Regio- and Enantioselective Synthesis of N-Substituted Pyrazoles by Rhodium-Catalyzed Asymmetric Addition to Allenes

Article abstract of DOI:10.1002/anie.201501758

Abstract The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)-ruxolitinib.

Full text of DOI:10.1002/anie.201501758

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501758
German Edition: DOI: 10.1002/ange.201501758
Synthetic Methods
Regio- and Enantioselective Synthesis of N-Substituted Pyrazoles by
Rhodium-Catalyzed Asymmetric Addition to Allenes**
Alexander M. Haydl, Kun Xu, and Bernhard Breit*
Abstract: The rhodium-catalyzed asymmetric N-selective
coupling of pyrazole derivatives with terminal allenes gives
access to enantioenriched secondary and tertiary allylic
pyrazoles, which can be employed for the synthesis of
medicinally important targets. The reaction tolerates a large
variety of functional groups and labelling experiments gave
insights into the reaction mechanism. This new methodology
was further applied in a highly efficient synthesis of JAK 1/2
inhibitor (R)-ruxolitinib.
N
itrogen-containing heterocycles such as chiral N-substi-
tuted pyrazoles can be found within the scaffolds of a large
variety of biologically active compounds, such as small-
molecule pharmaceuticals including ibrutinib (a Brutonꢀs
tyrosine kinase inhibiting anticancer agent),[1] ruxolitinib (a
JAK 1/2 kinase inhibitor),[2] and MK-0893 (a potent glucagon
receptor inhibitor; Figure 1).[3]
The preparation of such chiral pyrazoles either requires
multiple steps[4] or is accompanied by the generation of
stochiometric amounts of waste,[5] and there are also strong
limitations regarding the substrate variability.[6] In this respect
we report a rhodium-catalyzed chemo-, regio-, and enantio-
selective addition of substituted pyrazoles to terminal allenes
to furnish secondary and tertiary a-chiral N-allylated pyr-
azoles.[7]
Figure 1. Bioactive compounds possessing an a-chiral pyrazole scaf-
fold.
Our group recently developed the rhodium-catalyzed,
atom-economic, and regioselective addition[8] of different
pronucleophiles to allenes[9] and alkynes,[10] a method which
could be seen as an alternative to the metal-catalyzed allylic
substitution[11] and oxidation[12] to generate branched allylic
products. Pyrazoles and derivatives exist as a mixture of two
tautomers in which the equilibrium between both species is
highly dependent upon the substitution pattern of the hetero-
cycle.[13] Along these lines, the outcome of the addition of
different pyrazoles to allenes would in theory lead to the
formation of two possible regioisomers. We anticipated that
there might be an opportunity to control the ratio between
Scheme 1. Possible differentiation of the two tautomeric pyrazole
species by a rhodium catalyst, thus predominantly leading to the
desired N1 product.
the desired N1 and the undesired N2 by-product based upon
the choice of the phosphine ligand (Scheme 1).
[*] A. M. Haydl, Dr. K. Xu, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie
Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Initial reactivity assays were carried out using cyclo-
hexylallene and 4-bromopyrazole in the presence of [{Rh-
(cod)Cl}2] (2.0 mol%), PPTS (20 mol%), and the nonchiral
DPEphos ligand (L1; 5.0 mol%) in toluene at 808C (Table 1).
To our delight we obtained the branched secondary N1-
allylated pyrazole in excellent yield (90%; entry 1). Based on
this result the feasibility of 4-bromopyrazole as a promising
pronucleophile encouraged us to screen numerous chiral
bidentate diphosphine ligands.[14] We were pleased to discover
that JoSPOphos (L2) led to the desired product in both high
[**] This work was supported by the DFG, the International Research
Training Group “Catalysts and Catalytic Reactions for Organic
Synthesis” (IRTG 1038). We thank Solvias, Umicore, BASF, and
Wacker for generous gifts of chemicals. Vladislav Agabekov, Niels
Thieme, Dr. Vahid Khakyzadeh, Prof. Dr. Yuanzhi Xia, and Monika
Lutterbeck for preliminary experimental work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501758.
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Table 1: Rhodium-catalyzed regio- and enantioselective addition of
Table 2: Scope of the catalytic enantioselective addition of symmetric 4-
pyrazole derivatives to cyclohexylallene.[a]
substituted pyrazole derivatives to cyclohexylallene.[a,b]
Entry R1, R2, R3
Ligand N1/N2[b] Yield [%][c] ee [%][d]
1
2
R1 =R3 =H, R2 =Br
L1
L2
L2
L2
–
–
–
90
94
70
rac.
94
94
R1 =R3 =H, R2 =Br
R1 =R3 =H, R2 =Br
R1 =H, R2 =Br, R3 =Me
3[e]
4
89:11 78 (N1)
8 (N2)
88 (N1)
91 (N2)
87 (N1)
91 (N2)
5[f]
R1 =H, R2 =Br, R3 =Me
L2
71:29 56 (N1)
22 (N2)
[a] Reaction conditions: cyclohexylallene (1.0 mmol), pyrazole
(0.5 mmol), and PPTS (20 mol%) in 2.5 mL of toluene at 808C, 16 h.
[b] Regioselectivity determined by 1H NMR analysis of the crude reaction
mixture. [c] Yield of isolated product. [d] The ee values were determined
by HPLC analysis using a chiral stationary phase. [e] Reaction performed
with cyclohexylallene (0.6 mmol, 1.2 equiv), pyrazole (0.5 mmol), PPTS
(5 mol%), [{Rh(cod)Cl}2] (0.5 mol%), and L2 (1.25 mol%) in 2.5 mL of
toluene at 808C, 16 h. [f] Reaction in absence of PPTS. cod=1,5-
cyclooctadiene, Cy=cyclohexyl, PPTS=pyridinium p-toluenesulfonate.
[a] Yield of isolated product. [b] The ee values were determined by HPLC
analysis using a chiral stationary phase. Bpin=pinacolboronate.
well tolerated, thus resulting in 82-99% yield and 91-94% ee
(1h–k).
yield (94%) and high enantioselectivity (94% ee; entry 2). A
catalyst loading of only 0.5 mol% [{Rh(cod)Cl}2] and a lower
allene loading (1.2 equiv) led to an acceptable 70% yield and
an unchanged ee value (entry 3). Further investigations with
the unsymmetric 4-bromo-3-methyl-1H-pyrazole (entry 4)
under optimized reaction conditions furnished the N1 and
N2 products in a ratio of 89:11; the N1 product was isolated in
78% yield with 87% ee along with the separable minor N2-
allylated by-product. The presence of PPTS plays a significant
role in obtaining the desired N1 product with high regiose-
lectivity (entry 5).
Having the optimal reaction conditions in hand, the scope
of this process was studied (Tables 2 and 3). We found a wide
range of symmetric substituted pyrazoles to be suitable
reaction partners, and they gave the corresponding allylic
pyrazoles in good to excellent yields and enantioselectivities
(1a–k; Table 2). Other halogenated 4-pyrazoles, including the
iodo-substituted substrate, gave equally high ee values (1c)
and even a trisubstituted halogenated pyrazole reacted to give
the desired product in high yield and with an excellent
ee value of 98% (1a,b and 1d). A change of the substitution
pattern to electron-withdrawing groups at the 4-position
resulted in slightly diminished yields with no detrimental
effect on the ee values (1e,f). Even a pinacolboronate was
compatible in the reaction (1g), and allows further modifi-
cations by either transition-metal-catalyzed Suzuki–Miyaura
cross-coupling or derivatization to other functional groups.[15]
Alkyl, fluoroalkyl, phenyl, and unsubstituted pyrazoles were
Next, we moved on to expand the scope with respect to
the terminal allene, including mono- and 1,1-disubstituted
allenes, which are readily prepared in one or two steps from
either commercial or known starting materials (Table 3).[14]
As expected, cyclopentylallene was a suitable coupling
partner with different pyrazoles, thus leading to the products
2a and 2b in high yields and ee values. A single crystallization
of the latter product from n-heptane increased the ee value to
97%, thus demonstrating the utility of this method for the
synthesis of essentially enantiopure allylic pyrazole deriva-
tives. Even different linearly substituted allenes led to the
desired products in high yields and good enantioselectivities
(2c and 2d). Gratifyingly, among different oxygen-function-
alized allenes, even an unprotected hydroxy function was well
tolerated in the reaction (2g). Allenes bearing various other
functional groups, such as a phthalimide and a thioether,
reacted smoothly with excellent yields and good enantiose-
lectivities (2h and 2i). The 1,1-disubstituted allenes also
worked well in terms of yields and enantioselectivities (62–
68% ee). To the best of our knowledge, these products,
representing allylic pyrazoles with a tertiary stereocenter, are
not directly accessible by any known pathway (2j–l).
Based on these results, we further extended the scope to
various unsymmetric pyrazoles. To investigate the effects on
regio- and enantioselectivity, the substitution pattern of
different pyrazole derivatives was varied systematically
(Table 4). Structural modification of the model substrate, 4-
2
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Table 3: Scope of the catalytic enantioselective addition of pyrazoles to
Table 4: Extended scope of the catalytic enantioselective addition of
substituted terminal allenes.[a,b]
unsymmetric 3,4- or 3,5-substituted pyrazoles to cyclohexylallene.[a–f]
[a] Yield of isolated product. [b] The ee values were determined by HPLC
analysis using a chiral stationary phase. [c] Value within parentheses is
the ee value obtained after a single crystallization from n-heptane.
Bz=benzoyl, TBS=tert-butyldimethylsilyl, Phth=phthaloyl.
[a] Yield of the isolated N1 product. [b] Yield of the regioisomeric mixture
of N1 and N2 products. [c] Regioselectivity determined by 1H NMR
analysis of the crude reaction mixture. [d] Assignment of the products as
either the N1 or N2 product made by using HMBC and NOE experiments.
[e] The ee values were determined by HPLC analysis using a chiral
stationary phase. [f] For the ee value of the corresponding N2 product see
the Supporting Information.
bromopyrazole, by changing the carbon scaffold at the 3-
position, led to the desired N1 products in good yields along
with good regio- and enantioselectivities (3a,b). The product
3c was formed in a regioselective manner, albeit with only
moderate yield and ee value. To our surprise, even an indazole
worked well as a suitable coupling partner in terms of yield
(99%) and regioselectivity (> 99:1), and furnished 3d with
a high enantiomeric excess of 89% ee. Next, we modified the
substitution pattern at the 4-position (3e–h). In terms of yield
and N1 selectivity the electron-poor pyrazoles gave equally
high yields as did their electron-rich counterparts, including
high regio- and enantioselectivities (3e,f). Electron-rich
pyrazoles also worked well in the reaction and led to the
desired N1 products in excellent yields with high enantiomeric
excess, but with a slightly lower regioselectivity (3g,h).
Further modification of the substitution pattern (3i–l),
especially when attaching an electron-withdrawing group to
the 5-position (3j–l), led to N-allylated pyrazoles in good
yields along with high regio- and enantioselectivities (up to
98% ee and up to 99:1 N1 selectivity).
To explore the synthetic utility of allylated pyrazoles, we
subjected 1b and 1j to various transformations to get insight
into reactivity (Scheme 2). Hydroformylation of the terminal
double bond, using our self-assembly ligand 6-diphenylphos-
phinopyridone (6-DPPon), furnished 4 in high yield (93%)
and with an excellent linear/branched selectivity (95:5).[16]
C1 cleavage by ozonolysis of 1b led to 5 in 99% yield.[17a]
Furthermore, the double bond was easily modified by other
chemoselective transformations (6 and 7), thus leaving the
pyrazoles untouched.[17b,c] Bifunctional derivatization of the
pyrazole moiety gave easy access to the carbon-substituted
pyrazole 1j under Suzuki–Miyaura cross-coupling conditions
in high yield.[17d]
Inspired by these synthetic possibilities, this new pyrazole
allylation was applied to the synthesis of the JAK 1/2 kinase
inhibitor (R)-ruxolitinib (10; Scheme 3). By using 4-bromo-
pyrazole and cyclopentylallene in the previously described
rhodium-catalyzed coupling, 2a could be synthesized in
multigram quantities in a straightforward fashion. Function-
alization of the allylic double bond by hydroboration, and
subsequent oxidation of the alcohol led to the corresponding
aldehyde 8. The absolute configuration was determined at this
Concerning a possible reaction mechanism, preliminary
isotope-labeling experiments were carried out using 4-bromo-
[1D]-pyrazole under standard rhodium-catalyzed condi-
tions.[14] In accordance with our previous observations,
deuterium incorporation was observed at all positions of the
alkene.[8a–c]
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(R)-ruxolitinib. Further studies on extending this strategic
approach to other related nitrogen-containing heterocycles,
as well as their application in target-oriented synthesis, are
being pursued in our laboratory.
Keywords: allenes · allylic compounds · asymmetric catalysis ·
heterocycles · rhodium
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Scheme 3. Gram-scale catalysis and synthesis of (R)-ruxolitinib.
Reagents and conditions: a) Cyclohexylallene, 4-bromopyrazole, PPTS
(20 mol%), [{Rh(cod)Cl}2] (2.0 mol%) and L2 (5.0 mol%) in toluene
(0.2m) at 808C, 24 h, 95%, 90% ee. b) 9-BBN, THF, RT; then H2O2,
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n-heptane). e) B2pin2, [Pd(dppf)Cl2] (5.0 mol%), KOAc, DMSO, 908C.
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4
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Received: February 24, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
A. M. Haydl, K. Xu,
B. Breit*
&&&& — &&&&
Regio- and Enantioselective Synthesis of
N-Substituted Pyrazoles by Rhodium-
Catalyzed Asymmetric Addition to Allenes
Add on: The rhodium-catalyzed regio-
and enantioselective addition of terminal
allenes and functionalized pyrazoles per-
mits the atom-economic synthesis of
valuable branched allylic pyrazoles. The
synthesis of the small-molecule pharma-
ceutical(R)-ruxolitinib highlights the
potential of this method. FG=functional
group.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!