Regiocontrolled Synthesis of 6,7-Dihydro-4 H -pyrazolo[5,1- c ][1,4]oxazines

Article abstract of DOI:10.1055/s-0037-1610734

Synthetic access to 6,7-dihydro-4 H -pyrazolo[5,1- c ][1,4]oxazines has been achieved in 3-4 steps from commercially available pyrazoles. Optimization of a protected hydroxyethyl group on N1 enabled the regiocontrolled construction of pyrazole-5-aldehydes in high yields; subsequent deprotection and reduction generated fused heterocyclic scaffolds bearing multiple substitution patterns. Moreover, the intermediate pyrazole lactols were shown to be versatile synthetic building blocks.

Full text of DOI:10.1055/s-0037-1610734

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–N
paper
A
en
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
Regiocontrolled Synthesis of 6,7-Dihydro-4H-pyrazolo-
[5,1-c][1,4]oxazines
Peter J. Lindsay-Scott*
OTBS
Eloise Rivlin-Derrick
1) alkylation
2) LDA, DMF
3) aq TFA
4) Et3SiH
N
NH
N
N
O
N
N
Eli Lilly and Company Limited, Erl Wood Manor,
Windlesham, Surrey GU20 6PH, UK
lindsay-scott_peter@lilly.com
R
R
R
O
regiocontrolled
pyrazole functionalization
heterocycle
construction
Received: 27.08.2019
Accepted after revision: 17.09.2019
Published online: 08.10.2019
pered by low yields and/or a limited substrate scope. For ex-
ample, methodologies that rely on the N-alkylation of pyra-
zoles substituted with esters in the 5-position are generally
limited to substrates that also bear a nitro group at the 3-
position, in order to control the regiochemical outcome of
the alkylation reaction.4g Indeed, when the nitro group is
absent, 1H-pyrazole-3-esters have been shown to alkylate
preferentially on N1 rather than N2.7 A team at Wyeth de-
veloped a desymmetrization approach to circumvent these
regioselectivity challenges, whereby the alkylation of dieth-
yl 1H-pyrazole-3,5-dicarboxylate was employed during the
synthesis of a 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-
4-one ring system in 16% yield over 5 steps.5a Estrada and
co-workers reported a 6-step route that features an alkyl ni-
trate cyclization to give the corresponding 3-nitro-substi-
tuted ring systems.4d Other cyclization strategies to build
the pyrazole ring from morpholine precursors have also
been investigated, albeit with a very limited reported sub-
strate scope.8,9
Recently, we disclosed a flexible strategy for the synthe-
sis of pyrazolo[1,5-a]pyrazines 5 in a regioselective fashion
(Scheme 1a).10 Pyrazole derivatives 3, formed via alkylation
of 4-substituted pyrazoles 1 (R1 = H) with alkyl bromide 2,
were shown to successfully undergo regioselective formyla-
tion at the most acidic 5-position11 after treatment with
LDA and DMF to give the corresponding pyrazole aldehydes
4. In addition, the alkylation of 3- and 3,4-substituted pyra-
zoles 1 (R1 ≠ H) was achieved in a regiocontrolled manner to
give the N1-alkylated pyrazole derivatives 3, which were
subsequently formylated at the remaining 5-position.
Deprotection of the 2,2-dialkoxyethyl group on nitrogen
was accomplished under acidic conditions to give an inter-
mediate di-aldehyde, which underwent cyclization in the
presence of ammonia to deliver pyrazolo[1,5-a]pyrazines 5.
We wondered whether an alkylation–formylation approach
might also be feasible for the synthesis of 6,7-dihydro-4H-
DOI: 10.1055/s-0037-1610734; Art ID: ss-2019-c0483-op
Abstract Synthetic access to 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]ox-
azines has been achieved in 3–4 steps from commercially available pyr-
azoles. Optimization of a protected hydroxyethyl group on N1 enabled
the regiocontrolled construction of pyrazole-5-aldehydes in high yields;
subsequent deprotection and reduction generated fused heterocyclic
scaffolds bearing multiple substitution patterns. Moreover, the inter-
mediate pyrazole lactols were shown to be versatile synthetic building
blocks.
Key words heterocycles, pyrazoles, oxazines, regioisomers, cycliza-
tion
Nitrogen heterocycles are prevalent in many small-mol-
ecule drugs.1 The replacement of a CH group with an N
atom in a molecule can dramatically affect its molecular
and physicochemical properties and, as such, this strategy
has become a powerful design tool for drug discovery teams
in their pursuit of new medicines.2 In a similar vein, oxygen
heterocycles feature heavily in the structures of approved
pharmaceuticals, with morpholine derivatives being uti-
lized as treatments against a wide variety of diseases.3
Combining these structural elements, the 6,7-dihydro-4H-
pyrazolo[5,1-c][1,4]oxazine motif 9 has recently emerged
as a useful heterocyclic scaffold for drug discovery. Mole-
cules containing this moiety have been reported as kinase
inhibitors against a range of biological targets (e.g., CK1,4a
NIK,4b RIP1,4c LRRK2,4d,e BTK,4f,g SYK,4h and CDK94i) and as
potential therapies for cancer, immune disorders, and CNS
diseases. Additionally, this scaffold has been incorporated
into -lactamase inhibitors5 and fungicides.6
A general method for the synthesis of 6,7-dihydro-4H-
pyrazolo[5,1-c][1,4]oxazines 9 would therefore be highly
desirable, allowing this promising ring system to be further
explored. Current synthetic approaches tend to be ham-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
pyrazolo[5,1-c][1,4]oxazines 9 (Scheme 1b). We reasoned
that the alkylation of pyrazoles 1 with an appropriate bro-
moethanol derivative 6 followed by metalation and trap-
ping with DMF might furnish the corresponding pyrazole
aldehydes 7 regioselectively. Alcohol deprotection would
then provide access to pyrazole lactols 8, which could then
be reduced to give the target heterocycles 9.
aldehyde, which was then converted into a fused morpho-
line ring system under acidic conditions (60% yield over 2
steps).12 Moreover, a 3-bromopyrazole derivative bearing a
THP-protected hydroxyethyl group on N1 was shown to be
susceptible to lithiation and trapping with benzaldehyde;
subsequent acid-mediated ring closure furnished a substi-
tuted 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine com-
pound in 27% yield over 2 steps.4c
(a) Prior work: Regioselective synthesis of pyrazolo[1,5-a]pyrazines10
With these observations in mind, we set out to investi-
gate the effect of the hydroxyethyl protecting group on the
formylation of N1-alkylated pyrazoles, in the hope of devel-
oping a more robust, higher-yielding protocol (Table 1).
Thus, Bn-protected substrate 1013 (Table 1, entry 1) was ex-
posed to LDA at –78 °C and then treated with DMF. Exam-
ination of the crude reaction mixture by 1H NMR spectros-
copy revealed that some elimination had occurred under
the reaction conditions to give vinylpyrazole 16; subse-
quent chromatographic purification of the crude reaction
mixture delivered the pyrazole aldehyde 14 in 79% yield.
Similar results were obtained with the THP-protected sub-
strate 11 (entry 2), providing the corresponding formylated
product 15 in 74% yield. However, switching to the TBS-pro-
tecting group (see also Scheme 4, vide infra) resulted in
100% conversion of pyrazole 12a to afford pyrazole alde-
hyde 7a in 94% isolated yield (entry 3). Importantly, all
three substrates 10, 11, and 12a underwent formylation ex-
clusively at the 5-position.14 Interestingly, a greater degree
OEt
OEt
2
Br
N
N
N
NH
OEt
Alkylation
OEt
R1
R1
R2
R2
Regioselective
when R1≠ H
1
3
Formylation
LDA, DMF
ring
construction
Regioselective
when R1 = H
OEt
(i) acid
(ii) NH4OAc
N
N
N
N
OEt
N
R1
R1
Deprotection/
Cyclization
O
R2
R2
5
4
(b) This work: Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine synthesis
OTBS
(i)
6
Br
OTBS
(ii) LDA, DMF
N
N
N
NH
R1
R1
Table 1 Optimization of Formylation Step
Alkylation/
Formylation
O
R2
R2
OR
OR
1
7
Base (1.5 equiv)
DMF (1.8 equiv)
Competing elimination
minimized
N
N
N N
THF (10 mL/g)
T °C, 2 h
ring
construction
acid
Deprotection
O
Br
10, R = Bn
Br
14, R = Bn
11, R = THP
12a, R = TBS
13, R = H
15, R = THP
7a, R = TBS
N
N
N N
N
N
N
O
N
O
O
Et3SiH
R1
R1
Reduction
OH
OH
R2
R2
O
Br
Br
8a
16
9
8
Scheme 1 Regioselective alkylation–formylation strategy for the syn-
thesis of heterocyclic scaffolds 5 and 9 from pyrazoles 1
Entry
R
Base
Temp (°C)
Yield (%)a
1
2
3
4
5
6
7
Bn
THP
TBS
TBS
TBS
TBS
H
LDA
LDA
–78
–78
14, 79
15, 74
7a, 94
7a, 21
N/A
Key to the successful implementation of this strategy
would be the identification of a suitable hydroxyethyl moi-
ety to control the regioselectivity during the pyrazole meta-
lation step, whilst also serving as a building block for the
subsequent dihydro-oxazine ring construction. A recent re-
port into fused dihydro-4H-pyrazolo[5,1-c]oxazinyl com-
pounds as potential treatments against CNS disorders re-
vealed that an indazole bearing an unprotected hy-
LDA
–78
LiTMP
LiHMDS
LiHMDS
LDAb
–78
–78
4 to 20
–78
7a, 32
8a, 51c
a Isolated yields; N/A: not applicable.
b LDA used: 2.5 equiv.
c A 14:1 ratio of lactol to hydroxyaldehyde was determined by 1H NMR anal-
droxyethyl
group
on
nitrogen
could
undergo
ysis in DMSO-d6.
lithiation/formylation to give the corresponding indazole
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

C
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
of elimination was observed when LiTMP was employed as
the base (entry 4) and LiHMDS gave inferior results (entries
5 and 6). When no protecting group was used,15 the corre-
sponding pyrazole lactol 8a was generated from compound
13 in only 51% yield by utilizing 2.5 equivalents of LDA (en-
try 7).
OTBS
OH
OTBS
N
N
a
b
(ref. 16)
58%
HO
MsO
Br
18
19
12h
(>98% ee)
With an optimal protecting group strategy defined, a
range of alkylated pyrazoles 12a–g were prepared from the
corresponding commercially available pyrazoles 1 and alkyl
bromide 6 (Scheme 2). As expected, the 3,4-disubstituted
pyrazoles 12f and 12g were formed in a regioselective man-
ner.14 Whilst pyrazole 12g could be readily isolated as a sin-
gle regioisomer after column chromatography, pyrazole 12f
was taken forwards as a 5:1 mixture of regioisomers favor-
ing the desired N1-isomer. In addition, we prepared pyra-
zoles 12h and 12i, bearing substitution on the hydroxyethyl
chain (Scheme 3). 4-Bromo-1H-pyrazole (22) was alkylated
with chiral mesylate 1916 to furnish the corresponding pyr-
azole 12h in 58% yield (>98% ee).17 Epoxide 20 was opened
under basic conditions (89% yield) and the resultant pyra-
zole alcohol 21 was treated with TBSOTf to afford the pro-
tected pyrazole 12i in 91% yield.
OH
OTBS
O
N
N
b
c
N N
89%
91%
Br
Br
20
21
12i
Scheme 3 Construction of substituted pyrazoles 12h and 12i. Reagents
and conditions: a) See reference 16; b) 4-Bromo-1H-pyrazole (22),
Cs2CO3, MeCN, 80 °C, 16 h; c) TBSOTf, 2,6-dimethylpyridine, CH2Cl2,
4 to 20 °C, 1.5 h.
OTBS
OTBS
LDA (1.5 equiv)
DMF (1.8 equiv)
N
N
N
N
R1
R1
THF (10 mL/g)
–78 °C, 2 h
O
R2
12a–i
OTBS
R2
(6, 1.05 equiv)
OTBS
Br
7a–i
N
NH
N N
Cs2CO3 (1.5 equiv)
OTBS
OTBS
OTBS
R1
R1
MeCN (10 mL/g)
20 °C, 16 h
R2
1, 1 equiv
R2
12a–g
N
N
N
N
N N
O
O
O
Br
F
CF3
OTBS
OTBS
OTBS
7a, 94%
7b, 83%
7c, 74%
N
N
N
N
N N
OTBS
OTBS
OTBS
Br
12a, 87%
F
CF3
12c, 97%
N
N
N
N
N
N
12b, 87%
iPr
O
O
O
tBu
Br
O
OEt
7d, 80%
7e, 0%
7f, 82%a,b
OTBS
OTBS
OTBS
N
N
N
N
N N
OTBS
OTBS
OTBS
iPr
N
N
N
N
N
N
tBu
12e, 82%a
Br
12f, 75%a
O
OEt
12d, 99%
F3C
O
Br
O
O
(5:1 ratio of 12f:17)
Br
Br
7g, 88%
7h, 83%
7i, 70%
OTBS
TBSO
N
N
N N
N
N
F3C
iPr
Br
Br
12g, 70%a,c
(10:1 r.r.)b
17
tBu
23, 27%
Scheme 2 Alkylation of pyrazoles 1. a Reagents and conditions: 6 (1.55
equiv), Cs2CO3 (3 equiv), MeCN, 20 °C. b Ratio determined by 1H NMR
analysis of the crude reaction mixture. c Yield of pure isolated regioiso-
mer after chromatography.
Scheme 4 Formylation of alkylated pyrazoles 12. a Reagents and condi-
tions: LDA (2.4 equiv), DMF (2.2 equiv), THF, –78 °C. b Starting material
contained compound 17 as an impurity.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

D
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
Next, the alkylated pyrazoles 12a–i were subjected to
the optimized formylation reaction conditions (Scheme 4).
Gratifyingly, when 4-substituted pyrazoles 12a–d and 3,4-
disubstituted pyrazoles 12f and 12g were exposed to LDA
and DMF at low temperature the corresponding pyrazole al-
dehydes 7 were furnished as single regioisomers in 74–94%
yield.14 Moreover, substitution on the hydroxyethyl chain
was well tolerated, with formylation products 7h and 7i
synthesized in 83% and 70% yield, respectively. However,
the attempted formylation of t-Bu substituted pyrazole 12e
afforded only the eliminated product 23, rather than the in-
tended pyrazole aldehyde 7e.
With a range of pyrazole aldehydes in hand, the depro-
tection of the TBS group was then investigated (Scheme 5).
Initial experiments revealed that smooth deprotection
could be effected by employing either aqueous TFA or acetic
acid; however, whereas acetic acid gave a fairly sluggish re-
action (requiring 16 h to achieve full conversion at r.t.), the
use of TFA enabled a much more rapid deprotection proto-
col.18 Under the optimized reaction conditions, pyrazole al-
dehydes 7a–i were successfully deprotected in 78–99%
yield to give the corresponding pyrazole lactols 8a–i.
We then turned our attention to the key reduction step
to forge the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine
ring system 9 (Scheme 6). Unfortunately, our initial at-
tempts to accomplish this transformation using BF3·OEt2 in
concert with Et3SiH resulted in decomposition of the start-
ing material. However, switching from BF3·OEt2 to TFA en-
abled pyrazole lactols 8 to be smoothly converted into the
corresponding reduction products 9. It proved advanta-
geous to utilize TMSOTf in place of TFA during the reduc-
tion of methyl-substituted compound 8h in order to mini-
mize the production of several unidentified side-products
(as determined by LCMS analysis of the reaction mixture),
enabling the reduced product 9h to be isolated in 68% yield.
Importantly, the chiral integrity at the stereogenic center in
9h was preserved throughout the multi-step sequence.17
Et3SiH (6 equiv)
TFA (12 equiv)
N
N
N N
O
O
R1
R1
CH2Cl2 (30 mL/g)
4 °C to 20 °C, 16 h
OH
R2
8a–i
R2
9a–i
N
N
N
N
N N
O
O
O
Br
F
CF3
9a, 84%
9b, 78%
9c, 69%
OTBS
2:1:1 TFA/
2-MeTHF/H2O (8 mL/g)
N
N
N
N
N
N
N N
N
N
O
O
O
O
R1
iPr
F3C
R1
20 °C, 0.5 h
OH
R2
8a–i
Br
9f, 70%
Br
9g, 74%
O
R2
7a–i
O
OEt
9d, 78%
N
N
N
N
N N
O
O
O
N
N
N
N
O
O
OH
OH
OH
Br
F
CF3
8a, 95%
(14:1)a
8b, 93%
(3.7:1)a
8c, 99%
(>19:1)a
Br
9h, 68%a
(>98% e.e.)
Br
9i, 83%b
N
N
N
N
N
N
Scheme 6 Reduction of pyrazole lactols 8. Reagents and conditions:
a Et3SiH (3 equiv), TMSOTf (6 equiv), CH2Cl2, –78 to 4 °C, 3.5 h. b Et3SiH
(3 equiv), TFA (6 equiv), CH2Cl2, 20 °C, 2 h.
O
O
O
iPr
F3C
OH
OH
OH
Br
Br
O
OEt
8d, 78%
(>19:1)a
8f, 82%
(14:1)a
8g, 96%
(>19:1)a
Having secured access to a range of 6,7-dihydro-4H-pyr-
azolo[5,1-c][1,4]oxazines 9a–i, we then explored the reac-
tivity of pyrazole aldehyde 8a towards further synthetic
manipulations (Scheme 7). Substitution with either an allyl
or a cyano group was readily accomplished to give com-
pounds 24 and 25, whilst treatment with Ac2O afforded the
corresponding acetate 26 in 80% yield. In addition, olefina-
tion under Wittig conditions delivered alkene 27 in 77%
yield and oxidation provided access to pyrazole lactone 28
(92% yield), highlighting the versatile nature of 8a as a syn-
thetic building block.
N
N
N N
O
O
OH
OH
Br
Br
8i, 83%b
(3.5:1)a
8h, 95%
2:1 d.r.
(>19:1)a
Scheme 5 Deprotection of pyrazole aldehydes 7. a Ratio of lactol to hy-
droxyaldehyde determined by 1H NMR analysis in DMSO-d6. b Reaction
performed at 40 °C.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

E
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
Finally, we were intrigued to see whether the four-step
sequence to convert 4-bromo-1H-pyrazole (22) into 6,7-di-
hydro-4H-pyrazolo[5,1-c][1,4]oxazine (9a) could be accom-
plished on multigram scale. To this end, the alkylation,
formylation, deprotection, and reduction protocols were
performed utilizing only a single chromatographic purifica-
tion at the end of the sequence, which resulted in an overall
yield of 64% over the four steps (Scheme 8a). Furthermore,
we demonstrated that both the deprotection and reduction
steps could be accomplished in a one-pot manner upon
treatment of pyrazole aldehyde 7a with TMSOTf and Et3SiH
(Scheme 8b). Under these reaction conditions, the reduced
product 9a was generated in 93% yield. Performing the one-
pot reaction with TFA in place of TMSOTf resulted in a lower
isolated yield of the product (62%).
N
N
N
N
N N
O
O
O
N
Br
Br
Br
9a, 84%
24, 79%
25, 78%
a
b
c
N
N
O
OH
Br
e
8a
d
f
In summary, we have developed a regioselective meth-
od to prepare 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazines,
tolerant of substitution at the 2-, 3-, 6-, and 7-positions. In
addition, we have shown that the intermediate pyrazole
lactols serve as versatile intermediates that allow diverse
functionalization at the 4-position. The new methodology
successfully overcomes the low yields and limited substrate
scope associated with existing synthetic approaches to-
wards this ring system. Furthermore, the four-step process
was demonstrated on multigram scale and the deprotec-
tion-reduction sequence was achieved in a one-pot fashion.
OH
N
N
N
N
N
N
OEt
O
O
O
OAc
O
Br
Br
Br
26, 80%
27, 77%
28, 92%
Scheme 7 Synthetic transformations of pyrazole lactol 8a. Reagents
and conditions: a) See Scheme 6; b) allyltrimethylsilane, TMSOTf, CH2Cl2,
4 to 20 °C, 16 h; c) TMSCN, TMSOTf, CH2Cl2, 4 to 20 °C, 40 h; d) Ac2O,
Et3N, CH2Cl2, 4 to 20 °C, 3.5 h; e) (carbethoxymethylene)triphenylphos-
phorane, CH2Cl2, 20 °C, 1.5 h; f) TPAP, NMO, CH2Cl2, 20 °C, 2.5 h.
(a) Multigram-scale synthesis of compound 9a
All reactions were carried out under an atmosphere of N2 and com-
mercially available reagents were used as received. TLC was per-
formed on commercially available pre-coated TLC plates (0.25 mm sil-
ica gel with fluorescent indicator UV254) and visualization was
achieved by either the quenching of UV fluorescence or with a KMnO4
stain. 1H, 13C, and 19F NMR spectra were recorded on a Bruker AV-HD
400 spectrometer and Bruker Avance III 500 spectrometer. Signal po-
sitions were recorded in  (ppm) with the standard abbreviations for
multiplicities. All 1H NMR chemical shifts were referenced to SiMe4 as
an internal standard (0.00 ppm). All 13C NMR chemical shifts in CDCl3
were referenced to the residual solvent peak at 77.00 ppm. All 13C
NMR chemical shifts in DMSO-d6 were referenced to the residual sol-
vent peak at 39.52 ppm. All 19F NMR chemical shifts were referenced
to CFCl3 (0.00 ppm). All coupling constants, J, are quoted in hertz (Hz).
IR spectra were recorded on a Shimadzu IRAffinity 1 FT-IR spectro-
photometer. Melting points were obtained using a DSC 1 STARe sys-
tem. High-resolution electrospray ionization (ESI-TOF) mass spectra
were obtained with an Agilent Technologies 6230 series time-of-
flight mass spectrometer. Optical rotations were recorded on an An-
ton Paar MCP 500 polarimeter at a wavelength of 589 nm. Enantio-
meric excess values were determined by chiral supercritical fluid
chromatography with a Waters Acquity UPCC instrument using a chi-
ral stationary phase.
OTBS
(i)
6
Br
OTBS
N
N
N
NH
Cs2CO3, MeCN, 20 °C
(ii) LDA, DMF
THF, –78 °C
O
Br
Br
22, 2.11 g
7a
• 4 synthetic steps
• 1 chromatographic
purification
TFA
2-MeTHF, H2O
20 °C
ring
construction
Et3SiH, TFA
CH2Cl2
N
N
N
N
O
O
4 °C to 20 °C
OH
Br
Br
9a, 2.00 g
64% yield (from 22)
8a
(b) One-pot formation of compound 9a from pyrazole aldehdye 7a
OTBS
Et3SiH, TMSOTf
CH2Cl2
N
N
N N
O
−78 °C to 20 °C
O
Br
Br
9a, 93%
Alkylation of Pyrazoles; General Procedure 1
one-pot
deprotection/reduction
7a
The pyrazole 1 (1 equiv) was added to MeCN (8 mL/g) and the mixture
was stirred in an ice/water bath. To the solution was added Cs2CO3
(1.5 equiv) in one portion, followed by a solution of (2-bromoethoxy)-
tert-butyldimethylsilane (6; 1.05 equiv) in MeCN (2 mL/g) dropwise.
Scheme 8 Multigram-scale synthesis of 6,7-dihydro-4H-pyrazolo[5,1-
c][1,4]oxazine (9a) and one-pot transformation of pyrazole aldehyde
7a.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

F
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
The reaction mixture was stirred at r.t. for 16 h, then filtered through
Celite, washing with MTBE (20 mL/g). The filtrate was concentrated to
give a residue, which was purified as specified.
IR (neat): 2862, 2806, 1304, 1103 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.51 (s, 1 H), 7.46 (s, 1 H), 7.36–7.22
(m, 5 H), 4.47 (s, 2 H), 4.27 (t, J = 5.3 Hz, 2 H), 3.78 (t, J = 5.3 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 139.8, 137.5, 130.3, 128.4, 127.8,
127.6, 92.8, 73.2, 68.4, 52.9.
Alkylation of Pyrazoles; General Procedure 2
The pyrazole 1 (1 equiv) was added to MeCN (8 mL/g) and the mixture
was stirred in an ice/water bath. To the solution was added Cs2CO3
(1.5 equiv) in one portion, followed by a solution of (2-bromoethoxy)-
tert-butyldimethylsilane (6; 1.05 equiv) in MeCN (2 mL/g) dropwise.
The reaction mixture was stirred at r.t. for 16 h, then to the mixture
was added Cs2CO3 (1.5 equiv) in one portion, followed by 6 (0.5 equiv)
dropwise. The mixture was stirred at r.t. for the time specified, then
filtered through Celite, washing with MTBE (20 mL/g). The filtrate was
concentrated to give a residue, which was purified as specified.
HRMS (ESI+): m/z [M]+ calcd for C12H13BrN2O: 280.0211; found:
280.0216.
Data were consistent with those previously reported.13
4-Bromo-1-{2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl}-1H-pyra-
zole (11)
4-Bromo-1H-pyrazole (22; 0.500 g, 3.40 mmol) was added to MeCN
(4.00 mL) and the mixture was stirred in an ice/water bath. To the
solution was added Cs2CO3 (1.67 g, 5.10 mmol), followed by a solution
of (2-bromoethoxy)tetrahydro-2H-pyran (0.562 mL, 3.57 mmol) in
MeCN (1.00 mL) dropwise. The reaction mixture was stirred at r.t. for
16 h, then filtered through Celite, washing with MTBE (50 mL). The
filtrate was concentrated and the resultant residue was purified by
flash column chromatography (SiO2, 0–50% EtOAc/heptane) to give
pyrazole 11 as a colorless oil; yield: 0.881 g (3.20 mmol, 94%).
Formylation of Pyrazole Derivatives; General Procedure 3
To a flask was added THF (6 mL/g) and i-Pr2NH (1.6 equiv) at r.t. and
the mixture was stirred in a dry ice/acetone bath. To the mixture was
added n-BuLi solution (2.5 M in hexanes, 1.5 equiv) dropwise and the
mixture was stirred in a dry ice/acetone bath for 30 min. To the reac-
tion mixture was added a solution of the pyrazole 12 (1 equiv) in THF
(2 mL/g) dropwise and the mixture was stirred in a dry ice/acetone
bath for 30 min. To the mixture was added a solution of DMF (1.8
equiv) in THF (2 mL/g) dropwise and the mixture was stirred in a dry
ice/acetone bath for 1 h. To the mixture was added 2-propanol (2.5
equiv) dropwise and the mixture was transferred to an ice/water
bath. To the mixture was added sat. aq NH4Cl (20 mL/g) over 5 min
and H2O (5 mL/g). The mixture was extracted with MTBE (2 × 30
mL/g) and the combined organics were dried (Na2SO4) and concen-
trated to give a residue, which was purified as specified.
IR (neat): 2943, 1440, 1303, 1202, 1122, 1033 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.52 (s, 1 H), 7.45 (s, 1 H), 4.53 (t, J = 3.4
Hz, 1 H), 4.29 (ddd, J = 6.0, 4.5, 0.8 Hz, 2 H), 4.02 (ddd, J = 10.9, 5.9, 4.1
Hz, 1 H), 3.72 (ddd, J = 10.7, 6.1, 4.9 Hz, 1 H), 3.63 (ddd, J = 11.7, 8.4,
3.1 Hz, 1 H), 3.47–3.42 (m, 1 H), 1.79–1.62 (m, 2 H), 1.57–1.45 (m, 4
H).
13C NMR (100 MHz, CDCl3):  = 139.8, 130.3, 98.8, 92.7, 65.7, 62.1,
52.9, 30.4, 25.2, 19.2.
HRMS (ESI+): m/z [M]+ calcd for C10H15BrN2O2: 274.0317; found:
274.0325.
Deprotection of Pyrazole Derivatives; General Procedure 4
To a flask were added the pyrazole aldehyde 7 (1 equiv), 2-MeTHF (2
mL/g), H2O (2 mL/g), and TFA (4 mL/g) at r.t. The reaction mixture was
stirred at r.t. for 30 min, then sat. aq NaHCO3 (20 mL/g) was added.
The mixture was extracted with CH2Cl2 (2 × 30 mL/g) and the com-
bined organics were dried (Na2SO4) and concentrated to give a resi-
due, which was purified as specified.
4-Bromo-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1H-pyrazole
(12a)
4-Bromo-1H-pyrazole (22; 0.500 g, 3.40 mmol) was subjected to Gen-
eral Procedure 1. The resultant residue was purified by flash column
chromatography (SiO2, 0–25% EtOAc/heptane) to give pyrazole 12a as
a colorless oil; yield: 0.905 g (2.96 mmol, 87%).
IR (neat): 2953, 2929, 2858, 1256, 1112 cm–1
.
Reduction of Pyrazole Lactol Derivatives; General Procedure 5
1H NMR (400 MHz, CDCl3):  = 7.47 (s, 1 H), 7.46 (s, 1 H), 4.19 (t, J = 5.1
Hz, 2 H), 3.90 (t J = 5.1 Hz, 2 H), 0.85 (s, 9 H), –0.06 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 139.8, 130.7, 92.4, 62.0, 55.2, 25.7,
To a flask were added the pyrazole lactol 8 (1 equiv) and CH2Cl2 (30
mL/g) and the mixture was stirred in an ice/water bath. To the mix-
ture were added Et3SiH (3 equiv) and TFA (6 equiv) dropwise and the
reaction mixture was stirred at r.t. for 0.5 h. To the mixture were add-
ed Et3SiH (3 equiv) and TFA (6 equiv) dropwise and the mixture was
stirred at r.t. for 16 h, then sat. aq NaHCO3 (20 mL/g) was added. The
mixture was extracted with CH2Cl2 (2 × 30 mL/g) and the combined
organics were dried (Na2SO4) and concentrated to give a residue,
which was purified as specified.
18.2, –5.7.
HRMS (ESI+): m/z [M]+ calcd for C11H21BrN2OSi: 304.0607; found:
304.0601.
1-[2-(Benzyloxy)ethyl]-4-bromo-1H-pyrazole-5-carbaldehyde (14)
Pyrazole 10 (0.396 g, 1.41 mmol) was subjected to General Procedure
3. The resultant residue was purified by flash column chromatogra-
phy (SiO2, 0–25% EtOAc/heptane) to give pyrazole aldehyde 14 as a
colorless oil; yield: 0.347 g (1.12 mmol, 79%).
1-[2-(Benzyloxy)ethyl]-4-bromo-1H-pyrazole (10)
4-Bromo-1H-pyrazole (22; 0.500 g, 3.40 mmol) was added to MeCN
(4.00 mL) and the mixture was stirred in an ice/water bath. To the
solution was added Cs2CO3 (1.67 g, 5.10 mmol), followed by a solution
of [(2-bromoethoxy)methyl]benzene (0.565 mL, 3.57 mmol) in MeCN
(1.00 mL) dropwise. The reaction mixture was stirred at r.t. for 16 h,
then filtered through Celite, washing with MTBE (50 mL). The filtrate
was concentrated and the resultant residue was purified by flash col-
umn chromatography (SiO2, 0–50% EtOAc/heptane) to give pyrazole
10 as a colorless oil; yield: 0.850 g (3.02 mmol, 88%).
IR (neat): 2866, 1686, 1452, 1103 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.84 (s, 1 H), 7.56 (s, 1 H), 7.33–7.24
(m, 3 H), 7.20–7.17 (m, 2 H), 4.74 (t, J = 5.4 Hz, 2 H), 4.48 (s, 2 H), 3.80
(t, J = 5.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 179.3, 139.7, 137.6, 134.7, 128.3,
127.7, 127.5, 103.8, 72.8, 68.0, 52.0.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

G
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
HRMS (ESI+): m/z [M]+ calcd for C13H13BrN2O2: 308.0160; found:
308.0165.
1H NMR (400 MHz, CDCl3):  = 7.74 (s, 1 H), 7.70 (s, 1 H), 4.24 (t, J = 4.9
Hz, 2 H), 3.92 (t, J = 5.1 Hz, 2 H), 0.83 (s, 9 H), –0.08 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 137.0 (q, J = 2.9 Hz), 129.9 (q, J = 3.7
Hz), 122.7 (q, J = 264.4 Hz), 113.2 (q, J = 37.9 Hz), 61.7, 55.1, 25.6, 18.1,
–5.8.
4-Bromo-1-{2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl}-1H-pyra-
zole-5-carbaldehyde (15)
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –56.4.
HRMS (ESI+): m/z [M]+ calcd for C12H21F3N2OSi: 294.1375; found:
Pyrazole 11 (0.299 g, 1.09 mmol) was subjected to General Procedure
3. The resultant residue was purified by flash column chromatogra-
phy (SiO2, 0–30% EtOAc/heptane) to give pyrazole aldehyde 15 as a
white solid; yield: 0.246 g (0.811 mmol, 74%); mp 57–60 °C.
294.1367.
IR (neat): 2941, 1688, 1452, 1125, 1036 cm–1
.
Ethyl 1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-1H-pyrazole-4-
carboxylate (12d)
1H NMR (400 MHz, CDCl3):  = 9.90 (s, 1 H), 7.55 (s, 1 H), 4.81−4.68
(m, 2 H), 4.56 (t, J = 3.3 Hz, 1 H) 4.01 (ddd, J = 11.1, 6.6, 4.9 Hz, 1 H),
3.77 (ddd, J = 10.9, 6.2, 5.3 Hz, 1 H), 3.63 (ddd, J = 11.9, 9.0, 2.9 Hz, 1
H), 3.47–3.42 (m, 1 H), 1.74–1.44 (m, 6 H).
Ethyl 1H-pyrazole-4-carboxylate (0.508 g, 3.62 mmol) was subjected
to General Procedure 1. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 0–25% EtOAc/heptane) to
give pyrazole 12d as a colorless oil; yield: 1.07 g (3.59 mmol, 99%).
13C NMR (100 MHz, CDCl3):  = 179.2, 139.8, 134.9, 103.4, 98.2, 65.2,
61.7, 52.0, 30.2, 25.2, 18.9.
HRMS (ESI+): m/z [M]+ calcd for C11H15BrN2O3: 302.0266; found:
332.0258.
IR (neat): 2955, 1717, 1555, 1223, 1113 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.93 (s, 1 H), 7.89 (s, 1 H), 4.26 (q, J =
7.1 Hz, 2 H), 4.20 (t, J = 5.2 Hz, 2 H), 3.91 (t, J = 5.1 Hz, 2 H), 1.31 (t, J =
7.3 Hz, 3 H), 0.81 (s, 9 H), –0.09 (s, 6 H).
4-Bromo-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1H-pyrazole-
5-carbaldehyde (7a)
13C NMR (100 MHz, CDCl3):  = 163.0, 141.1, 133.9, 114.7, 61.6, 60.0,
55.0, 25.7, 18.1, 14.3, –5.8.
Pyrazole 12a (0.224 g, 0.734 mmol) was subjected to General Proce-
dure 3. The resultant residue was purified by flash column chroma-
tography (SiO2, 0–25% EtOAc/heptane) to give pyrazole aldehyde 7a as
a white solid; yield: 0.232 g (0.696 mmol, 94%); mp 60–62 °C.
HRMS (ESI+): m/z [M]+ calcd for C14H26N2O3Si 298.1713; found:
298.1704.
4-(tert-Butyl)-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1H-pyra-
zole (12e)
IR (neat): 2949, 1686, 1456, 1256, 1099 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.89 (s, 1 H), 7.55 (s, 1 H), 4.65 (t, J = 5.7
Hz, 2 H), 3.92 (t, J = 5.7 Hz, 2 H), 0.80 (s, 9 H), –0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 179.2, 139.7, 135.1, 103.3, 61.9, 54.2,
4-(tert-Butyl)-1H-pyrazole (0.505 g, 3.86 mmol) was subjected to
General Procedure 2 (reaction time 16 h after addition of second set of
reagents). The resultant residue was purified by flash column chro-
matography (SiO2, eluting with 0–20% EtOAc/heptane) to give pyra-
zole 12e as a colorless oil; yield: 0.904 g (3.20 mmol, 82%).
25.7, 18.1, –5.7.
HRMS (ESI+): m/z [M]+ calcd for C12H21BrN2O2Si: 332.0556; found:
332.0550.
IR (neat): 2957, 2859, 1464, 1254, 1115 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.37 (s, 1 H), 7.23 (s, 1 H), 4.15 (t, J = 5.1
Hz, 2 H), 3.91 (t, J = 5.1 Hz, 2 H), 1.24 (s, 9 H), 0.84 (s, 9 H), –0.08 (s, 6
1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-fluoro-1H-pyrazole
(12b)
H).
13C NMR (100 MHz, CDCl3):  = 136.7, 132.6, 126.7, 62.4, 54.5, 31.8,
29.3, 25.7, 18.1, –5.7.
HRMS (ESI+): m/z [M]+ calcd for C15H30N2OSi: 282.2127; found:
282.2119.
4-Fluoro-1H-pyrazole (0.215 g, 2.50 mmol) was subjected to General
Procedure 1. The resultant residue was purified by flash column chro-
matography (SiO2, 0–40% MTBE/heptane) to give pyrazole 12b as a
colorless oil; yield: 0.533 g (2.18 mmol, 87%).
IR (neat): 2930, 2859, 1580, 1109 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.35 (d, J = 4.7 Hz, 1 H), 7.33 (d, J = 4.1
Hz, 1 H), 4.12 (t, J = 5.3 Hz, 2 H), 3.90 (t, J = 5.1 Hz, 2 H), 0.86 (s, 9 H),
–0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 149.3 (d, J = 243 Hz), 126.1 (d, J = 13.2
Hz), 116.5 (d, J = 27.9 Hz), 62.1, 55.6, 25.7, 18.1, –5.7.
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –178.1.
HRMS (ESI+): m/z [M]+ calcd for C11H21FN2OSi: 244.1407; found:
4-Bromo-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-isopropyl-
1H-pyrazole (12f)
4-Bromo-3-isopropyl-1H-pyrazole (0.456 g, 2.36 mmol) was subject-
ed to General Procedure 2 (reaction time 6 h after addition of second
set of reagents). The resultant residue was purified by flash column
chromatography (SiO2, eluting with 0–25% MTBE/heptane) to give
pyrazole 12f as a colorless oil; yield: 0.750 g (2.16 mmol, 75%; yield
corrected for 5:1 mixture of 12f:17). Data listed for major product.
244.1414.
IR (neat): 2960, 2929, 1551, 1363, 1073 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.38 (s, 1 H), 4.12 (t, J = 5.0 Hz, 2 H),
3.88 (t, J = 5.0 Hz, 2 H), 3.04 (sept, J = 7.0 Hz, 1 H), 1.28 (d, J = 6.8 Hz, 6
H), 0.83 (s, 9 H), –0.09 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 155.7, 131.2, 91.2, 62.1, 55.0, 26.7,
25.7, 21.6, 18.2, –5.7.
1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-(trifluoromethyl)-1H-
pyrazole (12c)
4-(Trifluoromethyl)-1H-pyrazole (0.478 g, 3.51 mmol) was subjected
to General Procedure 1. The resultant residue was purified by flash
column chromatography (SiO2, 0–40% MTBE/heptane) to give pyra-
zole 12c as a colorless oil; yield: 1.01 g (3.43 mmol, 97%).
HRMS (ESI+): m/z [M]+ calcd for C14H27BrN2OSi: 346.1076; found:
346.1081.
IR (neat): 2954, 2860, 1576, 1236, 1117 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

H
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
4-Bromo-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-(trifluoro-
methyl)-1H-pyrazole (12g)
13C NMR (100 MHz, CDCl3):  = 140.3, 131.0, 93.0, 70.7, 62.3, 26.8.
HRMS (ESI+): m/z [M]+ calcd for C7H11BrN2O: 218.0055; found:
4-Bromo-3-(trifluoromethyl)-1H-pyrazole (0.507 g, 2.36 mmol) was
subjected to General Procedure 2 (reaction time 1 h after addition of
second set of reagents). The resultant residue (10:1 r.r. as determined
by 1H NMR analysis on the crude material) was purified by flash col-
umn chromatography (SiO2, eluting with 0–25% MTBE/heptane) to
give pyrazole 12g as a colorless oil; yield: 0.616 g (1.65 mmol, 70%).
218.0050.
4-Bromo-1-{2-[(tert-butyldimethylsilyl)oxy]-2-methylpropyl}-
1H-pyrazole (12i)
Pyrazole 21 (0.264 g, 1.21 mmol) was added to CH2Cl2 (2.64 mL) and
the mixture was stirred in an ice/water bath. To the solution were
added 2,6-dimethylpyridine (0.210 mL, 1.80 mmol) and TBSOTf
(0.330 mL, 1.40 mmol). The reaction mixture was stirred at r.t. for 1.5
h, then H2O (10 mL) was added. The mixture was extracted with
CH2Cl2 (3 × 15 mL) and the combined organics were dried (Na2SO4)
and concentrated. The resultant residue was purified by flash column
chromatography (SiO2, eluting with 0–20% EtOAc/heptane) to give
pyrazole 12i as a colorless oil; yield: 0.366 g (1.10 mmol, 91%).
IR (neat): 2930, 2858, 1260, 1119 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.56 (s, 1 H), 4.23 (t, J = 4.9 Hz, 2 H),
3.92 (t, J = 4.9 Hz, 2 H), 0.84 (s, 9 H), –0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 140.3 (q, J = 38.2 Hz), 133.4, 120.7 (q,
J = 268.5 Hz), 90.8, 61.6, 55.9, 25.6, 18.1, –5.8.
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –62.0.
HRMS (ESI+): m/z [M]+ calcd for C12H20BrF3N2OSi: 372.0480; found:
IR (neat): 2956, 2857, 1253, 1034 cm–1
1H NMR (400 MHz, CDCl3):  = 7.51 (s, 1 H), 7.42 (s, 1 H), 4.00 (s, 2 H),
.
372.0474.
1.21 (s, 6 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 139.1, 131.0, 92.4, 73.5, 64.7, 27.4,
25.8, 18.0, –2.2.
(R)-4-Bromo-1-{1-[(tert-butyldimethylsilyl)oxy]propan-2-yl}-1H-
pyrazole (12h)
4-Bromo-1H-pyrazole (22; 0.389 g, 2.65 mmol) was added to MeCN
(3.11 mL) and the mixture was stirred in an ice/water bath. To the
solution was added Cs2CO3 (1.30 g, 3.97 mmol), followed by a solution
of (S)-1-[(tert-butyldimethylsilyl)oxy]propan-2-yl methanesulfonate
(19; 0.745 g, 2.78 mmol) in MeCN (0.80 mL) dropwise. The reaction
mixture was stirred in a 80 °C heating block for 16 h, then was cooled
to r.t. and filtered through Celite, washing with MTBE (50 mL). The fil-
trate was concentrated and the resultant residue was purified by flash
column chromatography (SiO2, 0–10% MTBE/heptane) to give pyra-
HRMS (ESI+): m/z [M]+ calcd for C13H25BrN2OSi: 332.0920; found:
332.0913.
1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-fluoro-1H-pyrazole-5-
carbaldehyde (7b)
Pyrazole 12b (0.557 g, 2.28 mmol) was subjected to General Proce-
dure 3. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–20% MTBE/heptane) to give pyrazole
aldehyde 7b as a colorless oil; yield: 0.521g (1.91 mmol, 83%).
20
zole 12h as a colorless oil; yield: 0.497 g (1.56 mmol, 58%); []D
–13.9 (c 0.23, MeOH).
IR (neat): 2930, 2859, 1690, 1495, 1115 cm–1
.
IR (neat): 2929, 2858, 1252, 1097 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.88 (s, 1 H), 7.40 (d, J = 4.1 Hz, 1 H),
4.56 (d, J = 5.9 Hz, 2 H), 3.92 (d, J = 5.7 Hz, 2 H), 0.81 (s, 9 H), –0.06 (s,
6 H).
13C NMR (100 MHz, CDCl3):  = 176.9, 154.0 (d, J = 265.6 Hz), 125.7 (d,
J = 16.9 Hz), 125.3 (d, J = 11.7 Hz), 61.9, 54.6, 25.7, 18.1, –5.7.
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –168.2.
HRMS (ESI+): m/z [M]+ calcd for C12H21FN2O2Si: 272.1356; found:
1H NMR (400 MHz, CDCl3):  = 7.46 (s, 1 H), 7.46 (s, 1 H), 4.35 (sext, J =
6.2 Hz, 1 H), 3.77 (d, J = 5.3 Hz, 2 H), 1.49 (d, J = 6.8 Hz, 3 H), 0.84 (s, 9
H), –0.06 (s, 3 H), –0.08 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 139.4, 129.1, 92.0, 66.4, 60.3, 25.7,
18.1, 16.3, –5.7.
HRMS (ESI+): m/z [M]+ calcd for C12H23BrN2OSi: 318.0763; found:
318.0758.
272.1363.
1-(4-Bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (21)
1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-(trifluoromethyl)-1H-
4-Bromo-1H-pyrazole (22; 0.520 g, 3.54 mmol) was added to MeCN
(4.16 mL) and the mixture was stirred in an ice/water bath. To the
solution was added Cs2CO3 (1.74 g, 5.31 mmol), followed by a solution
of 2,2-dimethyloxirane (20; 0.345 mL, 3.71 mmol) in MeCN (1.04 mL)
dropwise. The reaction mixture was stirred in a 80 °C heating block
for 16 h, then to the mixture was added Cs2CO3 (1.74 g, 5.31 mmol),
followed by 2,2-dimethyloxirane (0.164 mL, 1.76 mmol) dropwise.
The mixture was stirred in a 80 °C heating block for 1 h, then was
cooled to r.t. and filtered through Celite, washing with MTBE (50 mL).
The filtrate was concentrated and the resultant residue was purified
by flash column chromatography (SiO2, 0–20% EtOAc/heptane) to give
pyrazole 21 as a white solid; yield: 0.691 g (3.16 mmol, 89%); mp 89–
91 °C.
pyrazole-5-carbaldehyde (7c)
Pyrazole 12c (0.256 g, 0.870 mmol) was subjected to General Proce-
dure 3. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–20% EtOAc/heptane) to give pyrazole
aldehyde 7c as a colorless oil; 0.209 g (0.648 mmol, 74%).
IR (neat): 2953, 2858, 1693, 1484, 1273 cm–1
1H NMR (400 MHz, CDCl3):  = 10.04 (s, 1 H), 7.79 (s, 1 H), 4.73 (t, J =
5.7 Hz, 2 H), 3.95 (t, J = 5.5 Hz, 2 H), 0.78 (s, 9 H), –0.09 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 178.7, 137.2 (q, J = 2.9 Hz), 136.6,
122.0 (q, J = 265.3 Hz), 118.2 (q, J = 39.4 Hz), 61.8, 54.3, 25.6, 18.0,
–5.8.
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –54.4.
HRMS (ESI+): m/z [M]+ calcd for C13H21F3N2O2Si: 322.1324; found:
.
IR (neat): 3315, 3311, 2985, 1386, 1191 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.50 (s, 1 H), 7.46 (s, 1 H), 4.04 (s, 2 H),
3.30 (s, 1 H), 1.17 (s, 6 H).
322.1318.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

I
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
Ethyl 1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-5-formyl-1H-pyra-
zole-4-carboxylate (7d)
4-Bromo-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-(trifluoro-
methyl)-1H-pyrazole-5-carbaldehyde (7g)
Pyrazole 12d (0.491 g, 1.65 mmol) was subjected to General Proce-
dure 3. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–40% EtOAc/heptane) to give pyrazole
aldehyde 7d as a colorless oil; yield: 0.432 g (1.32 mmol, 80%).
Pyrazole 12g (0.468 g, 1.25 mmol) was subjected to General Proce-
dure 3. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–20% EtOAc/heptane) to give pyrazole
aldehyde 7g as a colorless oil; yield: 0.446 g (1.11 mmol, 88%).
IR (neat): 2930, 2859, 1719, 1695, 1541, 1248, 1209 cm–1
.
IR (neat): 2932, 2858, 1699, 1227, 1142 cm–1
.
1H NMR (400 MHz, CDCl3):  = 10.47 (s, 1 H), 7.92 (s, 1 H), 4.49 (t, J =
5.7 Hz, 2 H) 4.36 (q, J = 7.2 Hz, 2 H), 3.93 (t, J = 5.7 Hz, 2 H), 1.37 (t, J =
7.1 Hz, 3 H), 0.78 (s, 9 H), –0.08 (s, 6 H).
1H NMR (400 MHz, CDCl3):  = 9.92 (s, 1 H), 4.71 (t, J = 5.4 Hz, 2 H),
3.95 (t, J = 5.4 Hz, 2 H), 0.79 (s, 9 H), –0.08 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 179.1, 140.2 (q, J = 38.4 Hz), 136.9,
120.1 (q, J = 270.5 Hz), 100.8, 61.5, 54.9, 25.6, 18.0, –5.8.
13C NMR (100 MHz, CDCl3):  =182.4, 162.3, 140.9, 138.9, 119.0, 61.8,
61.0, 54.2, 25.7, 18.1, 14.2, –5.7.
HRMS (ESI+): m/z [M]+ calcd for C15H26N2O4Si: 326.1662; found:
326.1655.
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –62.3.
HRMS (ESI+): m/z [M]+ calcd for C13H20BrF3N2O2Si: 400.0430; found:
400.0431.
4-(tert-Butyl)-1-vinyl-1H-pyrazole (23)
(R)-4-Bromo-1-{1-[(tert-butyldimethylsilyl)oxy]propan-2-yl}-1H-
Pyrazole 12e (0.307 g, 1.09 mmol) was subjected to General Proce-
dure 3. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–20% EtOAc/heptane) to give pyrazole
23 as a colorless oil; yield: 0.045 g (0.30 mmol, 27%).
pyrazole-5-carbaldehyde (7h)
Pyrazole 12h (0.401 g, 1.26 mmol) was subjected to General Proce-
dure 3. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–20% MTBE/heptane) to give pyrazole
20
IR (neat): 2924, 2855, 1462, 1260 cm–1
.
aldehyde 7h as a colorless oil; yield: 0.366 g (1.05 mmol, 83%); []D
+30.3 (c 0.23, MeOH).
IR (neat): 2982, 2857, 1691, 1107 cm–1
1H NMR (400 MHz, CDCl3):  = 9.89 (s, 1 H), 7.55 (s, 1 H), 5.45 (sext, J =
6.8 Hz, 1 H), 3.82 (dd, J = 10.2, 8.6 Hz, 1 H), 3.75 (dd, J = 10.2, 5.1 Hz, 1
H), 1.46 (d, J = 6.8 Hz, 3 H), 0.77 (s, 9 H), –0.06 (s, 3 H), –0.12 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.50 (s, 1 H), 7.39 (s, 1 H), 6.99 (dd, J =
16.0, 9.2 Hz, 1 H), 5.39 (dd, J = 15.8, 1.4 Hz, 1 H), 4.75 (dd, J = 9.2, 1.4
Hz, 1 H), 1.27 (s, 9 H).
13C NMR (100 MHz, CDCl3):  =138.7, 134.7, 133.3, 122.9, 98.3, 31.5,
29.4.
.
HRMS (ESI+): m/z [M]+ calcd for C9H14N2: 150.1157; found: 150.1160.
13C NMR (100 MHz, CDCl3):  = 179.4, 139.6, 135.2, 103.3, 66.5, 58.3,
25.6, 18.0, 16.1, –5.7, –5.8.
HRMS (ESI+): m/z [M]+ calcd for C13H23BrN2O2Si: 346.0712; found:
346.0714.
4-Bromo-1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-3-isopropyl-
1H-pyrazole-5-carbaldehyde (7f)
To a flask were added THF (0.88 mL) and i-Pr2NH (0.125 mL, 0.888
mmol) at r.t. and the mixture was stirred in a dry ice/acetone bath. To
the mixture was added n-BuLi solution (2.5 M in hexanes, 0.338 mL,
0.846 mmol) dropwise and the mixture was stirred in a dry ice/ace-
tone bath for 30 min. To the reaction mixture was added a solution of
pyrazole 12f (0.147 g, 0.352 mmol; corrected for 5:1 ratio of 12f:17)
in THF (0.29 mL) dropwise and the mixture was stirred in a dry
ice/acetone bath for 30 min. To the mixture was added a solution of
DMF (0.059 mL, 0.761 mmol) in THF (0.29 mL) dropwise and the mix-
ture was stirred in a dry ice/acetone bath for 1 h. To the mixture was
added 2-propanol (0.081 mL, 1.06 mmol) dropwise and then cooled
in an ice/water bath. To the mixture was added sat. aq NH4Cl (10 mL)
over 5 min and H2O (20 mL). The mixture was extracted with MTBE (3
× 25 mL) and the combined organics were dried (Na2SO4) and concen-
trated. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–10% MTBE/heptane) to give pyrazole
aldehyde 7f as a colorless oil; yield: 0.109 g (0.290 mmol, 82%).
4-Bromo-1-{2-[(tert-butyldimethylsilyl)oxy]-2-methylpropyl}-
1H-pyrazole-5-carbaldehyde (7i)
Pyrazole 12i (0.324 g, 0.972 mmol) was subjected to General Proce-
dure 3. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–20% MTBE/heptane) to give pyrazole
aldehyde 7i as a colorless oil; yield: 0.246 g (0.680 mmol, 70%).
IR (neat): 2956, 2930, 1691, 1253, 1044 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.89 (s, 1 H), 7.54 (s, 1 H), 4.53 (s, 2 H),
1.25 (s, 6 H), 0.78 (s, 9 H), –0.02 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 179.4, 139.5, 135.3, 103.4, 73.6, 61.8,
28.1, 25.7, 17.9, –2.2.
HRMS (ESI+): m/z [M]+ calcd for C14H25BrN2O2Si: 360.0869; found:
360.0863.
3-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-ol (8a)
IR (neat): 2957, 2930, 1689, 1456, 1117 cm–1
.
Method A: To a flask were added THF (1.19 mL) and i-Pr2NH (0.381
mL, 2.71 mmol) at r.t. and the mixture was stirred in a dry ice/acetone
bath. To the mixture was added n-BuLi solution (2.5 M in hexanes,
1.00 mL, 2.60 mmol) dropwise and the mixture was stirred in a dry
ice/acetone bath for 30 min. To the reaction mixture was added a
solution of 2-(4-bromo-1H-pyrazol-1-yl)ethan-1-ol (13;15 0.199 g,
1.04 mmol) in THF (0.40 mL) dropwise and the mixture was stirred in
a dry ice/acetone bath for 30 min. To the mixture was added a solu-
tion of DMF (0.145 mL, 1.88 mmol) in THF (0.40 mL) dropwise and
then cooled in a dry ice/acetone bath for 1 h, then the mixture was
stirred in an ice/water bath for 1 h. To the mixture was added
1H NMR (400 MHz, CDCl3):  = 9.85 (s, 1 H), 4.59 (t, J = 5.6 Hz, 2 H),
3.90 (t, J = 5.5 Hz, 2 H), 3.07 (sept, J = 7.0 Hz, 1 H), 1.30 (d, J = 7.0 Hz, 6
H), 0.79 (s, 9 H), –0.09 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 179.7, 155.5, 135.3, 102.1, 62.0, 53.9,
26.6, 25.7, 21.4, 18.1, –5.7.
HRMS (ESI+): m/z [M]+ calcd for C15H27BrN2O2Si: 374.1025; found:
374.1014.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

J
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
2-propanol (0.199 mL, 2.60 mmol) dropwise followed by sat. aq
NH4Cl (10 mL) over 5 min and H2O (20 mL). The mixture was extract-
ed with MTBE (3 × 25 mL) and the combined organics were dried
(Na2SO4) and concentrated. The resultant residue was purified by
flash column chromatography (SiO2, eluting with 0–40% EtOAc/hep-
tane) to give pyrazole lactol 8a as a white solid; yield: 0.118 g (0.539
mmol, 51%; 14:1 mixture of lactol to hydroxyaldehyde by 1H NMR).
Ethyl 4-Hydroxy-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-
carboxylate (8d)
Pyrazole aldehyde 7d (0.262 g, 0.802 mmol) was subjected to General
Procedure 4. The resultant residue was concentrated from toluene (3
× 5 mL) and then was purified by flash column chromatography (SiO2,
eluting with 0–10% MeCN/CH2Cl2) to give pyrazole lactol 8d as a
white solid; yield: 0.134 g (0.631 mmol, 78%; >19:1 mixture of lactol
to hydroxyaldehyde by 1H NMR); mp 105–107 °C.
Method B: Pyrazole aldehyde 7a (0.256 g, 0.768 mmol) was subjected
to General Procedure 4. The resultant residue was concentrated from
toluene (3 × 5 mL) to give pyrazole lactol 8a as a white solid; yield:
0.161 g (0.736 mmol, 95%; 14:1 mixture of lactol to hydroxyaldehyde
by 1H NMR); mp 128–130 °C.
NMR data listed for lactol component of mixture.
IR (neat): 3228, 2979, 1705, 1204, 1042 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.84 (s, 1 H), 7.30 (d, J = 5.7 Hz, 1
H), 6.16 (d, J = 5.7 Hz, 1 H), 4.38 (td, J = 11.1, 4.5 Hz, 1 H), 4.20 (q, J =
7.1 Hz, 2 H), 4.18–4.07 (m, 2 H), 3.98 (ddd, J = 11.6, 4.3, 1.8 Hz, 1 H),
1.26 (t, J = 7.1 Hz, 3 H).
NMR data listed for lactol component of mixture.
IR (neat): 3119, 1315, 1285, 1109, 1074 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.56 (s, 1 H), 7.29 (d, J = 4.5 Hz, 1
H), 5.86 (d, J = 4.3 Hz, 1 H), 4.28 (td, J = 10.3, 3.3 Hz, 1 H), 4.13–4.04
(m, 2 H), 4.02–3.97 (m, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 138.5, 136.1, 89.5, 86.2, 56.5, 46.9.
HRMS (ESI+): m/z [M]+ calcd for C6H7BrN2O2: 217.9696; found:
13C NMR (100 MHz, DMSO-d6):  = 161.9, 141.1, 140.1, 109.9, 86.1,
59.6, 55.2, 46.5, 14.2.
HRMS (ESI+): m/z [M]+ calcd for C9H12N2O4: 212.0797; found:
212.0798.
217.9691.
3-Bromo-2-isopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-
4-ol (8f)
3-Fluoro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-ol (8b)
Pyrazole aldehyde 7f (0.197 g, 0.525 mmol) was subjected to General
Procedure 4. The resultant residue was concentrated from toluene (3
× 5 mL) and then was purified by flash column chromatography (SiO2,
eluting with 0–10% MeOH/CH2Cl2) to give pyrazole lactol 8f as a white
solid; yield: 0.113 g (0.435 mmol, 82%; 14:1 mixture of lactol to hy-
droxyaldehyde by 1H NMR); mp 109–111 °C.
Pyrazole aldehyde 7b (0.515 g, 1.89 mmol) was subjected to General
Procedure 4. The resultant residue was concentrated from toluene (3
× 5 mL) to give pyrazole lactol 8b as a colorless oil; yield: 0.278 g (1.76
mmol, 93%; 3.7:1 mixture of lactol to hydroxyaldehyde by 1H NMR).
NMR data listed for lactol component of mixture.
NMR data listed for lactol component of mixture.
IR (neat): 3142, 2959, 1447, 1298, 1163, 1040 cm–1
1H NMR (400 MHz, DMSO-d6):  = 7.24 (d, J = 6.4 Hz, 1 H), 5.80 (d, J =
6.5 Hz, 1 H), 4.30–4.24 (m, 1 H), 4.06–3.94 (m, 3 H), 2.93 (sept, J = 7.0
Hz, 1 H), 1.20 (d, J = 7.0 Hz, 6 H).
IR (neat): 3117, 1593, 1427, 1364, 1188 cm–1
.
.
1H NMR (400 MHz, DMSO-d6):  = 7.46 (d, J = 4.4 Hz, 1 H), 7.28 (d, J =
6.5 Hz, 1 H), 6.01 (d, J = 6.5 Hz, 1 H), 4.27–4.20 (m, 1 H), 4.05–3.94 (m,
3 H).
13C NMR (100 MHz, DMSO-d6):  = 144.7 (d, J = 244.5 Hz), 125.0 (d, J =
11.7 Hz), 123.8, (d, J = 26.4 Hz), 85.7 (d, J = 3.7 Hz), 57.0, 46.7.
13C NMR (100 MHz, DMSO-d6):  = 153.4, 136.5, 88.2, 86.2, 56.5, 46.5,
26.1, 21.6, 21.5.
19F NMR (1H decoupled, 376 MHz, DMSO-d6):  = –178.1.
HRMS (ESI+): m/z [M]+ calcd for C6H7FN2O2: 158.0492; found:
HRMS (ESI+): m/z [M]+ calcd for C9H13BrN2O2: 260.0160; found:
260.0154.
158.0494.
3-Bromo-2-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo-
[5,1-c][1,4]oxazin-4-ol (8g)
3-(Trifluoromethyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-
ol (8c)
Pyrazole aldehyde 7g (0.231 g, 0.575 mmol) was subjected to General
Procedure 4. The resultant residue was concentrated from toluene (3
× 5 mL) to give pyrazole lactol 8g as a white solid; yield: 0.159 g
(0.555 mmol, 96%; >19:1 mixture of lactol to hydroxyaldehyde by 1H
NMR); mp 149–152 °C.
Pyrazole aldehyde 7c (0.222 g, 0.688 mmol) was subjected to General
Procedure 4. The resultant residue was concentrated from toluene (3
× 5 mL) to give pyrazole lactol 8c as a white solid; yield: 0.142 g (0.682
mmol, 99%;, >19:1 mixture of lactol to hydroxyaldehyde by 1H NMR);
mp 150–152 °C.
NMR data listed for lactol component of mixture.
NMR data listed for lactol component of mixture.
IR (neat): 3211, 1341, 1132, 1079, 1024 cm–1
.
IR (neat): 3169, 1682, 1578, 1198, 1103 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.52 (d, J = 6.8 Hz, 1 H), 5.91 (d, J =
6.6 Hz, 1 H), 4.30 (td, J = 10.9, 3.7 Hz, 1 H), 4.25–4.13 (m, 2 H), 4.05
(1H, ddd, J = 11.8, 3.9, 1.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 139.3, 137.7 (q, J = 36.6 Hz), 121.0
(q, J = 270.4 Hz), 88.2, 85.9, 56.3, 47.4.
19F NMR (1H decoupled, 376 MHz, DMSO-d6):  = –60.7.
HRMS (ESI+): m/z [M]+ calcd for C7H6BrF3N2O2: 285.9565; found:
1H NMR (400 MHz, DMSO-d6):  = 7.88 (s, 1 H), 7.49 (d, J = 6.4 Hz, 1
H), 6.04 (d, J = 6.1 Hz, 1 H), 4.32 (td, J = 11.1, 4.2 Hz, 1 H), 4.20–4.10
(m, 2 H), 4.02 (ddd, J = 12.0, 4.5, 2.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 137.7 (q, J = 3.2 Hz), 136.6 (q, J =
3.2 Hz), 122.9 (q, J = 265.6 Hz), 107.6 (q, J = 37.9 Hz), 86.0, 56.2, 46.5.
19F NMR (1H decoupled, 376 MHz, DMSO-d6):  = –54.5.
HRMS (ESI+): m/z [M]+ calcd for C7H7F3N2O2: 208.0460; found:
285.9558.
208.0464.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

K
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
(7R)-3-Bromo-7-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxaz-
in-4-ol (8h)
the second step. The resultant residue was taken forward without any
further purification and subjected to General Procedure 5, assuming a
100% yield for the third step. The resultant residue was purified by
flash column chromatography (SiO2, eluting with 0–40% MTBE/CH2Cl2)
to give pyrazole oxazine 9a as a white solid; yield: 2.00 g (9.87 mmol,
64% overall yield from 22).
Pyrazole aldehyde 7h (0.339 g, 0.976 mmol) was subjected to General
Procedure 4. The resulting residue was purified by azeotroping with
toluene (3 × 5 mL) to give pyrazole lactol 8h as a white solid; yield:
0.218 g (0.935 mmol, 95%; >19:1 mixture of lactol to hydroxyalde-
hyde, 2:1 mixture of diastereoisomers by 1H NMR); mp 135–140 °C.
Method C; One-Pot Preparation: To a flask were added pyrazole alde-
hyde 7a (0.195 g, 0.585 mmol) and CH2Cl2 (5.85 mL) and the mixture
was stirred in a dry ice/acetone bath. To the mixture were added
Et3SiH (0.283 mL, 1.76 mmol) and TMSOTf (0.648 mL, 3.51 mmol)
dropwise and the reaction mixture was stirred in a dry ice/acetone
bath for 1 h. Then, the mixture was first stirred in an ice/water bath
for 2 h and at r.t. for 16 h. To the mixture was added sat. aq NaHCO3
(10 mL) and the mixture was extracted with CH2Cl2 (2 × 10 mL). The
combined organics were dried (Na2SO4) and concentrated. The resul-
tant residue was purified by flash column chromatography (SiO2, elut-
ing with 0–40% MTBE/CH2Cl2) to give pyrazole oxazine 9a as a white
solid; yield: 0.111 g (0.547 mmol, 93%); mp 71–73 °C.
NMR data listed for mixture of lactol diastereoisomers.
IR (neat): 3142, 2917, 1335, 1265, 1041 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.58 (s, 0.67 H), 7.56 (s, 0.33 H),
7.30 (d, J = 7.0 Hz, 0.67 H), 7.28 (d, J = 7.0 Hz, 0.33 H), 5.86 (d, J = 5.5
Hz, 0.67 H), 5.84 (d, J = 5.0 Hz, 0.33 H), 4.35 (dd, J = 12.3, 3.7 Hz, 0.33
H), 4.30–4.25 (m, 0.33 H), 4.24–4.16 (m, 0.67 H), 4.01–3.91 (m, 1.34
H), 3.73 (d, J = 11.9 Hz, 0.33 H), 1.39 (d, J = 6.4 Hz, 2 H), 1.34 (d, J = 6.8
Hz, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 138.5, 138.3, 136.1, 135.5, 89.6,
89.2, 86.4, 86.3, 62.2, 61.4, 52.4, 52.2, 18.5, 14.9.
IR (neat): 2870, 1346, 1096, 1015 cm–1
.
HRMS (ESI+): m/z [M]+ calcd for C7H9BrN2O2: 231.9847; found:
1H NMR (400 MHz, CDCl3):  = 7.45 (s, 1 H), 4.75 (s, 2 H), 4.18–4.15
231.9851.
(m, 2 H), 4.10–4.08 (m, 2 H).
3-Bromo-6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxaz-
in-4-ol (8i)
13C NMR (100 MHz, CDCl3):  = 139.1, 134.5, 88.1, 64.4, 63.0, 47.1.
HRMS (ESI+): m/z [M]+ calcd for C6H7BrN2O: 201.9742; found:
To a flask were added pyrazole aldehyde 7i (0.219 g, 0.606 mmol), 2-
MeTHF (0.43 mL), H2O (0.43 mL), and TFA (0.875 mL, 11.4 mmol) at
r.t. The reaction mixture was stirred in a 40 °C heating block for 24 h,
then was cooled to r.t. and sat. aq NaHCO3 (10 mL) was added. The
mixture was extracted with CH2Cl2 (3 × 10 mL) and the combined or-
ganics were dried (Na2SO4) and concentrated. The resultant residue
was concentrated from toluene (3 × 5 mL) and then was purified by
flash column chromatography (SiO2, eluting with 0–50% MTBE/hep-
tane) to give pyrazole lactol 8i as a white solid; yield: 0.125 g (0.504
mmol, 83%; 3.5:1 mixture of lactol to hydroxyaldehyde by 1H NMR);
mp 95–98 °C.
201.9742.
3-Fluoro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (9b)
Pyrazole lactol 8b (0.233 g, 1.47 mmol) was subjected to General Pro-
cedure 5. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–40% MTBE/pentane) to give pyrazole
oxazine 9b as a colorless oil; yield: 0.164 g (1.15 mmol, 78%).
IR (neat): 2864, 1593, 1431, 1362, 1348, 1096, 1070 cm–1
1H NMR (400 MHz, CDCl3):  = 7.32 (d, J = 4.1 Hz, 1 H), 4.82 (d, J = 1.6
.
Hz, 2 H), 4.13–4.06 (m, 4 H).
NMR data listed for lactol component of mixture.
13C NMR (100 MHz, CDCl3):  = 144.2 (d, J = 242.1 Hz), 125.8 (d, J =
12.5 Hz), 121.3 (d, J = 27.1 Hz), 64.4, 61.6, 47.1.
IR (neat): 3260, 2979, 1388, 1184, 1040 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.57 (s, 1 H), 7.18 (d, J = 6.8 Hz, 1
H), 5.88 (d, J = 6.8 Hz, 1 H), 4.04 (d, J = 12.7 Hz, 1 H), 3.90 (d, J = 12.7
Hz, 1 H), 1.32 (s, 3 H), 1.25 (s, 3 H).
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –180.2.
HRMS (ESI+): m/z [M]+ calcd for C6H7FN2O: 142.0542; found:
142.0547.
13C NMR (100 MHz, DMSO-d6):  = 138.8, 134.9, 89.7, 86.2, 71.9, 55.9,
26.1, 25.5.
3-(Trifluoromethyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine
(9c)
HRMS (ESI+): m/z [M]+ calcd for C8H11BrN2O2: 246.0004; found:
245.9999.
Pyrazole lactol 8c (0.177 g, 0.850 mmol) was subjected to General
Procedure 5. The resultant residue was purified by flash column chro-
matography (SiO2, eluting with 0–10% MTBE/CH2Cl2) to give pyrazole
oxazine 9c as a white solid; yield: 0.113 g (0.587 mmol, 69%); mp 55–
57 °C.
3-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (9a)
Method A: Pyrazole lactol 8a (0.163 g, 0.744 mmol) was subjected to
General Procedure 5. The resultant residue was purified by flash col-
umn chromatography (SiO2, eluting with 0–40% MTBE/CH2Cl2) to give
pyrazole oxazine 9a as a white solid; yield: 0.128 g (0.630 mmol,
84%).
IR (neat): 2882, 1578, 1348, 1230, 1125 cm–1
.
1H NMR (400 MHz, (CD3)2SO):  = 7.90 (s, 1 H), 4.91 (s, 2 H), 4.18 (t, J =
5.2 Hz, 2 H), 4.09 (t, J = 5.2 Hz, 2 H).
Method B; Gram-Scale Preparation: 4-Bromo-1H-pyrazole (22; 2.11 g,
14.4 mmol) was subjected to General Procedure 1. The resultant resi-
due was taken forward without any further purification and subject-
ed to General Procedure 3, assuming a 100% yield for the first step.
The resultant residue was taken forward without any further purifi-
cation and subjected to General Procedure 4, assuming 100% yield for
13C NMR (125 MHz, (CD3)2SO):  = 136.4 (q, J =3.0 Hz), 136.3 (q, J = 2.7
Hz), 123.2 (q, J = 265.2 Hz), 105.9 (q, J = 37.5 Hz), 63.4, 61.7, 46.6.
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –56.0.
HRMS (ESI+): m/z [M]+ calcd for C7H7F3N2O: 192.0510; found:
192.0515.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

L
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
Ethyl 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylate
(9d)
by flash column chromatography (SiO2, eluting with 0–10% MTBE/
CH2Cl2) to give pyrazole oxazine 9h as a colorless oil; yield: 0.122 g
(0.562 mmol, 68%); []D20 –27.6 (c 0.23, MeOH).
Pyrazole lactol 8d (0.110 g, 0.518 mmol) was subjected to General
Procedure 5. The resultant residue was purified by flash column chro-
matography (SiO2, eluting with 0–10% MTBE/CH2Cl2) to give pyrazole
oxazine 9d as a white solid; yield: 0.079 g (0.404 mmol, 78%); mp 47–
49 °C.
IR (neat): 2978, 2845, 1337, 1097 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.45 (s, 1 H), 4.77 (d, J = 15.0 Hz, 1 H),
4.72 (d, J = 15.0 Hz, 1 H), 4.34–4.27 (m, 1 H), 4.10 (dd, J = 12.1, 4.1 Hz,
1 H), 3.71 (dd, J = 12.1, 6.4 Hz, 1 H), 1.51 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 138.9, 134.2, 87.9, 70.2, 63.3, 52.8,
16.9.
IR (neat): 2980, 1709, 1202, 1094, 1053 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.89 (s, 1 H), 5.04 (s, 2 H), 4.27 (q, J =
7.2 Hz, 2 H), 4.21 (t, J = 5.1 Hz, 2 H), 4.10 (t, J = 5.1 Hz, 2 H), 1.33 (t, J =
7.1 Hz, 3 H).
HRMS (ESI+): m/z [M]+ calcd for C7H9BrN2O: 215.9898; found:
215.9900.
13C NMR (100 MHz, CDCl3):  = 163.0, 140.7, 140.5, 109.7, 64.2, 63.8,
60.1, 46.9, 14.4.
3-Bromo-6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]ox-
azine (9i)
HRMS (ESI+): m/z [M]+ calcd for C9H12N2O3: 196.0848; found:
196.0851.
To a flask were added pyrazole lactol 8i (0.184 g, 0.745 mmol) and
CH2Cl2 (5.52 mL) and the mixture was stirred at r.t. To the mixture
were added Et3SiH (0.360 mL, 2.23 mmol) and TFA (0.344 mL, 4.47
mmol) dropwise and stirred at r.t. for 2 h. To the mixture was added
sat. aq NaHCO3 (10 mL) and the mixture was extracted with CH2Cl2
(2 × 10 mL); the combined organics were dried (Na2SO4), and concen-
trated. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–10% MTBE/CH2Cl2) to give pyrazole ox-
azine 9i as a colorless oil; yield: 0.144 g (0.622 mmol, 83%).
3-Bromo-2-isopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine
(9f)
Pyrazole lactol 8f (0.111 g, 0.425 mmol) was subjected to General Pro-
cedure 5. The resultant residue was purified by flash column chroma-
tography (SiO2, eluting with 0–20% MTBE/CH2Cl2) to give pyrazole ox-
azine 9f as a colorless oil; yield: 0.073 g (0.300 mmol, 70%).
IR (neat): 2965, 1363, 1097, 1038 cm–1
1H NMR (400 MHz, CDCl3):  = 4.70 (s, 2 H), 4.12–4.06 (m, 4 H), 3.03
(sept, J = 6.9 Hz, 1 H), 1.29 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3):  = 155.2, 134.9, 87.1, 64.6, 63.1, 46.9,
26.6, 21.5.
HRMS (ESI+): m/z [M]+ calcd for C9H13BrN2O: 244.0211; found:
244.0206.
.
IR (neat): 2977, 1372, 1209, 1076, 1006 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.46 (s, 1 H), 4.75 (s, 2 H), 3.92 (s, 2 H),
1.35 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 139.1, 133.4, 87.6, 71.5, 58.2, 56.3,
24.2.
HRMS (ESI+): m/z [M]+ calcd for C8H11BrN2O: 230.0055; found:
230.0052.
3-Bromo-2-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[5,1-
c][1,4]oxazine (9g)
4-Allyl-3-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (24)
To a flask were added pyrazole lactol 8a (0.130 g, 0.593 mmol) and
CH2Cl2 (3.90 mL) and the mixture was stirred in an ice/water bath. To
the mixture were added allyltrimethylsilane (0.286 mL, 1.78 mmol)
and TMSOTf (0.658 mL, 3.56 mmol) dropwise and the mixture was
stirred at r.t. for 16 h. To the mixture was added sat. aq NaHCO3 (10
mL) and the mixture was extracted with CH2Cl2 (2 × 10 mL); the com-
bined organics were dried (Na2SO4), and concentrated. The resultant
residue was purified by flash column chromatography (SiO2, eluting
with 0–20% MTBE/CH2Cl2) to give pyrazole oxazine 24 as a pale yellow
oil; yield: 0.114 g (0.469 mmol, 79%).
Pyrazole lactol 8g (0.161 g, 0.560 mmol) was subjected to General
Procedure 5. The resultant residue was purified by flash column chro-
matography (SiO2, eluting with 0–10% MTBE/CH2Cl2) to give pyrazole
oxazine 9g as a white solid; yield: 0.113 g (0.417 mmol, 74%); mp 40–
41 °C.
IR (neat): 2924, 1069, 1050, 1034 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 4.77 (s, 2 H), 4.21 (t, J = 5.2 Hz, 2 H),
4.10 (t, J = 5.2 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6):  = 138.1, 137.6 (q, J =36.6 Hz), 121.0
(q, J = 268.2 Hz), 85.6, 63.5, 61.7, 47.4.
19F NMR (1H decoupled, 376 MHz, CDCl3):  = –62.1.
HRMS (ESI+): m/z [M]+ calcd for C7H6BrF3N2O: 269.9616; found:
IR (neat): 2978, 2870, 1641, 1346, 1103 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.55 (s, 1 H), 5.78 (ddt, J = 17.0,
10.2, 6.8, 1 H), 5.14 (dd, J = 17.1, 1.8 Hz, 1 H), 5.06 (dd, J = 10.3, 1.1 Hz,
1 H), 4.91 (dd, J = 7.0, 3.7 Hz, 1 H), 4.20 (dt, J = 11.7, 3.8 Hz, 1 H), 4.10–
4.06 (m, 2 H), 3.89 (ddd, J = 11.8, 7.2, 5.3 Hz, 1 H), 2.80–2.67 (m, 2 H).
269.9620.
(R)-3-Bromo-7-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]ox-
13C NMR (100 MHz, DMSO-d6):  = 138.8, 136.0, 133.5, 117.9, 87.3,
azine (9h)
71.6, 61.8, 47.1, 35.8.
HRMS (ESI+): m/z [M]+ calcd for C9H11BrN2O: 242.0055; found:
242.0050.
To a flask were added pyrazole lactol 8h (0.192 g, 0.824 mmol) and
CH2Cl2 (5.76 mL) and the mixture was stirred in a dry ice/acetone
bath. To the mixture were added Et3SiH (0.399 mL, 2.47 mmol) and
TMSOTf (0.922 mL, 4.94 mmol) dropwise and the mixture was stirred
in a dry ice/acetone bath for 40 min, and in an ice/water bath for 3 h.
To the mixture was added sat. aq NaHCO3 (10 mL) and the mixture
was extracted with CH2Cl2 (2 × 10 mL); the combined organics were
dried (Na2SO4), and concentrated. The resultant residue was purified
3-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-4-carbo-
nitrile (25)
To a flask were added pyrazole lactol 8a (0.230 g, 1.05 mmol) and
CH2Cl2 (11.5 mL) and the mixture was stirred in an ice/water bath. To
the mixture were added TMSOTf (0.770 mL, 4.20 mmol) and TMSCN
(0.571 mL, 4.20 mmol) dropwise and the mixture was stirred at r.t.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

M
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
for 24 h. To the mixture were added TMSOTf (0.194 mL, 1.05 mmol)
and TMSCN (0.143 mL, 1.05 mmol) dropwise and the mixture was
stirred at r.t. for 16 h. To the mixture was added sat. aq NaHCO3 (10
mL) and the mixture was extracted with CH2Cl2 (2 × 10 mL); the com-
bined organics were dried (Na2SO4), and concentrated. The resultant
residue was purified by flash column chromatography (SiO2, eluting
with 0–15% MTBE/CH2Cl2) to give pyrazole oxazine 25 as a white sol-
id; yield: 0.187 g (0.821 mmol, 78%); mp 116–117 °C.
was added sat. aq Na2S2O3 (20 mL) and extracted with 2-MeTHF (3 ×
20 mL); the combined organics were dried (Na2SO4), and concentrat-
ed. The resultant residue was purified by flash column chromatogra-
phy (SiO2, eluting with 0–10% MTBE/CH2Cl2) to give pyrazole oxazine
28 as a white solid; yield: 0.202 g (0.931 mmol, 92%); mp 149–151 °C.
IR (neat): 3118, 1734, 1203, 1150, 1038 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.63 (s, 1 H), 4.71 (t, J = 5.5 Hz, 2 H),
4.47 (t, J = 5.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 155.5, 141.4, 126.9, 100.2, 65.9, 46.3.
HRMS (ESI+): m/z [M]+ calcd for C6H5BrN2O2: 215.9534; found:
215.9536.
IR (neat): 2936, 1347, 1088, 1004 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.55 (s, 1 H), 5.71 (s, 1 H), 4.39–4.23
(m, 4 H).
13C NMR (100 MHz, CDCl3):  = 139.9, 128.4, 113.9, 90.8, 62.6, 60.9,
46.6.
HRMS (ESI+): m/z [M]+ calcd for C7H6BrN3O: 226.9694; found:
226.9689.
Acknowledgment
We thank Christopher Reutter (Eli Lilly) for his assistance with high-
resolution mass spectrometry samples.
3-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-yl Acetate
(26)
To a flask were added pyrazole lactol 8a (0.194 g, 0.885 mmol) and
CH2Cl2 (3.49 mL) and the mixture was stirred in an ice/water bath. To
the mixture were added Et3N (0.186 mL, 1.33 mmol) and Ac2O (0.101
mL, 1.06 mmol) dropwise and the mixture was stirred at r.t. for 3.5 h.
To the mixture was added sat. aq NaHCO3 (10 mL) and the mixture
was extracted with CH2Cl2 (2 × 10 mL); the combined organics were
dried (Na2SO4), and concentrated. The resultant residue was purified
by flash column chromatography (SiO2, eluting with 0–20% MTBE/
CH2Cl2) to give pyrazole oxazine 26 as a white solid; yield: 0.186 g
(0.710 mmol, 80%); mp 146–148 °C.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610734.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References
(1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257.
IR (neat): 2929, 1755, 1746, 1349, 1217, 1102, 1010 cm–1
1H NMR (400 MHz, CDCl3):  = 7.51 (s, 1 H), 7.01 (s, 1 H), 4.38–4.16
.
(2) Pennington, L. D.; Moustakas, D. T. J. Med. Chem. 2017, 60, 3552.
(3) Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T.
J. Med. Chem. 2018, 61, 10996.
(m, 4 H), 2.16 (s, 3 H).
(4) (a) Velaparthi, U.; Kumaravel, S.; Karuppiah, A. M. S. S.;
Maheshwarappa, S. H.; Rachamreddy, C. R.; Wittman, M. D. WO
Patent 2015195880, 2015. (b) Stansfield, I.; Querolle, O. A. G.;
Ligny, Y. A. E.; Gross, G. M.; Jacoby, E.; Meerpoel, L.; Green, S. R.;
Hynd, G.; Kulagowski, J. J.; Macleod, C.; Mann, S. E. WO Patent
2018002219, 2018. (c) Patel, S.; Hamilton, G. WO Patent
2018109097, 2018. (d) Estrada, A. A.; Chan, B. K.; Baker-Glenn,
C.; Beresford, A.; Burdick, D. J.; Chambers, M.; Chen, H.;
Dominguez, S. L.; Dotson, J.; Drummond, J.; Flagella, M.; Fuji, R.;
Gill, A.; Halladay, J.; Harris, S. F.; Heffron, T. P.; Kleinheinz, T.;
Lee, D. W.; Le, Pichon. C. E.; Liu, X.; Lyssikatos, J. P.; Medhurst, A.
D.; Moffat, J. G.; Nash, K.; Scearce-Levie, K.; Sheng, Z.; Shore, D.
G.; Wong, S.; Zhang, S.; Zhang, X.; Zhu, H.; Sweeney, Z. K. J. Med.
Chem. 2014, 57, 921. (e) Baker-Glenn, C.; Chan, B. K.; Dotson, J.;
Estrada, A.; Heffron, T.; Lyssikatos, J.; Sweeney, Z. K. WO Patent
2013164323, 2013. (f) Crawford, J. J.; Ortwine, D. F.; Wei, B.;
Young, W. B. US Patent Appl. 2013116246, 2013. (g) Friedman,
M. M.; Cox, P.; Frank, K. E.; Hoemann, M. Z.; Osuma, A.; Wilson,
N. S.; Xu, X. WO Patent 2015157955, 2015. (h) Blomgren, P.;
Currie, K. S.; Kropf, J. E.; Lee, S. H.; Mitchell, S. A.; Schmitt, A. C.;
Xu, J.; Zhao, Z. WO Patent 2011112995, 2011. (i) Barlaam, B.; De
Savi, C.; Hawkins, J.; Hird, A.; Lamb, M.; Pike, K.; Vasbinder, M.
US Patent Appl. 20160376287, 2016.
13C NMR (100 MHz, CDCl3):  = 169.3, 139.6, 132.4, 91.4, 85.2, 59.5,
46.8, 20.8.
HRMS (ESI+): m/z [M]+ calcd for C8H9BrN2O3: 259.9797; found:
259.9802.
Ethyl(E)-3-[4-Bromo-1-(2-hydroxyethyl)-1H-pyrazol-5-yl]acrylate
(27)
To a flask were added pyrazole lactol 8a (0.219 g, 0.999 mmol), CH2Cl2
(2.19 mL), and (carbethoxymethylene)triphenylphosphorane (0.426
g, 1.20 mmol) and the reaction mixture was stirred at r.t. for 1.5 h,
and then concentrated. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 0–10% EtOAc/MTBE) to
give pyrazole oxazine 27 as a white solid; yield: 0.225 g (0.777 mmol,
77%); mp 98–100 °C.
IR (neat): 3385, 2981, 1710, 1638, 1291, 1183 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.56 (d, J = 16.2 Hz, 1 H), 7.54 (s, 1 H),
6.91 (d, J = 16.2 Hz, 1 H), 4.32 (t, J = 4.8 Hz, 2 H), 4.28 (q, J = 7.2 Hz, 2
H), 4.07–4.03 (m, 2 H), 2.77 (t, J = 6.2 Hz, 1 H), 1.35 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 166.4, 140.7, 134.9, 128.0, 122.6, 95.9,
61.2, 61.1, 52.2, 14.2.
HRMS (ESI+): m/z [M]+ calcd for C10H13BrN2O3: 288.0110; found:
288.0117.
(5) (a) Venkatesan, A. M.; Mansour, T. S.; Abe, T.; Yamamura, I.;
Takasaki, T.; Agarwal, A.; Santos, O. D.; Sum, F.-W.; Lin, Y.-I. WO
Patent 2003093279, 2003. (b) Venkatesan, A. M.; Agarwal, A.;
Abe, T.; Ushirogochi, H.; Yamamura, I.; Ado, M.; Tsuyoshi, T.;
Santos, O. D.; Gu, Y.; Sum, F.-W.; Li, Z.; Francisco, G.; Lin, Y.-I.;
Petersen, P. J.; Yang, Y.; Kumagai, T.; Weiss, W. J.; Shlaes, D. M.;
Knox, J. R.; Mansour, T. S. J. Med. Chem. 2006, 49, 4623.
3-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-one (28)
To a flask were added pyrazole lactol 8a (0.220 g, 1.00 mmol), CH2Cl2
(1.37 mL), NMO (0.165 g, 1.37 mmol), and TPAP (0.066 g, 0.18 mmol)
and the reaction mixture was stirred at r.t. for 2.5 h. To the mixture
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N

N
P. J. Lindsay-Scott, E. Rivlin-Derrick
Paper
Synthesis
(6) Mattes, A.; Helmke, H.; Hillebrand, S.; Peris, G.; Sudau, A.;
Rodefeld, L.; Gauger, S.; Benting, J.; Dahmen, P.; Meissner, R.;
Wachendorff-Neumann, U.; Hadano, H. WO Patent
2011124539, 2011.
(7) (a) 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. (b) Wright, S. W.; Arnold, E. P.; Yang, X. Tetrahe-
dron Lett. 2018, 59, 402.
(8) (a) Li, J.-X.; Li, L.; Zhou, M.-D.; Wang, H. Org. Chem. Front. 2018,
5, 1003. (b) Xia, T.; Hu, Z.; Ji, W.; Zhang, S.; Shi, H.; Liu, C.; Pang,
B.; Liu, G.; Liao, X. Org. Chem. Front. 2018, 5, 850.
(9) Prieto, A.; Bouyssi, D.; Monteiro, N. ACS Catal. 2016, 6, 7197.
(10) Lindsay-Scott, P. J.; Charlesworth, N. G.; Grozavu, A. J. Org. Chem.
2017, 82, 11295.
(13) Kohshi, U.; Keiko, T.; Teiji, K.; Noritaka, K.; Atsuhiko, K.;
Manabu, M.; Makoto, K.; Tadashi, O.; Koki, K.; Atsushi, S. US
Patent Appl. 20020019531, 2002.
(14) The regioselectivity during the alkylation and formylation steps
was confirmed by 1H NMR NOESY correlations.
(15) For the synthesis of compound 13, see: Zhang, D.; Zhang, X.; Ai,
J.; Zhai, Y.; Liang, Z.; Wang, Y.; Chen, Y.; Li, C.; Zhao, F.; Jiang, H.;
Geng, M.; Luo, C.; Liu, H. Bioorg. Med. Chem. 2013, 21, 6804.
(16) Enders, D.; Berg, T.; Raabe, G.; Runsink, J. Liebigs Ann. Recl. 1997,
345.
(17) Enantiomeric excess measurements were conducted by chiral
supercritical fluid chromatography with comparison to
racemic standard.
a
(18) 2-MeTHF was utilized as co-solvent during this transformation
due to its stability under acidic conditions, see: Aycock, D. F.
Org. Process Res. Dev. 2007, 11, 156.
(11) Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett. 2009, 11,
3326.
(12) Chytil, M.; Engel, S.; Hanania, T. G.; Alexandrov, V.; Leahy, E. WO
Patent 2016130790, 2016.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–N