Phototriggered Ketone Formation from an Aminocyclopropenone and a Carboxylic Acid

Article abstract of DOI:10.1021/acs.joc.8b02250

A novel phototriggered functionalization reaction of a carboxylic acid using an aminocyclopropenone has been developed. Irradiation of an aminocyclopropenone and carboxylic acid mixture generated ketones that possessed substituents from both the carboxylic acid and the aminocyclopropenone. This reaction occurred through two distinct phototriggered processes. Using this reaction, substituents in an aminocyclopropenone can be connected with a carboxylic acid containing molecule.

Full text of DOI:10.1021/acs.joc.8b02250

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Note
Phototriggered Ketone Formation from an
Aminocyclopropenone and a Carboxylic Acid
Kenji Mishiro, Yuki Yushima, and Munetaka Kunishima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02250 • Publication Date (Web): 27 Sep 2018
Downloaded from http://pubs.acs.org on September 27, 2018
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Page 1 of 11
The Journal of Organic Chemistry
Phototriggered Ketone Formation from an Aminocyclopropenone
and a Carboxylic Acid
Kenji Mishiro*†, Yuki Yushima‡ and Munetaka Kunishima*‡
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†Institute for Frontier Science Initiative, Kanazawa University, Kakumaꢀmachi, Kanazawa 920ꢀ1192 Japan
‡Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kaꢀ
kumaꢀmachi, Kanazawa 920ꢀ1192 Japan
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Supporting Information Placeholder
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ABSTRACT: A novel phototriggered functionalization reaction of a carboxylic acid using an aminocyclopropenone has been deꢀ
veloped. Irradiation of an aminocyclopropenone and carboxylic acid mixture generated ketones that possessed substituents from
both the carboxylic acid and the aminocyclopropenone. This reaction occurred through two distinct phototriggered processes. Using
this reaction, substituents in an aminocyclopropenone can be connected with a carboxylic acid containing molecule.
Phototriggered bond formation reactions have attracted conꢀ
siderable attention, especially in the fields of polymer science
intense light conditions; thus, they were likely produced via a
photochemically induced side reaction. Here, we report the
detailed study of the side reaction and a potential application
of it toward the functionalization of carboxylic acids.
,
and biological research.1 2 This technique has been used to
selectively construct stable bonds at the precise location where
a photoreactive group and the target molecule coexist. To date,
various photoreactive groups, such as benzophenone,3 diazirꢀ
ine,4 and azide,5 have been used for the phototriggered conjuꢀ
gations. These reaction precursors are photoexited and generꢀ
ate biradical, carbene, or nitrene as active species, respectively.
These species are so reactive that they can react with inert CꢀH
bonds, leading to effective bond formation with poorly reacꢀ
tive targets, while undesired bond formation or quenching of
the active species could be occasionally problematic. Recently
a photoaffinity labeling method of a carboxylic acid using a
tetrazole derivative was reported by Yao et al.6 In this method,
the tetrazole was used as a photolabile precursor of a nitrile
imine, which selectively reacts with a carboxylic acid to form
a stable acyl hydrazide. Because of the relatively high populaꢀ
tion of carboxylic acids on the surface area of proteins, a carꢀ
boxylic acid is a promising target for a ligand directed specific
functionalization method7. In fact, the phototriggered funcꢀ
tionalization of a carboxylic acid using a tetrazole derivative
could yield superior results compared to classical photoaffinity
Scheme 1. Mechanism of the phototriggered dehydration
condensation using an aminocyclopropenone.
In order to identify the structures of the side products from
the phototriggered dehydration condensation, the reaction
conditions were optimized to increase the side product yield.
Aminocyclopropenone 1a, carboxylic acid 2a, and amine 3a
were used as model substrates. A mixture of 1a, 2a, and 3a
were irradiated with UV light until 1a was completely conꢀ
sumed; thereafter, the products were analyzed after an aqueous
work up (Table 1). Under the optimal conditions for the phoꢀ
totriggered dehydration condensation (condition A: 6W handꢀ
held UVB lamp), 1a was completely consumed after 3 h, and
amide 4aa was obtained in 88% yield with a small amount of
the side products (entry 1). In contrast, under intense light
condition (condition B: 80 W medium pressure Hg lamp with
<300 nm cutoff filter), 1a was consumed rapidly (in 5 min)
and the 4aa yield decreased to 33%. On the other hand, the
side products were obtained in 44% combined yield, and they
were identified to be ketones 8aa, 9aa, and 10aa (entry 2).
When the irradiation was performed with the 6W handꢀheld
UV lamp (condition A) for 3 h and 80W Hg lamp (condition
B) for 5 min successively, 4aa was obtained in 87% and the
combined 8aa‒10aa yield was less than 3% (entry 3). Thereꢀ
6c
labeling methods.6b, In addition to biological studies, the
tetrazoleꢀbased phototriggered conjugation reaction has been
applied to the modification of polymers.8 As demonstrated in
these examples, phototriggered functionalization methods
targeting carboxylic acids could be useful tools for advancing
biology and polymer science.
Photodecarbonylation of a cyclopropenone is a useful reacꢀ
tion for generating a reactive alkyne derivative in situ, as
demonstrated by Popik et al.9 Recently, we reported a photoꢀ
triggered dehydration condensation of a carboxylic acid and an
amine using an aminocyclopropenone (Scheme 1).10 In this
reaction, photodecarbonylation of aminocyclopropenone 1
forms highly reactive ynamine 611 followed by a formation of
acyloxyenamine 7 from ynamine 6 and carboxylic acid 2.
Consequent aminolysis of 7 with 3 yields amide 4 and hydratꢀ
ed ynamine 5.12 In our original publication, unidentified side
products were found when irradiation was performed under
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fore, formation of 8aa‒10aa should occur before the amiꢀ various solvents were irradiated under condition B until 1a
1
2
3
4
5
6
7
8
dation reaction, probably by the photoinduced rearrangement
of the acyloxyenamine 7aa produced from the in situ generatꢀ
ed ynamine and a carboxylic acid (Scheme 2). When the reacꢀ
tion was performed without an amine, the combined 8aa‒10aa
yield was 20%. This indicated that acidic conditions were unꢀ
suitable for ketone formation (entry 4). It might be because
protonation of acyloxyenamine 7aa by a carboxylic acid deꢀ
composes 7aa or changes the photochemical reactivity of 7aa.
In the presence of 1.0 equiv. of triethylamine, the combined
8aa‒10aa yield increased to 75% (entry 5).
was consumed and the products were analyzed after an aqueꢀ
ous work up. Solvent screening showed that DCM was the
best reaction solvent. MeCN, THF, and AcOEt all afforded
8aa‒10aa in moderate yields. CHCl3 and toluene afforded
8aa‒10aa in relatively low yields. The regioselectivity of the
product ketones was independent of the reaction solvent (entry
1‒7). Remarkably, the reaction completed in 5 min even at
0 °C, and products 8aaꢀ10aa were obtained in comparable
yields to the reaction performed at 20 °C (entry 8). Under
aqueous conditions, the yield of the ketones decreased signifiꢀ
cantly due to the hydrolysis of the in situ generated ynamine
or acyloxyenamine (entry 9). Therefore, for the functionalizaꢀ
tion of a carboxylic acid in aqueous media, the reaction
chemoselectivity for a carboxylic acid over water must be
improved by structural modifications of an aminocyclopropeꢀ
none.
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Table 1. Irradiation conditions study for optimizing side
product formation.
Table 2. Optimization of the phototriggered ketone forꢀ
mation reaction.
entry
irradiation condition
yield (%)a
4aa 8aa 9aa 10aa
1b
2
A (3 h)
B (5 min)
A (3 h) + B (5 min)
B (5 min)
88
33
87
ꢀ
3
27
3
12
45
<1
11
<1
7
<1
6
<1
1
3
4c
5d
B (5 min)
ꢀ
19
11
Entry
solvent
temp.
(°C)
time
(min)
yield (%)a
8aa/9aa/10aa
irradiation condition A: 6W handꢀheld UVB lamp.
comꢀ
binedb
75
irradiation condition B: 80W medium pressure Hg lamp with
<300 nm cutoff filter.
1
2
3
4
5
6
7
8
9
DCM
CHCl3
MeCN
THF
20
20
20
20
20
20
20
0
5
10
5
45/19/11
16/5//2
b
c
aNMR yield. Data obtained from the reference10. 3a was not
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59
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65
57
45
80
4
added. d3a replaced with Et3N (1.0 equiv.).
40/12/7
40/12/6
42/17/6
38/12/7
28/12/5
50/19/11
4/<1/<1
5
Dioxane
AcOEt
Toluene
DCM
10
5
15
5
THF/H2O
(1/1)
0
10
aNMR yield. bCombined yield of the ketones.
To understand the phototriggered ketone formation reaction
in detail, a mechanistic study was performed. We hypotheꢀ
sized that ketones 8aa‒10aa were formed by the photochemiꢀ
cal rearrangement of acyloxyenamine 7aa as shown in
Scheme 2. However, it was too difficult to investigate the
physical properties and chemical reactivity of 7aa because it
was so unstable. Therefore, acyloxyenamine 7ba, which was
isolable by silica gel column chromatography was employed
for the mechanistic study (Scheme 3). First, aminocycloproꢀ
penone 1b was irradiated under condition B for 10 min to afꢀ
ford ynamine 6b. Addition of carboxylic acid 2a to the 6b
solution formed acyloxyenamine 7ba as a single diastereomer
(the geometry was not determined). Irradiation of 7ba under
condition B induced an acyl rearrangement to afford ketones
8ba and 9ba in 33% and 13% yield, respectively. Acyloxyeꢀ
namine 7ba was stable and the acyl rearrangement was not
observed without light irradiation under ambient conditions.
Therefore, the phototriggered rearrangement would be the
Scheme 2. Plausible pathways of the aminolysis and the
ketone formation.
The ketone formation reaction (formation of 8aa‒10aa) can
be regarded as a side reaction of the phototriggered dehydraꢀ
tion condensation. However, it may serve as another useful
method for the functionalization of carboxylic acids since the
reaction affords stable ketones where the substituents of the
carboxylic acids are covalently connected with substituents of
the aminocyclopropenone. The reaction completed in 5 min
even under low concentration (20 mM) conditions. Although
the intense UV light might induce undesired substrate decomꢀ
positions, the short reaction time could compensate for the
need to employ harsh irradiation conditions.
We further investigated the conditions for the phototrigꢀ
gered ketone formation reaction (Table 2). A mixture of amiꢀ
nocyclopropenone 1a, carboxylic acid 2a, and triethylamine in
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The Journal of Organic Chemistry
major rearrangement reaction pathway for ketone formation
from the corresponding acyloxyenamine. In Scheme 3, all the
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three reactions proceeded in moderate to high yield without
Et3N. The results suggest that Et3N is not necessary for the
phototriggered ketone formation if the intermediates are stable
enough under the reaction conditions.
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3
4
5
The UV spectra of aminocyclopropenone 1b, acyloxyenaꢀ
mine 7ba, and ketones 8ba and 9ba are shown in Figure 1.
Aminocyclopropenone 1b exhibited absorbance in the 220‒
350 nm region. Acyloxyenamine 7ba exhibited higher absorbꢀ
ance than 1b in the 330‒370 nm region. In contrast, ketones
8ba and 9ba exhibited weak absorbance in the >300 nm reꢀ
gion. For the ketone formation reaction to progress efficiently,
both the aminocyclopropenone and the acyloxyenamine
should have high absorbance. Simultaneously, ketones should
have low absorbance in the >300 nm region to avoid product
decomposition and prevent nonꢀconstructive light energy loss.
Therefore, the UV spectra in Figure 1 are reasonable for the
efficient phototriggered ketone formation under condition B.
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Scheme 4. Plausible mechanism for the phototriggered
ketone formation reaction.
Next, substrate scope of the phototriggered ketone forꢀ
mation was investigated (Table 3). Overall, less hindered satuꢀ
rated carboxylic acid afforded ketones in relatively good yield.
Octanoic acid afforded ketones 8ab‒10ab in 72% combined
yield (entry 2). The NꢀBoc group was tolerated and 8ac‒10ac
were obtained in 61% combined yield (entry 3). Secondary
carboxylic acids afforded ketones in moderate yields (entry 4
and 5). Dimethylacrylic acid mainly afforded the 1,3ꢀ
dicarbonyl product 8af (entry 6). The reaction with benzoic
acid resulted in multiple side products and 1,3ꢀdicarbonyl
product 8ag was obtained in only 29% yield (entry 7). The
reaction with pivalic acid resulted in low yields, possibly due
to decarbonylation of the pivaloyl radical to yield a stable tertꢀ
butyl radical (entry 8).14
Table 3. Scope of substrates.
Scheme 3. Phototriggered rearrangement of 7ba to ketones
8ba and 9ba.
2.5
2
1b
1.5
7ba
1
entry
RA of 2
PhCH2CH2 (2a)
CH3(CH2)6 (2b)
BocNHCH2 (2c)
iPr (2d)
time
(min)
5
yield (%)a
8/9/10
8ba
combinedb
80
0.5
9ba
1
2
3
4
5
6
7
8
50/19/11
(47/21/11)
45/19/8
(38/16/8)
40/19/2
(40/20/2)
41/15/8
(41/11/8)
37/18/8
(29/15/8)
46/2/ꢀc
(79)
72
(62)
61
(62)
64
(60)
63
(52)
48
(44)
29
(22)
25
0
10
10
5
220
260
300
λ (nm)
340
380
Figure 1. UV spectra in each stage of ketone formation.
The phototriggered rearrangement of the acyloxyenamine
probably consists of homolysis/recombination processes like
photoꢀFries rearrangement13, as shown in Scheme 4. Excitaꢀ
tion of acyloxyenamine 7 would produce an enoxyl radical
and an acyl radical followed by recombination of the radicals
to form the ketones. When the ketone formation reaction from
1a and 2a was performed in large scale, small amount of side
products that were presumably dimerized enoxyl radicals were
detected. This result strongly supports the homolyꢀ
sis/recombination mechanism (For the detailed information
about the dimer, see Experimental Section).
Cyclopropyl (2e)
(CH3)2C=CH (2f)
Ph (2g)
10
10
5
(41/3/0)
29/ꢀc /ꢀc
(22/0 /0)
25/ꢀc/ꢀc
tBu (2h)
5
(21/0/0)
(21)
b
aNMR yield. Isolated yields in parentheses. Combined yield
of the identified ketones. cNot identified.
An alkyne is a versatile functional group that is widely used
for the alkyneꢀazide click reaction.15 Additionally, an alkyne is
potentially useful as an imaging tag for Raman spectroscopy16
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and as an affinity tag for cobalt complexes17. Aminocycloproꢀ
recorded on SHIMADZU UVꢀ2400PC spectrophotometer.
Highꢀresolution mass spectrometry (HRMS) were performed
on JEOL JMSꢀT100TD (DART/TOF).
1
2
3
4
5
6
7
8
penone 1c, which has a terminal alkyne moiety, was prepared
and applied to the phototriggered ketone formation reaction.
The reaction completed in 5 min at 0 °C, and ketones 8ca and
9ca were obtained in 68% combined yield (Scheme 5). This
method may be useful for the introduction of an alkyne moiety
to a carboxylic acid.
General irradiation conditions
Condition A: The reaction solution was irradiated with 6 W
handꢀheld UVB lamp that was placed 8.0 cm from the reaction
vessel. The reaction temperature was kept constant using a
temperature controlled water bath.
9
Condition B: The reaction solution was irradiated with 80 W
medium pressure Hg lamp with <300 nm cutoff filter that was
placed 4.0 cm from the reaction vessel. The reaction temperaꢀ
ture was kept constant using temperature controlled water bath
or ice bath.
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Procedure for Table 1
Scheme 5. Phototriggered ketone formation using an alꢀ
kyne containing aminocyclopropenone and a carboxylic
acid.
Aminocyclopropenone 1a (11.5 mg, 50 ꢁmol), 3ꢀ
phenylpropionic acid (7.5 mg, 50 ꢁmol), amine (50 ꢁmol), and
DCM (2.5 mL) were added into a quartz test tube equipped
with a magnetic stir bar and a N2 balloon. The mixture was
irradiated with the irradiation condition A or B. The temperaꢀ
ture was kept at 20 °C using a temperature controlled water
bath. The reaction was monitored by TLC and the irradiation
was kept until the aminocyclopropenone 1 disappeared. After
1 disappeared, the mixture was diluted in DCM, washed with
aqueous 1N KHSO4, aqueous NaHCO3 and brine, dried over
Na2SO4, filtered and concentrated in vacuo. Product yield was
determined by qNMR using 1,3,5ꢀtrimethoxybenzene as an
internal standard.
In conclusion, we have discovered a novel phototriggered
ketone formation reaction that employs a carboxylic acid and
an aminocyclopropenone. Substituents on the aminocycloproꢀ
penone become conjugated with the carboxylic acid quite rapꢀ
idly, even under low reactant concentration and low temperaꢀ
ture conditions. This multiꢀstep reaction includes two distinct
photochemical steps, both of which occur quite efficiently.
Although the regiochemistry of the product was difficult to
control, this method could be useful for introduction of a funcꢀ
tional group such as alkyne to a carboxylic acid containing
molecule.
Procedure for Table 2
Aminocyclopropenone 1a (11.5 mg, 50 ꢁmol), 3ꢀ
Experimental Section
General information
phenylpropionic acid (7.5 mg, 50 ꢁmol), triethylamine (7.0
ꢁL, 50 ꢁmol), and solvent (2.5 mL) were added into a quartz
test tube equipped with a magnetic stir bar and a N2 balloon.
The mixture was irradiated with the irradiation condition B.
The temperature was kept at 20 °C using a temperature conꢀ
trolled water bath or kept at 0 °C using an ice bath. The reacꢀ
tion was monitored by TLC and the irradiation was kept until
the aminocyclopropenone 1 disappeared. After 1 disappered,
the mixture was diluted in DCM, washed with aqueous 1N
KHSO4, aqueous NaHCO3, brine, dried over Na2SO4, filtered
and concentrated in vacuo. Product yield was determined by
qNMR using 1,3,5ꢀtrimethoxybenzene as an internal standard.
All reactions were performed under air, unless otherwise notꢀ
ed. 6 W handheld UV lamp (FUNAKOSHI UVMꢀ57) was
used for UVB (280ꢀ350 nm) irradiation. 80 W medium presꢀ
sure Hg lamp with a <300 nm cutoff filter (YMC) was used
for intense light conditions. All solvents and commercial reaꢀ
gents were used as provided. Tetrachlorocyclopropene was
prepared according to a reported procedure.18 Aminocycloꢀ
propenone 1a and 1b were synthesized according to reported
procedure.10, 19 SiO2 column chromatography was performed
employing KANTO CHEMICAL Silica Gel 60 N (spherical,
neutral, 40ꢀ100 mesh). Thinlayer chromatography (TLC) was
Procedure for Table 3
1
performed on silica gel 60 F254 plates. H and 13C NMR were
The reaction was performed in 0.3ꢀ1.0 mmol scale. Because
the irradiation efficiency highly depends on the reaction volꢀ
ume and the reaction vessel, reproduction of the small scale
(50 ꢁmol scale) yield in the 0.3ꢀ1.0 mmol scale reaction in one
batch was very difficult. Therefore, the 0.3ꢀ1.0 mmol scale
reaction was conducted as follows.
recorded on JEOL JNMꢀECS400 (400 MHz) spectrometers.
For all the 13C NMR measurement, broadband proton decouꢀ
1
pling technique was used. Data for H NMR are reported as
follows: chemical shift (δ ppm), multiplicity (s = singlet, brs =
broad singlet, d = doublet, t = triplet, q = quartet, qt = quintet,
sx = sextet, sep = septet, m = multiplet), coupling constant
(Hz), and integration. Data for 13C NMR are reported in terms
1
Aminocyclopropenone 1a, carboxylic acid, trimethylamine,
and DCM were mixed and divided into some equal aliquots.
Each aliquot was transferred into a quartz test tube equipped
with a magnetic stir bar and a N2 balloon. Each reaction mixꢀ
of chemical shift. For H NMR, chemical shifts were reported
as δ values relative to tetramethylsilane (0 ppm) as an internal
standard. For 13C NMR, chemical shifts were calibrated
against solvent peaks in CDCl3 (77.00 ppm). UV spectra were
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The Journal of Organic Chemistry
1.25 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 203.4,
ture was irradiated with the irradiation condition B. The reacꢀ
1
2
3
4
5
6
7
8
tion was monitored by TLC and the irradiation was kept until
the aminocyclopropenone 1 was completely consumed. After
1 was consumed, the mixture was diluted in DCM and
quenched with aqueous 1N KHSO4. All the quenched reaction
mixtures were combined, washed with aqueous NaHCO3 and
brine, dried over Na2SO4, filtered and concentrated in vacuo.
Product yield was determined by qNMR using 1,3,5ꢀ
trimethoxybenzene as an internal standard. The mixture was
purified with SiO2 column chromatography or preparative
TLC to isolate the ketones 8‒10.
169.5, 141.5, 138.3, 135.8, 131.9, 131.2, 128.43, 128.40,
128.2, 126.6, 126.0, 48.7, 45.8, 42.7, 40.4, 30.2, 20.74, 20.66.
HRMS (DART+) Calcd for C23H30NO2 ([M + H+]+): 352.2277,
found: 352.2292.
N,Nꢀdiisopropylꢀ2ꢀ(4ꢀ(2ꢀ
phenylethylcarbonyl)phenyl)acetamide (10aa)
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.33
(d, J = 8.2 Hz, 2H), 7.33ꢀ7.15 (m, 5H), 3.92 (sept, J = 6.8 Hz,
1H), 3.73 (s, 2H), 3.40 (br s, 1H), 3.28 (t, J = 7.8 Hz, 2H),
3.06 (t, J = 7.8 Hz, 2H), 1.41 (d, J = 6.9 Hz, 6H), 1.04 (d, J =
6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 198.8, 168.9,
141.4, 141.3, 135.3, 128.9, 128.5, 128.4, 126.1, 49.4, 45.9,
43.2, 40.4, 30.1, 20.7, 20.4. HRMS (DART+) Calcd
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Table 3. entry 1.
The reaction was performed in 1.0 mmol scale. 1a (229.3 mg,
1.0 mmol), 3ꢀphenylpropionic acid (2a) (150.2 mg, 1.0 mmol),
triethylamine (138.6 ꢁL, 1.0 mmol) and DCM (50 mL) are
mixed. The mixture was divided into 20 aliquots. Each aliquot
was transferred into a quartz tube equipped with a magnetic
stir bar and a N2 balloon. Each reaction mixture was irradiated
with the irradiation condition B for 5 min. After completion of
the reaction, all the aliquots were diluted in DCM, quenched
with 1 N aqueous KHSO4. All the reaction mixtures were
combined. The DCM phase was separated, washed with satuꢀ
rated aqueous NaHCO3 and brine, dried over Na2SO4, filtered
and concentrated. NMR yield was determined by qNMR using
1,3,5ꢀtrimethoxybenzene as an internal standard
(8aa/9aa/10aa = 50%/19%/11%). Isolation yield was deterꢀ
mined after purification with SiO2 column chromatography
(AcOEt/hexane = 1/19 – 1/4) and PTLC (AcOEt/hexane =
1/19). 8aa was obtained as a colorless solid (166.9 mg, 47%).
9aa was obtained as a colorless solid (73.3 mg, 21%). 10aa
was obtained as a colorless solid (37.7 mg, 11%). In the reacꢀ
tion, product 11 (colorless solid, 3.2 mg) and 12 (1.5 mg, colꢀ
orless solid) were obtained as minor products. According to 1H
NMR and HRMS, these compounds are presumably meso or
dl isomer of N1,N1,N4,N4ꢀtetraisopropylꢀ2,3ꢀ
for C23H30NO2 ([M + H+]+): 352.2277, found: 352.2262.
11 and 12 are presumably meso or dl isomer of N1,N1,N4,N4ꢀ
tetraisopropylꢀ2,3ꢀdiphenylsuccinamide
O
O
NiPr2
NiPr2
NiPr2
NiPr2
or
O
O
11
1H NMR (400 MHz, CDCl3) δ 7.09ꢀ7.03 (m, 6H), 6.94ꢀ6.87
(m, 4H), 4.47 (s, 2H), 4.17 (sept, J = 6.6 Hz, 2H), 3.26 (sept, J
= 6.8 Hz, 2H), 1.42 (d, J = 6.9 Hz, 6H), 1.35 (d, J = 6.9 Hz,
6H), 1.28 (d, J = 6.9 Hz, 6H), 0.59 (d, J = 6.4 Hz, 6H). HRMS
(DART+) Calcd for C28H41N2O2 ([M + H+]+): 437.3168,
found: 437.3169.
12
1H NMR (400 MHz, CDCl3) δ 7.57ꢀ7.52 (m, 4H), 7.30ꢀ7.17
(m, 6H), 4.76 (s, 2H), 4.25 (sept, J = 6.7 Hz, 2H), 3.08 (sept, J
= 6.9 Hz, 2H), 1.18 (d, J = 6.9 Hz, 6H), 0.92 (d, J = 6.4 Hz,
6H), 0.86 (d, J = 6.9 Hz, 6H), 0.84 (d, J = 6.4 Hz, 6H). HRMS
(DART+) Calcd for C28H41N2O2 ([M + H+]+): 437.3168,
found: 437.3168.
diphenylsuccinamide, that were produced by dimerization of
the enoxyl radicals generated in the phototriggered reaction. A
similar radical dimerization reaction to produce a 2,3ꢀ
diphenylsuccinamide derivative was reported20. The 1H NMR
pattern of 11 and 12 were similar to the reported 2,3ꢀ
diphenylsuccinamide derivative.
N,Nꢀdiisopropylꢀ3ꢀoxoꢀ2,5ꢀdiphenylpentanamide (8aa)
Table 3. entry 2.
1H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.08 (m, 10H), 4.66 (s,
1H), 3.73 (sept, J = 6.6 Hz, 1H), 3.34 (br sept, J = 6.4 Hz, 1H),
2.97ꢀ2.52 (m, 4H), 1.45 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 6.9
The reaction was performed in 0.3 mmol scale. 1a (68.8 mg,
0.3 mmol), nꢀoctanoic acid (2b) (47.5 ꢁL, 0.3 mmol), triethylꢀ
amine (42 ꢁL, 0.3 mmol) and DCM (15 mL) are mixed. The
mixture was divided into 6 aliquots. Each aliquot was transꢀ
ferred into a quartz tube equipped with a magnetic stir bar and
a N2 balloon. Each reaction mixture was irradiated with the
irradiation condition B for 10 min. After completion of the
reaction, all the aliquots were diluted in DCM, quenched with
1 N aqueous KHSO4. All the reaction mixtures were comꢀ
bined. The DCM phase was separated, washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, filtered and
concentrated. NMR yield was determined by qNMR using
1,3,5ꢀtrimethoxybenzene as an internal standard
Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H), 0.66 (d, J = 6.4 Hz, 3H). 13
C
NMR (100 MHz, CDCl3) δ 204.8, 167.8, 141.3, 134.1, 128.9,
128.8, 128.39, 128.35, 127.8, 125.9, 65.1, 49.5, 46.1, 43.5,
30.2, 20.8, 20.6, 20.0, 19.6. HRMS (DART+) Calcd
for C23H30NO2 ([M + H+]+): 352.2277, found: 352.2287.
N,Nꢀdiisopropylꢀ2ꢀ(4ꢀ(2ꢀ
phenylethylcarbonyl)phenyl)acetamide (9aa)
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.8 Hz, 1H), 7.39
(t, J = 7.3 Hz, 1H), 7.33ꢀ7.14 (m, 7H), 4.10 (sept, J = 6.6 Hz,
1H), 3.96 (s, 2H), 3.44 (br sept, J = 6.2 Hz, 1H), 3.26 (t, J =
7.8 Hz, 2H), 2.99 (t, J = 7.8 Hz, 2H), 1.39 (d, J = 6.9 Hz, 6H),
(8ab/9ab/10ab = 45%/19%/8%). Isolation yield was deterꢀ
mined after purification with SiO2 column chromatography
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Page 6 of 11
(AcOEt/hexane = 1/19 – 1/4) and PTLC (MeCN/DCM =
as a colorless solid (23.1 mg, 20%). 10ac was obtained as a
colorless solid (2.0 mg, 2%).
1
2
3
4
5
6
7
8
1/19). 8ab was obtained as a colorless solid (39.2 mg, 38%).
9ab was obtained as a colorless solid (16.4 mg, 16%). 10ab
was obtained as a colorless solid (8.0 mg, 8%).
tertꢀbutyl (4ꢀ(diisopropylamino)ꢀ2,4ꢀdioxoꢀ3ꢀ
phenylbutyl)carbamate (8ac)
N,Nꢀdiisopropylꢀ3ꢀoxoꢀ2ꢀphenyldecanamide (8ab)
1H NMR (400 MHz, CDCl3) δ 7.42ꢀ7.20 (m, 5H), 5.22 (br s,
1H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.22 (m, 5H), 4.74 (s, 1H),
3.81 (sept, J = 6.6 Hz, 1H), 3.36 (br sept, J = 6.4 Hz, 1H),
2.63ꢀ2.52 (m, 1H), 2.44ꢀ2.34 (m, 1H), 1.60ꢀ1.33 (m, 2H) 1.45
(d, J = 6.9 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 1.31ꢀ1.12 (m,
8H), 1.17 (d, J = 6.9 Hz, 3H), 0.85 (t, J = 6.9 Hz, 3H), 0.71 (d,
J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 205.6, 167.8,
134.3, 128.80, 128.78, 127.6, 64.7, 49.4, 46.0, 41.8, 31.5,
29.0, 28.9, 23.8, 22.5, 20.7, 20.5, 19.9, 19.6, 14.0. HRMS
(DART+) Calcd for C22H35NO2 ([M + H+]+): 346.2746, found:
346.2740.
1H), 4.83 (s, 1H), 4.13 (dd, A of ABX, JAB = 19.2 Hz, JAX
5.0 Hz, 1H), 3.98 (dd, B of ABX, JAB = 19.2 Hz, JBX = 5.5 Hz,
=
1H), 3.79 (sept, J = 6.6 Hz, 1H), 3.34 (br sept, J = 6.6 Hz, 1H),
1.46 (d, J = 6.9 Hz, 3H), 1.43 (s, 9H), 1.39 (d, J = 6.9 Hz, 3H),
1.19 (d, J = 6.4 Hz, 3H), 0.63 (d, J = 6.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 201.6, 167.6, 155.7, 133.0, 129.0, 128.8,
128.0, 79.7, 62.3, 50.2, 49.7, 46.2, 28.3, 20.7, 20.4, 19.8, 19.4.
HRMS (DART+) Calcd for C21H33N2O4 ([M + H+]+):
377.2440, found: 377.2447.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tertꢀbutyl (2ꢀ(2ꢀ(2ꢀ(diisopropylamino)ꢀ2ꢀoxoethyl)phenyl)ꢀ2ꢀ
oxoethyl)carbamate (9ac)
N,Nꢀdiisopropylꢀ2ꢀ(2ꢀoctanoylphenyl)acetamide (9ab)
1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 7.8, 1.4 Hz, 1H),
7.39 (td, J = 7.6, 1.4 Hz, 1H), 7.31 (td, J = 7.3, 1.4 Hz, 1H),
7.22 (br d, J = 7.8 Hz, 1H), 4.08 (sept, J = 6.6 Hz, 1H), 3.96
(s, 2H), 3.42 (br sept, J = 6.9 Hz, 1H), 2.91 (t, J = 7.6 Hz, 2H),
1.66 (quin, 2H, J = 7.1 Hz), 1.40ꢀ1.20 (m, 8H), 1.37 (d, J = 6.9
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.3 Hz, 1H), 7.43
(t, J = 7.1 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.22 (d, J = 7.3
Hz, 1H), 5.49 (br s, 1H), 4.50 (d, J = 5.0 Hz, 2H), 4.09 (sept, J
= 6.7 Hz, 1H), 3.95 (s, 2H), 3.44 (br s, 1H), 1.45 (s, 9H), 1.35
(d, J = 6.4 Hz, 6H), 1.27 (d, J = 6.9 Hz, 6H). 13C NMR (100
MHz, CDCl3) δ 199.8, 169.3, 155.8, 136.1, 136.0, 132.0,
131.7, 127.7, 126.7, 79.5, 48.9, 48.7, 45.9, 40.2, 28.3, 20.7,
20.6. HRMS (DART+) Calcd for C21H33N2O4 ([M + H+]+):
377.2440, found: 377.2426.
Hz, 6H), 1.22 (d, J = 6.9 Hz, 6H), 0.88 (t, J = 6.9 Hz, 3H). 13
C
NMR (100 MHz, CDCl3) δ 204.9, 169.5, 138.5, 135.7, 131.8,
131.0, 128.3, 126.5, 48.7, 45.8, 41.1, 40.3, 31.7, 29.3, 29.1,
24.2, 22.6, 20.7, 20.6, 14.1. HRMS (DART+) Calcd
for C22H35NO2 ([M + H+]+): 346.2746, found: 346.2732.
tertꢀbutyl (2ꢀ(4ꢀ(2ꢀ(diisopropylamino)ꢀ2ꢀoxoethyl)phenyl)ꢀ2ꢀ
oxoethyl)carbamate (10ac)
N,Nꢀdiisopropylꢀ2ꢀ(4ꢀoctanoylphenyl)acetamide (10ab)
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.34
(d, J = 8.2 Hz, 2H), 3.93 (sept, J = 6.6 Hz, 1H), 3.73 (s, 2H),
3.42 (br s, 1H), 2.94 (t, J = 7.3 Hz, 2H), 1.72 (quin, J = 7.3 Hz,
2H), 1.41 (d, J = 6.9 Hz, 6H), 1.40ꢀ1.22 (m, 8H), 1.05 (d, J =
6.4 Hz, 6H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 200.2, 169.0, 141.1, 135.5, 128.8, 128.4, 49.4, 45.9,
43.2, 38.6, 31.7, 29.3, 29.1, 24.4, 22.6, 20.6, 20.4, 14.1.
HRMS (DART+) Calcd for C22H35NO2 ([M + H+]+): 346.2746,
found: 346.2747.
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.37
(d, J = 7.8, 2H), 5.54 (br s, 1H), 4.64 (d, J = 4.6 Hz, 2H), 3.92
(sept, J = 6.7 Hz, 1H), 3.74 (s, 2H), 3.41 (br s, 1H), 1.48 (s,
9H), 1.41 (d, J = 6.9 Hz, 6H), 1.06 (d, J = 6.9 Hz, 6H). 13C
NMR (100 MHz, CDCl3) δ 194.0, 168.7, 155.7, 142.5, 132.9,
129.2, 128.2, 79.8, 49.4, 47.4, 45.9, 43.2, 28.3, 20.7, 20.4.
HRMS (DART+) Calcd for C21H33N2O4 ([M + H+]+):
377.2440, found: 377.2443.
Table 3. entry 4.
Table 3. entry 3.
The reaction was performed in 0.3 mmol scale. 1a (68.8 mg,
0.30 mmol), isobutyric acid (2d) (26.4 mg, 0.30 mmol), triꢀ
ethylamine (42 ꢁL, 0.30 mmol) and DCM (15 mL) were
mixed. The mixture was divided into 6 aliquots. Each reaction
mixture was transferred into a quartz tube equipped with a
magnetic stir bar and a N2 balloon. The reaction mixture was
irradiated with the irradiation condition B for 5 min. After
completion of the reaction, the reaction mixture was diluted in
DCM and quenched with 1 N aqueous KHSO4. All the aliꢀ
quots were combined. The DCM phase was separated, washed
with saturated aqueous NaHCO3 and brine, dried over Na2SO4,
filtered and concentrated in vacuo. NMR yield was determined
by qNMR using 1,3,5ꢀtrimethoxybenzene as an internal standꢀ
ard (8ad/9ad/10ad = 41%/15%/8%). Isolation yield was deꢀ
termined after purification with SiO2 column chromatography
(AcOEt/hexane = 1/19 – 1/4) and PTLC (AcOEt/hexane =
1/19). 8ad was obtained as a colorless solid (33.6 mg, 41%).
The reaction was performed in 0.3 mmol scale. 1a (68.8 mg,
0.3 mmol), BocꢀGlyꢀOH (2c) (52.6 mg, 0.3 mmol), triethylaꢀ
mine (42 ꢁL, 0.3 mmol) and DCM (15 mL) are mixed. The
mixture was divided into 6 aliquots. Each aliquot was transꢀ
ferred into a quartz tube equipped with a magnetic stir bar and
a N2 balloon. Each reaction mixture was irradiated with the
irradiation condition B for 10 min. After completion of the
reaction, all the aliquots were diluted in DCM, quenched with
1 N aqueous KHSO4. All the reaction mixtures were comꢀ
bined. The DCM phase was separated, washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, filtered and
concentrated. NMR yield was determined by qNMR using
1,3,5ꢀtrimethoxybenzene as an internal standard (8ac/9ac/10ac
= 40%/19%/2%). Isolation yield was determined after purifiꢀ
cation with SiO2 column chromatography (AcOEt/hexane =
1/10 – 1/2) and PTLC (AcOEt/hexane = 1/1). 8ac was obꢀ
tained as a colorless solid (45.7 mg, 40%). 9ac was obtained
6
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The Journal of Organic Chemistry
1H NMR (400 MHz, CDCl3) δ 7.42ꢀ7.28 (m, 5H), 4.90 (s, 1H),
9ad was obtained as a colorless solid (9.1 mg, 11%). 10ad was
1
2
3
4
5
6
7
8
obtained as a colorless oil (7.2 mg, 8%).
3.87 (sept, J = 6.6 Hz, 1H), 3.39 (br sept, J = 6.4 Hz, 1H), 2.06
(tt, J = 8.0, 3.9 Hz, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.43 (d, J =
6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.14ꢀ0.75 (m, 4H), 0.81
(d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 205.7,
167.6, 134.4, 129.0, 128.8, 127.6, 65.4, 49.3, 46.2, 20.7, 20.5,
20.4, 20.1, 19.9, 12.1, 11.5. HRMS (DART+) Calcd
N,Nꢀdiisopropylꢀ4ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylpentanamide (8ad)
1H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.20 (m, 5H), 4.92 (s, 1H),
3.87 (sept, J = 6.6 Hz, 1H), 3.33 (br sept, J = 6.6 Hz, 1H), 2.86
(sept, J = 6.9 Hz, 1H), 1.46 (d, J = 6.9 Hz, 3H), 1.39 (d, J =
6.9 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H),
1.01 (d, J = 6.9 Hz, 3H), 0.70 (d, J = 6.9 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 208.5, 167.6, 134.1, 129.0, 128.7, 127.5,
63.0, 49.5, 46.1, 40.0, 20.7, 20.4, 19.9, 19.6, 19.0, 18.7.
HRMS (DART+) Calcd for C18H28NO2 ([M + H+]+): 290.2120,
found: 290.2116.
for C18H26NO2 ([M + H+]+): 288.1964, found: 288.1955.
2ꢀ(2ꢀ(cyclopropanecarbonyl)phenyl)ꢀN,Nꢀ
diisopropylacetamide (9ae)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.3, 1.4 Hz, 1H),
7.40 (td, J = 7.3, 1.4 Hz, 1H), 7.34 (td, J = 7.6, 1.4 Hz, 1H),
7.25 (br d, J = 7.3 Hz, 1H), 4.05 (sept, J = 6.7 Hz, 1H), 3.94
(s, 2H), 3.40 (br sept, J = 6.4 Hz, 1H), 2.50 (tt, J = 7.8, 3.9 Hz,
1H), 1.38 (d, J = 6.8 Hz, 6H), 1.21ꢀ1.14 (m, 2H), 1.17 (d, J =
6.4 Hz, 6H), 1.05ꢀ0.99 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ 204.8, 169.5, 139.5, 134.9, 131.2, 130.8, 128.4, 126.4, 48.7,
45.7, 40.0, 20.6, 20.5, 20.2, 11.9. HRMS (DART+) Calcd for
C18H26NO2 ([M + H+]+): 288.1964, found: 288.1955.
2ꢀ(2ꢀisobutyrylphenyl)ꢀN,Nꢀdiisopropylacetamide (9ad)
1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 7.8, 1.3 Hz, 1H),
7.41 (td, J = 7.5, 1.4 Hz, 1H), 7.31 (td, J = 7.8, 1.4 Hz, 1H),
7.27 (br d, J = 7.8 Hz, 1H), 4.07 (sept, J = 6.8 Hz, 1H), 3.93
(s, 2H), 3.41 (sept, J = 6.9 Hz, 2H), 1.38 (d, J = 6.9 Hz, 6H),
1.18 (d, J = 5.7 Hz, 6H), 1.17 (d, J = 6.4 Hz, 6H). 13C NMR
(100 MHz, CDCl3) δ 208.6, 169.6, 137.7, 136.0, 131.6, 131.0,
128.1, 126.5, 48.8, 45.7, 40.3, 38.2, 20.7, 20.6, 18.9. HRMS
(DART+) Calcd for C18H28NO2 ([M + H+]+): 290.2120, found:
290.2117.
2ꢀ(4ꢀ(cyclopropanecarbonyl)phenyl)ꢀN,Nꢀ
diisopropylacetamide (10ae)
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.2 Hz, 2H), 7.36
(d, J = 8.2 Hz, 2H), 3.94 (sept, J = 6.7 Hz, 1H), 3.75 (s, 2H),
3.40 (br s, 1H), 2.67 (tt, J = 8.0, 4.1 Hz, 1H), 1.42 (d, J = 6.9
Hz, 6H), 1.27ꢀ1.20 (m, 2H), 1.04 (d, J = 6.9 Hz, 6H), 1.07ꢀ
1.00 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 200.2, 169.0,
141.0, 136.4, 128.7, 128.4, 49.4, 45.9, 43.3, 20.6, 20.4, 17.0,
11.6. HRMS (DART+) Calcd for C18H26NO2 ([M + H+]+):
288.1964, found: 288.1957.
2ꢀ(4ꢀisobutyrylphenyl)ꢀN,Nꢀdiisopropylacetamide (10ad)
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.34
(d, J = 8.2, 2H), 3.94 (sept, J = 6.8 Hz, 1H), 3.73 (s, 2H), 3.54
(sept, J = 6.8 Hz, 1H), 3.40 (brs, 1H), 1.41 (d, J = 6.4 Hz, 6H),
1.21 (d, J = 6.9 Hz, 6H), 1.05 (d, J = 6.4 Hz, 6H), 1.07ꢀ1.00
(m, 2H). 13C NMR (100 MHz, CDCl3) δ 204.1, 169.0, 141.0,
134.6, 128.9, 128.7, 49.4, 45.9, 43.2, 35.3, 20.7, 20.5, 19.1.
HRMS (DART+) Calcd for C18H28NO2 ([M + H+]+): 290.2120,
found: 290.2119.
Table 3. entry 6.
The reaction was performed in 0.3 mmol scale. 1a (68.8 mg,
0.30 mmol), 3ꢀmethylcrotonic acid (2f) (26.4 mg, 0.30 mmol),
triethylamine (41.6 ꢁL, 0.30 mmol) and DCM (15 mL) were
mixed. The mixture was divided into 6 aliquots. Each aliquot
was transferred into a quartz tube equipped with a magnetic
stir bar and a N2 balloon. The reaction mixture was irradiated
with the irradiation condition B for 10 min. After completion
of the reaction, each aliquot was diluted in DCM, quenched
with 1 N aqueous KHSO4. All the reaction mixtures were
combined. The DCM phase was separated, washed with satuꢀ
rated aqueous NaHCO3 and brine, dried over Na2SO4, filtered
and concentrated in vacuo. NMR yield was determined by
qNMR using 1,3,5ꢀtrimethoxybenzene as an internal standard
(8af/9af = 46%/2%). Isolation yield was determined after puriꢀ
fication with SiO2 column chromatography (AcOEt/hexane =
1/19 – 1/4) and PTLC (Et2O/hexane = 1/1). 8af was obtained
as a colorless solid (37.0 mg, 41%). 9af was obtained as a
colorless solid (2.6 mg, 3%).
Table 3. entry 5.
The reaction was performed in 0.5 mmol scale. 1a (114.7 mg,
0.50 mmol), cyclopropanecarboxylic acid (2e) (48.6 ꢁL, 0.50
mmol), triethylamine (69.7 ꢁL, 0.50 mmol) and DCM (25 mL)
were mixed. The mixture was divided into 10 aliquots. Each
reaction mixture was transferred into a quartz tube equipped
with a magnetic stir bar and a N2 balloon. The reaction mixꢀ
ture was irradiated with the irradiation condition B for 5 min.
After completion of the reaction, the reaction mixture was
diluted in DCM and quenched with 1 N aqueous KHSO4. All
the aliquots were combined. The DCM phase was separated,
washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, filtered and concentrated in vacuo. NMR yield was
determined by qNMR using 1,3,5ꢀtrimethoxybenzene as an
internal standard (8ae/9ae/10ae = 37%/18%/8%). Isolation
yield was determined after purification with SiO2 column
chromatography (AcOEt/hexane = 1/19 – 1/3) and PTLC
(AcOEt:hexane = 1/3). 8ae was obtained as a colorless solid
(41.1 mg, 29%). 9ae was obtained as a colorless solid (22.0
mg, 15%). 10ae was obtained as a colorless oil (11.9 mg, 8%).
N,Nꢀdiisopropylꢀ5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylhexꢀ4ꢀenamide (8af)
1H NMR (400 MHz, CDCl3) δ 7.39ꢀ7.25 (m, 5H), 6.11 (sept, J
= 1.4 Hz, 1H), 4.76 (s, 1H), 3.86 (sept, J = 6.6 Hz, 1H), 3.37
(br s, 1H), 2.15 (d, J = 1.4 Hz, 3H), 1.84 (d, J = 1.4 Hz, 3H),
1.46 (d, J = 6.8 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 1.17 (d, J =
6.9 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz,
3ꢀcyclopropylꢀN,Nꢀdiisopropylꢀ3ꢀoxoꢀ2ꢀphenylpropanamide
(8ae)
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CDCl3) δ 194.3, 167.8, 156.9, 134.7, 129.1, 128.7, 127.4,
The DCM phase was separated, washed with saturated aqueꢀ
ous NaHCO3 and brine, dried over Na2SO4, filtered and conꢀ
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3
4
5
6
7
8
122.9, 65.3, 49.2, 46.1, 40.0, 28.0, 21.0, 20.7, 20.5, 20.1, 20.0.
HRMS (DART+) Calcd for C19H28NO2 ([M + H+]+): 302.2120,
found: 302.2108.
centrated in vacuo. The product (8ah) was characterized by 1H
NMR spectra, which was identical to previously reported data.
NMR yield was determined by qNMR using 1,3,5ꢀ
trimethoxybenzene as an internal standard (25%). Isolation
yield was determined after purification with PTLC
(Et2O/hexane = 1/5 and DCM /hexane = 3/7). 8ah was obꢀ
tained as a colorless solid (18.8 mg, 21%).
N,Nꢀdiisopropylꢀ2ꢀ(2ꢀ(3ꢀmethylbutꢀ2ꢀenoyl)phenyl)acetamide
(9af)
1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.8, 1.4 Hz, 1H),
7.37 (td, J = 7.8, 1.4 Hz, 1H), 7.32ꢀ7.23 (m, 2H), 6.48 (sept, J
= 1.4 Hz, 1H), 4.06 (sept, J = 6.7 Hz, 1H), 3.94 (s, 2H), 3.41
(br s, 1H), 2.14 (d, J = 1.4 Hz, 3H), 1.96 (d, J = 1.4 Hz, 3H),
1.37 (d, J = 6.9 Hz, 6H), 1.16 (d, J = 6.9 Hz, 6H). 13C NMR
(100 MHz, CDCl3) δ 195.5, 169.8, 156.0, 135.3, 131.1, 130.5,
128.3, 126.4, 124.4, 48.9, 45.8, 39.9, 27.9, 21.0, 20.7, 20.5.
HRMS (DART+) Calcd for C19H28NO2 ([M + H+]+): 302.2120,
found: 302.2109.
9
N,Nꢀdiisopropylꢀ4ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylpentanamide (8ah)
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28
29
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1H NMR (400 MHz, CDCl3) δ 7.37ꢀ7.16 (m, 5H), 5.21 (s, 1H),
3.94 (sept, J = 6.6 Hz, 1H), 3.28 (sept, J = 6.8 Hz, 1H), 1.44
(d, J = 6.9 Hz, 3H), 1.37 (d, J = 6.9 Hz, 3H), 1.20 (d, J = 6.9
Hz, 3H), 0.62 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 207.9, 166.8, 134.8, 129.0, 128.5, 127.3, 58.5, 49.6,
46.1, 44.6, 26.5, 20.7, 20.2, 19.8, 19.5. HRMS (DART+)
Calcd for C19H30NO2 ([M + H+]+): 304.2277, found: 304.2276.
Table 3. entry 7.
The reaction was performed in 0.3 mmol scale. 1a (68.8 mg,
0.30 mmol), pivalic acid (2g) (36.7 mg, 0.30 mmol), triethylꢀ
amine (41.6 ꢁL, 0.30 mmol) and DCM (15 mL) were mixed.
The mixture was divided into 6 aliquots. Each aliquot was
transferred into a quartz tube equipped with a magnetic stir bar
and a N2 balloon. The reaction mixture was irradiated with the
irradiation condition B for 5 min. After completion of the reꢀ
action, each aliquot was diluted in DCM, quenched with 1 N
aqueous KHSO4. All the reaction mixtures were combined.
The DCM phase was separated, washed with saturated aqueꢀ
ous NaHCO3 and brine, dried over Na2SO4, filtered and conꢀ
centrated in vacuo. The product (8ag) was characterized by 1H
NMR spectra, which was identical to previously reported data.
NMR yield was determined by qNMR using 1,3,5ꢀ
Procedure for Scheme 3. (Mechanistic study of the photoꢀ
triggered ketone formation)
Aminocyclopropenone 1b (59.6 mg, 0.2 mmol) was dissolved
in DCM (10 mL) and divided into 4 aliquots. Each aliquot was
transferred into a quartz test tube equipped with a magnetic
stir bar and a N2 balloon. Each aliquot was irradiated with
condition B for 10 min at. Disappearance of 1b was confirmed
by TLC. After the irradiation, to each reaction mixture, 3ꢀ
phenylpropionic acid (6.0 mg, 0.004 mmol, 0.8 equiv) was
added at 20 °C and stirred for 21 h. Disappearance of 6b was
confirmed by TLC. After the reaction completion, the reaction
mixture was combined, concentrated in vacuo and purified
with SiO2 column (hexane/AcOEt = 80:1 – 40:1) to afford 7ba
as a colorless solid (62 mg, 74%).
trimethoxybenzene as an internal standard (29%). Isolation
yield was determined after purification with SiO2 column
chromatography (AcOEt/hexane = 1/19 – 3/7) and PTLC
(AcOEt/hexane = 1/9). 8ag was obtained as a colorless solid
(21.5 mg, 22%).
7ba (62 mg, 0.0148 mmol) was dissolved in DCM (7.4 mL)
and divided into 4 aliquots. Each aliquot was transferred into a
quartz test tube equipped with a magnetic stir bar and a N2
balloon. Each aliquot was irradiated with condition B for 5
min. Consumption of 7ba was confirmed by TLC. After the
reaction completion, the mixture was concentrated and puriꢀ
fied with PTLC (hexane/Et2O = 1/1 and DCM) to afford keꢀ
tones 8ba (pale yellow solid, 20.5 mg, 33%) and 9ba (pale
yellow oil, 8.2 mg, 13%).
N,Nꢀdiisopropylꢀ3ꢀoxoꢀ2,3ꢀdiphenylpropanamide (8ag)
1H NMR (400 MHz, CDCl3) δ 7.99ꢀ7.92 (m, 2H), 7.56ꢀ7.28
(m, 8H), 5.63 (s, 1H), 4.03 (sept, J = 6.5 Hz, 1H), 3.36 (sept, J
= 6.8 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H), 1.38 (d, J = 6.4 Hz,
3H), 1.26 (d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H). 13
C
NMR (100 MHz, CDCl3) δ 193.5, 167.3, 136.7, 134.1, 132.9,
129.5, 128.7, 128.5, 128.3, 127.6, 60.3, 49.7, 46.2, 20.7, 20.2,
20.1, 20.0. HRMS (DART+) Calcd for C21H26NO2 ([M +
H+]+): 324.1964, found: 324.1971.
1ꢀ(diphenylamino)ꢀ2ꢀphenylvinyl 3ꢀphenylpropanoate (7ba)
1H NMR (400 MHz, CDCl3) δ 7.35ꢀ6.90 (m, 20H), 5.97 (s,
1H), 2.69 (t, J = 7.8 Hz, 2H), 2.47 (t, J = 7.8 Hz, 2H). 13
C
NMR (100 MHz, CDCl3) δ 171.1, 143.42, 143.35, 140.1,
132.9, 128.9, 128.5, 128.2, 127.7, 127.6, 126.6, 126.2, 123.3,
122.6, 110.3, 35.5, 30.5. HRMS (DART+) Calcd
Table 3. entry 8.
for C29H26NO2 ([M + H+]+): 420.1964, found: 420.1954.
The reaction was performed in 0.3 mmol scale. 1a (68.8 mg,
0.30 mmol), pivalic acid (2h) (30.6 mg, 0.30 mmol), triethylꢀ
amine (41.6 ꢁL, 0.30 mmol) and DCM (15 mL) were mixed.
The mixture was divided into 6 aliquots. Each aliquot was
transferred into a quartz tube equipped with a magnetic stir bar
and a N2 balloon. The reaction mixture was irradiated with the
irradiation condition B for 5 min. After completion of the reꢀ
action, each aliquot was diluted in DCM, quenched with 1 N
aqueous KHSO4. All the reaction mixtures were combined.
3ꢀoxoꢀN,N,2,5ꢀtetraphenylpentanamide (8ba)
1H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.05 (m, 20H), 4.74 (s,
1H), 2.85ꢀ2.45 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 203.9,
168.4, 142.2, 142.1, 140.8, 133.3, 129.8, 129.5, 129.1, 128.9,
128.7, 128.4, 128.3, 128.0, 126.4, 126.3, 126.0, 64.3, 43.1,
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1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.2 Hz, 2H), 7.01
29.7. HRMS (DART+) Calcd for C29H26NO2 ([M + H+]+):
1
2
3
4
5
6
7
8
420.1964, found: 420.1956.
(d, J = 8.2 Hz, 2H), 4.73 (s, 2H), 4.15 (sept, J = 6.8 Hz, 1H),
3.61 (sept, J = 6.5 Hz, 1H), 2.56 (s, 1H), 1 .42ꢀ1.32 (m, 12H);
13C NMR (100 MHz, CDCl3) δ 157.8, 145.9, 139.4, 130.6,
118.7, 115.3, 110.0, 78.0, 75.9, 55.8, 54.7, 47.7, 23.6, 21.3.
HRMS (DART+) Calcd for C18H22NO2 ([M + H+]+): 284.1651,
found: 284.1637.
N,Nꢀdiphenylꢀ2ꢀ(2ꢀ(3ꢀphenylpropanoyl)phenyl)acetamide
(9ba)
1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 7.8, 1.4 Hz, 1H),
7.65ꢀ7.00 (m, 18H), 3.85 (s, 2H), 3.26 (t, J = 7.6 Hz, 2H), 3.03
(t, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 202.7,
171.0, 143.0, 141.4, 137.5, 135.6, 132.6, 131.5, 129.7, 129.2,
128.8, 128.4, 127.9, 126.9, 126.4, 126.0, 42.4, 41.7, 30.2.
HRMS (DART+) Calcd for C29H26NO2 ([M + H+]+): 420.1964,
found: 420.1954.
Procedure for Scheme 5. (Phototriggered ketone formation
using an alkyne containing aminocyclopropenone and a
carboxylic acid)
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1c (85 mg, 0.3 mmol), 3ꢀphenylpropionic acid (2a) (30 mg,
0.2 mmol), triethylamine (27.9 ꢁL, 0.2 mmol) and DCM (20
mL) are mixed. The mixture was divided into 8 aliquots. Each
aliquot was transferred into a quartz tube equipped with a
magnetic stir bar and a N2 balloon. Each reaction mixture was
irradiated with the irradiation condition B for 5 min. After
completion of the reaction, all the aliquots were diluted in
DCM, quenched with 1 N aqueous KHSO4. All the reaction
mixtures were combined. The DCM phase was separated,
washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, filtered and concentrated. The residue was purified
with SiO2 column chromatography (AcOEt/hexane = 1/19 –
1/7) and PTLC (Et2O:hexane = 1:2). 8ca was obtained as a
colorless solid (47.3 mg, 58%). 9ca was obtained as a colorꢀ
less solid (8.0 mg, 10%).
Synthetic procedure for 1c
To a stirred solution of AlCl3 (2.39 g, 17.9 mmol) in MeNO2
(2.5 mL), tetrachlorocyclopropene (686 ꢁL, 5.63 mmol) in
DCM (5.0 mL) was added at 0 °C under N2 atmosphere. After
5 min, the mixture was cooled to ‒78 °C. To the mixture, a
solution of propargyloxybenzene (677 mg, 5.12 mmol) in
DCM (7.5 mL) was added over 5 min. After stirring for 30
min at ‒78 °C, the mixture was poured into ice cooled water
(50 mL). DCM phase was separated and aqueous phase was
extracted with DCM (10 mL x 2). Combined DCM phase was
dried over Na2SO4, filtered and concentrated in vacuo. The
residue was dissolved in acetone/water (20mL/4mL) at 0 °C
and stirred for 1 h. After reaction completion, the mixture was
diluted with DCM (30mL). DCM phase was separated and
aqueous phase was extracted with DCM (30 mL). Combined
DCM phase was dried over Na2SO4, filtered and concentrated
in vacuo to give a colorless solid. The crude material was puriꢀ
fied by recrystallization from DCM/hexane to give 13 as a
colorless solid (596 mg, 53%).
N,Nꢀdiisopropylꢀ3ꢀoxoꢀ5ꢀphenylꢀ2ꢀ(4ꢀ(propꢀ2ꢀynꢀ1ꢀ
yloxy)phenyl)pentanamide (8ca)
1H NMR (400 MHz, CDCl3) δ 7.28ꢀ7.09 (m, 5H), 7.14 (d, J =
8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 4.68 (d, J = 2.4 Hz, 2H),
4.61 (s, 1H), 3.73 (sept, J = 6.7 Hz, 1H), 3.34 (br sept, J = 6.4
Hz, 1H), 2.94ꢀ2.65 (m, 4H), 2.52 (t, J = 2.3 Hz, 1H), 1.46 (d, J
= 6.9 Hz, 3H), 1.39 (d, J = 6.9 Hz, 3H), 1.14 (d, J = 6.8 Hz,
3H), 0.70 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
205.0, 167.9, 157.1, 141.2, 129.9, 128.4, 128.3, 127.0, 125.9,
115.3, 78.3, 75.6, 64.1, 55.8, 49.5, 46.1, 43.4, 30.2, 20.8, 20.5,
20.0, 19.8. HRMS (DART+) Calcd for C26H32NO3 ([M +
H+]+): 406.2382, found: 406.2390.
2ꢀchloroꢀ3ꢀ(4ꢀ(propꢀ2ꢀynꢀ1ꢀyloxy)phenyl)cyclopropꢀ2ꢀenꢀ1ꢀ
one (13)
N,Nꢀdiisopropylꢀ2ꢀ(2ꢀ(3ꢀphenylpropanoyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀ
yloxy)phenyl)acetamide (9ca)
1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.13
(d, J = 8.4 Hz, 2H), 4.80 (d, J = 2.4 Hz, 2H), 2.58 (t, J = 2.5
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.5, 156.6, 148.7,
133.2, 127.7, 115.7, 115.5, 77.2, 76.6, 56.0. HRMS (DART+)
Calcd for C12H8ClO2 ([M + H+]+): 219.0213, found: 219.0209.
1H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.17 (m, 6H), 7.13 (d, J =
8.2 Hz, 1H), 7.01 (dd, J = 8.2, 1.8 Hz, 1H), 4.66 (s, 2H), 4.09
(sept, J = 6.8 Hz, 1H), 3.87 (s, 2H), 3.43 (br sept, J = 6.4 Hz,
1H), 3.23 (t, J = 7.6 Hz, 2H), 2.98 (t, J = 7.8 Hz, 2H), 2.51 (s,
1H), 1.38 (d, J = 6.8 Hz, 6H), 1.25 (d, J = 6.4 Hz, 6H). 13
C
To a stirred solution of 13 (500 mg, 2.29 mmol) in DCM (5.5
mL), a solution of diisopropylamine (769 ꢁL, 5.49 mmol) in
DCM (5.5 mL) was added at 0 °C under N2 atmosphere. After
15 min, the mixture was diluted with DCM (20 mL), washed
with 1 N aqueous HCl (10 mL) and water (10 mL x 2) succesꢀ
sively, dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified with SiO2 column chromatography
(AcOEt/hexane = 1/2 – 1/0) to give 1c as a colorless solid.
(532 mg, 82%).
NMR (100 MHz, CDCl3) δ 203.1, 169.6, 156.0, 141.4, 139.3,
132.9, 128.6, 128.45, 128.42, 126.0, 116.9, 115.7, 78.2, 75.8,
56.0, 48.6, 45.8, 42.6, 39.5, 30.2, 20.8, 20.7. HRMS (DART+)
Calcd for C26H32NO3 ([M + H+]+): 406.2382, found:406.2363.
ASSOCIATED CONTENT
NMR spectra
The Supporting Information including NMR spectra is available
free of charge on the ACS Publications website.
2ꢀ(diisopropylamino)ꢀ3ꢀ(4ꢀ(propꢀ2ꢀynꢀ1ꢀ
yloxy)phenyl)cyclopropꢀ2ꢀenꢀ1ꢀone (1c)
AUTHOR INFORMATION
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Corresponding Author
1
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*Eꢀmail (Kenji Mishiro): mishiro@p.kanazawaꢀu.ac.jp
*Eꢀmail (Munetaka Kunishima): kunisima@p.kanazawaꢀu.ac.jp
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Marin, V.; Patterson, M.; Miesbauer, L.; Ready, D.; Williams, J.;
Notes
Vasudevan, A.; Lin, Q., 2ꢀArylꢀ5ꢀcarboxytetrazole as a New Phoꢀ
toaffinity Label for Drug Target Identification. J. Am. Chem. Soc.
2016, 138 (44), 14609ꢀ14615. (d) Cheng, K.; Lee, J. S.; Hao, P.; Yao,
S. Q.; Ding, K.; Li, Z., TetrazoleꢀBased Probes for Integrated Phenoꢀ
typic Screening, AffinityꢀBased Proteome Profiling, and Sensitive
Detection of a Cancer Biomarker. Angew. Chem. Int. Ed. 2017, 56
(47), 15044ꢀ15048. (e) Tian, Y.; Jacinto, M. P.; Zeng, Y.; Yu, Z.; Qu,
J.; Liu, W. R.; Lin, Q., Genetically Encoded 2ꢀArylꢀ5ꢀ
carboxytetrazoles for SiteꢀSelective Protein PhotoꢀCrossꢀLinking. J.
Am. Chem. Soc. 2017, 139 (17), 6078ꢀ6081.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by MEXT KAKENHI, Grant No.
18K14864. This work was supported by Kanazawa Univerity
SAKIGAKE project 2018. K.M. acknowledges the support from
the Program to Disseminate Tenure Tracking System, MEXT.
K.M. acknowledges Prof. Tristan H. Lambert (Cornell University)
for helpful discussion.
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7 (a) Tamura, T.; Tsukiji, S.; Hamachi, I., Native FKBP12 Engineerꢀ
ing by LigandꢀDirected Tosyl Chemistry: Labeling Properties and
Application to PhotoꢀCrossꢀLinking of Protein Complexes in Vitro
and in Living Cells. J. Am. Chem. Soc. 2012, 134 (4), 2216ꢀ2226. (b)
Kunishima, M.; Nakanishi, S.; Nishida, J.; Tanaka, H.; Morisaki, D.;
Hioki, K.; Nomoto, H., Convenient modular method for affinity labelꢀ
ing (MoAL method) based on a catalytic amidation. Chem. Commun,
2009, (37), 5597ꢀ5599. (c) Nakanishi, S.; Tanaka, H.; Hioki, K.;
Yamada, K.; Kunishima, M., Labeling study of avidin by modular
method for affinity labeling (MoAL). Bioorg. Med. Chem. Lett. 2010,
20 (23), 7050ꢀ7053. (d) Kunishima, M.; Kato, D.; Nakanishi, S.;
Kitamura, M.; Yamada, K.; Terao, K.; Asano, T., Specific labeling of
streptavidin for better understanding of ligand modification in moduꢀ
lar method for affinity labeling (MoAL). Chem. Pharm. Bull. 2014,
62 (11), 1146ꢀ1150.
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