I2-Catalyzed Aerobic α,β-Dehydrogenation and Deamination of Tertiary Alkylamines: Highly Selective Synthesis of Polysubstituted Pyrimidines via Hidden Acyclic Enamines

Article abstract of DOI:10.1021/acs.orglett.0c02001

A novel and efficient entrance to the pyrimidine skeleton has been presented via the α,β-dehydrogenation and deamination of tertiary alkylamines. This I2-catalyzed dehydrogenative multicomponent procedure utilizes simple aldehydes to trap the hidden enami

Full text of DOI:10.1021/acs.orglett.0c02001

pubs.acs.org/OrgLett
Letter
I2‑Catalyzed Aerobic α,β-Dehydrogenation and Deamination of
Tertiary Alkylamines: Highly Selective Synthesis of Polysubstituted
Pyrimidines via Hidden Acyclic Enamines
Qinghe Gao,* Manman Wu, Ke Zhang, Ning Yang, Mengting Liu, Juan Li, Lizhen Fang, Suping Bai,
and Yongtao Xu*
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ABSTRACT: A novel and efficient entrance to the pyrimidine
skeleton has been presented via the α,β-dehydrogenation and
deamination of tertiary alkylamines. This I2-catalyzed dehydrogen-
ative multicomponent procedure utilizes simple aldehydes to trap
the hidden enamine intermediates and suspend generation of
azadienes from amidines, enabling the difunctionalization of a
vicinal C(sp3)−H bond. These studies provide valuable possibil-
ities for the introduction of aliphatic substituents and show how to
switch to a new reactive modality.
Scheme 1. From Amidines to Pyrimidines via
Dehydrogenative Multicomponent Cyclization
yrimidines are the key skeletons in numerous bioactive
compounds and natural products. In particular, a variety
P
of pyrimidine-derived drugs have demonstrated interesting
biological activities such as antibacterial, anticancer, antiviral,
and antidiabetic properties.1 Therefore, there is a continuous
need for new and efficient synthetic procedures that allow the
acquisition of highly functionalized pyrimidines from simple
building blocks.2 Recently, the dehydrogenative multicompo-
nent assembly of pyrimidines from amidines has become a
powerful and useful strategy.3 In 2015, Kempe et al. reported
the first multicomponent dehydrogenative coupling reaction of
alcohols with amidines for the synthesis of various pyrimidines,
in which the two different alcohols were oxidized to carbonyl
compounds by the Ir catalyst and further aldol condensation
gave α,β-unsaturated ketone intermediates (Scheme 1a).4
Later on, the Jiang group established a palladium-catalyzed
oxidative dehydrogenation strategy to the core scaffold of
pyrimidine carboxamides, and it proceeded via the key
enamide intermediates from styrene and DMF (Scheme
1b).5 Recently, Wu and co-workers found the K2S2O8-
mediated multicomponent cyclization with amidines and
methyl ketones to construct pyrimidines ring by using
DMSO as a C1 building block (Scheme 1c).6 With this
remarkable progress, in situ generation of the α,β-unsaturated
carbonyl compounds via the dehydrogenative coupling was a
crucial process. Thus, it offers an opportunity to design a new
fragment reassembly manner for the preparation of pyrimidines
from readily available reaction partners. Herein, we realize the
first example of an I2-catalyzed dehydrogenative multi-
component avenue to access polysubstituted pyrimidines
from simple aldehydes and amidines with trialkylamines as
the C2 building blocks (Scheme 1d).
Enamines are promising intermediates that could be the
wide application in β-functionalization of amines.7,8 In
contrast, despite its apparent simplicity, α,β-difunctionalization
of amines has been overlooked in recent years with regard to
the cyclization reaction.9 A possible reason is that the electron-
Received: June 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02001
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
rich nitrogen atom in tertiary alkylamines preferred the well-
established α-functionalization for the direct incorporation of
one carbon in cyclization reactions.10 For example, the Jiang
group developed a facile synthesis of 1,3,5-triazines via aerobic
copper-catalyzed cyclization of amidines with triethylamine as
a C1 building block.10a In this process, triethylamine was
transformed into a common imine-type intermediate, and a
sequential irreversibly nucleophilic attack of amidines directly
resulted in the formation the triazines. In fact, a hidden
enamine intermediate with the iminium intermediate existed in
equilibrium by tautomerization.8b−e It is theoretically possible
that the irreversible trapping of this hidden enamine
intermediate might suspend the traditional reaction pathway
and switch to a new favored pathway.11 As a consequence, the
present work exploits simple aldehydes to convert the reaction
pathway from α-functionalization into α,β-difunctionalization
of an aliphatic amine for the synthesis of pyrimidines with
good functional group tolerance and operational simplicity
(Scheme 2).
Table 1. Optimization of the Reaction Conditions
b
entry
[I]
I2
NH4I
NIS
KI
TBAI
oxidant
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
DCP
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
toluene
dioxane
CH3CN
NMP
DCE
DMF
DMSO
THF
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
150
120
110
150
150
150
85
81
83
78
80
39
17
74
69
67
24
75
67
0
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
9
BPO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
TBPB
CHP
H2O2
DMSO
K2S2O8
Oxone
air
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
Scheme 2. From α-Functionalization to α,β-
Difunctionalization of Tertiary Alkylamines
0
31
84
41
40
32
0
82
0
27
93
78
69
93
78
c
28
29
d
e
f
30
93 (76)
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (1.5 mmol),
b
[I] (0.5 mmol), oxidant (1.0 mmol), solvent (2 mL) for 8 h. Isolated
yields. I2 (0.1 mmol, 20 mol %). I2 (0.1 mmol, 20 mol %), 3a (0.5
mmol, 1.0 equiv). I2 (0.1 mmol, 20 mol %), 3a (1.0 mmol, 2.0
equiv), DTBP (0.5 mmol, 1.0 equiv). 1a (10 mmol), 2a (10 mmol),
c
d
To verify this conceptual hypothesis, we selected easily
accessible benzamidine hydrochloride (1a), benzaldehyde
(2a), and triethylamine (3a) as the model substrates, and it
was subjected to a preliminary condition with I2 and DTBP
(di-tert-butyl peroxide) in chlorobenzene at 130 °C for 8 h. To
our delight, the desired 2,4-diphenylpyrimidine (4aa) was
indeed furnished efficiently in 85% yield (Table 1, entry 1),
while the reported triazine was not detected by GC−HRMS
analysis. We found that other iodine resources, such as NH4I,
NIS, KI, and TBAI, were all effective, and the yield of 4aa was
dramatically decreased to 39% in the absence of elemental
iodine (Table 1, entries 2−6). A number of oxidants including
TBHP (tert-butyl hydroperoxide), DCP (dicumyl peroxide),
BPO (benzoyl peroxide), TBPB (tert-butyl peroxybenzoate),
CHP (cumene hydroperoxide), H2O2, DMSO, K2S2O8, and
Oxone were then evaluated (Table 1, entries 7−15). It turned
out the reaction was very sensitive to oxidants and DTBP still
exhibited the best reactivity. Notably, without DTBP the
reaction also occurred and produced 4aa in 31% yield (Table
1, entry 16). By changing chlorobenzene to toluene or DMF,
the reaction yield was isolated in 84% and 82% yields,
respectively, and other solvents were unsuitable for this
dehydrogenative multicomponent cyclization (Table 1, entries
17−24). Surprisingly, the yield of 4aa was increased to 93%
e
f
3a (20 mmol).
upon vigorous reflux of the mixture at 150 °C (Table 1, entry
25). Encouragingly, the reaction had no distinct influence
when we used 20 mol % of I2 and 1.0 equiv of DTBP (Table 1,
entry 30). Significantly, the transformation could be carried out
on a gram scale without any difficulty to give product 4aa in
76% yield.
With the optimal reaction conditions in hand (Table 1, entry
30), we evaluated the scalability and scope of this I2-catalyzed
dehydrogenative cyclization with a variety of amidine salts
(Scheme 3A). Benzamidines with a wide range of electronic
properties at the para-position of the benzene ring all
underwent the transformation with good performance to
furnish the desired 2,4-disubstituted pyrimidines in good to
excellent yields (62−94%; 4ab−4ah). These results showed
that there was no obvious electronic effect in this reaction. In
comparison, the core pyrimidines were formed in lower yields
(54−78%; 4ai−4ak) when the reaction was run with meta-/
ortho-substituted arylamidines. Notably, halo groups (F, Cl,
and Br) and the nitro group were compatible under the
B
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investigated under the standard conditions. N,N-Diethylani-
line, N-ethylmorpholine, and N,N-diisopropylethylamine could
be utilized as C2 cyclization building blocks for the acquisition
of 4aa in yields of 52%, 78%, and 57%, respectively.
Interestingly, diethylamine13 was also a suitable substrate
(see the Supporting Information).
Scheme 3. Substrate Scope of Amidine Salts and Tertiary
Alkylamines
Encouraged by these results, we were obligated to explore
the participation of aldehydes with diverse steric and electronic
properties (Scheme 4). Delightfully, aromatic aldehydes,
Scheme 4. Substrate Scope of Aldehydes
substituted with either electron-rich (Me, OMe, and OEt) or
halo (F, Cl, Br, and CF3) or electron-deficient (CN and NO2)
groups at the para position or at the meta position, all
proceeded well in the reaction and afforded the products in
moderate to good yields (48−94%; 4ba−4na). A steric effect
was observed when the ortho-substituted pyrimidine deriva-
tives were obtained in lower yields (49−69%; 4oa−4qa).
Specifically, the good compatibility of bioactive-related
functionalities such as Me, CF3, and CN illustrated the
potential medicinal use of the products. Meanwhile, reactions
attempting the use of other aromatic aldehydes including
naphthalene, pyridine, thiophene, and furan also provided the
respective cyclization products in up to 75% yield (4ra−4va).
Astonishingly, in the case of aliphatic aldehydes that are prone
to interfere with iminium from 3a, the desired alkylated
pyrimidines (4wa−4ya) were isolated with decreased yields
(31−37%).
To probe the mechanism of the present cyclization, we set
out to conduct the control experiment by adding a non-
oxidative radical scavenger BHT to the model reaction of 1a,
2a, and 3a. The target product (4aa) was still obtained in high
yield (Scheme 5a). Instead of DTBP, TEMPO could also serve
as an oxidant to promote this reaction (Scheme 5b). It means
that radical intermediate may not be generated in the process.
Utilization of cinnamaldehyde (5) as a substrate did furnish
the pyrimidine product (Scheme 5c). However, when
acetaldehyde was treated under standard conditions, only a
trace amount of 4aa could be detected (Scheme 5d). Then the
reaction between benzaldehyde and acetaldehyde only under
standard conditions, providing a convenient handle for further
divergent late-stage modifications. In the same manner,
heteroaryl amidines such as isonicotinamidine and nicotina-
midine gave rise to the anticipated products in satisfactory
yields (72−74%; 4al−4am). Remarkably, aliphatic amidines
were the appropriate candidates for the present reaction,
delivering the corresponding pyrimidine derivatives (4an and
4ao) in 89% and 47% yields, respectively. It is noteworthy that
an important pharmaceutical intermediate (68%; 4ap) was
successfully produced from the guanidine. In addition, the
structure of 4ah was unambiguously confirmed by single-
crystal X-ray diffraction (CCDC 1995256).
We next focused on the scope of this dehydrogenation and
deamination process with respect to the representative tertiary
alkylamines (Scheme 3B). Other acyclic trialkyl amines were
found to display reactivities similar to that of triethylamine.
The tertiary amines with different lengths of alkyl chains 3
reacted well with 1a and 2a to afford the corresponding alkyl-
substituted products in satisfactory yields (58−79%; 4aq−
4ax). Compared with linear tripropylamine (79%; 4aq) and
tripentylamine (69%; 4as), the bulky triisoamylamine led to
inferior conversion (58%; 4ar). Importantly, these results
revealed that tertiary alkylamines could contribute the C2
fragments to the pyrimidine rings and simultaneously
introduce linear or branched aliphatic moieties at the C-5
position in this system. Notoriously, the direct functionaliza-
tion of pyrimidine at C-5 position was extremely difficult.12
Subsequently, several cyclic and acyclic ethyl amines were
C
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Scheme 5. Control Experiments
Scheme 7. Plausible Mechanism
capture the hidden enamine intermediate B and consequently
prevent a prevalent reaction of A and amidine (1a).
Subsequently, the nucleophilic addition of 1a to the higher
electrophilic α,β-unsaturated iminium (C) gives the inter-
mediate D. Finally, the intermediate E undergoes intra-
molecular deamination cyclization and oxidative aromatization
process to provide the desired product 4aa.
In summary, we have reported the first I2-catalyzed
dehydrogenative multicomponent cyclization of aldehydes
and amidines with trialkylamines, which is promoted by
combination with DTBP and molecular oxygen as the oxidants.
A series of amidines and aldehydes are allowed to react well
with compatible useful functionalities. Various tertiary amines
with long carbon chains are smoothly converted to the C-5-
alkylated pyrimidine derivatives. The key to this transformation
is the utilization of simple aldehydes to trap the hidden
enamine intermediates and transform α-functionalization into
α,β-difunctionalization of tertiary alkylamines.
the standard conditions produced a trace amount of 5. These
results indicated that a alternate pathway was indeed operative
involving a new conversion form of triethylamine. Expressively,
the reaction was performed with N,N-diethylethenamine (7),14
leading to the desired product in 76% yield (Scheme 5e).
Obviously, these consequences revealed that enamine was the
key intermediate in this system. In addition, the higher
electrophilic α,β-unsaturated iminium from enamine and
benzaldehyde was detected by HRMS (see the Supporting
Information). On the basis of the blank experiments, it was
proved that DTBP and O2 with I2 synergistically accelerated
this dehydrogenative multicomponent assembly of pyrimidines
(Scheme 5f).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02001.
General experimental procedures and spectroscopic data
for the corresponding products (PDF)
Nevertheless, a deuterium-labeling experiment was con-
ducted under the standard conditions, demonstrating that the
α-C and β-C of triethylamine were integrated into the final
pyrimidine (Scheme 6a). We also performed an H/D exchange
Accession Codes
CCDC 1995256 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 6. Deuterium-Labeling Experiment and H/D
Exchange Experiment
AUTHOR INFORMATION
Corresponding Authors
■
Qinghe Gao − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P.R. China;
orcid.org/0000-0002-6207-8933; Email: gao_qinghe@
xxmu.edu.cn
Yongtao Xu − School of Medical Engineering, Xinxiang Key
Laboratory of Biomedical Information Research, Henan
Engineering Laboratory of Combinatorial Technique for
Clinical and Biomedical Big Data, Xinxiang Medical University,
Xinxiang, Henan 453003, P.R. China; Email: yxu@
xxmu.edu.cn
experiment with D2O as a deuterium source. NMR analysis of
the isolated product revealed that significant H/D exchange
was detected at the C-5 position (Scheme 6b).
On the basis of the above observations and previous
reports,8,9,15 a plausible mechanism has been proposed
(Scheme 7). Initially, the oxidations of 3a with I2 and DTBP
should afford the iminium intermediate A, which allows the in
situ generation of the acyclic enamine intermediate B by the
tautomerization. It is critical that the aldehyde (2a) can
Authors
Manman Wu − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P.R. China
D
https://dx.doi.org/10.1021/acs.orglett.0c02001
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Ke Zhang − School of Pharmacy, Xinxiang Medical University,
Xinxiang, Henan 453003, P.R. China
Ning Yang − School of Pharmacy, Xinxiang Medical University,
Xinxiang, Henan 453003, P.R. China
Mengting Liu − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P.R. China
Juan Li − Department of MRI, The First Affiliated Hospital of
Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Lizhen Fang − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P.R. China;
orcid.org/0000-0001-8594-4710
Suping Bai − School of Pharmacy, Xinxiang Medical University,
Xinxiang, Henan 453003, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02001
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 21672182), the University Key Research Projects
of Henan Province (No. 19A350010), and Training Programs
of Innovation and Entrepreneurship for Undergraduate of
Henan Province (No. S201910472031) for financial support.
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