Hydrazones as Productive Dienophiles in the Inverse Electron Demand Diels-Alder Reactions of 1,3,5-Triazines

Article abstract of DOI:10.1002/ejoc.201500499

Enamines, ynamines and amidines are common dienophiles for inverse electron demand Diels-Alder (IEDDA) reactions of 1,3,5-triazines, however, their wide utilization may be limited due to their poor stability to conventional purification methods such as silica gel chromatography. To address this limitation, oximes and hydrazones are envisioned as potential alternative dienophiles, even though they are primarily used as protecting groups due to their excellent stability or lack of reactivity. Through investigation of substituent effects and optimization of reaction conditions, oximes and hydrazones were developed as productive dienophiles for 1,3,5-triazine IEDDA reactions, leading to the desired IEDDA products in moderate (for oximes) to excellent (for hydrazones) yields. Hydrazones are air-stable and can be conveniently purified by conventional methods, therefore the introduction of hydrazones as productive dienophiles further expanded the scope of 1,3,5-triazine IEDDA reactions. Through investigation of substituent effects and optimization of reaction conditions, oximes and hydrazones are introduced as productive dienophiles to expand the scope of the inverse electron demand Diels-Alder (IEDDA) reactions of 1,3,5-triazines, leading to the desired IEDDA products in moderate (for oximes) to excellent (for hydrazones) yields.

Full text of DOI:10.1002/ejoc.201500499

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500499
Hydrazones as Productive Dienophiles in the Inverse Electron Demand
Diels–Alder Reactions of 1,3,5-Triazines
Kai Yang,[a] Zhen Yang,[a] Qun Dang,*[a] and Xu Bai*[a]
Keywords: Hydrazones / Dienophiles / Heterocycles / Diels–Alder reactions / Cycloaddition
Enamines, ynamines and amidines are common dienophiles
for inverse electron demand Diels–Alder (IEDDA) reactions
of 1,3,5-triazines, however, their wide utilization may be
limited due to their poor stability to conventional purification
and optimization of reaction conditions, oximes and hydraz-
ones were developed as productive dienophiles for 1,3,5-tri-
azine IEDDA reactions, leading to the desired IEDDA prod-
ucts in moderate (for oximes) to excellent (for hydrazones)
methods such as silica gel chromatography. To address this yields. Hydrazones are air-stable and can be conveniently
limitation, oximes and hydrazones are envisioned as poten- purified by conventional methods, therefore the introduction
tial alternative dienophiles, even though they are primarily
used as protecting groups due to their excellent stability or
lack of reactivity. Through investigation of substituent effects
of hydrazones as productive dienophiles further expanded
the scope of 1,3,5-triazine IEDDA reactions.
dienophiles to those that could be readily distilled. To
address this limitation, the development of stable alterna-
tive dienophiles is necessary and significant. On the other
hand, oximes and hydrazones are commonly used as pro-
tecting groups for ketones because of their ease of prepara-
tion and excellent stability or lack of reactivity.[9] Therefore,
if oximes and hydrazones could be developed as productive
dienophiles, the scope of the IEDDA reaction could be fur-
ther expanded, which should facilitate wider utilization of
this methodology. We envisioned that oximes and hydraz-
ones could tautomerize to enamines under thermal condi-
tions, thus could potentially act as productive dienophiles
in 1,3,5-triazine IEDDA reactions (Scheme 1). Unfortu-
nately, no systematic study of oxime/hydrazone tautomeri-
zation was found in the literature. It is encouraging to find
that oximes and hydrazones have been reported to partici-
pate in the IEDDA reactions of 1,2,4,5-tetrazines.[10] How-
ever, 1,2,4,5-tetrazines are highly reactive azadienes com-
Introduction
Inverse electron demand Diels–Alder (IEDDA) reactions
of azadienes have been studied extensively due to their
proven utility in the rapid synthesis of nitrogen-containing
heterocycles, which include various natural products and
biologically active compounds.[1] To further expand the
scope and gain a fundamental understanding of the mecha-
nism of IEDDA reactions, additional efforts continue to be
devoted into this field.[2] Over the past three decades, the
development of 1,3,5-triazine IEDDA reactions has led to
the total syntheses of a series of natural products contain-
ing a pyrimidine moiety[3] and the preparation of highly
functionalized pyrimidines.[4] Among the reported examples
of 1,3,5-triazine IEDDA reactions, productive dienophiles
could be categorized into two groups: the classical non-aro-
matic electron-rich alkenes and alkynes such as en-
amines,[4a,4b,5] ynamines[4b] and amidines[4c] (which tauto-
merize to 1,1-diamino-alkenes), and the later discovered
electron-rich aromatic heterocycles, such as aminoimid-
azoles,[4e,6] aminopyrazoles,[4d,7] aminoindoles[2i,8] etc. En-
amines/ynamines are highly reactive species, therefore they
are moisture sensitive and will readily decompose/hydrolyze
under normal silica gel chromatography purification condi-
tions. Consequently, enamines/ynamines are often purified
by vacuum distillation,[4b] which limit the scope of enamine
[a] 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 Lu, Changchun, Jilin 130021, P. R. China
E-mail: dang3qun2@yahoo.com
xbai@jlu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500499.
Scheme 1. Design of oxime/hydrazone IEDDA reactions of 1,3,5-
triazines.
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Eur. J. Org. Chem. 2015, 4344–4347

Inverse Electron Demand Diels–Alder Reactions of 1,3,5-Triazines
pared with 1,3,5-triazines.[1f] It is of interest to develop ox- amount of IEDDA product (Ͻ 1% by LC-MS detection),
imes and hydrazones into productive dienophiles for and both starting materials remained (Table 1, entries 1–3).
IEDDA reactions of 1,3,5-triazines. Herein, we report the To drive the reaction to completion, we also tested the reac-
investigation of the IEDDA reactions of 1,3,5-triazines with tion under basic conditions: in the presence of diisopropyl-
oximes and hydrazones.
ethylamine (DIPEA), triazine 3a was consumed rapidly, but
no desired IEDDA product was detected (Table 1, entry 4).
Given that acids could activate triazines by protonation and
could potentially facilitate oxime/hydrazone tautomeri-
zation, we hypothesized that acetic acid might be too weak
to promote the current IEDDA reactions. Thus, pTsOH
and trifluoroacetic acid (TFA) were studied with acetic acid
as the solvent: to our delight, the desired IEDDA product
was isolated in moderate yields (Table 1, entries 5 and 6).
Using DMF as the solvent and TFA as the acid did not
produce appreciable IEDDA product (Table 1, entry 7), in-
dicating that strong acidic conditions are preferred. Optimi-
zation of the amount of TFA while keeping acetic acid as
the solvent led to the identification of TFA/AcOH = 1:9 as
the best conditions, producing the IEDDA product in 47%
yield (Table 1, entry 8).
Having discovered suitable conditions that enabled oxime
1a to participate in IEDDA reactions directly (likely by
tautomerization to its enamine form) leading to moderate
yields of IEDDA product, we turned our attention to
hydrazones by selecting hydrazone 2a for the initial investi-
gations. We reasoned that the enamine form of a hydrazone
might be more electron-rich than its corresponding oxime,
thus could be more reactive towards the IEDDA reaction
with a triazine. In contrast to the case of oxime 1a (Table 1,
entry 1), treatment of hydrazone 2a with triazine 3a in
DMF at 60 °C led to the desired IEDDA product 4.1 in
56% yield (Table 1, entry 9), without any acid present as an
additive. The much higher reactivity observed for hydraz-
one 2a compared with oxime 1a in the IEDDA reactions
could be due to either the higher reactivity of the enamine
form of hydrazone 2a compared with the enamine form of
oxime 1a or the higher propensity of hydrazone tautomeri-
zation to enamine compared with oxime tautomerization.
Further optimization of the reaction conditions with re-
gards to an acid additive and reaction temperature revealed
that addition of acetic acid speeds up the IEDDA reaction,
and the conditions of DMF/AcOH (1:1) as solvents at
60 °C is optimal for the current IEDDA reaction, produc-
ing IEDDA product 4.1 in excellent yield (92%, Table 1,
entry 13). It is noted that using the DMF/AcOH (1:1) as a
mixed solvent system, the IEDDA reaction with hydrazone
2a even proceeded at room temperature, albeit much slower
than under thermal conditions. Given that the oxime and
hydrazone of the same ketone will produce the same
IEDDA product and the much higher reactivity observed
for hydrazone 2a, we decided to conduct the IEDDA reac-
tion scope investigation only using hydrazones as the dieno-
Results and Discussion
To participate in IEDDA reactions, oximes and hydraz-
ones must first tautomerize to their corresponding enamine
forms. Therefore, it is critical to identify reaction conditions
that will facilitate the key tautomerization process. Unfortu-
nately, we could not find any systematic investigation of
oxime and hydrazone tautomerization in the literature.
Thus, we set out to investigate 1,3,5-triazine IEDDA reac-
tions with oximes and hydrazones under basic, neutral and
acidic conditions. Initially, triazine 3a and oxime 1a (oximes
and hydrazones were prepared using conventional methods
and experimental details are reported in the Supporting In-
formation) were selected for the study of various IEDDA
reaction conditions, Table 1.
Table 1. Exploration of triazine IEDDA reactions with oxime 1a
and hydrazone 2a.[a]
Entry Dienophile
Conditions
Time Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
DMF, 120 °C
DMF/AcOH (1:1), 120 °C
AcOH, 120 °C
2 d
2 d
0[c]
0[c]
0[c]
0[d]
17
37
0[c]
47
42
56
50
80
92
85
2 d
6 h
DIPEA (2 equiv.), DMF, 25–120 °C
pTsOH (2.0 equiv.), AcOH, 100 °C
TFA (2.0 equiv.), AcOH, 100 °C
TFA (2.0 equiv.), DMF, 120 °C
TFA/AcOH (1:9), 100 °C
TFA/AcOH (2:8), 100 °C
DMF, 60 °C
5 h
1.5 d
2 d
24 h
16 h
2 d
DMF/AcOH (1:1), 25 °C
DMF/AcOH (1:1), 50 °C
DMF/AcOH (1:1), 60 °C
DMF/AcOH (1:1), 80 °C
14 d
20 h
6 h
3 h
[a] All reactions were conducted using 0.5 mmol 3a (1.0 equiv.) and
1.0 mmol 1a or 2a (2.0 equiv.) in a specified solvent (1 mL) under
nitrogen and monitored by LC-MS. [b] Isolated yield. [c] Both
starting materials remained. [d] 3a was consumed.
IEDDA reactions with azadienes are often conducted in philes.
polar solvents and sometimes in the presence of a weak
Before embarking on the investigation of the scope of
acid (acetic acid).[4c–4e,6] Therefore, thermal conditions with hydrazone–triazine IEDDA reactions, we explored the N,N-
DMF and AcOH as the solvents were selected for the initial substituents of the hydrazones (Scheme 1, R3, R4) since
studies. Reactions of triazine 3a and oxime 1a in either they could also impact the rate of the key tautomerization
DMF or AcOH, or a mixture of them only produced trace step (1 to A, Scheme 1), Table 2, entries 1–8.
Eur. J. Org. Chem. 2015, 4344–4347
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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K. Yang, Z. Yang, Q. Dang, X. Bai
SHORT COMMUNICATION
Table 2. Investigation of the N,N-substituents of hydrazones in tri- observations. Having established that hydrazones of 1-in-
azine IEDDA reactions.[a]
danone could function as productive dienophiles in IEDDA
reactions with triazines, it is important to demonstrate that
hydrazones from other ketones could also participate in
IEDDA reactions directly.
To explore the scope of hydrazones, N-piperidin-1-yl
hydrazones from various ketones were subjected to the
IEDDA reactions with triazine 3a and the results are sum-
marized in Table 3.
Table 3. IEDDA reactions of hydrazones 2i–2u and triazines 3a.[a]
Entry
X (NR3R4)
2
3
Time
4
Yield [%][b]
1
2
3
4
5
6
7
8
9
1-piperidinyl
NH2
NHPh
N(Me)Ph
NPh2
2a
2b
2c
2d
2e
2f
2g
2h
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
6 h
12 h
24 h
22 h
2.5 d
9 h
12 h
10 d
4 h
4.1
4.1
4.1
4.1
4.1
4.1
4.1
4.1
4.2
4.3
92
0
0
72
43
76
88
35
75
60[c]
NMe2
N(Me)Bn
N(Me)Ac
1-piperidinyl
1-piperidinyl
Entry
R1
R2
2
Temp [°C] Time [h]
4
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Me 2i
Me 2i
60
80
60
80
80
80
80
80
80
100
60
60
60
60
80
60
80
72
9
96
10.5
22
9
32
12
9
24
4
16
18
36
12
60
16
4.4
4.4
4.5
4.5
4.6
4.7
4.8
4.9
4.10
–
4.11
4.12
4.13
4.14
4.14
4.15
4.15
78
75
70
79
75
89
68
74
90
0[b]
75
82
88
70
68
72
74
10
24 h
[a] All reactions were conducted using 0.5 mmol 3 (1.0 equiv.) and
1.0 mmol 2 (2.0 equiv.) in DMF/AcOH (1:1, 1 mL) under nitrogen
at 60 °C and monitored by LC-MS. 3 was completely consumed in
all reactions. [b] Isolated yield. [c] This reaction was conducted
using 0.5 mmol 3c (1.0 equiv.), 1.0 mmol 2a (2.0 equiv.) and
1.0 mmol AcOH (2.0 equiv.) in 1,4-dioxane (1 mL) under nitrogen
at 60 °C for 24 h.
H
H
H
H
H
H
H
2j
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
Ph
p-ClPh
p-MeOPh
p-NO2Ph
2-pyridyl
2-furanyl
–(CH2)2–
–(CH2)3–
–(CH2)4–
–(CH2)5–
In contrast to the excellent yield obtained with hydraz-
one 2a, hydrazones 2b and 2c did not generate any detect-
able amount of IEDDA product (Table 2, entries 1–3) even
though all triazine 3a was consumed. We suspected that the
nucleophilic amino group (R4 = H) could react with tri-
azine 3a[4c–4e,6] which consumed triazine 3a thus preventing
the desired IEDDA reaction from occurring. It is interest-
ing to note that triazine 3a was also consumed under basic
reaction conditions (Table 1, entry 4) without producing the
–(CH2)2OCH2–
–(CH2)2OCH2–
–(CH2)2SCH2–
–(CH2)2SCH2–
2t
2u
2u
[a] All reactions were conducted using 1.0 mmol 3a (1.0 equiv.) and
2.0 mmol 2 (2.0 equiv.) in DMF/AcOH (1:1, 2 mL) under nitrogen;
yields are based on isolated products. [b] Triazine 3a was consumed
and some hydrazone 2p remained, but no IEDDA product was
desired IEDDA product. Hydrazones with various aryl and detectable.
alkyl groups (R3 and R4) are tolerated by the current
IEDDA reaction. However, lower yields of the IEDDA
Hydrazones (2i–2o) from acyclic ketones were investi-
product were observed compared with hydrazone 2a gated first (Table 3, entries 1–9). The reaction between
(Table 2, entries 4–7). To probe the electronic effects of the hydrazone 2i and triazine 3a proceeded much slower and
R3 group on the tautomerization of hydrazones, an elec- gave a lower yield of the IEDDA product 4.4 than the case
tron-withdrawing group (an acetyl group, entry 8, Table 2) with hydrazone 2a (Table 1, entry 13). The higher reactivity
was tested, even though it could reduce the activity of the observed for hydrazone 2a compared with 2i could be due
resulting enamine generated by the tautomerization of a to the ring strain energy of 2a. However, raising the reaction
hydrazone. Reaction of hydrazone 2h with triazine 3a was temperature to 80 °C did speed up the reaction to a similar
much slower and gave much lower yield compared with the rate compared with the case with hydrazone 2a. Similar to
reaction with hydrazone 2a. This observation indicates that hydrazone 2i, hydrazone 2j showed higher reactivity at
acetyl as R3 did not help to promote the tautomerization 80 °C without compromising the yield of the IEDDA prod-
of 2h, but did reduce its reactivity in the current IEDDA uct. Therefore, we studied the IEDDA reactions with the
reaction. Investigation of R3 and R4 groups revealed that remaining hydrazones (2k–2o) at 80 °C (Table 3, entries 5–
the N-piperidin-1-yl hydrazone is optimal for the current 9). Aryl hydrazones (2k–2m) with various functional
IEDDA reactions. Thus, hydrazone 2a was selected to ex- groups, such as halo, alkoxy and nitro groups, are good
plore the scope of triazines. Reaction of triazine 3b with substrates producing IEDDA products in good to excellent
hydrazone 2a proceeded smoothly, but gave a slightly lower yields (Table 3, entries 5–7). Heteroaryl hydrazones (2n–2o)
yield compared with triazine 3a (entry 9, Table 2). The un- are also productive dienophiles for the current IEDDA re-
substituted triazine 3c is much less reactive (Table 2, entry action (Table 3, entries 8 and 9). It is noted that electron-
10) than triazines 3a and 3b, which is consistent with past rich hydrazones (2l and 2o) are more reactive and give
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Inverse Electron Demand Diels–Alder Reactions of 1,3,5-Triazines
higher yields of the IEDDA products than other acyclic
hydrazones (2i–2k, 2m–2n). In addition to the indane
hydrazone 2a, other carbocyclic and heterocyclic hydraz-
ones (2p–2u) were studied (Table 3, entries 10–17). With the
exception of cyclobutyl hydrazone 2p, all cyclic hydrazones
effectively participated in the current IEDDA reaction gen-
erating desired IEDDA products in good to excellent yields.
Triazine 3a did react with hydrazone 2p, but the desired
IEDDA product was not detected, which could be due to
that the high strain energy of the final IEDDA product pre-
vents its formation.
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Conclusions
To expand the scope of the IEDDA reactions of 1,3,5-
triazines, oximes and hydrazones are introduced as pro-
ductive dienophiles for the first time. The unexpected real-
ization of hydrazones as productive dienophiles in the
IEDDA reactions of 1,3,5-triazines was the result of a study
of oximes and hydrazones with regards to substituent ef-
fects and reaction conditions. Our investigation revealed
that hydrazones are more reactive than oximes, producing
the desired IEDDA products in good to excellent yields.
The scope for the hydrazone IEDDA reactions were further
investigated using various acyclic and cyclic hydrazones.
Acyclic aryl hydrazones (2k–2m) and heteroaryl hydrazones
(2n–2o) with various functional groups, such as halo, alkoxy
and nitro groups, are good substrates producing IEDDA
products in good to excellent yields (68–90%). Moreover,
carbocyclic and heterocyclic hydrazones (2q–2u) are pro-
ductive dienophiles for the current IEDDA reaction gener-
ating IEDDA products in good to excellent yields (70–
88%). The broad scope for this new hydrazone IEDDA re-
action and the easy accessibility of a wide range of hydraz-
ones should complement existing IEDDA methodologies
and further expand the scope for 1,3,5-triazine IEDDA re-
actions.
[3]
[4]
Experimental Section
General Procedure for the Synthesis of Pyrimidines 4 from Hydraz-
ones 2: A solution of 1,3,5-triazine 3 (1.0 mmol) in DMF/AcOH
(2.0 mL) under N2 was treated with hydrazone 2 (2.0 mmol). The
resulting mixture was heated to 60 °C for corresponding time, then
cooled to room temperature, and quenched with saturated
NaHCO3 (10 mL). The aqueous layer was separated and extracted
with CH2Cl2 (3ϫ 10 mL). The combined organic layers were dried
with MgSO4, filtered, and concentrated in vacuo. Purification of
the resulting residue by flash column chromatography afforded the
product 4.
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Acknowledgments
The authors are very grateful to Ms. Zhuoqi Zhang for her help
and support in the current research, in particular, LC-MS measure-
ments. This work was supported by a grant from the National Nat-
ural Science Foundation of China (No. 81072526). Additional sup-
port was provided by Changchun Discovery Sciences, Ltd.
Received: April 21, 2015
Published Online: June 3, 2015
Eur. J. Org. Chem. 2015, 4344–4347
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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