Reaction of Aldehydes/Ketones with Electron-Deficient 1,3,5-Triazines Leading to Functionalized Pyrimidines as Diels-Alder/Retro-Diels-Alder Reaction Products: Reaction Development and Mechanistic Studies

Article abstract of DOI:10.1021/acs.joc.6b02570

Catalytic inverse electron demand Diels-Alder (IEDDA) reactions of heterocyclic aza-dienes are rarely reported since highly reactive and electron-rich dienophiles are often found not compatible with strong acids such as Lewis acids. Herein, we disclose that TFA-catalyzed reactions of electron-deficient 1,3,5-triazines and electron-deficient aldehydes/ketones can take place. These reactions led to highly functionalized pyrimidines as products in fair to good yields. The reaction mechanism was carefully studied by the combination of experimental and computational studies. The reactions involve a cascade of stepwise inverse electron demand hetero-Diels-Alder (ihDA) reactions, followed by retro-Diels-Alder (rDA) reactions and elimination of water. An acid was required for both ihDA and rDA reactions. This mechanism was further verified by comparing the relative reactivity of aldehydes/ketones and their corresponding vinyl ethers in the current reaction system.

Full text of DOI:10.1021/acs.joc.6b02570

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Article
Reaction of Aldehydes/Ketones with Electron Deficient 1,3,5-Triazines
Leading to Functionalized Pyrimidines as Diels-Alder/Retro-Diels-Alder
Reaction Products: Reaction Development and Mechanistic Studies
Kai Yang, Qun Dang, Pei-Jun Cai, Yang Gao, Zhi-Xiang Yu, and Xu Bai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02570 • Publication Date (Web): 23 Jan 2017
Downloaded from http://pubs.acs.org on January 24, 2017
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Reaction of Aldehydes/Ketones with Electron Deficient
1,3,5ꢀTriazines Leading to Functionalized Pyrimidines as
DielsꢀAlder/RetroꢀDielsꢀAlder Reaction Products: Reaction
Development and Mechanistic Studies
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Kai Yang,† Qun Dang,† PeiꢀJun Cai,‡ Yang Gao,‡ ZhiꢀXiang Yu,*,‡ and Xu Bai*,†
† The Center for Combinatorial Chemistry and Drug Discovery of Jilin University,
The College of Chemistry and The School of Pharmaceutical Sciences, Jilin
University, 1266 Fujin Rd., Changchun, Jilin 130021, P. R. China
‡
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College
of Chemistry, Peking University, Beijing 100871, China
* Email: yuzx@pku.edu.cn, xbai@jlu.edu.cn
Insert Table of Contents
Reaction Development & Mechanistic Studies
X
X
R2
R2
TFA, EtOH, reflux
N
N
+
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R1
O
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N
R1
NCX, H2O
dienophile
diene
Aldehydes/ketones (but not their enol derivatives) as dienophiles for IEDDA
Abstract
Catalytic inverse electron demand DielsꢀAlder (IEDDA) reactions of heterocyclic
azaꢀdienes are rarely reported since highly reactive and electronꢀrich dienophiles are
often found not compatible with strong acids such as Lewis acids. Herein we disclose
that TFAꢀcatalyzed reactions of electronꢀdeficient 1,3,5ꢀtriazines and
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electronꢀdeficient aldehydes/ketones can take place. These reactions led to highly
functionalized pyrimidines as products in fair to good yields. The reaction mechanism
was carefully studied by the combination of experimental and computational studies.
The reactions involve a cascade of stepwise inverse electron demand
heteroꢀDielsꢀAlder (ihDA) reactions followed by retroꢀDielsꢀAlder (rDA) reactions
and elimination of water. An acid was required for both ihDA and rDA reactions. This
mechanism was further verified by comparing the relative reactivity of
aldehydes/ketones and their corresponding vinyl ethers in the current reaction system.
Introduction
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Improvement of existing methodologies in organic synthesis is an ongoing focus
for chemists and success in this field empowers chemists with tools for rapid
synthesis of natural products and/or biologically important compounds for medicinal
chemistry projects. For example, the metalꢀcatalyzed coupling reactions for CꢀC and
Cꢀheteroatom bond formation reactions produced profound impacts to both organic
and medicinal chemistry.1 Traditionally, the more reactive aryl bromide or iodide are
most often reported and thought to be required for most coupling reactions; later on,
aryl chloride was introduced to expand the scope of coupling reactions.2 However,
direct arene couplings via CꢀH activation were discovered against the traditional way
of thinking which revolutionized our understanding about coupling reactions.3 The
inverse electron demand DielsꢀAlder (IEDDA) reactions of azaꢀdienes (such as
triazines and tetrazines) have been widely used for the synthesis of diverse
nitrogenꢀcontaining heterocycles including natural products and bioꢀactive
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compounds (Scheme 1a).4 Traditionally, azaꢀdiene IEDDA reactions require
electronꢀrich dienophiles, such as enamines, ynamines, amidines and electronꢀrich
heterocycles.4, 5 It is therefore not surprising to observe that most attempts of using
Lewis acids to active azaꢀdienes often failed due to the nonꢀproductive consumption
of the electronꢀrich dienophiles (during the preparation of this manuscript, Boger et al
published their results of solvent (perfluoroalcohols) catalyzed reactions6). On the
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other
hand,
the
development
of
IEDDA
reactions
of
2,4,6ꢀtris(ethoxycarbonyl)ꢀ1,3,5ꢀtriazine has led to the total syntheses of bleomycin
A2, Pꢀ3A (Scheme 1b),7 and the syntheses of many other bleomycinꢀrelated agents.8
Recently, we disclosed that hydrazones could function as productive dienophiles in
IEDDA reaction with 1,3,5ꢀtriazine, which avoids the needs to prepare air and
moisture sensitive dienophiles such as enamines, ynamines, and amidines (Scheme
1c).9 This improvement to azaꢀdiene IEDDA reactions expanded the scope of
dienophiles and gave chemists the flexibility to store a variety of hydrazone
dienophiles and conduct IEDDA reactions on demand, without the inconvenience to
freshly prepare those moisture sensitive dienophiles.9 It would be a further improvent
of this methodology if we could utilize directly the readily available ketones and
aldehydes as dienophiles without convertion to their corresponding hydrazones.
However, vinyl ethers have been tested as dienophiles with the relatively unreactive
1,3,5ꢀtriazines unsuccessfully (Scheme 1d), indicating that the enol form of
aldehydes/ketones might not be reactive enough to function as productive dienophiles.
On the other hand, Haddadin, Schubert and Li found that aldehydes/ketones could
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react with those highly reactive 1,2,4,5ꢀtetrazines and 1,2,4ꢀtriazines (Scheme 1e),10
which provided encouragement for the further investigation of aldehydes/ketones as
potential dienophiles with 1,3,5ꢀtriazines. With the contradictory implications in mind,
we endeavored the investigations of the direct reaction of aldehydes/ketones with the
less reactive and electronꢀdeficient 1,3,5ꢀtriazines. Herein, we report the successful
development of reaction conditions that enable aldehydes/ketones to react with
1,3,5ꢀtriazines directly leading to IEDDA products in high yields (Scheme 1f).
Moreover, investigation of the mechanism of this new reaction processes was carried
out via both experimental and theoretical studies to provide further insights into this
new cascade reaction.
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Scheme 1. Design of IEDDA reactions of aldehydes/ketones with 1,3,5ꢀtriazines.
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Results and Discussion
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Investigations of direct reactions of aldehydes/ketones with 1,3,5ꢀtriazines.
Ketone 2a was studied with triazine 1a under various reaction conditions and the
results were summarized in Table 1. We envisioned that there are two ways to increase
the probability of success for aldehydes/ketones to function as productive dienophiles:
one way is to facilitate the enolization of aldehydes/ketones and the other is to
increase the reactivity of 1,3,5ꢀtriazines. To promote enolization of aldehydes/ketones,
strong basic conditions have been used in the IEDDA reactions of 1,2,4ꢀtriazines and
1,2,4,5ꢀtetrazines.10 However, only a trace amount of desired IEDDA product 3a was
detected (entries 1ꢀ3) and prolonged heating led to decomposition of triazine 1a,
which was consistent with our previous observations that 1,3,5ꢀtriazines are not stable
under basic conditions.9 To enhance the reactivity of 1,3,5ꢀtriazines, acids might be
needed, which acts as either a catalyst or an additive. We reasoned that protonation of
1,3,5ꢀtriazines could decrease LUMO energies of triazines, and this would
promote/speed up IEDDA reactions.5ꢀ9
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Considering our past success with TFA in IEDDA reactions of 1,3,5ꢀtriazines, we
began to use TFA as either a catalyst or an additive to promote the desired reaction,
and explore other reaction conditions with DMF as the solvent (Table 1, entries 5ꢀ7).
To our delight, the first reaction conditions tested using 10 mol % TFA as a catalyst
produced pyrimidine 3a in 72% yield after 2 days of heating (entry 5). An increase of
the amount of TFA did not lead to higher yields nor shorter reaction time, suggesting
that subꢀstoichiometric acid is preferred by the current reaction (entries 6ꢀ7). A Lewis
acid, boron trifluoride etherate, was also tested, but only moderate yield of the desired
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IEDDA product was obtained (entry 8). After the identification of TFA as an effective
acid catalyst, various solvents were screened to see if the reaction time could be
shortened (entries 9ꢀ13). Traditionally polar solvents are preferred for azaꢀdiene
IEDDA reactions, likely due to their polar transition states of the cascade reactions.11
Among the polar solvents tested, ethanol truly stood out since higher yield and shorter
reaction time were observed (entry 12). The current reaction was slower and gave
lower yield in DMSO compared to ethanol, which is surprising since the reaction was
carried out at 20 oC higher temperature and DMSO is more polar than ethanol (Table1,
entry 13). Moreover, TFA was also confirmed as a useful catalyst in ethanol (Table1,
entry 14). With the optimized reaction condition (entry 12 in Table 1) in hand, the
scope of this new IEDDA reaction was explored and results are summarized in Table
2.
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Table 1. Exploration of IEDDA Reaction Conditions of 1a with 2a.a
entry
conditions
KOH (0.1 equiv), EtOH, reflux
KOH (1.0 equiv), EtOH, reflux
tꢀBuOK (1.0 equiv), EtOH, reflux
DMF, 100 oC
time
1 d
yield, %
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3 d
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TFA (0.1 equiv), DMF, 100 oC
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TFA (0.5 equiv), DMF, 100 oC
TFA (1.0 equiv), DMF, 100 oC
2 d
1.7 d
8 d
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BF3 Et2O (0.1 equiv), 1,4ꢀdioxane, 100 oC
TFA (0.1 equiv), 1,4ꢀdioxane, 100 oC
TFA (0.1 equiv), CH3CN, reflux
TFA (0.1 equiv), DCE, reflux
TFA (0.1 equiv), EtOH, reflux
TFA (0.1 equiv), DMSO, 100 oC
EtOH, reflux
.
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2.5 d
4 d
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12 d
20 h
5 d
2 d
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), additive and solvent (1 mL) was
stirred at the indicated temperature under nitrogen atmosphere, and monitored by
LCꢀMS until all 1a was consumed.
As evident from Table 2, almost all the tested ketones were good substrates for the
current IEDDA reaction leading to moderate to high yields of the desired IEDDA
products. Carbocyclic ketones (2aꢀ2d) gave high yields of the desired IEDDA
products (3aꢀ3d), while heterocyclic ketones (2eꢀ2g) produced the desired products
(3eꢀ3g) in moderate to high yields (41%ꢀ87%). The presence of a basic amine group
in ketone 2g led to only 28% of 3g under the current conditions. Increasing the
amount of TFA to 2.1 equivalent improved the yield to 41% (3g). Acyclic ketones
(2hꢀ2j), including even the lowꢀboiling acetone (2h), were good substrates to produce
the highly functionalized pyrimidines (3hꢀ3j) in good to excellent yields (71%ꢀ85%),
together with excellent control of regiochemistry outcomes.
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Table 2. IEDDA Reaction of Aldehydes/Ketones 2 with 1,3,5ꢀTriazines 1.a
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a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), and TFA (0.1 mmol) was stirred in
EtOH (2 mL) at reflux under nitrogen atmosphere until complete consumption of 1 as
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b
indicated by LCꢀMS. Reaction time and yields of isolated product are given. 2.1
mmol TFA was used. c Reactions were conducted using 1a (1.0 mmol) and aldehyde 2
(2.0 mmol) in EtOH (2 mL) at reflux under nitrogen atmosphere, and after 24h
additional 2.0 mmol of aldehyde 2 was added.
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It was known that aldehydes generally have higher propensity to enolize compared
to ketones.12 We expected that aldehydes should be more reactive than ketones in the
1,3,5ꢀtriazine IEDDA reactions. However, we found that aldehydes gave much lower
yields than ketones in the current IEDDA reaction (3kꢀ3m). We suspected that
aldehydes might be unstable under the thermal and acidic conditions, which may
account for the lower observed yields. Therefore, we decided to explore the optimal
reaction conditions for the IEDDA reaction of aldehydes 2l with 1,3,5ꢀtriazine 1a. The
optimal reaction conditions for aldehydes are: heating 1a and 4.0 equivalent 2l (which
was added by two portions) in EtOH without acidic additive (details of this
optimization were summarized in the Supporting Information). Then, these conditions
were applied to other aldehydes to produce the pyrimidine products in low to
moderate yields (3kꢀ3m, 31%ꢀ58%).10b Other 1,3,5ꢀtriazines (1bꢀ1c) were also
explored and found to be suitable dienes for the current IEDDA reactions, leading to
3nꢀ3o in moderate to high yield (60%ꢀ81%).
Through the above investigations, we demonstrated that aldehydes/ketones can
react directly with the relatively unreactive 1,3,5ꢀtriazines leading to highly
functionalized pyrimidines as IEDDA products. Considering that aldehydes and
ketones are electronꢀdeficient, it is counterintuitive to observe them as productive
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dienophiles in IEDDA reactions with electronꢀdeficient 1,3,5ꢀtriazines, which
prompted us to carry out both experimental and computational studies of the
mechanism of the present reaction. 13
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Isolation of reaction intermediates and stepwise reaction process. It is well
established that IEDDA reactions of 1,3,5ꢀtriazines are cascade reactions.4 Therefore,
if some of the intermediates could be isolated and identified, it will help us elucidate
the reaction mechanism. To this end, we selected the less reactive ketone 2d and
deliberately terminated its reactions with triazine 1a and 1b before completion.
Fortunately, two intermediates were detected by TLC and were isolated (4a and 4b,
Scheme 2). Furthermore, the structure of intermediate 4b was unambiguously
assigned based on the Xꢀray crystallography analysis (ORTEP drawing of 4b was
shown in the Supporting Information).14
Scheme 2. Isolation of Intermediates 4a and 4b.
To confirm compounds 4a and 4b are relevant intermediates, not just side products,
we subjected compound 4a to the current reaction conditions and obtained the
corresponding IEDDA product 3d in 68% yield, Scheme 2. It was further determined
that an acid was required for ketone 2d to function as a productive dienophile in the
IEDDA reaction with triazine 1a, since after one week of heating in EtOH, only trace
amount of intermediate 4a (<5%) (but no final product 3d) was detected by TLC and
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LCꢀMS. These results suggested that the acid is essential for the initial formation of
intermediate 4a. Furthermore, heating of 4a in refluxing ethanol for two days did not
produce any trace of compound 3d, which indicated that the presence of an acid was
required for the subsequent conversion of the intermediate 4a to the final IEDDA
product 3d. Therefore, these results provide strong experimental evidence that the
current IEDDA reaction occurred through a stepwise mechanism and an acid is
required to catalyze both steps of reactions.11
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Quantum chemical calculations of the stepwise pathways of IEDDA reaction
between protonated triazine and acetone. Quantum chemical calculations15 with
B3LYP functional16 and 6ꢀ31G(d) basis set in ethanol solution using SMD model17
were carried out to understand the detailed process of the IEDDA reaction between
triazine and ketones/aldehydes.11,18 Then energy evaluations were performed using
MP2 single point energy calculations19 using 6ꢀ311+G(d,p) basis set20 in ethanol
solvent using SMD model, since B3LYP was found to overestimate the aromatization
energy for aromatic compounds.11 More discussions of computational methods are
given in the Supporting Information. The discussed energies here are enthalpies in
ethanol solution.
To simplify the calculations, trimethyl 1,3,5ꢀtriazineꢀ2,4,6ꢀtricarboxylate (A) and
acetone 2h were chosen as the model substrates. Considering the fact that
subꢀstoichiometric TFA was used in the current reaction, we hypothesized that
protonated 1,3,5ꢀtriazineꢀ2,4,6ꢀtricarboxylate (HꢀA) is the real reactive species for the
cascade reaction. This hypothesis was supported by our calculations given in Figures
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1 and 2 (see more discussions in the Supporting Information). Based on quantum
chemical calculations, we proposed that the cascade reaction started from the
formation of a complex, COM, between Enol and HꢀA, which is exothermic by 10.7
kcal/mol (here we did not consider the complex formation of acetone and HꢀA). The
subsequent CꢀC bond formation (via transition state TS1) is facile with an activation
enthalpy of only 1.7 kcal/mol and this step is exothermic by 12.9 kcal/mol, giving rise
to intermediate INT1a. Then INT1a is converted to a more stable intermediate,
INT1b, via rapid CꢀC bond rotation. Initially we proposed that INT1b could be
converted to INT1c via the C2ꢀN1 bond formation, then INT1c underwent C3ꢀN1
bond cleavage to give INT2. We successfully located C3ꢀN1 bond cleavage transition
state TS2, but failed to locate intermediate INT1c, which is not a stationary point.
IRC calculations from TS2 suggested that this transition state is connected by INT1b
and INT2. During the process from TS2 to INT1b, intermediate INT1c was observed
in the IRC calculation (If an alcohol is present nearby, this intermediate can be located,
see Figure S5 of the Supporting Information). This suggests that, once INT1a is
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formed,
it
then
undergoes
a
series
of
transformations
of
INT1a→INT1b→INT1c→TS2→INT2.
The followed step in the cascade reaction is the liberation of nitrile from INT2 via
transition state TS3, which needs an activation enthalpy of 6.5 kcal/mol and generates
INT3. Finally elimination of water from INT3 gives the protonated cycloadduct and
this step is exothermic by 21.0 kcal/mol.
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Figure 1. Energy profiles of the IEDDA reaction between HꢀA and acetone calculated
at the MP2/6ꢀ311+G(d,p)ꢀSMD(EtOH)//B3LYP/6ꢀ31G(d)ꢀSMD(EtOH) level of
theory.
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Figure 2. Key structures calculated at the B3LYP/6ꢀ31G(d)ꢀSMD(EtOH) level of
theory.
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The above calculations showed that the rateꢀdetermining step is the C3ꢀN1 bond
cleavage step and an overall activation enthalpy is 25.4 kcal/mol (from INT1b to
TS2). This suggest that INT1b, which is the most stable intermediate in the potential
energy surface, could be isolated if it is deprotonated. This DFTꢀlocated intermediate
was supported by the observation of 4a in the experiment (actually, the existence of
INT1b predicted by calculations was before the experimental isolation of 4a
intermediate).
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Cross Over Experiment. Based on the above studies, we considered that
aldehydes/ketones underwent enolization before participation in the current IEDDA
reaction. We reasoned that vinyl ethers locked in the presumed reactive forms should
be more reactive than corresponding aldehydes/ketones. Therefore, it would be
interesting to compare the relative reactivities of vinyl ethers and aldehydes/ketones
in the current reaction to verify this hypothesis.
Since heating 1,3,5ꢀtriazine 1a and aldehydes in EtOH without acidic additive is the
optimal reaction conditions for aldehydes, and vinyl ethers were not stable in acids
(results of reactions of vinyl ethers with 1a under acidic conditions were summarized
in the Supporting Information), the relative reactivities of vinyl ethers and
aldehydes/ketones were compared under the same neutral conditions, and the results
are summarized in Table 3.
Table 3. The reactivity comparison among 2a, 2m, 5a, 5b in the IEDDA reaction.a
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entry
1
dienophile
product
time, d
yieldb ,%
72
2
7
2
3
4
<5c
45/36d
<5c
3a
3/2.8d
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3m
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5b+2me
5a+2me
6.5
8.5
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3m
3a
a
b
Unless specified, 0.5 mmol 1a, 1.0 mmol 2a/5a, or 2.0 mmol 2m/5b was used.
Yields of isolated product. c 1a remained. d 4.0 mmol 2m. e 0.05 mmol 2m.
Even though vinyl ethers 5a and 5b are locked in the presumed reactive forms, they
proved to be significantly less reactive than their corresponding ketones and
aldehydes 2a/2m (entries 1ꢀ4). This observation was surprising to us and must be
explained.
On the basis of above observations, we hypothesized that under neutral conditions,
triazine 1a could function as a base to promote the enolization of ketone/aldehyde
2a/2m, and during the process triazine 1a becomes protonated and the protonated
triazine serves as the reactive diene for the IEDDA reaction to proceed smoothly
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(Scheme 3). Moreover, this selfꢀactivation process of triazineꢀketone/aldehyde system
does not require high concentration of the protonated triazine since the proton is not
consumed during the reaction sequence (Figure 1).
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Scheme 3. Selfꢀactivation within the triazineꢀketone system.
On the other hand, when vinyl ethers 5a and 5b were used as dienophiles, triazine
1a could not be activated via protonation and the vinyl ethers themselves are not
electronꢀrich enough to undergo the traditional [4+2] cycloaddition reactions with
freeꢀbase form triazine (entries 2 and 4). If the above hypothesis is correct， then
addition of aldehydes/ketones to the vinyl ether reaction system could help to
catalyze/promote the IEDDA reactions with vinyl ethers. Indeed, addition of
subꢀstoichiometric aldehyde 2m into the reaction of vinyl ether 5b and triazine 1a
produced the desired IEDDA product 3m in comparable yield as the reaction with 2m
as the dienophile (entry 5); albeit the reaction took longer time to go to completion. A
crossover study was also conducted with vinyl ether 5a, and aldehyde 2m also
showed catalytic activity for the IEDDA reaction of vinyl ether 5a with triazine 1a
leading to the desired product 3a (entry 6). In order to demonstrate that the observed
effect is not simple due to the presence of carbonyl group, but an enolizable carbonyl
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group capable of delivering a proton, the reaction was conducted with benzophenone,
which is not enolizable thus cannot provide a proton. We found that benzophenone
cannot catalyze/promote the IEDDA reaction of 1a with 5b (details of this reaction
were summarized in the Supporting Information). These experiments supported our
hypothesis and the proposed reaction mechanism (Figure 1 and Scheme 3).
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Conclusion
In summary, the inverse electron demand DielsꢀAlder (IEDDA) reactions of
electronꢀdeficient 1,3,5ꢀtriazines and electronꢀdeficient aldehydes/ketones have been
developed and can be used to synthesize highly functionalized pyrimidines. In this
reaction, aldehydes/ketones are directly introduced as productive dienophiles for the
IEDDA reactions. The reaction mechanism was carefully studied by the combination
of experimental investigation and computational studies. The experimental results
indicated that the ihDA reactions occurred through a stepwise mechanism and an acid
was required for both ihDA and rDA reactions. Quantum chemical calculations
showed that aldehydes/ketones first protonated triazine to give enol and protonated
triazine, which are the real reactants for the DA reaction. The DA reaction is stepwise
and starts from CꢀC bond formation via TS1，which is then followed by cleavage of
C3ꢀN1 bond and release of nitrile (Figure 1). The rateꢀdetermining step is the C3ꢀN1
bond cleavage step via TS3 and the overall activation energy is 25.4 kcal/mol. This
mechanism was further supported by the discovery that aldehydes/ketones can
provide a proton to activate triazines, which can then take part in the otherwise
difficult IEDDA reaction with nonꢀproductive vinyl ethers. Our studies should break
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the dogma and traditional thinking of electronꢀrich dienophiles are required for the
IEDDA reaction with 1,3,5ꢀtriazines. The discovery of this new reaction should
provide impetus for chemists to rethink the classical IEDDA reactions, which may
open new areas/directions for IEDDA reactions. Based on the results and observation
from these studies, other IEDDA reactions with aldehydes/ketones will be designed
and developed.
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Experimental Section
General Methods. Acetonitrile (CH3CN), N,Nꢀdimethylformamide (DMF) and
Dichloroethane (DCE) was dried with CaH2 and distilled. 1,4ꢀDioxane and ethanol
(EtOH) were dried with Na and distilled. DMSO was dried with MgSO4 and distilled.
All other commercial reagents were used as received without additional purification.
Melting point was uncorrected. Mass spectra were obtained using the ESI method. 1H
13
NMR and C NMR spectra were recorded on 300 MHz and 75 MHz spectrometers
respectively with TMS as the internal standard, using CDCl3 or DMSOꢀd6 as solvents.
Data for 1H NMR spectra are reported as follows: chemical shift δ (ppm), referenced
to TMS; Multiplicities are indicated as the following: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; dd, doublet of doublets; coupling constants (Hz) and integration.
13
Data for C NMR spectra are reported in terms of chemical shift δ (ppm) relative to
residual solvent peak (CDCl3: 77.16 ppm; DMSOꢀd6: 39.50 ppm). HRMS was
recorded on an LC TOF (ES). Compounds 3aꢀ3c, 3eꢀ3f, 3iꢀ3j, 3o are known
compounds, and have been reported in the previous references.5b, 9, 21
General procedure for the synthesis of pyrimidines from ketones. To a stirred
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mixture of 1 (1.0 mmol) and ketone 2 (2.0 mmol) in EtOH (2.0 mL) was added TFA
(8.0 µL, 0.1 mmol) under nitrogen atmosphere. The resulting solution was stirred for
the corresponding time under reflux and then cooled to room temperature, quenched
with saturated NaHCO3 (10 mL). The aqueous layer was separated and extracted with
DCM (3 x 10 mL). The combined organic layer was dried over MgSO4, filtered, and
concentrated in vacuum. Purification of the resulting residue by flash column
chromatography (eluting with PE/EtOAc 5:1 to 2:1, v/v) afforded the product 3.
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Diethyl 6,7ꢀdihydroꢀ5Hꢀcyclopenta[d]pyrimidineꢀ2,4ꢀdicarboxylate (3a).21 (222 mg,
o
84%); yellow solid, mp: 43ꢀ44 C; 1H NMR (300 MHz, CDCl3) δ 4.58ꢀ4.46 (m, 4H),
3.39 (t, J = 7.8 Hz, 2H), 3.21 (t, J = 7.8 Hz, 2H), 2.30ꢀ2.19 (m, 2H), 1.49ꢀ1.43 (m,
6H). 13C NMR (75 MHz, CDCl3): δ 180.2, 164.3, 163.5, 155.9, 150.2, 138.5, 62.9,
62.6, 34.3, 30.7, 22.2, 14.31, 14.27. MS (ESI): m/z 265.1 [M + H+].
Diethyl 5,6,7,8ꢀtetrahydroquinazolineꢀ2,4ꢀdicarboxylate (3b).21 (217 mg, 78%);
o
1
yellow solid, mp: 41ꢀ42 C; H NMR (300 MHz, CDCl3) δ 4.57ꢀ4.43 (m, 4H),
3.10ꢀ2.99 (m, 4H), 1.98ꢀ1.83 (m, 4H), 1.47ꢀ1.41 (m, 6H). 13C NMR (75 MHz, CDCl3):
δ 170.1, 164.8, 163.5, 155.8, 153.8, 131.5, 62.8, 62.5, 33.0, 25.4, 21.7, 21.6, 14.3,
14.2. MS (ESI): m/z 279.1 [M + H+].
Diethyl 6,7,8,9ꢀtetrahydroꢀ5Hꢀcyclohepta[d]pyrimidineꢀ2,4ꢀdicarboxylate (3c).21
1
(251 mg, 86%); yellow oil; H NMR (300 MHz, CDCl3) δ 4.56ꢀ4.43 (m, 4H),
3.22ꢀ3.18 (m, 2H), 2.96ꢀ2.92 (m, 2H), 1.93ꢀ1.89 (m, 2H), 1.77ꢀ1.71 (m, 4H),
1.47ꢀ1.40 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 175.3, 165.4, 163.5, 156.2, 154.0,
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135.3, 62.8, 62.5, 39.0, 32.9, 29.2, 26.7, 25.7, 14.3, 14.2. MS (ESI): m/z 293.1 [M +
H+].
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Diethyl 5Hꢀindeno[1,2ꢀd]pyrimidineꢀ2,4ꢀdicarboxylate (3d). (271 mg, 87%);
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o
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yellow solid, mp: 142ꢀ144 C; H NMR (300 MHz, CDCl3) δ 8.36ꢀ8.33 (m, 1H),
7.71ꢀ7.53 (m, 3H), 4.63ꢀ4.53 (m, 4H), 4.37 (s, 2H), 1.54ꢀ1.49 (m, 6H). 13C NMR (75
MHz, CDCl3) δ 172.2, 164.3, 163.9, 156.9, 149.9, 146.0, 137.5, 136.5, 132.6, 128.0,
125.6, 123.5, 62.9, 62.7, 35.5, 14.3. HRMS (ESIꢀTOF): calcd. for C17H17N2O4 [M +
H]+ 313.1188; found 313.1191.
Diethyl 7,8ꢀdihydroꢀ5Hꢀpyrano[4,3ꢀd]pyrimidineꢀ2,4ꢀdicarboxylate (3e).9 (199 mg,
71%); yellow solid, mp: 82ꢀ83 C; 1H NMR (300 MHz, CDCl3) δ 5.13ꢀ5.12 (m, 2H),
o
4.58ꢀ4.45 (m, 4H), 4.10 (t, J = 6.0 Hz, 2H), 3.24ꢀ3.20 (m, 2H), 1.49ꢀ1.43 (m, 6H). 13C
NMR (75 MHz, CDCl3): δ 167.5, 164.1, 163.2, 154.9, 151.3, 132.0, 65.7, 64.2, 63.1,
63.0, 32.3, 14.3, 14.2. MS (ESI): m/z 281.1 [M + H+].
Diethyl 7,8ꢀdihydroꢀ5Hꢀthiopyrano[4,3ꢀd]pyrimidineꢀ2,4ꢀdicarboxylate (3f).9 (201
mg, 68%); yellow solid, mp: 50ꢀ51 C; 1H NMR (300 MHz, CDCl3) δ 4.57ꢀ4.45 (m,
o
4H), 4.08 (s, 2H), 3.40 (t, J = 6.3 Hz, 2H), 3.03 (t, J = 6.3 Hz, 2H), 1.48ꢀ1.42 (m, 6H).
13C NMR (75 MHz, CDCl3): δ 169.0, 164.3, 163.1, 154.4, 154.2, 129.6, 63.0, 62.9,
34.3, 26.3, 25.2, 14.2, 14.1. MS (ESI): m/z 297.1 [M + H+].
Diethyl 6ꢀmethylꢀ5,6,7,8ꢀtetrahydropyrido[4,3ꢀd]pyrimidineꢀ2,4ꢀdicarboxylate (3g).
o
1
(120 mg, 41%); yellow solid, mp: 124ꢀ125 C; H NMR (300 MHz, CDCl3) δ
4.66ꢀ4.36 (m, 4H), 3.94 (s, 2H), 3.25 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H), 2.55
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(s, 3H), 1.48ꢀ1.42 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 168.1, 164.3, 163.3, 154.4,
152.6, 130.5, 62.9, 62.7, 54.3, 51.1, 45.8, 33.0, 14.2, 14.1. HRMS (ESIꢀTOF): calcd.
for C14H20N3O4 [M + H]+ 294.1448; found 294.1456.
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Diethyl 6ꢀmethylpyrimidineꢀ2,4ꢀdicarboxylate (3h). (174 mg, 73%); yellow solid,
mp: 37ꢀ38 oC; 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 4.53 (m, 4H), 2.76 (s, 3H),
13
1.59ꢀ1.33 (m, 6H). C NMR (75 MHz, CDCl3) δ 171.1, 163.7, 163.3, 157.3, 155.8,
122.1, 63.0, 62.9, 24.6, 14.2, 14.1. HRMS (ESIꢀTOF): calcd. for C11H15N2O4 [M +
H]+ 239.1026; found 239.1038.
Diethyl 5ꢀmethylꢀ6ꢀphenylpyrimidineꢀ2,4ꢀdicarboxylate (3i).9 (223 mg, 71%);
o
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yellow solid, mp: 83ꢀ84 C; H NMR (300 MHz, CDCl3) δ 7.63ꢀ7.59 (m, 2H),
7.53ꢀ7.48 (m, 3H), 4.56ꢀ4.47 (m, 4H), 2.52 (s, 3H), 1.48ꢀ1.43 (m, 6H). 13C NMR (75
MHz, CDCl3): δ 169.0, 165.1, 163.4, 158.3, 154.3, 136.9, 130.0, 129.2, 128.7, 128.6,
62.8, 62.6, 16.1, 14.2, 14.1; MS (ESI): m/z 315.1 [M + H+].
Diethyl 6ꢀphenylpyrimidineꢀ2,4ꢀdicarboxylate (3j).21 (255 mg, 85%); yellow solid,
o
mp: 115ꢀ116 C; 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.28ꢀ8.25 (m, 2H),
7.59ꢀ7.54 (m, 3H), 4.60ꢀ4.52 (m, 4H), 1.52ꢀ1.47 (m, 6H). 13C NMR (75 MHz, CDCl3):
δ 167.3, 164.0, 163.5, 158.0, 156.8, 135.1, 132.3, 129.3, 127.8, 117.8, 63.1, 62.9, 14.2.
MS (ESI): m/z 301.1 [M + H+].
2,4ꢀBis(trifluoromethyl)ꢀ6,7ꢀdihydroꢀ5Hꢀcyclopenta[d]pyrimidine (3n). (207 mg,
1
81%); yellow oil; H NMR (300 MHz,CDCl3) δ 3.29ꢀ3.19 (m , 4H), 3.37ꢀ2.27 (m,
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2H). 13C NMR (75 MHz, CDCl3) δ 181.3, 135.2, 34.2, 28.8, 22.3. HRMS (ESIꢀTOF):
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calcd. for C9H7F6N2 [M + H]+ 257.0508; found 257.0501.
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6,7ꢀDihydroꢀ5Hꢀcyclopenta[d]pyrimidine (3o).5b (73 mg, 60%); yellow oil; 1H
NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 8.52 (s, 1H), 3.05ꢀ2.96 (m, 4H), 2.21ꢀ2.11 (m,
2H). 13C NMR (75 MHz, CDCl3) δ 157.1, 152.1, 34.2, 28.5, 22.6. MS (ESI): m/z
121.0 [M + H+].
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General procedure for the synthesis of pyrimidines from aldehydes. A mixture
of 1a (1.0 mmol) and aldehyde 2 (2.0 mmol) in EtOH (2.0 mL) was stirred in EtOH (2
mL) at reflux under nitrogen atmosphere. After 24 h, additional 2.0 mmol aldehyde 2
was added. The resulting solution was stirred for the corresponding time at reflux and
then cooled to room temperature, quenched with saturated NaHCO3 (10 mL). The
aqueous layer was separated and extracted with DCM (3 x 10 mL). The combined
organic layer was dried over MgSO4, filtered, and concentrated in vacuum.
Purification of the resulting residue by flash column chromatography (eluting with
PE/EtOAc 8:1 to 4:1, v/v) afforded the product 3.
1
Diethyl 5ꢀethylpyrimidineꢀ2,4ꢀdicarboxylate (3k). (78 mg, 31%); yellow oil; H
NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 4.55ꢀ4.46 (m, 4H), 2.94 (q, J = 7.5 Hz, 2H),
1.52ꢀ1.40 (m, 6H), 1.31 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 164.4,
163.0, 160.3, 155.9, 154.6, 137.7, 62.9, 62.7, 23.4, 14.9, 14.2, 14.1. HRMS
(ESIꢀTOF): calcd. for C12H17N2O4 [M + H]+ 253.1183; found 253.1185.
1
Diethyl 5ꢀmethylpyrimidineꢀ2,4ꢀdicarboxylate (3l). (115 mg, 48%); yellow oil; H
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NMR (300 MHz, CDCl3) δ 8.89 (d, J = 0.6 Hz, 1H), 4.58ꢀ4.46 (m, 4H), 2.59 (d, J =
0.6 Hz, 3H), 1.49ꢀ1.43 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 172.0, 165.1, 163.4,
156.6, 153.8, 121.1, 62.4, 62.3, 22.3, 14.0, 13.9. HRMS (ESIꢀTOF): calcd. for
C11H15N2O4 [M + H]+ 239.1026; found 239.1038.
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Diethyl pyrimidineꢀ2,4ꢀdicarboxylate (3m). (130 mg, 58%); yellow oil; H NMR
(300 MHz, CDCl3) δ 9.16 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 5.1 Hz, 1H), 4.60ꢀ4.49 (m,
4H), 1.51ꢀ1.44 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 163.1, 162.6, 159.8, 157.1,
156.0, 122.2, 62.7, 13.9, 13.8. HRMS (ESIꢀTOF): calcd. for C10H13N2O4 [M + H]+
225.0870; found 225.0877.
General procedure for the synthesis of Intermediates 4a and 4b. To a stirred
mixture of 1 (1.0 mmol) and ketone 2d (2.0 mmol) in EtOH (2.0 mL) was added TFA
(8 µL, 0.1 mmol) under nitrogen atmosphere. The resulting solution was stirred for
the corresponding time under reflux and then cooled to room temperature, quenched
with saturated NaHCO3 (10 mL). The aqueous layer was separated and extracted with
DCM (3 x 10 mL). The combined organic layer was dried over MgSO4, filtered, and
concentrated in vacuum. Purification of the resulting residue by flash column
chromatography (eluting with PE/DCM/EtOAc 3:1:1 to 1:1:1, v/v) afforded the
product 4.
Triethyl
4ꢀ(1ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀindenꢀ2ꢀyl)ꢀ1,4ꢀdihydroꢀ1,3,5ꢀtriazineꢀ2,4,6ꢀtricarboxylate
1
(4a). (73 mg, 17%); yellow oil; H NMR (300 MHz, DMSOꢀd6) δ 10.15 (s, 1H),
7.68ꢀ7.55 (m, 3H), 7.43ꢀ7.38 (m, 1H), 4.32ꢀ4.17 (m, 6H), 3.74 (dd, J = 8.1, 4.8 Hz,
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1H), 3.25 (dd, J = 17.4, 8.1 Hz, 1H), 2.89 (dd, J = 17.4, 8.1 Hz, 1H), 1.28ꢀ1.18 (m,
9H). 13C NMR (75 MHz, DMSOꢀd6) δ 203.3, 167.8, 159.62, 159.59, 153.5, 145.2,
144.7, 136.8, 134.7, 127.3, 126.7, 122.9, 81.1, 62.7, 62.6, 61.4, 54.9, 29.0, 13.8, 13.73,
13.68. HRMS (ESIꢀTOF): calcd. for C21H24N3O7 [M + H]+ 430.1609; found
430.1627.
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2ꢀ(2,4,6ꢀTris(trifluoromethyl)ꢀ2,5ꢀdihydroꢀ1,3,5ꢀtriazinꢀ2ꢀyl)ꢀ2,3ꢀdihydroꢀ1Hꢀinden
o
1
ꢀ1ꢀone (4b). (311 mg, 75%); white solid oil; Mp 95ꢀ96 C; H NMR (300 MHz,
DMSOꢀd6) δ 12.94 (s, 1H), 7.74ꢀ7.64 (m, 3H), 7.45 (t, J = 7.5 Hz, 1H), 3.45 (s, 3H).
13C NMR (75 MHz, DMSOꢀd6) δ 202.2, 153.0, 135.8, 135.4, 127.7, 126.6, 124.3,
123.2, 120.5, 52.2, 27.4. HRMS (ESIꢀTOF): calcd. for C15H9F9N3O [M + H]+
418.0596; found 418.0605.
Acknowledgments
The JLU authors are very grateful to Ms. Zhuoqi Zhang for her help and support in
the current research, in particular, LCꢀMS measurements. The experimental work was
supported by a grant from the National Natural Science Foundation of China (No.
81072526) and a grant from the SciꢀTech Development Project of Jilin Province in
China (No. 20140309010YY), and research support was provided by Changchun
Discovery Sciences, Ltd. ZXY thanks the Natural Science Foundation of China
(21232001) for financial support.
Supporting Information statement
This supporting information is available free of charge on the ACS Publications
website.
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Additional data for Tables 2 and 3 and quantum chemical calculations, the
crystallographic data, and copies of the 1H and 13C NMR (PDF)
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Crystal structure of 4b (CIF)
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