Phototriggered Dehydration Condensation Using an Aminocyclopropenone

Article abstract of DOI:10.1021/acs.orglett.7b02383

A phototriggered dehydration condensation using an aminocyclopropenone has been developed. The UV irradiation of an aminocyclopropenone generated a highly reactive ynamine in situ and the dehydration condensation of a carboxylic acid and an amine coexisting in the reaction solution smoothly proceeded to afford an amide. This reaction is completely controllable by the ON/OFF states of a UV lamp.

Full text of DOI:10.1021/acs.orglett.7b02383

Letter
pubs.acs.org/OrgLett
Phototriggered Dehydration Condensation Using an
Aminocyclopropenone
Kenji Mishiro,*,† Yuki Yushima,‡ and Munetaka Kunishima*,‡
‡
†Institute for Frontier Science Initiative and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health
Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 Japan
S
* Supporting Information
ABSTRACT: A phototriggered dehydration condensation using an amino-
cyclopropenone has been developed. The UV irradiation of an amino-
cyclopropenone generated a highly reactive ynamine in situ and the
dehydration condensation of a carboxylic acid and an amine coexisting in the
reaction solution smoothly proceeded to afford an amide. This reaction is
completely controllable by the ON/OFF states of a UV lamp.
hototriggered chemical reactions have attracted consider-
able attention because of the following unique features: (i)
acid to an acid anhydride, and a carboxylic acid and an amine to
an amide.15 Despite the high reactivity, ynamines are rarely used
in synthesis because of their low stability and complicated
preparation procedure. Recently, an ynamide was reported as a
stable and racemization-free condensing agent.16 However, an
ynamide is generally less reactive than an electron-rich ynamine
as a compensation for its high stability.
We envisioned that if a highly reactive ynamine is photolyti-
cally generated from an aminocyclopropenone and used for the
following reaction in situ, the high reactivity of the ynamine can
be exploited without complicated handling and the generation of
the ynamine would be controllable by the ON/OFF states of
light irradiation (Scheme 1).
P
the reaction can be initiated and terminated whenever required,
(ii) the location of the reaction can be controlled by regulating
the irradiation site, (iii) the activation of a specific chromophore
is possible by selecting an appropriate wavelength, and (iv)
highly reactive species can be generated in situ under mild
conditions. These features are particularly useful for the fine
control of the polymer synthesis1 and the chemical modification
of biomolecules.2 In phototriggered chemical reactions, photo-
excited species could form reversible active intermediates3 or
photolytically generate active species, such as radicals,4
carbenes,5 nitrenes6 and nitrile imines.7 These species have
mostly been used for insertion, addition, and abstraction
reactions. To the best of our knowledge, there has been no
report focusing on phototriggered dehydration condensation.
Because dehydration condensation is abundantly observed in
multiple situations, such as polymer synthesis, biomolecule
synthesis, and biological processes, phototriggered dehydration
condensation would be useful for the local control of these
reactions with light.
Aminocyclopropenones with various substituents 4a−f were
readily prepared according to the procedures reported in the
literature14 (Scheme 2). All of 4a−f was isolable using SiO2
column chromatography. These compounds are colorless or
Scheme 1. Design of a Phototriggered Dehydration
Condensation
Herein, we report the first phototriggered dehydration
condensation using an aminocyclopropenone as a photolabile
“caged” dehydrating agent. Cyclopropenone is a highly strained
cyclic enone with 2π aromaticity, which was first reported by
Breslow.8 Because of the strain, the ring-opening reaction occurs
in the presence of an appropriate nucleophile.9 The ring strain is
also released by thermal8,10 or photochemical11 decarbonylation
to afford the corresponding alkyne. Cyclopropenones are
normally stable under ambient conditions, and the thermal
decarbonylation occurs at a high temperature.8 In contrast,
photochemical decarbonylation efficiently occurs at ambient
temperature with a quantum yield of 0.2−0.8.11b Popik
demonstrated a broad range of applications of the phototriggered
alkyne formation, such as phototriggered alkyne−azide click
reaction12 and phototriggered en-diyne formation.13 Kresge
reported photoexcitation of an aminocyclopropenone generates
carbon monoxide and an aminoalkyne (ynamine).14 An ynamine
acts as a potent dehydrating agent, which converts a carboxylic
Received: August 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02383
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Organic Letters
Letter
5). In general, electron-rich ynamines are more reactive than
electron-poor ynamines.17 Thus, the decompositions observed
for 4a−c were possibly related to the high reactivity of the
produced ynamines. Consequently, for 4a−c, corresponding
ynamines were indirectly detected as stable amides 6a−c that are
formed by the hydration of the ynamines under the MeCN/H2O
(1/1) condition (entries 2, 4, and 6).
Scheme 2. Synthesis of Aminocyclopropenones 4a−f
Subsequently, the phototriggered dehydration condensation
was examined (Table 2). A solution of 4, carboxylic acid 7a, and
Table 2. Phototriggered Dehydration Condensation Using
Aminocyclopropenones
slightly yellow and stable under household fluorescent light. The
UV spectra were recorded for synthesized 4a−f in MeCN
(Figure 1). All of the aminocyclopropenones showed similar
a
a
time
(h)
9aa yield
(%)
dark conditions yield
(%)
entry
NR1R2
1
2
3
4
5
6
NEt2 (4a)
3
2
5
5
5
2
57
55
15
30
14
0
1
0
2
0
0
0
NiPr2 (4b)
NBn2 (4c)
NMePh (4d)
NPh2 (4e)
NiPrAc (4f)
a
Figure 1. UV spectra of 4a−f in MeCN.
NMR yield.
spectra pattern having absorption around the 200−350 nm
region. The decomposition of the aminocyclopropenones during
the UV measurement was negligibly small.
First, the phototriggered ynamine generation from 4 was
examined (Table 1). Unexpectedly, a weak hand-held UV lamp,
amine 8a in MeCN was irradiated under the same conditions as
that of the ynamine formation experiment until 4 disappeared.
After the irradiation was stopped, the reaction was rapidly
quenched by the acid/base workup, and the yield of amide 9aa
was determined via NMR analysis. The condensation of 7a and
8a satisfactorily proceeded to afford 9aa for most of 4. Ethyl- and
isopropyl-substituted aminocyclopropenones resulted in a
relatively high 9aa yield (entries 1 and 2), while the benzyl-
substituted aminocyclopropenone resulted in a low yield of 9aa,
and a considerable number of byproducts were observed (entry
3). Aryl- substituted aminocyclopropenones resulted in a low
yield of 9aa, probably because of the low reactivity of the
generated ynamines (entries 4 and 5). For 4f, 9aa was not
obtained, and ynamine 5f was recovered in 70% yield (entry 6).
A plausible mechanism for the phototriggered reaction is
shown in Scheme 3. The photoexcitation of an amino-
Table 1. Ynamine Generation from Aminocyclopropenones
a
time
(h)
major
product
yield
(%)
entry
NR1R2
solvent
MeCN
1
2
NEt2 (4a)
3
3
dec
54
MeCN/water
(1/1)
6a
6b
3
4
NiPr2 (4b)
NBn2 (4c)
MeCN
2
3
dec
65
MeCN/water
(1/1)
Scheme 3. Plausible Mechanism of the Phototriggered
Dehydration Condensation
5
6
MeCN
5
5
dec
70
MeCN/water
(1/1)
6c
7
NMePh
(4d)
MeCN
5
5d
85
8
9
NPh2 (4e)
MeCN
5
2
5e
5f
92
63
NiPrAc (4f) MeCN
a
NMR yield.
which is generally used for TLC analysis, was sufficient for the
photolysis reaction. The MeCN solutions of 4 in a quartz tube
were irradiated with a 6 W UVB lamp (280−350 nm) that was
placed 4 cm from the reaction vessel until complete consumption
of 4. Aryl- or acyl-substituted aminocyclopropenones 4d−f
produced the corresponding ynamines 5d−f in 63%−92% yield
(entries 7−9), while alkyl-substituted aminocyclopropenones
4a−c resulted in unidentified complex mixtures (entries 1, 3, and
cyclopropenone 4 produces an ynamine 5. Subsequently, 5
reacts with a carboxylic acid 7 to form a carboxylic acid−ynamine
adduct 10. Finally, 10 reacts with an amine 8 to afford a
condensed product 9 and a hydrated ynamine 6.
For 4a and 4c, a small amount of 9aa was formed even under
dark conditions (Table 2, entries 1 and 3). The background
reaction in these conditions did not yield the hydrated ynamine
6, which should be observed if the ynamine 5 would be involved
B
DOI: 10.1021/acs.orglett.7b02383
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Organic Letters
Letter
in 9aa formation. Therefore, the background reaction would
occur with a mechanism different from that of the phototriggered
dehydration condensation.18
Because 4b resulted in a good condensation yield without the
background reactions, the reaction condition was further
optimized with 4b (Table 3). For all conditions, UV irradiation
Table 3. Optimization of the Conditions
UV
conditions
b
concn temp
(lamp,
time yield
a
entry
solvent
MeCN
(mM) (°C) distance )
(h)
(%)
1
20
20
20
20
20
20
20
20
20
40
20
40
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
40
0
UVB, 4 cm
UVB, 4 cm
UVB, 4 cm
UVB, 4 cm
UVB, 4 cm
UVB, 4 cm
UVB, 4 cm
UVB, 4 cm
UVB, 4 cm
UVB, 4 cm
UVB, 8 cm
UVB, 8 cm
UVC, 4 cm
UVB, 8 cm
UVB, 8 cm
2
3
2
2
2
2
2
2
2
2
3
5
4
3
3
55
1
2
MeCN/H2O (1/1)
THF
Figure 2. Monitoring of the phototriggered reaction by NMR.
3
39
39
60
80
80
80
66
85
88
85
84
87
77
4
1,4-dioxane
AcOEt
In the NMR study, intermediates such as an ynamine and an
active ester were not observed, and the reaction did not progress
under dark conditions. The results indicated that the
condensation rapidly completed after the ynamine generation
and that the reaction is completely controllable by ON/OFF
states of the UV irradiation.
5
6
CH2Cl2
7
CHCl3
8
1,2-DCE
toluene
9
10
11
12
13
14
15
CH2Cl2
The phototriggered condensation with various substrates
proceeded with approximately 70−90% yield (Figure 3). For the
CH2Cl2
CH2Cl2
CH2Cl2
1,2-DCE
CH2Cl2
a
b
Distance between the lamp and the reaction vessel. NMR yield.
was performed until 4b disappeared. Solvent screening showed
that chlorinated solvents were the best candidates for this
reaction (entries 1−9). In the presence of water, the
condensation yield was very low probably because the photo-
generated ynamine was rapidly hydrated (entry 2). Higher
concentration and longer irradiation distance resulted in higher
9aa yield but decreased the photodecarbonylation rate. The
slower rate was probably due to a lower irradiation efficiency
(entries 10−12). The UVC (240−260 nm) also initiated the
reaction and resulted in a good yield (entry 13). The temperature
difference did not affect the photodecarbonylation rate.
However, low temperature conditions resulted in a slightly
lower condensation yield (entries 14 and 15). Consistently, for
low-yielding conditions, multiple byproducts were observed.
Although the byproducts have not been identified yet, they could
have been formed by thermal rearrangements or photoexcitation
of the reaction intermediates competing with the dehydration
condensation to afford 9aa. In general, photochemical reactions
efficiently occur under intense light and low concentration
conditions. However, for the phototriggered dehydration
condensation using aminocyclopropenones, the light should
not be too intense and the concentration should not be too low
to avoid the undesired side reactions.
Figure 3. Phototriggered dehydration condensation of various
substrates. (a) 1.0 equiv carboxylic acid was used. (b) 2.0 equiv
carboxylic acid was used. (c) NMR yield. (d) Isolated yield.
secondary and tertiary carboxylic acids, 2.0 equiv of carboxylic
acid was used to improve the yield. In general, less reactive bulky
starting materials tended to afford multiple byproducts, which
were probably generated by thermally or photochemically
induced side reactions of the intermediates.
Finally, a naphthalene-conjugated aminocyclopropenone 4g
was synthesized and employed for the phototriggered dehy-
dration condensation. As shown in Figure 4, 4g absorbed longer
wavelengths than 4b. For the phototriggered reactions, UVA
(330−400 nm), UVB (280−350 nm), or UVC (240−260 nm)
were used as light sources (Table 4). The reactions with 4g
To investigate the details of the phototriggered dehydration
condensation, the reaction progress was monitored by 1H NMR
(Figure 2). A solution of 4b, 7a, 8a, and 1,3,5-trimethoxybenzene
(as an internal standard) in CDCl3 was irradiated with the UVB
in a glass NMR tube. The NMR spectrum was observed within
20 min after the irradiation was stopped.
C
DOI: 10.1021/acs.orglett.7b02383
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
■
This research was supported by MEXT KAKENHI, Grant No.
16H06824. K.M. acknowledges support from the Program to
Disseminate Tenure Tracking System, MEXT. K.M. acknowl-
edges Prof. Tristan H. Lambert (Columbia University) for
helpful discussions.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02383.
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Detailed experimental procedures for the synthesis of
1
aminocyclopropenones and photochemical reactions; H
and 13C NMR spectra of all new compounds (PDF)
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̈
̈
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mishiro@p.kanazawa-u.ac.jp.
*E-mail: kunisima@p.kanazawa-u.ac.jp.
(18) For more detailed information, see the Supporting Information.
ORCID
Kenji Mishiro: 0000-0002-5071-7574
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b02383
Org. Lett. XXXX, XXX, XXX−XXX