Diastereoselective in and Zn-mediated allylation of pyrazol-4-yl derived (R)-tert-butanesulfinyl imines: Synthesis of enantiomerically pure 6-(pyrazol-4-yl)-piperidin-2,4-diones

Article abstract of DOI:10.1016/j.tetasy.2014.03.003

The In and Zn-mediated allylation of substituted pyrazol-4-yl derived (R)-N-tert-butanesulfinyl imines proceeds with high diastereoselectivity depending on the conditions and additives (up to 99.4% de). Thus, the synthesized diastereomeric homoallylsulfinamides were isolated and characterized as pure diastereomers, which were then converted into the corresponding pyrazol-4-yl-derived N-Boc-homoallylamines via consecutive treatment with HCl and Boc₂O. The latter were then subjected to a sequence of reactions: cyclobromocarbamation with NBS and enolate-isocyanate rearrangement with tBuOK to give novel enantiomerically pure (S)-6-(pyrazol-4-yl)-piperidine-2,4-diones in 88-96% yield. The absolute configurations of the allylation products were assigned by X-ray single crystal analysis of the intermediate bromomethylurethanes.

Full text of DOI:10.1016/j.tetasy.2014.03.003

Tetrahedron: Asymmetry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective In and Zn-mediated allylation of pyrazol-4-yl
derived (R)-tert-butanesulfinyl imines: synthesis of enantiomerically
pure 6-(pyrazol-4-yl)-piperidin-2,4-diones
a
a
a,b,
Nikolai Yu. Kuznetsov a,b, , Victor N. Khrustalev , Tatyana V. Strelkova , Yuri N. Bubnov
⇑
⇑
a A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991 Moscow, Russia
b N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr. 47, 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The In and Zn-mediated allylation of substituted pyrazol-4-yl derived (R)-N-tert-butanesulfinyl imines
proceeds with high diastereoselectivity depending on the conditions and additives (up to 99.4% de). Thus,
the synthesized diastereomeric homoallylsulfinamides were isolated and characterized as pure diaste-
reomers, which were then converted into the corresponding pyrazol-4-yl-derived N-Boc-homoallylam-
ines via consecutive treatment with HCl and Boc2O. The latter were then subjected to a sequence of
reactions: cyclobromocarbamation with NBS and enolate–isocyanate rearrangement with tBuOK to give
novel enantiomerically pure (S)-6-(pyrazol-4-yl)-piperidine-2,4-diones in 88–96% yield. The absolute
configurations of the allylation products were assigned by X-ray single crystal analysis of the intermediate
bromomethylurethanes.
Received 13 February 2014
Accepted 4 March 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
N
1. Introduction
NH2
O
F
F
N
Among heterocycles, that are found in a variety of natural
products, piperidines occupy one of the privileged places.1 The
excellent biological activity of this particular class of nitrogen
heterocycles has stimulated the search for novel syntheses of
known molecules as well as the design of new piperidine deriva-
tives. Over the course of our studies, we turned our attention to
piperidine-2,4-diones, which are valuable building blocks, since
they can be readily functionalized at different sites of the piperi-
dine ring. Moreover, piperidine-2,4-diones have shown high
biological activity (Fig. 1).2 Amid the available 6-substituted piper-
idine-2,4-diones, there are only a few examples with heterocyclic
units at the 6-position.3 Moreover, until now there has been no
convenient method described for the preparation of enantiomeri-
cally pure piperidine-2,4-dione derivatives with a heterocyclic
substituent.
F
N
O
O
N
H
O
N
O
H
highly potent hypoglycemic agent
cell division cycle (Cdc7) kinase inhibitor
(anticancer agent)
R1
O
O
N
NH
H2N
N
R2
O
N
H
COOH
heat shock protein 90 inhibitors
(anticancer, antiviral etc. agents)
bacterial dihydroorotase inhibitor
Figure 1. Biologically active piperidine-2,4-dione derivatives.
Recently, we have elaborated upon a concise and efficient
approach to 6-substituted piperidine-2,4-diones based on the
transformations of homoallylamines (Fig. 2).4
In order to expand upon the scope of our method, we have
targeted the preparation of diones with a heteroaryl substituent.
Among the variety of heteroaryls, we selected pyrazoles for the
stereoselective synthesis of new 6-pyrazole substituted piperi-
dine-2,4-diones. Over the past decades, interest in pyrazole chem-
istry has significantly increased mainly due to the discovery of
interesting biological properties exhibited by a great number of
pyrazole derivatives.5 We believe that the combination of pyrazole
and piperidine-2,4-dione fragments might be helpful in the design
⇑
Corresponding authors. Tel.: +7 4991350446.
E-mail addresses: nkuznff@ineos.ac.ru (N.Yu. Kuznetsov), bubnov@ineos.ac.ru
(Y.N. Bubnov).
http://dx.doi.org/10.1016/j.tetasy.2014.03.003
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kuznetsov, N. Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.003

2
N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
O
the preparation of ketimine 2e suffered from it being a slow reac-
tion and only the use of neat reagents provided satisfactory reac-
tivity. We took advantage of the condensation procedure under
microwave irradiation9 at 85 °C, but even in this case, to bring
the reaction to completion, it required 24 h. Although the micro-
wave irradiation was not essential and could be substituted by
conventional heating, the reaction under irradiation proceeded
more cleanly.
1. NBS
R1
R2
R1
R2
2. tBuOK
NHBoc
O
N
H
Br
O
O-K+
O
O
Δ
R1
R2
R1
tBuOK,
R1
N
O-K+
R2
N
O-K+
N
R2
Although the allylation of imines in general is well elaborated,
the presence of a heterocyclic substrate may have considerable
influence on the reactivity and diastereoselectivity of the allyla-
tion, due to the formation of additional coordination bonds with
heteroatoms. The N-substituted pyrazols are appropriate hetero-
aryl models for the determination of such effects because of the ex-
pected coordination between the metal and nitrogen’s lone pair.
However, the strength of this coordination, how other factors
interplay and their influence on the diastereoselectivity would be
interesting to know. The allylation of imines 2 began with N-ethyl
substituted derivative 2a, which was allylated with an allylBr/Zn/
DMF (Barbier conditions, all reagents mixed together) system at
0 °C (Table 1, run 1). The reaction proceeded well with the forma-
tion of diastereomeric allylamides 4a and 3a. The de of the allyla-
mides was quite low (76%); decreasing the temperature to ꢀ10 °C
led to a slight enhancement of the de up to 80% (run 2). The influ-
ence of Zn-coordination on the de was also determined, thus the
addition of extra Zn ions with Zn(OTf)2 strongly decreased the de
to 50% (run 3). It should be noted that all of the reactions were
homogeneous during all of the process except for the presence of
insoluble metals, hence the variation of diastereoselectivity de-
pends only on the nature of the interacting compounds rather than
experimental variables. These results are in agreement with con-
ception7 that allylation (in generally nucleophilic addition) to N-
tert-butanesulfinyl imines passes through two competing ways;
with chelation control and open chain steric control (Fig. 3). In or-
der to clarify the preferred routes for the pyrazolyl imines, the
reaction was carried out in the presence of a chelate-breaking
agent TMEDA, since it was shown that addition of TMEDA may to-
tally reverse the diastereoselectivity in THF.8a A high level of dia-
stereoselectivity was observed (98%, run 4) even at the expense
of the yield and conversion, clearly indicating that the pathway
via TS2 was a highly diastereoselective process, although the reac-
tivity of the imine was not high enough. Allylation of 2a with Zn in
THF gave the reverse selectivity (run 5, 26% de) with the major
(R,S)-isomer (see Scheme 1) being obtained, thus indicating the
slight preference of chelation control TS1 in this case. It was sug-
gested that the In-mediated allylation (Barbier conditions) may
improve the selectivity, because it has to proceed via TS1. Indeed
application of the protocol developed by Xu and Lin8b with In/NaBr
aqueous saturated solution gave the major (R,S)-isomer with >98%
de, although the yield was only 15% leaving the rest of 2a
R1 = -Alk, -Ph, -COOR, -CH2COOR, -CH2F
2 = -H, -Me, -All
R
Figure 2. Transformation of N-Boc-homoallylamines into piperidine-2,4-diones.
and synthesis of new pharmaceuticals, because both of these frag-
ments are active pharmacophores.
There are many methods for the stereoselective synthesis of
homoallyamines,6 but for our particular synthetic task, we carried
out the allylation of N-tert-butanesulfinyl imines with the corre-
sponding Zn and In derivatives.7 It has been shown that allylation
of N-tert-butanesulfinyl imines with Zn/HMPA or In/THF proceeds
with a high level of diastereoselectivity.8a Xu et al. reported that
Zn-mediated allylation of imines in DMF gave only 24% de, but
with HMPA, the de level reached 98% (for a simple Ph-imine deriv-
ative). However, HMPA is not a common solvent for most reactions,
because it is carcinogenic, so in a later publication, an ecologically
friendly aqueous system was designed for the In mediated reac-
tion, which was appropriate for heteroaryl imines as well.8b Carry-
ing out the allylation in a saturated NaBr solution generally gave a
high de of the product,8b–e however, low chemical yields were ob-
served in some cases. Conversely, the Zn-mediated allylation of
highly electrophilic trifluoromethyl imines in DMF proceeded well
with up to 90% de8f being achieved. With regards to the In or Zn-
mediated allylation of N-tert-butanesulfinyl ketimines in THF, the
diastereoselectivity is less predictable and varies considerably
depending on the ketimine structure, although in some cases can
achieve >98% de.8g With these precedent studies in mind, we
started the allylation of pyrazol-derived N-tert-butanesulfinyl imi-
nes with the aim of obtaining enantiomerically pure pyrazolyl-de-
rived homolallyamines. The enantiomeric purity of amines is an
important point because further amplification of ee for the iso-
meric bromourethanes or final diones is less fruitful.
2. Results and discussion
The starting N-tert-butanesulfinyl imines 2a–d, (Scheme 1)
were prepared in reasonable quantitative yield in THF by the reac-
tion of carbonyl compounds 1a–d, with (R)-tert-butanesulfinamide
in the presence of titanium tetraisopropoxide at 50 °C. However,
O-
O-
O-
O-
R3
S+
R3
R3
R2
R2
R2
R3
H2N
(R)
S+
S+
S+
Br
R2
N
O
(R)
(S)
N
N
H
N
H
(R)
(R)
(R)
N
N
N
+
Zn or In
solvent
Ti(OiPr)4
N
N
N
N
R1
R1
R1
R1
1a-e
2a-e
4a-e
3a-e
R1 = Et, R2 = H, R3 = H a
1 = Me, R2 = H, R3 = H b
R1 = Et, R2 = Me, R3 = H c
1 = Ph, R2 = H, R3 = H d
R1 = Me, R2 = H, R3 = Me e
R
R
Scheme 1. Synthesis of pyrazol-4-yl N-tert-butanesulfinyl imines and the allylation reaction.
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N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
3
Table 1
Diastereoselective allylation of pyrazol-4-yl N-tert-butanesulfinyl imines
Run
Subst.
Metal
Additive
Temp (°C)
Time (h)
Solvent
4:3, dra
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
2c
2d
2d
2d
2e
2e
2e
Zn
Zn
Zn
Zn
Zn
In
In
In
In
In
—
—
0
ꢀ10
0
ꢀ15
20
20
0
1
0.5
1
1.5
0.5
24
4
DMF
DMF
DMF
DMF
THF
H2O
DMF
DMA
THF
THF
THF
DMF
DMF
DMF
THF
THF
DMF
DMF
THF
THF
DMF
THF
THF
THF
12:88
10:90
25:75
1:99
63:37
>99:1
94:6
85
75
90
50
92
15
90
85
89
95
95
75
56
30
95
98
80
88
98
70
90
97
95
98
b
Zn(OTf)2
TMEDAc
—
NaBrd
—
—
0
4
97:3
96:4
DMF/H2Oe
20
20
20
ꢀ10
ꢀ15
ꢀ15
20
20
0
14
14
14
0.5
1.5
1.5
14
0.5
6
DMF/H2Oe
97:3
In
DMF/H2Oe
93:7f
11:89
1:99
Zn
Zn
Zn
In
Zn
In
In
Zn
In
—
TMEDAcc
TMEDAc
15:85
90:10
83:17
99:1
DMF/H2Oe
—
—
—
—
0
6
98:2g
73:27
97:3
20
20
0
20
20
0
0.5
14
6
3
0.5
0.5
DMF/H2Oe
In
—
—
94:6
93:7
Zn
Zn
Zn
b
Zn(OTf)2
Zn(OTf)2
98.5:1.5
b
99.7:0.3h
Typical run: imine 2 (1 mmol), In (3 mmol) or Zn (3 mmol), allylBr (3 mmol), solvent (2 mL).
a
dr was determined by integration of the intensities of the protons of the NH groups in PMR spectra; absolute configurations were assigned on the basis of X-ray data.
b
c
d
e
f
1 equiv to 2.
1 equiv to Zn.
NaBr saturated aqueous solution (7 mL).
DMF (1.2 equiv)/H2O (0.5 equiv) to In.
15 mmol scale.
10 mmol scale.
g
h
HPLC analysis, Daicel Chiralpak IB-3, eluent n-C6H14/iso-PrOH = 4:1, rate 1 mL/min, UV 254 nm.
product is formed in good yield and with similar selectivity to that
in neat DMF (run 9).
O
(R)
S
Allylation of N-methyl derivative 2b gave similar results (runs
10–13). The optimized conditions for the allylation of N-alkyl
substituted substrates 2a,b used either THF with a DMF/H2O addi-
tive or neat DMF, with both systems showing close selectivity.
However, when we attempted to scale up the reaction to 15 mmol
the de decreased to 85%. The other substrate, imine 2c, was less
reactive for the allylation probably because of the unfavorable ste-
ric influence of the 3-methyl group in the pyrazole ring. TMEDA
showed moderate de (70%) and low chemical yield (30%) of the
allylation products 3c/4c (run 14). This experiment could be a ‘lit-
mus test’ for the reactivity toward organometallic compounds in
the absence of activation of the imine’s C@N bond via a chelation
effect (TS1). The use of a more ‘chelating’ system In/THF with a
DMF/H2O additive improved the de (up to 80%) and chemical yield
(run 15). It should be noted that a Zn/THF system gives the same
major isomer as with In (run 16) which clearly demonstrates the
poor reactivity of 2c via an open transition state (compare runs 5
and 16). In-mediated allylation of 2c in DMF perfectly matched
the activation via a chelated transition state and the product was
formed with 98% de. Scaling the reaction up to 10 mmol led to a
slight deterioration in de (95%) (run 18). Allylation of phenyl-pyr-
azol derivative 2d under the optimized conditions with In gave
similar selectivities (compare runs 20, 21 with 7, 9, and 10) with
Me- and Et-derivatives. However, the Zn-mediated allylations of
2d (run 19, 46% de) and 2a (run 5, 26% de) showed the slight influ-
ence of N-substituents on the de. Moreover, in case of 2c, the pres-
ence of two Me-groups had a more profound effect (run 16, 66%
de). This means that the 2-pyrazol nitrogen with a lone pair would
participate in the transition state of allylation in THF via coordina-
tion with a metal ion. The more bulky substituents that are present
around the 2-nitrogen of the pyrazole ring, the less accessible it be-
N
M
+
H(Me)
Pyr
Pyr
M
MLn
TS1
TS2
N
H
O
N
H(Me)
S
Pyr
O
chelation control
steric control
O
O
(R) S
(R) S
HN H(Me)
HN
Pyr
H
(S)
Pyr
(R)
Figure 3. Proposed six-membered transition state with chelation TS1 and open
transition state with steric TS2 control for the metal-mediated (R)-N-tert-butylsul-
finyl imines allylation.
unchanged (run 6). Changing the solvent to DMF or DMA gave the
product with high de and good yield (runs 7 and 8). Unexpectedly
we found the use of the conventional protocol with In/THF system
was not possible. The reaction does not proceed even at elevated
temperature, since the In turnings were covered with a film of
insoluble salt. It could be feasible that the pyrazol fragment
responsible for this behavior of In, forms insoluble complexes
which block the In surface. Nevertheless, the addition of some
(Table 1, note d) DMF/H2O (10:1) initiates the reaction and the
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4
N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
comes for coordination and weakens this undesirable effect. All of
the products 3/4a–d were separated by chromatography to diaste-
reomerically pure compounds that allowed us to unambiguously
detect isomers by proton NMR spectra and safely use isomers 4
for further synthetic transformations. It was assumed that keti-
mine 2e would be inert toward non-activating open transition
state TS2 and the best system could be In-based. Unfortunately,
we were unable to initiate the In-mediated addition in our stan-
dard conditions. Therefore, we tested the Zn/THF system and found
that the reaction proceeded smoothly to give a product with high
de (86%) in nearly quantitative yield (run 19). The addition of
Zn(OTf)2 led to a further improvement of de of up to 97% (run
20). Decreasing the temperature to 0 °C and slightly changing the
experimental conditions allowed us to obtain a pure diastereoiso-
mer (it was impossible to detect the second isomer by NMR) thus
avoiding tedious purification techniques, because we were unable
to separate the mixture of 3e/4e into individual isomers by using
conventional chromatography. Having in hand enough of the pure
material, we started the synthesis of the target piperidine-2,4-
diones.
Figure 4. Major isomer (S,R)-6b with 50% probability ellipsoids.
On the first stage sulfinylamides 4a–e were converted to N-Boc
derivatives 5a–e in a one pot reaction (Scheme 2).
It is well documented that the acid catalyzed cleavage of sulfi-
nylamides occurs without racemization7 and gives the correspond-
ing homoallylamines. Methanolic solutions of sulfinylamides 4a–e
were treated with 4 M HCl in dioxane. After the cleavage was com-
pleted, as was monitored by TLC, the excess HCl and MeOH were
removed by evaporation. The resulting solid of the dihydrochloride
of the pyrazolyl substituted homoallylamine was treated with Boc-
anhydride in the presence of excess of Et3N and after purification
N-Boc amines 5a–e were obtained in high yield. The cyclobromo-
carbamation reaction was carried out by the treatment of TFA salt
5a–e with NBS to furnish mixtures of diastereoisomers 6a–e in dif-
ferent ratios. It is worth noting that TFA addition was critical in this
transformation. The action of NBS on unprotonated pyrazol deriv-
atives only led to low yields of bromourethanes. The ratio of diaste-
reomeric bromides 5a–c was approximately 1.4:1, 5d—2.5:1 and
5e (1:3.4). The major isomers (S,R)-6b and (S,S)-6e were obtained
in pure form via consecutive crystallizations of bromide mixtures
from EtOAc. Their absolute configurations were established by X-
ray single crystal analysis (Figs. 4 and 5), which allowed us to as-
sign the configuration of all the products by analogy. The central
six-membered heterocycle in (S,R)-6b adopts an unsymmetrical
half-boat conformation with deviations of the C4 and C5 atoms
from the mean plane of the other ring atoms. The bulky bromo-
methyl and 1-methyl-1H-pyrazole substituents occupy the more
Figure 5. Major isomer (S,S)-6e with 50% probability ellipsoids.
sterically favorable equatorial positions. The absolute configura-
tions of the asymmetric centers were established as (4S,6R).
Compound 6e crystallizes in the monoclinic space group P21
with two crystallographically independent molecules in the unit
cell. The geometries of these independent molecules are very sim-
ilar. The central six-membered heterocycle in 6e adopts an unsym-
metrical half-chair conformation with deviations of the C4 and C5
atoms from the mean plane of the other ring atoms. The bulky
Br
O
H
O-
R3
R3
O
R2
R2
R2
R2
R3
R3
S+
1. TFA (1eq.)
2. NBS/DCM
1. HCl/MeOH
tBuOK
(S)
(S)
N
H
(R)
(S)
NHBoc
O
N
H
N
H
O
(S)
N
N
N
N
THF
2. Et3N/Boc2O
THF, reflux
N
N
N
N
R1
R1
R1
R1
7a-e
5a-e
6a-e
4a-e
R1, R2, R3 5, Yield
6, Yield, cis/trans
6a, 85%, 1.4:1
6b, 83%, 1.4:1
6c, 78%, 1.5:1
6d, 78%, 2.5:1
6e, 92%, 1:3.4
7, Yield
7a, 92%
7b, 96%
7c, 90%
7d, 88%
7e, 95%
Et, H,
Me, H,
H
H
5a, 91%
5b, 88%
5c, 90%
5d, 86%
Et, Me, H
Ph, H,
H
Me, H, Me 5e, 85%
Scheme 2. Transformation of diastereomerically pure sulfinamides to (S)-6-pyrazolylpiperidine-2,4-diones.
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N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
5
Br
Br
O
O
H
O- K+
[H+]
O
O
Δ
R2
R2
tBuOK,
O- K+
R3
R3
R3
t-BuOK
THF
R3
R3
N
O- K+
N
N
O
O
N
H
N
H
Pyr
Pyr
Pyr
N
N
O
N
N
R1
R1
6a-e
7a-e
Scheme 3. Base mediated enolate–isocyanate rearrangement to piperidine-2,4-diones.
bromomethyl substituent occupies the more sterically favorable
equatorial position, whereas the bulky 1-methyl-1H-pyrazole sub-
stituent is in an axial position. The absolute configurations of the
asymmetric centers were established as (4S,6S).
The relative configuration of the substituents in 6e was also
determined in a NOESY experiment where NOE was observed be-
tween the CH proton in the oxazinane cycle and one of the CH pro-
tons in the pyrazole ring. This means that all the major isomers 3 of
allylated sulfinylamides have an (S,R)-configuration, if the allyl
addition goes through the TS1 (Fig. 2).
The mixtures of isomeric bromourethanes 6a–e were subjected
to a base (tBuOK) mediated rearrangement in THF (Scheme 2).
All of the reactions proceeded smoothly when using 2.5 equiv of
tBuOK at 20–25 °C and were completed within 30–40 min. The
potassium salt of the diones precipitated during the reaction;
quenching the reaction mixture with acetic acid gave the target
6-(pyrazol-4-yl)-piperidine-2,4-diones in high yields. It should be
noted that upon acidification, the temperature of the reaction mix-
ture must not be higher than ꢀ10 °C, otherwise side products are
formed. The proposed mechanism of the transformation includes
several stages (Scheme 3).4
At first, tBuOK abstracts the acidic N–H proton to form a potas-
sium salt. In the next stage, the abstraction of HBr occurred via an
anionic substrate giving an unstable anionic enolate, which under-
goes enolate–isocyanate rearrangement in the third stage. The
resulting enolato-isocyanate is irreversibly cyclized to the piperi-
dine-2,4-dione potassium salt, while the latter after acidification
with AcOH releases the final product. Compounds 7a–e were iso-
lated in pure form by flash chromatography.
Nesmeyanov Institute of Organoelement Compounds RAS
(Moscow).
4.2. Experimental procedures
4.2.1. (R)-N-[(1-Ethyl-1H-pyrazol-4-yl)methylidene]-2-methyl-
2-propanesulfinamide 2a
A
solution of 1-ethyl-1H-pyrazole-4-carbaldehyde (1.20 g,
9.67 mmol), (R)-2-methyl-2-propanesulfinamide (1.28 g,
10.63 mmol), and Ti(OiPr)4 (14.2 g, 15 mL, 50 mmol) in THF
(30 mL) was stirred with heating on a water bath at 50 °C for
20 h. The resulting mixture was poured into water (70 mL) with
stirred for 15 min, then filtered and the precipitate was washed
twice with DCM. The filtrate was diluted with water (100 mL)
and extracted with DCM (20 mL ꢁ 3). The combined extracts were
dried over K2CO3, filtered through the pad of silica gel, and evapo-
rated under reduced pressure and dried in vacuo to afford pure 2a
2.09 g (95.8%). ½a D25
ꢂ
= ꢀ121.5 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3): d 8.44 (s, 1H, CH@N), 7.86 (s, 1H, CHpyr), 7.82 (s, 1H, CHpyr),
4.17 (q, J = 7.3 Hz, 2H, Et), 1.48 (t, J = 7.3 Hz, 3H, Et), 1.17 (s, 9H,
tBu). 13C NMR (100 MHz, CDCl3):
d 154.42, 139.82, 130.48,
119.56, 57.30, 47.47, 22.41 3C, 15.27. MS (70 eV, EI): m/z
(%) = 228 (14) [MH]+, 185 (12), 171 (100), 144 (11), 137 (14), 123
(49), 122 (20), 97 (14), 96 (12), 95 (40), 94 (29), 68 (11), 41 (7). C10-
H17N3OS (227.3): calcd C 52.83, H 7.54, N 18.48; found C 52.62, H
7.41, N 18.35.
4.2.2. (R)-2-Methyl-N-[(1-methyl-1H-pyrazol-4-yl)methylidene]-
2-propanesulfinamide 2b
A solution of 1-methyl-1H-pyrazole-4-carbaldehyde (2.73 g,
24.80 mmol), (R)-2-methyl-2-propanesulfinamide (3.30 g, 27.30
mmol), and Ti(OiPr)4 (35.2 g, 37.1 mL, 0.124 mol) in THF (60 mL)
was stirred with heating on a water bath at 50 °C for 20 h. The
resulting mixture was poured into water (100 mL) with stirring
for 15 min, then filtered and the precipitate was washed twice with
DCM. The filtrate was diluted with water (100 mL) and extracted
with DCM (20 mL ꢁ 3). The combined extracts were dried over
K2CO3, filtered through the pad of silica gel, and evaporated under
reduced pressure and dried in vacuo to afford pure 2b 5.16 g (97%).
3. Conclusion
The In and Zn-mediated allylation of substituted pyrazol-4-yl
derived (R)-N-tert-butanesulfinyl imines was found to proceed
with highly diastereoselectivity (up to >99%) depending on the
conditions and additives. The diastereomeric homoallylsulfina-
mides synthesized were isolated and characterized as pure diaste-
reomers, which were then converted via consecutive treatment
with HCl and Boc2O into the corresponding pyrazol-4-yl-derived
N-Boc-homoallylamines. The N-Boc-protected amines was sub-
jected to a sequence of reactions: cyclobromocarbamation with
NBS and enolate–isocyanate rearrangement with tBuOK, to give
new enantiomerically pure (S)-6-(pyrazol-4-yl)-piperidine-2,4-
diones in high yields.
½
a 2D5
ꢂ
= ꢀ130.7 (c 1, CHCl3), 1H NMR (400 MHz, CDCl3): d 8.41 (s, 1H,
CH@N), 7.83 (s, 1H, CHpyr), 7.78 (s, 1H, CHpyr), 3.89 (s, 3H, Me), 1.15
(s, 9H, tBu). 13C NMR (100 MHz, CDCl3): d 154.28, 139.91, 132.14,
119.86, 57.30, 39.29, 22.39 3C. MS (70 eV, EI): m/z (%) = 214 (60)
[MH]+, 157 (100), 130 (10), 109 (56), 108 (48), 83 (18), 82 (20),
81 (8), 41 (7). C9H15N3OS (213.3): calcd C 50.68, H 7.09, N 19.70,
S 15.03, found C 50.42, H 7.11, N 19.55, S 14.88.
4. Experimental section
4.1. General
4.2.3. (R)-N-[(1-Ethyl-3-methyl-1H-pyrazol-4-yl)methylidene]-
The manipulations were carried out under an inert atmosphere
of dry Ar. NMR spectra were recorded on Bruker Avance-300, 400
and 600 MHz instruments. Mass spectra were recorded on Finni-
gan Polaris Q Ion Trap spectrometer. Column chromatography
was carried out using silica gel 60–230 mesh (Merck). Elemental
analyses were performed in the microanalysis department of the
2-methyl-2-propanesulfinamide 2c
A
solution of 1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde
(1.40 g, 10.1 mmol), (R)-2-methyl-2-propanesulfinamide (1.36 g,
11.2 mmol), and Ti(OiPr)4 (14.2 g, 15 mL, 50 mmol) in THF
(30 mL) was stirred with heating on a water bath at 50 °C for
20 h. The resulting mixture was poured into water (70 mL) with
Please cite this article in press as: Kuznetsov, N. Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.003

6
N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
stirring for 15 min, then filtered and the precipitate was washed
twice with DCM. The filtrate was diluted with water (100 mL)
and extracted with DCM (20 mL ꢁ 3). The combined extracts were
dried over K2CO3, filtered through the pad of silica gel, evaporated
under reduced pressure, and dried in vacuo that afford pure 2c
4.2.6. (R)-N-[(1R)-1-(1-Ethyl-1H-pyrazol-4-yl)-3-butenyl]-2-
methyl-2-propanesulfinamide 3a and (R)-N-[(1S)-1-(1-ethyl-
1H-pyrazol-4-yl)-3-butenyl]-2-methyl-2-propanesulfinamide
4a
To a solution of 2a (1.44 g, 6.0 mmol) in THF (12 mL) were
added In turnings (2.07 g, 18.0 mmol), allylBr (2.18 g, 1.57 mL,
18.0 mmol), an activating additive—DMF/H2O (10:1, 0.6 mL) and
the mixture was stirred for 14 h at 20 °C. The reaction mixture
was quenched with satd NH4Cl (40 mL), extracted with Et2O
(20 mL ꢁ 3), and the combined extracts were washed with brine,
dried over MgSO4, and evaporated under reduced pressure to dry-
ness. The ratio of diastereomers 4a/3a was 96:4 in the residue, and
were separated by FC on silica gel with n-hexane/EtOAc = 1:2 to af-
ford (1.38 g) 4a and (0.052 g) 3a as oils, total yield: 1.43 g (89%).
2.72 g (97%). ½a 2D5
ꢂ
= ꢀ93.7 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3):
d 8.44 (s, 1H, CH@N), 7.72 (s, 1H, CHpyr), 4.09 (q, J = 7.2 Hz, 2H, Et),
2.41 (s, 3H, Me), 1.45 (t, J = 7.2 Hz, 3H, Et), 1.17 (s, 9H, tBu). 13C
NMR (100 MHz, CDCl3): d 154.57, 149.67, 131.99, 116.92, 56.95,
47.12, 22.34 3C, 15.27, 13.40. MS (70 eV, EI): m/z (%) = 242 (10)
[MH]+, 202 (7), 185 (45), 138 (10), 137 (68), 136 (10), 111 (19),
110 (25), 109 (26), 108 (17), 83 (11). C11H19N3OS (241.3): calcd C
54.74, H 7.93, N 17.41; found C 54.60, H 7.88, N 17.49.
4.2.4. (R)-2-Methyl-N-[(1-phenyl-1H-pyrazol-4-yl)methylidene]-
2-propanesulfinamide 2d
Compound 4a, Rf max: 0.12 (n-hexane/EtOAc, 1:2). ½a D25
= ꢀ81.5
ꢂ
(c 1, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.41 (s, 1H, CHpyr), 7.32
(s, 1H, CHpyr), 5.77–5.67 (m, 1H, CH@), 5.16–5.11 (m, 2H, CH2@),
4.44 (td, J = 3.5, 7.0 Hz, 1H, CHN), 4.13 (q, J = 7.3 Hz, 2H, Et), 3.94
(d, J = 3.2 Hz, 1H, NH), 2.60–2.47 (m, 2H, CH2), 1.44 (t, J = 7.3 Hz,
3H, Et), 1.17 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3): d 137.52,
133.98, 127.33, 122.04, 119.14, 55.80, 49.71, 46.91, 42.59, 22.62
3C, 15.43. C13H23N3OS (269.4): calcd C 57.96, H 8.61, N 15.60;
found C 57.82, H 8.65, N 15.44. Compound 3a Rf min: 0.06 (n-hex-
A
solution of 1-phenyl-1H-pyrazole-4-carbaldehyde (5.0 g,
29.0 mmol), (R)-2-methyl-2-propanesulfinamide (3.51 g,
29.0 mmol) and Ti(OiPr)4 (47.7 g, 50 mL, 0.168 mol) in THF
(50 mL) was stirred with heating on a water bath at 50 °C for
20 h. The resulting mixture was poured into water (250 mL) with
stirring for 15 min, then filtered, and the precipitate was washed
twice with DCM. The filtrate was diluted with water (200 mL)
and extracted with DCM (50 mL ꢁ 3). The combined extracts were
dried over K2CO3, filtered through the pad of silica gel and evapo-
rated under reduced pressure, and crystallized from iPr2O/n-hex-
ane to afford pure 2d 6.78 g (85%). Rf: 0.5 (EtOAc/n-hexane, 1:1)
ane/EtOAc, 1:2). ½a D25
ꢂ
= ꢀ33.8 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.42 (s, 1H, CHpyr), 7.39 (s, 1H, CHpyr), 5.72–5.63 (m,
1H, CH@), 5.06–5.01 (m, 2H, CH2@), 4.39 (td, J = 6.3, 5.6 Hz, 1H,
CHN), 4.07 (q, J = 7.3 Hz, 2H, Et), 3.40 (d, J = 5.6 Hz, 1H, NH),
2.60–2.48 (m, 2H, CH2), 1.40 (t, J = 7.3 Hz, 3H, Et), 1.15 (s, 9H,
½
a 2D5
ꢂ
= ꢀ98.7 (c 1, CHCl3). Mp 67.5–68.5 °C (iPr2O/n-hexane). 1H
NMR (400 MHz, CDCl3): d 8.58 (s, 1H, CH@N), 8.34 (s, 1H, CHpyr),
8.13 (s, 1H, CHpyr), 7.72 (d, J = 7.9 Hz, 2H, Ph), 7.51–7.47 (m, 2H,
Ph), 7.38–7.34 (m, 1H, Ph), 1.26 (s, 9H, tBu) ppm. 13C NMR
(100 MHz, CDCl3): d 154.21, 141.15, 139.33, 129.63 2C, 128.62,
127.59, 121.38, 119.56 2C, 57.56, 22.51 3C ppm. MS (70 eV, EI):
m/z (%) = 276 (27) [MH]+, 220 (14), 219 (91), 218 (11), 172 (21),
171 (100), 170 (24), 145 (12), 144 (52), 77 (11). C14H17N3OS
(275.4): calcd C 61.06, H 6.22, N 15.26, S 11.64; found C 60.93, H
6.19, N 15.25, S 11.64.
tBu). 13C NMR (100 MHz, CDCl3):
d 137.18, 134.17, 127.61,
123.07, 118.20, 56.04, 51.50, 47.00, 41.02, 22.66 3C, 15.45. MS
(70 eV, EI): m/z (%) = 270 (2.5) [MH]+, 213 (25), 172 (17), 170
(12), 150 (56), 149 (100), 147 (14), 135 (10), 122 (12), 121 (17),
109 (10), 108 (10), 97 (11), 94 (37), 41 (7). C13H23N3OS (269.4):
calcd C 57.96, H 8.61, N 15.60; found C 57.79, H 8.70, N 15.66.
4.2.7. (R)-2-Methyl-N-[(1R)-1-(1-methyl-1H-pyrazol-4-yl)-3-
butenyl]-2-propanesulfinamide 3b and (R)-2-methyl-N-[(1S)-1-
(1-methyl-1H-pyrazol-4-yl)-3-butenyl]-2-propanesulfinamide
4b
The procedure was the same as that described for the synthesis
of 4a/3a mixture (2 mmol scale). After work-up and evaporation, a
residue was obtained consisting of two diastereomers 4b/
3b = 96.7:3.3, which were separated by FC on silica gel with n-hex-
ane/EtOAc, 1:2 to afford (0.47 g) 4b and (0.015 g) 3b as oils, total
yield: 0.49 g (95%). Compound 4b, Rf max: 0.34 (EtOAc).
4.2.5. (R)-2-Methyl-N-[1-(1-methyl-1H-pyrazol-4-yl)ethylidene]-
2-propanesulfinamide 2e
1-(1-Methyl-1H-pyrazol-4-yl)-1-ethanone (1.05 g, 8.46 mmol),
(R)-2-methyl-2-propanesulfinamide (0.96 g, 7.9 mmol) and
Ti(OiPr)4 (9.1 g, 9.57 mL, 32 mmol) were mixed in a high pressure
tube, sealed and irradiated in a microwave reactor at 85 °C
(50 W) for 24 h. The progress of the reaction was monitored by
1H NMR. After disappearance of the sulfinamide signals, the reac-
tion mixture was diluted with THF (30 mL) and poured into water
(70 mL). After 20 min of stirring, the suspension was filtered
through a pad of Super Cel, and the precipitate was washed two
times with DCM. The filtrate was diluted with water (100 mL)
and extracted with DCM (20 mL ꢁ 3). The combined extracts were
dried over K2CO3 and evaporated under reduced pressure. The res-
idue was recrystallized from diethyl ether to afford 2e (1.59 g, 88%)
½
a 2D5
ꢂ
= ꢀ110.2 (c 1, CHCl3) 1H NMR (400 MHz, CDCl3): d 7.36 (s,
1H, CHpyr), 7.25 (s, 1H, CHpyr), 5.71 (dddd, J = 6.4, 7.9, 10.3,
6.6 Hz, 1H, CH@), 5.15–5.11 (m, 2H, CH2@), 4.44–4.40 (m, 1H,
CHN), 3.83 (s, 3H, Me), 3.57 (d, J = 2.8 Hz, 1H, NH), 2.58–2.43 (m,
2H, CH2), 1.15 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3): d 137.87,
134.01, 128.8, 122.58, 119.30, 55.58, 49.26, 42.78, 38.97, 22.61
3C. MS (70 eV, EI): m/z (%) = 256 (8) [MH]+, 199 (32), 158 (18),
136 (71), 135 (100), 133 (22), 121 (12), 109 (21), 108 (47), 95
(17), 94 (25), 93 (12), 83 (17), 67 (9), 41 (7). C12H21N3OS (255.4):
calcd C 56.44, H 8.29, N 16.45; found C 56.39, H 8.27, N 16.30. Com-
as a beige crystalline solid. Rf: 0.26 (EtOAc). ½a D25
= ꢀ73.7 (c 1,
ꢂ
pound 3b, Rf min: 0.19 (EtOAc). ½a D25
ꢂ
= ꢀ40.6 (c 1, CHCl3). 1H NMR
CHCl3). Mp 88–89 °C (Et2O). 1H NMR (400 MHz, CDCl3): d 7.84 (s,
1H, CHpyr), 7.81 (s, 1H, CHpyr), 3.93 (s, 3H, NMe), 2.60 (s, 3H,
MeC@N), 1.27 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3): d 171.19,
139.40, 130.98, 124.47, 56.74, 39.36, 22.26 3C, 20.87. MS (70 eV,
EI): m/z (%) = 228 (12) [MH]+, 211 (2), 172 (12), 171 (100), 170
(12), 130 (51), 123 (36), 108 (72), 107 (18), 89 (12), 82 (34), 81
(10). C10H17N3OS (227.3): calcd C 52.83, H 7.54, N 18.48, S 14.11;
found C 52.80, H 7.55, N 18.35, S 13.97.
(400 MHz, CDCl3): d 7.38 (s, 1H, CHpyr), 7.36 (s, 1H, CHpyr), 5.71
(ddt, J = 17.2, 10.2, 7.0 Hz, 1H, CH@), 5.07–5.12 (m, 2H, CH2@),
4.38 (q, J = 6.3 Hz, 1H, CHN), 3.80 (s, 3H, Me), 3.34 (d, J = 5.7 Hz,
1H, NH), 2.59–2.47 (m, 2H, CH2), 1.15 (s, 9H, tBu). 13C NMR
(100 MHz, CDCl3):
d 137.42, 134.10, 129.25, 123.47, 118.26,
55.99, 51.38, 41.02, 38.96, 22.66 3C. C12H21N3OS (255.4): calcd C
56.44, H 8.29, N 16.45; found C 56.40, H 8.19, N 16.25.
Please cite this article in press as: Kuznetsov, N. Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.003

N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
7
4.2.8. (R)-N-[(1R)-1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-3-
4.2.10. (R)-2-Methyl-N-[(1S)-1-methyl-1-(1-methyl-1H-pyrazol-
butenyl]-2-methyl-2-propanesulfinamide 3c and (R)-N-[(1S)-1-
(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-butenyl]-2-methyl-2-
propanesulfinamide 4c
4-yl)-3-butenyl]-2-propanesulfinamide 4e
To Zn (0.53 g, 8.2 mmol) dust activated by stirring for 10 min
with two drops of TMSCl in THF (20 mL) allylBr (0.99 g, 0.71 mL,
8.2 mmol) and Zn(OTf)2 (0.98 g, 2.7 mmol) were added at 0 °C.
The mixture was then stirred at this temperature for a minute fol-
lowed by the dropwise addition of 2e (0.62 g, 2.7 mmol) in THF
(4 mL) for 5 min. The reaction mixture was stirred additionally
for 30 min (TLC control) and quenched with a satd NH4Cl solution.
The reaction mixture was diluted with ether, and the organic layer
was separated, washed with brine, dried over MgSO4, filtered, and
evaporated under reduced pressure to give pure 4e (0.72 g, 98%).
According to crude 1H NMR, only a single diastereomer was de-
tected. An analytical sample was obtained by passing crude 4e
through a short pad of silica gel in EtOAc/n-hexane = 2:1. The ratio
of 4e/3e isomers was determined by chiral HPLC to be 99.7:0.3;
retention times: major peak—2.53 min; minor peak—2.06 min. Col-
umn Diacel Chiralpak IB-3, eluent n-C6H14/iPrOH = 4:1, rate 1 mL/
min, UV 254 nm. Compound 4e, Rf min: 0.09 (EtOAc/n-hexane,
To a solution of 2c (2.30 g, 9.54 mmol) in DMF (30 mL) were
added In turnings (3.28 g, 28.6 mmol) and allylBr (4.60 g,
3.30 mL, 38.0 mmol) and the mixture was stirred for 6 h at 0 °C.
The reaction mixture was quenched with sat. NH4Cl (20 mL), fil-
tered through a pad of Super Cel and the filtrate was extracted with
Et2O (20 mL ꢁ 3). The combined extracts were washed with brine,
dried over MgSO4, and evaporated under reduced pressure to dry-
ness. The residue consisted of two diastereomers 4c/3c = 97.5:2.5,
which were separated by FC on silica gel with n-hexane/EtOAc,
1:2 to afford 2c (0.2 g), 4c (2.32 g), and 3c (0.059 g) as oils, total
yield: 2.38 g (88%). Compound 4c Rf max: 0.09 (n-hexane/EtOAc,
1:2). ½a 2D5
ꢂ
= ꢀ107.7 (c 1, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.21
(s, 1H, CHpyr), 5.79–5.65 (m, 1H, CH@), 5.17–5.11 (m, 2H, CH2@),
4.39–4.34 (m, 1H, CHN), 4.04 (q, J = 7.3 Hz, 2H, Et), 3.54 (d,
J = 1.9 Hz, 1H, NH), 2.60–2.44 (m, 2H, CH2), 2.23 (s, 3H, Me), 1.42
(t, J = 7.3 Hz, 3H, Et), 1.16 (s, 9H, tBu). 13C NMR (75 MHz, CDCl3):
d 146.31, 134.43, 127.86, 118.89, 118.75, 55.38, 49.12, 46.68,
41.99, 22.62 3C, 15.53, 12.44. MS (70 eV, EI): m/z (%) = 284 (33)
[MH]+, 227 (6), 226 (6), 186 (11), 164 (25), 163 (100), 161 (10),
149 (15), 135 (16), 133 (9), 111 (16), 108 (12), 94 (9). C14H25N3OS
(283.4): calcd C 59.33, H 8.89, N 14.83; found C 59.42, H 8.90, N
14.76. Compound 3c Rf min: 0.04 (n-hexane/EtOAc, 1:2).
2:1). ½a 2D5
ꢂ
= ꢀ75.5 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.40
(s, 1H, CHpyr), 7.32 (s, 1H, CHpyr), 5.79–5.68 (m, 1H, CH@), 5.18–
5.15 (m, 2H, CH2@), 3.89 (s, 3H, NMe), 3.56 (s, 1H, NH), 2.63 (dd,
J = 6.6, 13.5 Hz, 1H, CHAHB), 2.56 (dd, J = 8.0, 13.5 Hz, 1H, CHAHB),
1.67 (s, 3H, Me), 1.20 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3): d
137.49, 133.24, 128.32, 127.49, 119.89, 55.93, 55.42, 49.15, 39.03,
28.32, 22.73 3C. MS (70 eV, EI): m/z (%) = 270 (10) [MH]+, 228 (4),
172 (18), 150 (37), 149 (100), 147 (8), 135 (12), 108 (24), 95
(24), 83 (6). C13H23N3OS (269.4): calcd C 57.96, H 8.61, N 15.60, S
11.90, found C 57.78, H 8.65, N 15.55, S 11.79.
½
a 2D5
ꢂ
= ꢀ63.5 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.30 (s,
1H, CHpyr), 5.74–5.64 (m, 1H, CH@), 5.12–5.06 (m, 2H, CH2@),
4.39 (ddd, J = 3.3, 6.4, 7.0 Hz, 1H, CHN), 4.07 (q, J = 7.2 Hz, 2H, Et),
3.37 (d, J = 2.6 Hz, 1H, NH), 2.66 (dt, J = 6.8, 13.8 Hz, 1H, CHAHB)
2.53 (dt, J = 7.0, 13.8 Hz, 1H, CHAHB), 2.25 (s, 3H, Me), 1.45 (t,
J = 7.2 Hz, 3H, Et), 1.20 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3): d
146.08, 134.23, 127.69, 119.34, 118.26, 55.69, 50.28, 46.76, 40.73,
22.62 3C, 15.55, 12.30. C14H25N3OS (283.4): calcd C 59.33, H 8.89,
N 14.83; found C 59.26, H 8.84, N 14.79.
4.2.11. General procedure for the transformation of sulfinamides
to N-Boc derivatives
Sulfinamide (6 mmol) was dissolved in MeOH (10 mL) after
which HCl 4 M solution in dioxane (6 mL, 24 mmol) was added
and the mixture was left for 2 h. The solution was then evaporated
under reduced pressure to dryness. To the solid residue were
added THF (15 mL) and Et3N (3.0 g, 4.2 mL, 30 mmol), after which
the suspension was stirred at reflux for 10 min; next Boc2O (2.18 g,
10 mmol) was added and the heating was continued for 2 h. The
suspension was concentrated on a rotary evaporator, then diluted
with n-hexane (15 mL) and water (10 mL). The organic layer was
separated, dried over K2CO3, evaporated, and the residual oil
was subjected to FC in n-hexane/EtOAc, 4:1 to remove the excess
Boc2O, then in n-hexane/EtOAc, 2:1 to afford the N-Boc derivative.
4.2.9. (R)-2-Methyl-N-[(1R)-1-(1-phenyl-1H-pyrazol-4-yl)-3-
butenyl]-2-propanesulfinamide 3d and (R)-2-methyl-N-[(1S)-1-
(1-phenyl-1H-pyrazol-4-yl)-3-butenyl]-2-propanesulfinamide
4d
The procedure was the same as that used for the preparation of
3c/4c. Isomers 3d/4d were separated by FC on silica gel with
n-hexane/EtOAc/iPrOH, 10:10:0.15 to afford 3d (0.12 g) as an oil
and 4d (1.81 g) as a solid, total yield: 1.93 g (90%). Compound 4d
Rf min: 0.33 (n-hexane/EtOAc/iPrOH, 10:10:0.15). Mp 84–85 °C
(Et2O/n-hexane), ½a D25
ꢂ
= ꢀ100.9 (c 1, CHCl3). 1H NMR (400 MHz,
4.2.12. (S)-tert-Butyl N-[1-(1-ethyl-1H-pyrazol-4-yl)-3-butenyl]
CDCl3): d 7.89 (s, 1H, CHpyr), 7.69 (s, 1H, CHpyr), 7.67–7.66 (narr.m,
2H, Ph), 7.48–7.44 (m, 2H, Ph), 7.29–7.28 (m, 1H, Ph), 5.86–5.75
(m, 1H, CH@), 5.25–5.21 (m, 2H, CH2@), 4.60–4.56 (m, 1H, CHN),
3.68 (d, J = 2.2 Hz, NH), 2.71–2.56 (m, 2H, CH2), 1.23 (s, 9H, tBu).
13C NMR (100 MHz, CDCl3): d 139.97, 139.77, 133.79, 129.44 2C,
126.46, 125.43, 124.59, 119.62, 118.89 2C, 55.70, 49.28, 42.66,
22.63 3C. MS (70 eV, EI): m/z (%) = 318 (14) [MH]+, 261 (27), 260
(8), 220 (8), 199 (8), 198 (53), 197 (100), 195 (8), 182 (9), 171
(11), 170 (14), 145 (15), 77 (12). C17H23N3OS (317.4): calcd C
64.32, H 7.30, N 13.24, S 10.10, found C 64.18, H 7.25, N 13.26, S
10.11. Compound 3d Rf va[: 0.43 (n-hexane/EtOAc/iPrOH,
carbamate 5a
Yield: 91%. Rf: 0.43 (EtOAc). ½a D25
ꢂ
= ꢀ40.8 (c 1, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.39 (s, 1H, CHpyr), 7.29 (s, 1H, CHpyr), 5.75
(ddt, J = 7.0, 9.9, 14.0 Hz, 1H, CH@), 5.13–5.06 (m, 2H, CH2@),
4.75 (br m, 2H, NH and CHN), 4.11 (q, J = 7.3 Hz, 2H, Et), 2.57–
2.46 (br m, 2H, CH2), 1.45 (t, J = 7.3 Hz, 3H, Et), 1.43 (s, 9H, tBu).
13C NMR (100 MHz, CDCl3): d 155.26, 136.93, 134.13, 126.33,
123.09, 118.08, 79.35, 46.95, 45.97, 40.35, 28.38 3C, 15.49. MS
(70 eV, EI): m/z (%) = 266 (3) [MH]+, 168 (100), 150 (12), 149
(12), 124 (57), 122 (13), 97 (25), 96 (33), 69 (14), 41 (7).
C14H23N3O2 (265.4): calcd C 63.37, H 8.74, N 15.84, found C
10:10:0.15). ½a D25
ꢂ
= ꢀ30.2 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3):
63.41, H 8.69, N 15.75.
d 8.03 (s, 1H, CHpyr), 7.67 (s, 2H, Ph), 7.65 (s, 1H, CHpyr), 7.43–
7.39 (m, 2H, Ph), 7.27–7.23 (m, 1H, Ph), 5.82–5.72 (m, 1H, CH@),
5.15–5.10 (m, 2H, CH2@), 4.53 (dd, J = 6.4, 12.6 Hz, 1H, CHN),
3.49 (d, J = 5.9 Hz, 1H, NH), 2.71–2.59 (m, 2H, CH2), 1.22 (s, 9H,
4.2.13. (S)-tert-Butyl N-[1-(1-methyl-1H-pyrazol-4-yl)-3-butenyl]
carbamate 5b
Yield: 88%. Rf: 0.38 (EtOAc). ½a D25
= ꢀ41.2 (c 1, CHCl3). Mp 62–
ꢂ
tBu). 13C NMR (100 MHz, CDCl3):
d
139.94, 139.40, 133.90,
63 °C (n-hexane). 1H NMR (400 MHz, CDCl3): d 7.34 (s, 1H, CHpyr),
7.22 (s, 1H, CHpyr), 5.71 (ddt, J = 7.0, 10.2, 17.2 Hz, 1H, CH@),
5.12–5.06 (m, 2H, CH2@), 4.77–4.07 (br m, 2H, NH and CHN),
3.80 (s, 3H, NMe), 2.54–2.41 (m, 2H, CH2), 1.39 (s, 9H, tBu). 13C
129.38 2C, 126.48, 126.04, 125.38, 119.03 2C, 118.59, 56.15,
51.46, 40.95, 22.69 3C. C17H23N3OS (317.4): calcd C 64.32, H 7.30,
N 13.24, S 10.10, found C 64.25, H 7.33, N 13.25, S 10.09.
Please cite this article in press as: Kuznetsov, N. Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.003

8
N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
NMR (100 MHz, CDCl3): d 155.22, 137.15, 134.08, 128.01, 123.49,
118.11, 79.35, 45.91, 40.34, 38.89, 28.37 3C. MS (70 eV, EI): m/z
(%) = 252 (2) [MH]+, 210 (4), 155 (7), 154 (100), 136 (12), 135
(11), 110 (49), 108 (14), 83 (42), 41 (7). C13H21N3O2 (251.32): calcd
C 62.13, H 8.42, N 16.72, found C 62.20, H 8.41, N 16.69.
4.2.18. (4S,6R)-6-(Bromomethyl)-4-(1-ethyl-1H-pyrazol-4-yl)-
1,3-oxazinan-2-one 6a
Yield: 85% as a mixture cis/trans = 1.4:1, cis-6a. Mp 166–167 °C
(EtOAc), ½a 2D5
ꢂ
= +1.6 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.43
(s, 1H, CHpyr), 7.42 (s, 1H, CHpyr), 6.01 (s, 1H, NH), 4.63 (dd, J = 4.3,
11.6 Hz, 1H, CHNH), 4.52 (dddd, J = 2.2, 4.4, 6.8, 11.4 Hz, 1H, CHO),
4.13 (q, J = 7.3 Hz, 2H, Et), 3.56 (dd, J = 4.4, 10.7 Hz, 1H, CHaHbBr),
3.45 (dd, J = 6.7, 10.7 Hz, 1H, CHaHbBr), 2.42 (dddt, J = 1.7, 3.8,
13.7 Hz, 1H, CHaHbCHN), 1.86 (dt, J = 11.6, 13.7 Hz, 1H, CHaHbCHN),
1.45 (t, J = 7.3 Hz, 3H, Et) ppm. 13C NMR (100 MHz, CDCl3):
d = 152.97, 136.73, 126.27, 121.08, 75.66, 47.29, 46.58, 34.47,
32.60, 15.47 ppm. MS (70 eV, EI): m/z (%) = 288/286 (2) [MꢀH]+,
209 (10), 208 (100), 164 (65), 162 (15), 137 (28), 122 (15), 108
(17), 107 (40), 95 (20), 83 (12), 41 (10). C10H14BrN3O2 (288.14):
calcd C 41.68, H 4.90, N 14.58, Br 27.73, found C 41.52, H 4.75, N
14.45, Br 27.93.
4.2.14. (S)-tert-Butyl N-[1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-
3-butenyl]carbamate 5c
Yield: 90%. Rf: 0.49 (EtOAc). ½a D25
= ꢀ39.1 (c 1, CHCl3). Mp 68–
ꢂ
69 °C (n-hexane). 1H NMR (400 MHz, CDCl3): d 7.18 (s, 1H, CHpyr),
5.78–5.68 (m, 1H, CH@), 5.11–5.04 (m, 2H, CH2@), 4.64 (br m,
2H, NH and CHN), 4.03 (q, J = 7.3 Hz, 2H, Et), 2.49 (br m, 2H,
CH2), 2.22 (s, 3H, Me), 1.43–1.39 (m, 12H, Et and tBu). 13C NMR
(100 MHz, CDCl3):
d 155.08, 146.00, 134.39, 126.56, 120.03,
117.75, 79.27 br, 46.64, 45.77 br, 40.21, 28.36 3C, 15.61, 12.13.
MS (70 eV, EI): m/z (%) = 280 (5) [MH]+, 183 (10), 182 (100), 164
(9), 163 (13), 138 (40), 136 (9), 111 (47), C15H25N3O2 (279.4): calcd
C 64.49, H 9.02, N 15.04, found C 64.45, H 9.06, N 14.96.
4.2.19. (4S,6R)-6-(Bromomethyl)-4-(1-methyl-1H-pyrazol-4-yl)-
1,3-oxazinan-2-one 6b
4.2.15. (S)-tert-Butyl N-[1-(1-phenyl-1H-pyrazol-4-yl)-3-butenyl]
carbamate 5d
Yield: 83% as a mixture cis/trans = 1.4:1, cis-6b. Mp 185–186 °C
(EtOAc), ½a 2D5
ꢂ
= +0.5 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.45
The product was precipitated from n-hexane extracts during
isolation and after recrystallization from n-heptane, the yield was
(s, 1H, CHpyr), 7.42 (s, 1H, CHpyr), 6.26 (s, 1H, NH), 4.65 (dd, J = 4.4,
11.8 Hz, 1H, CHNH), 4.57–4.52 (m, 1H, CHO), 3.89 (s, 3H, Me), 3.59
(dd, J = 4.4, 10.5 Hz, 1H, CHaHbBr), 3.47 (dd, J = 6.7, 10.5 Hz, 1H,
CHaHbBr), 2.42 (dm, J = 11.4 Hz, 1H, CHaHbCHN), 1.88 (dt, J = 11.4,
13.4 Hz, 1H, CHaHbCHN). 13C NMR (100 MHz, CDCl3): d 153.08,
136.90, 127.98, 121.43, 75.65, 46.46, 39.20, 34.42, 32.61. MS
(70 eV, EI): m/z (%) = 274/272 (4) [MꢀH]+, 195 (12), 194 (100),
150 (61), 148 (11), 123 (25), 109 (21), 108 (50), 107 (12), 95
(19), 83 (13), 41 (10). C9H12BrN3O2 (274.1): calcd C 39.43, H 4.41,
N 15.33, Br 29.15, found C 39.46, H 4.50, N 15.28, Br 28.97.
86%. Rf: 0.62 (EtOAc/n-hexane, 1:2). ½a D25
= ꢀ53.7 (c 1, CHCl3). Mp
ꢂ
107–108 °C (n-heptane). 1H NMR (400 MHz, CDCl3): d 7.84 (s, 1H,
CHpyr), 7.67 (s, 1H, CHpyr), 7.64 (s, 2H, Ph), 7.46–7.42 (m, 2H, Ph),
7.30–7.26 (m, 1H, Ph), 5.85–5.75 (m, 1H, CH@), 5.19–5.12 (m, 2H,
CH2@), 4.84 (br s, 2H, NH and CHN), 2.65–2.53 (br m, 2H, CH2),
1.46 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3): d 155.26, 140.05,
139.22, 133.83, 129.42 2C, 126.43, 125.42 br, 124.69 br, 118.97
2C, 118.49, 79.63 br, 45.95 br, 40.26 br, 28.41 3C. MS (70 eV, EI):
m/z (%) = 314 (14) [MH]+, 272 (8), 217 (12), 216 (97), 198 (15),
197 (16), 173 (12), 172 (100), 145 (35), 118 (8), 77 (10), 41 (9).
4.2.20. (4S,6R)-6-(Bromomethyl)-4-(1-ethyl-3-methyl-1H-pyrazol-
4-yl)-1,3-oxazinan-2-one 6c
C18H23N3O2 (313.4): calcd C 68.98, H 7.40, N 13.41, found C
69.04, H 7.50, N 13.41.
Yield: 78% as a mixture cis/trans = 1.4:1. Major isomer 1H NMR
(400 MHz, CDCl3): d 7.33 (s, 1H, CHpyr), 6.04 (s, 1H, NH), 4.59–4.51
(m, 2H, CHNH and CHO), 4.05 (q, J = 7.3 Hz, 2H, Et), 3.56 (dd, J = 4.4,
10.8 Hz, 1H, CHaHbBr), 3.46 (dd, J = 6.5, 10.8 Hz, 1H, CHaHbBr), 2.35
(d, J = 13.7 Hz, 1H, CHaHbCHN), 2.21 (s, 3H, Me), 1.83 (dt, J = 11.7,
13.7 Hz, 1H, CHaHbCHN), 1.43 (t, J = 7.3 Hz, 3H, Et). 13C NMR
(100 MHz, CDCl3): d 153.21, 145.32, 126.83, 118.11, 75.66, 46.91,
46.43, 33.87, 32.78, 15.50, 12.03. MS (70 eV, EI): m/z (%) = 303/
301 (1) [M]+, 302/300 (2) [MꢀH]+, 223 (14), 222 (100), 179 (13),
178 (38), 161 (28), 151 (19), 137 (15), 136 (18), 135 (12), 123
(10), 111 (27), 109 (23), 108 (25). C11H16BrN3O2 (302.2): calcd C
43.72, H 5.34, N 13.91, Br 26.44, found C 43.86, H 5.40, N 13.83,
Br 26.30.
4.2.16. (S)-tert-Butyl N-[1-methyl-1-(1-methyl-1H-pyrazol-4-yl)-
3-butenyl]carbamate 5e
Yield: 85%. Rf: 0.56 (EtOAc/n-hexane, 1:2). ½a D25
= ꢀ21.3 (c 1,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3): d 7.34 (s, 1H, CHpyr), 7.23 (s,
1H, CHpyr), 5.72–5.61 (m, 1H, CH@), 5.11–5.07 (m, 2H, CH2@),
4.81 (br s, 1H, NH), 3.82 (s, 3H, NMe), 2.75–2.70 (br m, 1H, CHAHB,
allyl), 2.53 (dd, J = 7.4, 13.5 Hz, 1H, CHAHB, allyl), 1.56 (s, 3H, Me),
1.37 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3): d 154.21 br, 136.61,
133.53, 128.43 br, 127.36, 118.93, 79.01 br, 52.24, 45.89 br,
38.91, 28.34 3C, 26.92 br. MS (70 eV, EI): m/z (%) = 266 (14)
[MH]+, 224 (8), 169 (9), 168 (100), 150 (16), 149 (25), 124 (67),
108 (9), 83 (39), 42 (12), 41 (9). C14H23N3O2 (265.4): calcd C
63.37, H 8.74, N 15.84, found C 63.30, H 8.81, N 15.82.
4.2.21. (4S,6R)-6-(Bromomethyl)-4-(1-phenyl-1H-pyrazol-4-yl)-
1,3-oxazinan-2-one 6d
Yield: 78% as a mixture cis/trans = 2.5:1; cis-6d. Mp 103–104 °C
(CCl4), ½a 2D5
ꢂ
= +5.6 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.96 (s,
4.2.17. General procedure of the bromocyclocarbamation
reaction
1H, CHpyr), 7.64–7.62 (m, 3H, CHpyr, Ph), 7.44–7.40 (m, 2H, Ph),
7.29–7.25 (m, 1H, Ph), 6.63 (s, 1H, NH), 4.69 (dd, J = 4.3, 11.6 Hz,
1H, CHNH), 4.55–4.50 (m, 1H, CHO), 3.54 (dd, J = 4.4, 10.7 Hz, 1H,
CHaHbBr), 3.46 (dd, J = 6.6, 10.8 Hz, 1H, CHaHbBr), 2.44 (dm,
J = 13.7 Hz, 1H, CHaHbCHN), 1.83 (dt, J = 11.6, 13.7 Hz, 1H, CHaHb-
CHN). 13C NMR (100 MHz, CDCl3): d 153.29, 139.77, 138.66,
129.53 2C, 126.89, 124.90, 123.30, 119.16 2C, 75.60, 46.45, 34.26,
32.61. MS (70 eV, EI): m/z (%) = 335/337 (16) [M]+, 257 (17), 256
(100), 212 (37), 198 (11), 197 (14), 185 (16), 171 (18), 170 (31),
169 (20), 145 (22), 144 (24), 143 (10), 117 (8), 104 (11), 77 (18),
41 (8). C14H14BrN3O2 (336.18): calcd C 50.02, H 4.20, N 12.50, Br
23.77, found C 50.10, H 4.23, N 12.42, Br 23.68.
To a solution of N-Boc derivative (2 mmol) in DCM was added
TFA (1 equiv) dropwise, followed by the addition of NBS
(1.4 equiv). The mixture was stirred for 2 h, the progress of the
reaction was monitored by TLC. The solvent was evaporated under
reduced pressure, after which the residue was treated with an
Et2O/EtOAc (2:1) mixture (15 mL) and NaOH 10% (5 mL) with rig-
orous stirring for 15 min. The organic layer was separated, dried
over MgSO4, evaporated, and the residue was subjected to FC in
EtOAc to give a mixture of diastereomeric bromides. Where indi-
cated, the bromides were obtained as single isomers by recrystal-
lization from EtOAc.
Please cite this article in press as: Kuznetsov, N. Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.003

N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
9
4.2.22. (4S,6S)-6-(Bromomethyl)-4-methyl-4-(1-methyl-1H-
pyrazol-4-yl)-1,3-oxazinan-2-one 6e
2.84 (dd, J = 4.1, 16.5 Hz, 1H, CHaHbCH), 2.71 (dd, J = 8.9, 16.5 Hz,
1H, CHaHbCH), 2.25 (s, 3H, Me), 1.44 (t, J = 7.3 Hz, 3H, Et). 13C
NMR (100 MHz, CDCl3): d 202.79, 168.91, 145.54, 126.62, 117.42,
47.28, 46.99, 45.65, 44.49, 15.49, 12.09. MS (70 eV, EI): m/z
(%) = 221 (35) [M]+, 179 (58), 178 (21), 177 (24), 164 (100), 163
(20), 137 (44), 136 (76), 109 (50), 108 (46), 81 (16), 32 (44), 28
(83). C11H15N3O2 (221.2): calcd C 59.71, H 6.83, N 18.99, found C
59.73, H 6.80, N 19.06.
Yield: 92% as a mixture trans/cis = 3.4:1, Rf: 0.18 (EtOAc), trans-
6e. Mp 125–126 °C (EtOAc), ½a D25
ꢂ
= +17.5 (c 1, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.33 (s, 2H, 2CHpyr), 7.22 (s, 1H, NH), 4.33–
4.30 (m, 1H, CHO), 3.88 (s, 3H, NMe), 3.50 (dd, J = 10.8, 4.5 Hz,
1H, CHAHBBr), 3.45 (dd, J = 10.8, 6.1 Hz, 1H, CHAHBBr), 2.28 (d,
J = 13.4 Hz, 1H, CHAHB), 1.96 (dd, J = 12.0, 13.4 Hz, 1H, CHAHB),
1.61 (s, 3H, Me). 13C NMR (100 MHz, CDCl3): d 153.62, 135.66 br,
128.52 br, 127.82 br, 73.44, 51.79, 40.07, 39.15, 32.86, 31.60. MS
(70 eV, EI): m/z (%) = 290/288 (6) [MH]+, 274/272 (100), 230/228
(27), 208 (6), 165 (5), 164 (7), 149 (14), 148 (92), 123 (15), 122
(14), 121 (12), 108 (39), 107 (58), 95 (12), 83 (11), 42 (10). C10H14-
BrN3O2 (288.14): calcd C 41.68, H 4.90, N 14.58, Br 27.73, found C
41.60, H 4.83, N 14.62, Br 27.62.
4.2.27. (S)-6-(1-Phenyl-1H-pyrazol-4-yl)-piperidine-2,4-dione 7d
Yield: 88% as a solid, Rf: 0.27 (EtOAc/isoPrOH, 60:1). Mp 149–
150 °C (EtOAc), ½a D25
ꢂ
= ꢀ27.4 (c 0.5, CHCl3). 1H NMR (400 MHz,
CDCl3):
d 7.94 (s, 1H, CHpyr), 7.69 (s, 1H, CHpyr), 7.66 (d,
J = 8.0 Hz, 2H, Ph), 7.48–7.44 (m, 2H, Ph), 7.40 (s, 1H, NH), 7.34–
7.31 (m, 1H, Ph), 4.95–4.94 (m, 1H, CHN), 3.37 (d, J = 20.0 Hz, 1H,
CHAHBCON), 3.32 (d, J = 20.0 Hz, 1H, CHAHBCON), 2.96 (dd, J = 4.5,
16.4 Hz, 1H, CHAHB), 2.84 (d, J = 7.9, 16.4 Hz, 1H, CHAHB). 13C
NMR (100 MHz, CDCl3): d 202.26, 169.09, 139.65, 138.66, 129.58
2C, 127.10, 124.74, 122.77, 119.21 2C, 47.37, 45.92, 44.67. MS
(70 eV, EI): m/z (%) = 256 (20) [MH]+, 255 (100) [M]+, 213 (73),
212 (29), 199 (10), 198 (78), 185 (18), 184 (13), 172 (30), 171
(39), 170 (52), 169 (19), 145 (28), 144 (51), 143 (12), 118 (11),
117 (11), 116 (10), 115 (11), 77 (24), 51 (11). C14H13N3O2
(255.27): calcd C 65.87, H, 5.13, N, 16.46, found: C 65.75, H, 5.23,
N, 16.29.
4.2.23. General procedure for the tBuOK-mediated rearrangement
to 6-pyrazolyl-piperidine-2,4-diones
To a solution of a mixture of the isomeric bromides was added
tBuOK (2.5 equiv). The mixture was then stirred for 1 h at ambient
temperature. The progress of the reaction was monitored by TLC
(EtOAc/MeOH, 9:1). After completion (30–40 min), the reaction
mixture was cooled to ꢀ10 °C and quenched with AcOH (3.0 equiv)
in THF. Water was then added to precipitate the salts and the sus-
pension was filtered through a pad of Super Cel. The filtrate was
evaporated under reduced pressure at 40 °C and the residue was
subjected to FC on silica gel first in EtOAc in order to remove the
excess AcOH then in EtOAc/MeOH, 9:1 for product elution to finally
afford the target dione.
4.2.28. (S)-6-Methyl-6-(1-methyl-1H-pyrazol-4-yl)-piperidine-
2,4-dione 7e
Yield: 95% as an oil, Rf: 0.32 (EtOAc/MeOH, 9:1). ½a D25
ꢂ
= +49.0 (c
0.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.84 (s, 1H, NH), 7.36 (s,
1H, CHpyr), 7.25 (s, 1H, CHpyr), 3.85 (s, 3H, NMe), 3.22 (d,
J = 20.7 Hz, 1H, CHAHBCON), 3.13 (d, J = 20.8 Hz, 1H, CHAHBCON),
2.97 (d, J = 15.7 Hz, 1H, CHAHB), 2.75 (d, J = 15.7 Hz, 1H, CHAHB),
1.64 (s, 3H, Me). 13C NMR (100 MHz, CDCl3): d 202.70, 169.46,
136.09, 127.04, 126.89, 52.72, 51.24, 45.74, 39.16, 31.22. MS
(70 eV, EI): m/z (%) = 208 (1.5) [MH]+, 193 (11), 192 (100), 179
(7), 164 (7), 150 (20), 124 (20), 108 (26), 107 (44), 83 (8), 42 (6).
4.2.24. (S)-6-(1-Ethyl-1H-pyrazol-4-yl)-piperidine-2,4-dione 7a
Yield: 92% as an oil, Rf: 0.28 (EtOAc/MeOH, 9:1), ½a D25
= ꢀ28.0 (c
ꢂ
0.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.41 (s, 1H, CHpyr), 7.40
(br s, 1H, NH), 7.37 (s, 1H, CHpyr), 4.84–4.80 (m, 1H, CHNH), 4.11
(q, J = 7.4 Hz, 2H, Et), 3.29 (d, J = 19.9 Hz, 1H, CHaHbCON), 3.21 (d,
J = 19.9 Hz, 1H, CHaHbCON), 2.85 (dd, J = 4.5, 16.3 Hz, 1H,
CHaHbCH), 2.73 (dd, J = 8.0, 16.3 Hz, 1H, CHaHbCH), 1.43 (t,
J = 7.2 Hz, 3H, Et). 13C NMR (100 MHz, CDCl3): d 202.71, 169.21,
136.75, 126.28, 120.54, 47.29, 47.25, 45.93, 44.62, 15.43. MS
(70 eV, EI): m/z (%) = 207 (50) [M]+, 165 (80), 164 (30), 150 (100),
137 (30), 136 (36), 124 (21), 123 (20), 122 (80), 121 (26), 97
(17), 96 (32), 95 (57), 94 (97), 93 (20), 81 (17), 80 (10), 69 (23),
68 (17), 67 (12). C10H13N3O2 (207.2): calcd C 57.96, H 6.32, N
20.28, found C 57.90, H 6.44, N 20.17.
C10H13N3O2 (207.23): calcd C 57.96, H 6.32, N 20.28, found: C
57.74, H 6.40, N 20.17.
4.2.29. X-ray structure determination
The crystal of (S,R)-6b (C9H12N3O2Br, M = 274.13) was ortho-
rhombic, space group P212121, at T = 100 K: a = 7.0532(2) Å,
b = 8.1579(3) Å,
dcalcd = 1.684 g/cm3, F(000) = 552,
reflections (3131 unique reflections, Rint = 0.032) were measured
on a three-circle Bruker APEX-II CCD diffractometer (k (MoK )-
radiation, graphite monochromator, and scan mode,
c = 18.7940(6) Å,
V = 1081.39(6) Å3,
= 3.786 mm–1
Z = 4,
. 14278 total
l
4.2.25. (S)-6-(1-Methyl-1H-pyrazol-4-yl)-piperidine-2,4-dione 7b
Yield: 96% as a solid, Rf: 0.24 (EtOAc/MeOH, 9:1). Mp 154–
a
155 °C (EtOAc), ½a D25
ꢂ
= ꢀ54.4 (c 0.5, CHCl3). 1H NMR (400 MHz,
u
x
CDCl3): d 7.60 (s, 1H, NH), 7.41 (s, 1H, CHpyr), 7.36 (s, 1H, CHpyr),
4.85–4.82 (m, 1H, CHNH), 3.87 (s, 3H, Me), 3.29 (d, J = 20.0 Hz,
1H, CHaHbCON), 3.21 (d, J = 20.0 Hz, 1H, CHaHbCON), 2.86 (dd,
J = 4.4, 16.5 Hz, 1H, CHaHbCH), 2.74 (dd, J = 7.6, 16.5 Hz, 1H, CHaHb-
CH). 13C NMR (100 MHz, CDCl3): d 202.73, 169.28, 136.93, 127.69,
120.99, 47.25, 45.89, 44.52, 39.17. MS (70 eV, EI): m/z (%) = 193
(30) [M]+, 151 (85), 150 (40), 136 (100), 123 (30), 122 (38), 108
(80), 107 (35), 82 (20), 81 (63), 80 (90), 64 (22), 57 (15).
C9H11N3O2 (193.2): calcd C 55.95, H 5.74, N 21.75, found C 56.03,
H 5.77, N 21.67.
2hmax = 60°) and corrected for absorption (Tmin = 0.451,
Tmax = 0.601).10a The structure was determined by direct methods
and refined by full-matrix least squares technique on F2 with
anisotropic displacement parameters for non-hydrogen atoms.
The absolute structure was objectively determined by the refine-
ment of the Flack parameter, which has become equal to
0.015(8). The hydrogen atom of the NH-group was localized in
the difference-Fourier map and included in the refinement
with fixed positional and isotropic displacement parameters
[Uiso(H) = 1.2Ueq(N)]. The other hydrogen atoms were placed in
calculated positions and refined within riding model with fixed
isotropic displacement parameters [Uiso(H) = 1.2Ueq(C)]. The final
divergence factors were R1 = 0.026 for 2890 independent reflec-
4.2.26. (S)-6-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-piperidine-2,4-
dione 7c
Yield: 90% as a solid, Rf: 0.14 (EtOAc/MeOH, 9:1). Mp 130–
tions with I > 2r (I) and wR2 = 0.062 for all independent reflections,
131 °C (EtOAc) ½a D25
ꢂ
= ꢀ70.4 (c 0.5, CHCl3). 1H NMR (400 MHz,
S = 1.004. All calculations were carried out using the SHELXTL
CDCl3): d 7.29 (s, 1H, CHpyr), 6.97 (s, 1H, NH), 4.11 (ddd, J = 1.9,
4.1, 8.9 Hz, 1H, CHNH), 4.07 (q, J = 7.3 Hz, 2H, Et), 3.36 (d,
J = 19.7 Hz, 1H, CHaHbCON), 3.28 (d, J = 20.0 Hz, 1H, CHaHbCON),
program.10b
The crystal of (S,S)-6e (C10H14N3O2Br, M = 288.15) was mono-
clinic, space group P21, at T = 120 K: a = 8.2769(8) Å,
Please cite this article in press as: Kuznetsov, N. Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.003

10
N. Yu. Kuznetsov et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
In Pelletier, S. W., Ed.; Wiley: New York, 1983; Vol. 1, pp 33–84.
2. (a) Vanotti, E.; Amici, R.; Bargiotti, A.; Berthelsen, J.; Bosotti, R.; Ciavolella, A.;
Cirla, A.; Cristiani, C.; D’Alessio, R.; Forte, B.; Isacchi, A.; Martina, K.;
Menichincheri, M.; Molinari, A.; Montagnoli, A.; Orsini, P.; Pillan, A.; Roletto,
F.; Scolaro, A.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi, D.; Santocanale, C. J.
Med. Chem. 2008, 51, 487–501; (b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989; (c) Desmaele, D.;
Mekouar, K.; d’Angelo, J. J. Org. Chem. 1997, 62, 3890–3901; (d) Beard, R. L.;
Meyers, A. I. J. Org. Chem. 1991, 56, 2091–2096; (e) Xie, Y.; Raffo, A.; Ichise, M.;
Deng, S.; Harris, P. E.; Landry, D. W. Bioorg. Med. Chem. Lett. 2008, 18, 5111–
5114; (f) Menichincheri, M.; Bargiotti, A.; Berthelsen, J.; Bertrand, J. A.; Bossi,
R.; Clavolella, A.; Cirla, A.; Cristiani, C.; Croci, V.; D’Alessio, R.; Fasolini, M.;
Fiorentini, F.; Forte, B.; Isacchi, A.; Martina, K.; Molinari, A.; Montagnoli, A.;
Orsini, P.; Orzi, F.; Pesenti, E.; Pezzetta, D.; Pillan, A.; Poggesi, I.; Roletto, F.;
Scolaro, A.; Tato, M.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi, D.;
Santocanale, C.; Vanotti, E. J. Med. Chem. 2009, 52, 293–307; (g) Erichsen, M.
N.; Huynh, T. H. V.; Abrahamsen, B.; Bastlund, J. F.; Bundgaard, C.; Monrad, O.;
Bekker-Jensen, A.; Nielsen, C. W.; Frydenvang, K.; Jensen, A. A.; Bunch, L. J. Med.
Chem. 2010, 53, 7180–7191; (h) Li, Y.; Raushel, F. M. Bioorg. Chem. 2005, 33,
470–483; (i) Peukert, S.; Sun, Y.; Zhang, R.; Hurley, B.; Sabio, M.; Shen, X.; Gray,
C.; Dzink-Fox, J. A.; Tao, J.; Cebula, R.; Wattanasin, S. Bioorg. Med. Chem. Lett.
2008, 18, 1840–1844.
3. (a) Kawecki, R. Tetrahedron 2001, 57, 8385–8390; (b) Leflemme, N.;
Dallemagne, P.; Rault, S. Tetrahedron Lett. 2001, 42, 8997–8999; (c) Sieburth,
S. M.; Rucando, D.; Lin, C.-H. J. Org. Chem. 1999, 64, 954–959; (d) Liu, J.; Lin, S.;
Ding, H.; Wei, Y.; Liang, F. Tetrahedron Lett. 2010, 51, 6349–6352; (e)
Machajewski, T. D.; Shafer, C. M.; Mcbride, C. 2-Amino-7,8-dihydro-6H-
pyrido[4,3-D]pyrimidine-5-ones. Patent WO2007/041362, 2007:410828
CAN146:422010 CAPLUS.
4. Kuznetsov, N. Yu.; Maleev, V. I.; Khrustalev, V. N.; Mkrtchyan, A. F.; Godovikov,
I. A.; Strelkova, T. V.; Bubnov, Yu. N. Eur. J. Org. Chem. 2012, 334–344.
5. Fustero, S.; Sanchez-Rosell, M.; Barrio, P.; Simon-Fuentes, A. Chem. Rev. 2011,
111, 6984–7034.
b = 7.5148(7) Å, c = 19.0336(18) Å, b = 97.266(2)°, V = 1174.37(19)
Å3, Z = 2, dcalcd = 1.630 g/cm3, F(000) = 584, = 3.490 mm–1
15086 total reflections (6803 unique reflections, Rint = 0.037) were
l
.
measured on a three-circle Bruker APEX-II CCD diffractometer
(k (MoK
a)-radiation, graphite monochromator, u and x scan mode,
2hmax = 60°) and corrected for absorption (Tmin = 0.421, Tmax
=
0.542).10a The structure was determined by direct methods and re-
fined by full-matrix least squares technique on F2 with anisotropic
displacement parameters for non-hydrogen atoms. The absolute
structure was objectively determined by the refinement of the Flack
parameter, which has become equal to 0.008(6). The hydrogen atom
of the NH-group was localized in the difference-Fourier map and in-
cluded in the refinement with fixed positional and isotropic
displacement parameters [Uiso(H) = 1.2Ueq(N)]. The other hydrogen
atoms were placed in calculated positions and refined within riding
model with fixed isotropic displacement parameters [Uiso(H) =
1.2Ueq(C)]. The final divergence factors were R1 = 0.034 for 5807
independent reflections with I > 2r (I) and wR2 = 0.068 for all inde-
pendentreflections, S = 0.919. Allcalculationswere carriedoutusing
the SHELXTL program.10b
Crystallographic data for the investigated compounds have
been deposited with the Cambridge Crystallographic Data Center,
CCDC 952411 for (S,R)-6b and CCDC 952410 for (S,S)-6e. Copies
of this information may be obtained free of charge from the Direc-
tor, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223
336033, e-mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk).
6. (a) Yus, M.; González-Gómez, J. C.; Foubelo, F. Chem. Rev. 2013, 113, 5595–
5698; (b) Ref. 4 and references therein.
7. Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600–3740.
8. (a) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979–4982; (b) Sun, X.-
W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 1259–1262; (c) Fadeyi, O.
O.; Senter, T. J.; Hahn, K. N.; Lindsley, C. W. Chem. Eur. J. 2012, 18, 5826–5831;
(d) Schulte, M. L.; Lindsley, C. W. Org. Lett. 2011, 13, 5684–5687; (e) Senter, T. J.;
Schulte, M. L.; Konkol, L. C.; Wadzinski, T. E.; Lindsley, C. W. Tetrahedron Lett.
2013, 54, 1645–1648; (f) Mimura, H.; Kawada, K.; Yamashita, T.; Sakamoto, T.;
Kikugawa, Y. J. Fluorine Chem. 2010, 131, 477–486; (g) Sirvent, J. A.; Foubelo, F.;
Yus, M. Chem. Commun. 2012, 2543–2545.
9. Collados, J. F.; Toledano, E.; Guijarro, D.; Yus, M. J. Org. Chem. 2012, 77, 5744–
5750.
10. (a) Sheldrick, G. M. SADABS, v. 2.03, Bruker/Siemens Area Detector Absorption
Correction Program; Bruker AXS: Madison, WI, 2003; (b) Sheldrick, G. M. Acta
Crystallogr. 2008, A64, 112–122.
Acknowledgements
This work was supported by Presidium of RAS (No. 18, coordi-
nator—V.A. Tartakovsky). The authors are grateful to Dr. D. Chusov
for chiral HPLC analysis.
References
1. (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic Press:
Orlando, 1985; Vol. 26, pp 89–183; (b) Fodor, G. B.; Colasanti, B. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York,
1985; Vol. 3, pp 1–90. piperidine-2-ones; (c) Jones, T. H.; Blum, M. S. In
Please cite this article in press as: Kuznetsov, N. Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.003