Catalytic asymmetric hydrogenation of pyrimidines

Article abstract of DOI:10.1002/anie.201410607

The asymmetric hydrogenation of pyrimidines proceeded with high enantioselectivity (up to 99% ee) using an iridium catalyst composed of [IrCl(cod)]₂, a ferrocene-containing chiral diphosphine ligand (Josiphos), iodine, and Yb(OTf)₃ (cod=1,5-cyclooctadiene). The chiral catalyst converted various 4-substituted pyrimidines into chiral 1,4,5,6-tetrahydropyrimidines in high yield. The lanthanide triflate is crucial for achieving the high enantioselectivity as well as for activating the heteroarene substrate.

Full text of DOI:10.1002/anie.201410607

Angewandte
Chemie
DOI: 10.1002/anie.201410607
Asymmetric Catalysis
Catalytic Asymmetric Hydrogenation of Pyrimidines**
Ryoichi Kuwano,* Yuta Hashiguchi, Ryuhei Ikeda, and Kentaro Ishizuka
Abstract: The asymmetric hydrogenation of pyrimidines
proceeded with high enantioselectivity (up to 99% ee) using
an iridium catalyst composed of [IrCl(cod)]2, a ferrocene-
containing chiral diphosphine ligand (Josiphos), iodine, and
Yb(OTf)3 (cod = 1,5-cyclooctadiene). The chiral catalyst con-
verted various 4-substituted pyrimidines into chiral 1,4,5,6-
tetrahydropyrimidines in high yield. The lanthanide triflate is
crucial for achieving the high enantioselectivity as well as for
activating the heteroarene substrate.
bonyl).[8,9] The hydrogenation yielded the chiral imidazoline
products with up to 99% ee using the chiral [Ru(h3-
methallyl)2(cod)]–PhTRAP catalyst (cod = 1,5-cycloocta-
diene; PhTRAP = 2,2’-bis[1-(diphenylphosphino)ethyl]-1,1’-
biferrocene). Structural analogy between imidazoles and
pyrimidines inspired us to attempt the hydrogenation of 4-
methyl-2-phenylpyrimidine (1a) with the PhTRAP–ruthe-
nium catalyst. No hydrogenation of the pyrimidine, however,
was detected and the substrate 1a remained intact after the
reaction mixture was stirred at 808C for 4 hours under
a hydrogen atmosphere (5.0 MPa). Thus, our attention turned
to the use of an iridium catalyst, which is commonly used for
the hydrogenation of 6-membered arenes containing one or
two nitrogen atoms. First, the hydrogenation of 1a was
attempted using a [IrCl(cod)]2–L1–I2 catalytic system, where
L1 is (R)-BINAP (Table 1, entry 1; BINAP = 2,2ꢀ-bis(diphe-
nylphosphino)-1,1’-binaphthyl). Using the iridium catalyst, it
was possible to produce the desired 1,4,5,6-hydrogenated
product 2a at 1008C, but in low yield and with low
stereoselectivity. To enhance the reactivity of 1a, the asym-
metric reduction was carried out in the presence of Brønsted
acids, which have been often used for activating nitrogen-
T
he catalytic asymmetric hydrogenation of azaarenes is
a useful method to prepare optically active nitrogen-contain-
ing heterocycle constituents, which are present in numerous
alkaloids. In the last decade, a variety of azaarenes have been
reduced with high enantioselectivities by using various
asymmetric catalysts,[1] including using organocatalysts.[2]
Iridium is frequently used for the highly enantioselective
hydrogenation of 6-membered azaarene rings.[3–6] However,
the highly enantioselective reduction of some nitrogen-
containing heteroarenes still remains difficult.
The asymmetric hydrogenation of pyrimidines has been
an unexplored issue in organic synthesis. The reaction will be
an attractive method for the synthesis of 6-membered cyclic
amidines, which often occur in natural products and potent
pharmaceutical compounds.[7] However, the generation of the
amidine functionality may cause a problem in the develop-
ment of the asymmetric reduction of pyrimidines because the
product binds strongly to the metal atom in the catalyst as
a result of its strong Lewis basicity. Herein, we report the
highly enantioselective hydrogenation of pyrimidines. To
achieve a high yield of the amidine product as well as high
enantioselectivity, a chiral iridium complex was used as the
catalyst in combination with a lanthanide triflate.
Table 1: Optimization of reaction conditions for the catalytic asymmetric
hydrogenation of 1a.[a]
Entry
Ligand
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L2
L2
L2
L2
None
11
25
27
43
56
63
64
68
55
51
61
53
49
24 (+)
18 (+)
10 (+)
11 (+)
72 (À)
40 (À)
45 (À)
6 (+)
65 (À)
72 (À)
33 (À)
78 (À)
89 (À)
87 (À)
88 (À)
TsOH·H2O
Cu(OTf)2
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Previously, we reported a highly enantioselective hydro-
genation of N-Boc-imidazoles (Boc = tert-butoxycar-
[*] Prof. R. Kuwano, Y. Hashiguchi, R. Ikeda, Dr. K. Ishizuka
Department of Chemistry, Graduate School of Sciences, and
International Research Center for Molecular Systems (IRCMS)
Kyushu University, 6-10-1 Hakozaki, Higashi-ku
Fukuoka 812-8581 (Japan)
9
10
11
12
13[d]
14[d,e]
15[d,e,g]
E-mail: rkuwano@chem.kyushu-univ.jp
Prof. R. Kuwano
>99[f]
94[f]
JST ACT-C, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
Dr. K. Ishizuka
Education Center for Global Leaders in Molecular Systems for
Devices, Kyushu University
774 Motooka, Nishi-ku, Fukuoka, 819-0395 (Japan)
[a] Unless otherwise noted, reactions were conducted on a 0.2 mmol
scale in EtOAc (1.0 mL) under H2 (5.0 MPa) at 1008C for 12 h. The ratio
of 1a:[IrCl(cod)]2:ligand:I2:additive was 100:1.0:2.2:4.0:20. [b] Deter-
mined by 1H NMR spectroscopic analysis. [c] Determined by chiral HPLC
analysis after treating 2a with (Boc)2O. Signs of optical rotations are
given in parentheses. [d] At 508C. [e] For 72 h. The ratio of 1a/Yb(OTf)3
was 100:50. [f] Yield of isolated product. [g] On a 1.0 mmol scale.
OTf=trifluoromethanesulfonate.
[**] This work was partly supported by ACT-C (JST). We thank the
Cooperative Research Program of the “Network Joint Research
Center for Material and Devices” for HRMS measurement.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410607.
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Table 2: Catalytic asymmetric hydrogenation of 2,4-disubstituted pyri-
midines 1.[a]
containing substrates in catalytic asymmetric hydrogenation
reactions.[10–12] The use of p-toluenesulfonic acid resulted in
a slight increase in the yield of 2a (entry 2). Next, we turned
our attention to use of Lewis acids. After screening various
metal salts, lanthanide triflates were found to remarkably
improve the hydrogenation of 1a (entry 4). However, the
enantiomeric excess of 2a still remained low.
A broad range of chiral phosphine ligands were evaluated
for the iridium-catalyzed hydrogenation of 1a in the presence
of Dy(OTf)3 (Figure 1).[13] The enantioselectivity was remark-
Entry
R1
R2
1
Yield [%][b]
ee [%][c]
1[d]
2[d]
3
4
5
4-CF3C6H4
4-MeOC6H4
2-FC6H4
2-ClC6H4
2-MeC6H4
2-MeOC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
Ph
2-MeC6H4
2-MeC6H4
2-MeC6H4
Ph
2-MeC6H4
2-MeC6H4
Me
Me
Me
Me
Me
Me
Me
Et
cHex
tBu
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
87
93
92
92
98
86
86
92
94
95
87
96
97
–
6
7
99
>99
68[e]
0[f]
92
94
98
98
80
94
80
8[d]
9
10[d]
11[d]
12[d]
13[d]
14
15
16
17[d]
18[d,h]
Ph
Ph
97[g]
99
98
99
88
9
22
92
91
Figure 1. Structures of Josiphos ligands employed in this study.
cHex=cyclohexyl.
4-CF3C6H4
4-MeOC6H4
CH2OAc
CF3
CO2Et
Ph
ably enhanced by using Josiphos ligand L2 (Table 1,
entry 5).[14] The catalytic activity of the Josiphos–iridium
complex was little affected by the substituents R1 and R2 on
its phosphorus atoms (entries 5–11). In contrast, changing the
substituents has an impact on the enantioselectivity of the
reaction. The selectivity significantly decreased when either
the tert-butyl or the phenyl group on L2 was replaced by
a cyclohexyl group (entries 6 and 7, using ligands L3 and L4,
respectively). Furthermore, use of Josiphos L5 bearing two
diarylphosphino groups resulted in the formation of an almost
racemic product (entry 8). Installing electron-deficient aryl
groups as the R2 substituent caused a slight decrease in
enantioselectivity (entry 9). The stereoselectivity of methoxy-
substituted Josiphos L7 was comparable to L2 (entry 10). The
chiral induction of the iridium catalyst is controlled not only
by the combination of R1 and R2 substituents but also by their
relative positions. Significantly lower enantioselectivity was
observed in the reaction using ligand L8, which has tert-butyl
and phenyl groups as substituents R2 and R1, respectively
(entry 11). Furthermore, a series of lanthanide triflates were
evaluated for the iridium-catalyzed hydrogenation of 1a with
ligand L2.[13] Relatively high enantioselectivities were
observed in the reactions using Yb(OTf)3 (entry 12) as well
as Pr(OTf)3, Sm(OTf)3, Gd(OTf)3, and Tb(OTf)3 (see
Table S2 in the Supporting Information). The stereoselectiv-
ity was improved without significant loss of the yield by
conducting the reaction at 508C (entry 13).[15,16] Furthermore,
the complete conversion of 1a into 2a was accomplished by
using 0.5 equivalents of Yb(OTf)3 per 1 equivalent of 1a
(entry 14). The desired product 2a was quantitatively
obtained with 87% ee.
92
87
NMe2
Ph
1s
[a] Unless otherwise noted, reactions were conducted on a 0.2 mmol
scale in EtOAc (1.0 mL) under H2 (5.0 MPa) at 508C for 72 h. The ratio of
1:[IrCl(cod)]2:L2:I2:Yb(OTf)3 was 100:1.0:2.2:4.0:50. [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis after treating 2 with
(Boc)2O. [d] For 96 h. [e] 3i was formed in 25% yield (calculated by
1H NMR spectroscopy). [f] 3j was formed in 99% yield (calculated by
1H NMR spectroscopy). [g] The absolute configuration of 2k is R. [h] At
1008C.
stereoselectivity (entries 3–6). In particular, 2-(o-tolyl)pyri-
midine derivative 1 f gave the desired product 2 f with
95% ee. The pyrimidines bearing a substituent other than
methyl group as the R2 group also undergo hydrogenation
with high stereoselectivity. 4-Ethylpyrimidine 1h was quanti-
tatively transformed into 2h with 96% ee (entry 7). The
hydrogenation of 1i, which has a secondary alkyl group,
proceeded with high stereoselectivity (entry 8). The substrate
was completely consumed within 48 hours, but the reaction
mixture at 96 hours contained 4-cyclohexyl-1,6-dihydropyri-
midine 3i in 25% yield. Pyrimidine 1j also underwent the
hydrogenation at its N1 C6 bond, but the C4 C5 double
bond of 3j remained intact (entry 9). The aryl groups on the
C4 atom of 1k–1n (i.e. the R2 substituents) are favorable for
achieving high stereoselectivity (entries 10–13). It is note-
worthy that the amidines 2l–2n were obtained with 98–
99% ee. The acetoxy group of 1o was compatible with the
reaction, leading to the formation of product 2o with 88% ee
(entry 14). Chiral amidines 2p and 2q, each with an electron-
withdrawing group at the stereogenic center, were also
obtained in high yields from the asymmetric hydrogenation
(entries 15 and 16). However, the enantiomeric excesses of 2p
and 2q were very low. The L2–iridium catalyst also showed
high enantioselectivity for the hydrogenation of pyrimidines
bearing R1 substituents other than aryl groups (entries 17
and 18). Cyclic guanidine 2s was produced with 91% ee in
À
À
As shown in Table 2, the optimized reaction conditions
allow a variety of 2,4-disubstituted pyrimidines 1 to be
converted into cyclic amidines 2 with high enantiomeric
excesses and in high yields. The enantioselectivity of the
hydrogenation was scarcely affected by the para substituents
on the 2-aryl groups in 1b and 1c (entries 1 and 2). Installing
a substituent at the ortho position led to improvements in the
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high yield by the hydrogenation of 1s, although the reaction
required a higher reaction temperature (1008C). Pyrimidine
1t bearing no substituent at the C2 position (i.e. R1 = H) was
also hydrogenated to form 2t with a high enantiomeric excess
(Scheme 1). The chiral product was obtained as protected 1,3-
diamine 4 after treatment with TsCl (p-toluenesulfonyl
chloride) and alkali, because 2t could not be purified by
chromatography.
completely replaced by deuterium. It has been established
that the hydrogenation reaction using the [IrCl(cod)]2–
bisphosphine–I2 catalytic system proceeds through
a
hydridoiridium(III) species.[3b,11d,17] Consequently, the
observed deuterium distribution suggests that the hydro-
genation of 1 proceeds through the following pathway
(Scheme 2). The pyrimidine 1 is activated by coordination
Scheme 2. Proposed pathway for the hydrogenation of 1 to form 2.
X=I or Cl.
Scheme 1. Catalytic asymmetric hydrogenation of 4-phenylpyrimidine
(1t). Reagents and conditions: a) H2 (5.0 MPa), [IrCl(cod)]2
(1.0 mol%), L2 (2.2 mol%), I2 (4.0 mol%), Yb(OTf)3 (0.5 equiv),
EtOAc, 508C, 72 h; b) TsCl (2.2 equiv), Et3N (2.2 equiv), CH2Cl2,
followed by treatment with saturated aqueous Na2CO3. Cumulative
yield of 4: 83% from 1t.
to Yb(OTf)3.[17a] The N1 C6 bond of 1 is reduced with H2 to
À
À
give the dihydropyrimidine 3. The C4 C5 double bond of 3 is
À
inserted into the Ir H bond to form intermediate 5. The
transformation of 5 into 2 would proceed through the
migration of the iridium atom from C5 to C6, because
deuterium should be incorporated in 100% at the pro-
R position on C5 if the hydrogenation proceeded without the
migration. In the deuteration of 3l, the hydride on iridium in
intermediate 6 might be replaced by deuterium through
a molecular D2 complex.[18] Consequently, the hydrogen/
deuterium exchange would cause the 51% deuterium incor-
The formation of 3 in entries 8 and 9 of Table 2 implies
that the iridium-catalyzed hydrogenation of 1 proceeds
À
through stepwise additions of two H2 molecules to the N1
À
C6 and C4 C5 bonds. To confirm this speculation, the
hydrogenation of 3l was carried out with the [IrCl(cod)]2–
L2–I2–Yb(OTf)3 catalytic system [Eq. (1)]. The dihydropyr-
imidine was converted into 2l with 99% ee in high yield as
expected. The Lewis acid is required for the reduction of 3 as
well as for the dearomatization of the pyrimidine, because 2l
was obtained with only 20% ee in low yield without using
Yb(OTf)3. Furthermore, the reaction was accompanied by the
formation of 1l (see entry 11 in Table 2 for the structure). The
dehydrogenation indicates that 1l and 3l are in equilibrium in
the presence of the iridium catalyst. However, the undesirable
reverse reaction might be restricted by using the lanthanide
triflate in the reaction.[13]
À
poration at the C5 atom in [D]-2l. The Ir C6 bond in 7 would
be protonated through s-bond metathesis with H2 or
a sequence composed of oxidative addition followed by
reductive elimination. Furthermore, the deuteration of 1a
was conducted using the L2–iridium catalyst [Eq. (3)]. The
deuteration was also accompanied by hydrogen/deuterium
scrambling at the C5 position and complete incorporation of
deuterium at the C6 position.
In conclusion, we have successfully developed a chiral
catalyst for the asymmetric hydrogenation of 4-substituted
pyrimidines 1. A broad range of pyrimidines were converted
into the corresponding 1,4,5,6-tetrahydropyrimidines 2 with
high enantiomeric excesses using an [IrCl(cod)]2–Josiphos–I2
catalytic system. Furthermore, the addition of Yb(OTf)3
brought about a remarkable improvement of the stereoselec-
tivity as well as an enhanced yield of 2. The lanthanide triflate
facilitates the hydrogenation of 1,6-dihydropyrimidine inter-
To investigate the pathway from intermediate 3 to product
2, the deuteration of 3l was undertaken [Eq. (2)]. In the
product [D]-2l, the deuterium atom was incorporated in more
than 99% on the C4 center. Hydrogen/deuterium scrambling
took place at the pro-R position on the C5 atom. To our
surprise, the pro-S hydrogen on the C6 atom in 3l was
À
mediate 3 as well as the initial reduction of the N1 C6 double
bond in pyrimidine 1.
Received: October 31, 2014
Revised: December 6, 2014
Published online: January 7, 2015
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Kashiwabara, N. Kameyama, Angew. Chem. Int. Ed. 2012, 51,
4136 – 4139; Angew. Chem. 2012, 124, 4212 – 4215.
[10] For a review on the activation of nitrogen-containing substrates
with Brønsted acids for catalytic asymmetric hydrogenations,
see: Z. Yu, W. Jin, Q. Jiang, Angew. Chem. Int. Ed. 2012, 51,
6060 – 6072; Angew. Chem. 2012, 124, 6164 – 6177.
Keywords: asymmetric catalysis · heterocycles · hydrogenation ·
iridium · lanthanides
.
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1
[15] The H NMR spectra of mixtures of 2a and Yb(OTf)3 suggest
that the amidine interacts with the Lewis acid in a solution to
form a Yb-2a complex. The ligand exchange of 2a on the Yb
center is fast on the NMR timescale. See the Supporting
Information.
[16] One reviewer pointed out that the pyrimidine substrate may be
activated with triflic acid, which is eliminated from Yb(OTf)3.
However, the activation with the Brønsted acid is ruled out in
this asymmetric hydrogenation. A mixture of some unidentified
compounds and remaining 1a (ca. 60%) was obtained when
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lanthanide triflate under the optimized conditions (at 12 h). The
strong acid might cause the ring cleavage of 1a or 3a.
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