 145.02, 139.73, 130.78,
129.13, 128.81, 128.77, 106.43, 50.94, 36.65, 36.05. HRMS: m/z
calcd for C13H16N3O [M + H]+: 230.1288; found: 230.1287.
(12) Some strongly electron-deficient pyrazoles like 3a led to over-
alkylated products. The side reaction was minimized by per-
forming the reaction at 0 °C (Figure 2).
O2N
Me2N
N
N
O
O
NMe2
3a-N2-bis
Figure 2
(13) Using 20 mol% MgBr2, 3f-N2 and 3g-N2 were formed in regiose-
lectivities of 89:11 (53% conversion) and 79:21 (100% conver-
sion), respectively.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E