Enantioselective Construction of Pyrimidine-Fused Diazepinone Derivatives Bearing a Tertiary Stereogenic Center Enabled by Iridium-Catalysed Intramolecular Allylic Substitution

Article abstract of DOI:10.1002/adsc.202100444

The iridium-catalysed enantioselective intramolecular allylic substitution of pyrimidine-tethered allylic carbonates was developed. A wide range of chiral pyrimidine-fused diazepinone derivatives were successfully constructed in 88–96% yields with 85–99%

Full text of DOI:10.1002/adsc.202100444

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DOI: 10.1002/adsc.202100444
Enantioselective Construction of Pyrimidine-Fused Diazepinone
Derivatives Bearing a Tertiary Stereogenic Center Enabled by
Iridium-Catalysed Intramolecular Allylic Substitution
Xiaoding Jiang,a Bendu Pan,a Xu Qian,a Hao Liang,a Yaqi Zhang,a Bin Chen,a
Xiaobo He,a Hoi Shan Chan,b Albert S. C. Chan,a and Liqin Qiua,*
a
School of Chemistry, Guangdong Key Lab of Chiral Molecules and Drug Discovery, Sun Yat-Sen University, Guangzhou
510275, People’s Republic of China
Fax: +(86)-20-8411-0996
E-mail: qiuliqin@mail.sysu.edu.cn
Department of Chemistry, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China.
b
Manuscript received: April 10, 2021; Revised manuscript received: May 18, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100444
pyrimidine derivatives with binucleophilic reagents
Abstract: The iridium-catalysed enantioselective
(Scheme 1a).[7] Despite some progress in the syntheses
intramolecular allylic substitution of pyrimidine-
of these skeletons, the establishment of chiral centers
tethered allylic carbonates was developed. A wide
in these traditional approaches is still challenging and
range of chiral pyrimidine-fused diazepinone deriv-
asymmetric construction of these frameworks remains
atives were successfully constructed in 88–96%
unexplored as of now. With regard to the importance
yields with 85–99% ees. This work further high-
of chiral drugs, development of enantioselective
lights the power of chiral-bridged biphenyl phos-
synthetic approaches to these frameworks is of great
phoramidites in asymmetric synthesis.
importance to increase molecular diversity and com-
plexity.
Over the past decades, iridium-catalyzed allylic
Keywords: Pyrimidine-fused diazepinones; Asym-
substitution reactions have emerged as powerful
metric catalysis; Iridium; Allylic substitution; Chiral-
approaches for the construction of carbon-carbon or
bridged biphenyl phosphoramidites
carbon-heteroatom bonds in organic synthesis.[9] The
Pyrimidine-fused diazepinones, as structural analogues
of benzodiazepinones, are important and privileged N-
heterocyclic scaffolds in drug discovery. It was well
documented that these compounds exhibited a broad
spectrum of pharmacological properties, such as
anticonvulsant effect,[1] analgesic,[2] anti-HIV-1
activities[3] as well as the capability of acting as PDK1
inhibitor,[4] NK1 antagonist,[5] EGFR kinase inhibitor,[6]
VGCC α2δ-1 inhibitor (Figure 1).[7] Given the bio-
logical importance of the heterocyclic systems, medic-
inal chemists have devoted considerable efforts to their
synthesis. For instance, Dhgosz unexpectedly obtained
pyrimidobenzodiazepines via cyclization with diethyla-
niline as catalyst.[2] Habibi et al provided access to
Figure 1. Representative bioactive molecules containing a pyr-
imidine-fused diazepinone fragment.
pyrimidine-fused 1,5-benzodiazepines using an enami- ability to incorporate synthetically useful allylic
none-based approach.[8] More recently, Cuevas-Cor- functionality into various substrates under mild con-
dobés and co-workers prepared novel bicyclic tetrahy- ditions makes it valuable as a tool for the synthesis of
dropyrimidodiazepine compounds by the reaction of chiral building blocks and biologically active
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combination of [Ir(cod)Cl]2 (2 mol%) and L1
(4 mol%) as catalyst precursors (Table 1, entry 1), 72%
yield of the desired product 7a was obtained in 91%
°
ee with K3PO4 (2.0 equiv.) as the base in THF at 50 C
for 8 h.[19] Careful investigation showed that bases
would not only affect the yield, but also impact on the
enantioselectivity. In the absence of base, notably, the
reaction didn’t occur even if it lasted for 12 h (Table 1,
entry 2). When Et3N was adopted, the substrate was
not converted as well (Table 1, entry 6). With Cs2CO3
or K2CO3 as the base, the reactions were sluggish,
albeit with good enantioselectivities (Table 1, entries 3
& 4). Both the yield and enantioselectivity could be
improved by utilizing DABCO or DBU, and DBU
provided the highest yield and enantioselectivity (90%
yield, 95% ee, Table 1, entry 10). Solvent had little
influence on the enantioselectivity, but had some
impact on the yield (see Table S1 for detail informati-
on). DME was found to be a superior solvent compare-
d with THF, dioxane, toluene, MTBE, DCM, DCE and
CH3CN. Lower reaction temperatures were also tried.
Gratifyingly, there was no erosion of the yield and
enantioselectivity when the reaction was carried out at
Scheme 1. Traditional approaches for the synthesis of pyrimi-
dine-fused diazepinones (a) and the concept of our work (b).
compounds.[10] Among them, the pioneering research 30 C or 25 C (Table 1, entries 12 & 13). However,
°
°
°
of Trost and Helmchen groups has led to the develop- performing the reaction at 0 C would slow down the
ment
of
intramolecular
asymmetric
allylic reaction progress despite not much deterioration in the
amination.[11] To date, many catalytic systems involv- enantioselectivity (Table 1, entry 14). Encouraged by
ing chiral ligands have been developed to afford these results, we then evaluated the profiles of various
excellent levels of regio- and enantioselectivity. Un- chiral phosphoramidite ligands. As demonstrated in
arguably, the most representative ligands are chiral Table 2, both the reaction activity and enantioselectiv-
phosphoramidites such as Feringa’s[12]/Alexakis’s P,C ity were dramatically affected by ligands. Interestingly,
ligands,[13] Carreira’s P,olefin ligand,[14] and You’s Me- the absolute configuration of these two products with
THQphos ligand.[15] All of the common ligands were Ligand L1 and L2 was opposite, and L2 led to
derived from 1,1’-bi-2-naphthol (BINOL) and the significant decrease in the yield and enantioselectivity
differences among them mainly exist in the amine (Table 2, entries 1 vs 2). Similar phenomenon was also
moiety. Whereas, the changes in the axial chiral unit observed between L3 and L4 (Table 2, entries 3 vs 4).
are limited. Recently, our group developed an array of These results demonstrated the considerable effects of
novel chiral-bridged biphenyl phosphoramidite ligands matching/mismatching between stereochemical ele-
and successfully applied them to the iridium-catalyzed ments of the chiral amine and axial chirality of the
asymmetric addition of arylboronic acids to N- ligands. Employing L5 with 2-methyl-1,2,3,4-tetrahy-
protected isatins.[16] In addition, these ligands were droquinoline moiety[20] as the ligand, we were de-
found to be highly efficient in the iridium-catalysed lighted to find that the ee value of the desired product
enantioselective syntheses of chiral tricyclic was increased to 98%. The absolute configuration of
benzimidazoles.[17] Impressively, the chiral-bridged the product is contrary when using L1 and L5
biphenyl phosphoramidite ligands with tunable dihe- respectively (Table 2, entries 1 & 5). With (S,S,Ra,S)-
dral angles exhibited obvious advantages over the L6 as the ligand, both the yield and the enantioselec-
bisphenol-based and BINOL-derived ligands in these tivity decreased to some extent (84% yield, 90% ee).
asymmetric transformations. In continuation of our Besides, the difference of ligand’s bridge linker would
interest in the preparation of chiral heterocyclic bring in different catalytic effect. For example, ligand
derivatives, we herein report the outcome of iridium- L3 with a pentanediol bridge linker performed much
catalysed asymmetric intramolecular allylic aminations worse than L1, which implies that an appropriate
to access diversely substituted pyrimidine-fused diaze- dihedral angle of the bridged ligands is essential for
pinones bearing a tertiary stereogenic center as the first better catalytic results. The bisphenol-based ligand L7
examples (Scheme 1b).
was mediocre in terms of both the yield and the
At the outset, we prepared pyrimidine-tethered enantioselectivity. Using Feringa’s (R)-BINOL-derived
allylic carbonates 6 as substrates from simple and ligands L8–L9, the enantioselectivity didn’t take
readily accessible starting materials.[18] Using the advantage over that of L5, albeit in good yield. This
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Table 1. Optimization of the bases and temperatures.[a]
Entry
Base
Solvent
Time
Yield [%][b]
Ee [%][c]
1
2
3
4
5
6
7
8
K3PO4
–
Cs2CO3
K2CO3
DMAP
Et3N
KF
BSA
DABCO
DBU
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DME
DME
DME
DME
8
72
–
85
80
76
–
54
79
88
90
92
95
95
82
91
-
89
92
83
-
76
82
93
95
96
96
96
93
12
12
8
8
12
12
12
4
4
4
4
4
4
9
10
11
12
13
14
DBU
DBU[d]
DBU[e]
DBU[f]
[a] Conditions: [Ir(cod)Cl]2 (2 mol%), L1 (4 mol%), base (200 mol%), and 6a (0.2 mmol) in solvent (2.0 mL).
[b] Isolated yields.
[c] Determined by chiral HPLC analysis.
[d]
°
30 C.
[e]
°
25 C.
[f]
°
0 C.
provides further evidence of necessity and effective-
ness of the chiral bridge regulation on the asymmetric
catalytic performance of the ligand. Reducing catalyst
loading to 1 mol% would lead to lower enantioselec-
tivity (Table 2, entry 10). Taken together, the optimal
conditions were ultimately identified as follows:
substrate (1.0 equiv.), [Ir(cod)Cl]2 (2 mol%), L5
°
(4 mol%), and DBU (2.0 equiv.) in DME at 25 C for
4 h.
With the optimal conditions in hand, we next turned
our attention to the generality of the transformation.
The variations of R1 were initially probed. The mild
reaction conditions allowed the use of a variety of
substrates containing different R1 (Scheme 2). Either
aryl or alkyl groups at R1 were viable, delivering the
expected products in high yields with excellent
enantioselectivities. Both electron-rich substituents
t
(OCH3, Bu) and electron-deficient substituent (CF3) at
para-position of the aromatic ring at R1 underwent the
Scheme 2. Substrate scope with respect to R1. Conditions: 6a–
6l (0.2 mmol, 1.0 equiv.), [Ir(cod)Cl]2 (2 mol%), L5 (4 mol%),
reaction smoothly to afford products 7b–7d in good
yields. The installation of substituents (CH3, Pr) at the
ortho-position of the phenyl ring did not hamper the
yields and enantioselectivities (7e, 7g). With respect
to alkyl group at R1, linear or branched alkyl groups
i
°
and DBU (2.0 equiv.), DME (2.0 mL), 25 C, 4 h.
were also compatible, furnishing products 7h and 7i in selectivities as well. Besides, benzyl group was well
good yields with excellent enantioselectivities. Reac- accommodated and afforded the product with up to
tions of substrates possessing cycloalkyl groups such 99% ee.
as cyclopropyl, cyclohexyl all gave excellent enantio-
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Table 2. Screening of the ligands.[a]
Entry
L
Yield Ee
Entry
L
Yield Ee
[%][b] [%][c]
[%][b] [%][c]
Scheme 3. Substrate scope with respect to R2. Conditions: 6m–
6ab (0.2 mmol, 1.0 equiv.), [Ir(cod)Cl]2 (2 mol%), L5
1
2
3
4
5
L1 95
L2 76
L3 65
L4 24
L5 95
96 (S)
82 (S)
81 (R)
69 (R)
6
7
8
9
L6 84
L7 80
L8 90
L9 95
L5 90
90 (R)
75 (S)
85 (S)
95 (R)
94 (R)
°
(4 mol%), and DBU (2.0 equiv.), DME (2.0 mL), 25 C, 4 h.
98 (R) 10[d]
[a] Conditions: [Ir(cod)Cl]2 (2 mol%), ligand (4 mol%), 6a
the synthesis of 7ab in 90% yield with 89% ee. All
results demonstrate the wide adaptability of this
synthetic methodology. The absolute configuration of
(R)-7m was determined by X-ray crystallographic
analysis (see SI for details), and those of other products
were assigned by analogy.
°
(0.2 mmol), and DBU (200 mol%) in DME (2.0 mL) at 25 C.
[b] Isolated yields.
[c] Determined by HPLC analysis.
[d] 1 mol% of Ir-catalyst was used.
To further demonstrate the generality of this
On the basis of the above catalytic results and the
reaction, various substitutents at R2 were subsequently reported mechanism study on allylic substitution,[22]
a
introduced by simple synthetic steps including nucleo- possible mechanism for the catalytic process was
philic substitution reaction or Suzuki coupling proposed as depicted in Scheme 4. The catalytically
reaction.[21] As illustrated in Scheme 3, the reaction
proceeded well with all studied substrates. The
morpholino group could be replaced with OCH3 or
CH3 without a significant effect on the results for the
corresponding products (7m–7n). Reactions of the
substrates having N-methylpiperazinyl, pyrrolidinyl,
piperidinyl group at R2 all gave excellent enantioselec-
tivities as well. Phenyl or 1-naphthyl group at R2 was
also feasible. Moreover, the introduction of 4-PhO,
3,5-(MeO)2 or 3,4,5-(MeO)3 substituted aryl groups to
the substrate had no notable influence on the reaction
outcome (7u, 7w and 7x). Heteroaryl groups, com-
monly found in pharmaceuticals, such as 2-furyl, 3-
thienyl ring or 6-methoxyl-3-pyridinyl were also
compatible with this protocol, furnishing the corre-
sponding products with excellent stereocontrol (7y, 7z
and 7aa). In particular, when the substrate with
phenylamino group at R2 was subjected to the standard
reaction conditions, excellent regioselection ensured
Scheme 4. Proposed mechanism for the catalytic process.
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CCDC-2074944 contains supplementary crystallographic data
for compound (R)-7m. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
inactive complex K1 was initially formed by mixing
[Ir(cod)Cl]2 and ligand L5. Upon addition of base, the
metalacyclic iridium complex K2 was generated via
C(sp2)À H bond activation of the phenyl group. Since
K2 was coordinatively saturated and its ligand could
be easily replaced by other ligands, K3 was postulated
as the most likely active species in the catalytic cycle.
The reaction of K3 with allylic substrates led to the
formation of π-allyliridium complex K4. In the
presence of the base, K4 was easily deprotonated to
form K5, and then the cyclization product was
obtained by intramolecular nucleophilic attack to the
π-allyliridium moiety.
In summary, we have developed an iridium-
catalyzed asymmetric intramolecular allylic amination
of pyrimidine-tethered allylic carbonates. The reaction
proceeded successfully under mild reaction conditions,
and a wide range of chiral pyrimidine-fused diazepi-
none derivatives bearing an allyl moiety were obtained
in 88–96% yields and with 85–99% ees. Substrates
with alkyl or aryl groups all underwent the desired
reactions smoothly. Besides, the electronic and steric
effect had no much deleterious impact on the catalytic
efficiency. The research further highlights the power of
chiral-bridged biphenyl phosphoramidites in asymmet-
ric synthesis. Additional mechanistic studies and
applications are currently underway in our laboratory.
Acknowledgements
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grant No. 21772238)
and Natural Science Foundation of Guangdong Province
(Grant No. S2011010001305). Meanwhile, it’s much appreci-
ated that Prof. Qing-Hua Fan and Prof. Yong-Gui Zhou
provided us the enantiopure 2-methyl-1,2,3,4-tetrahydroquino-
line.
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Experimental Section
General procedure for compound 6. To a solution of 5
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General Procedure for compound 7. In a dry Schlenk tube
filled with argon, [Ir(cod)Cl]2 (2.7 mg, 0.004 mmol, 2 mol%),
phosphoramidite ligand L5 (3.6 mg, 0.008 mmol, 4 mol%), and
n-propylamine (0.5 mL) were dissolved in THF (1.0 mL). The
°
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volatile solvents were removed in vacuum to give a yellow
solid. In this tube, substrates 6 (0.2 mmol), DBU (60 mg,
0.4 mmol, 200 mol%) and DME (2.0 mL) were added and the
°
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