Elusive 2-aminofuran Diels-Alder substrates for a straightforward synthesis of polysubstituted anilines

Article abstract of DOI:10.1039/c3ob41411f

The first multicomponent coupling of isocyanides, α,β- unsaturated carbonylic compounds and dienophiles, based on the trapping of unstable intermediate 2-aminofurans, is described. This novel tandem [4 + 1]-[4 + 2] cycloaddition is efficiently catalysed by yttrium triflate and constitutes an operationally simple and highly convergent approach to a variety of polysubstituted anilines. Moreover, this methodology permits the use of tert-butylisocyanide as a convertible isocyanide to yield directly N-unprotected anilines in the same pot.

Full text of DOI:10.1039/c3ob41411f

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Elusive 2-aminofuran Diels-Alder substrates for a straightforward
synthesis of polysubstituted anilines
Ana G. Neo,a Ana Bornadiego,a Jesús Díaz,a Stefano Marcaccini§b and Carlos F. Marcos*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The first multicomponent coupling of isocyanides, α,β-unsaturated carbonylic compounds and
dienophiles, based on the trapping of unstable intermediate 2-aminofurans, is described. This novel
tandem [4+1]-[4+2] cycloaddition is efficiently catalysed by yttrium triflate and constitutes an
operationally simple and highly convergent approach to a variety of polysubstituted anilines. Moreover,
10 this methodology permits to use tert-butylisocyanide as a convertible isocyanide to yield directly N-
unprotected anilines in the same pot.
45 undergo further in situ [4+2] cycloaddition with dienophiles,
resulting in a convenient and direct synthesis of polysubstituted
anilines, (Scheme 1), which are key intermediates in the
preparation of diverse biologically active compounds.13
Several tandem and sequential synthesis of anilines have been
50 reported,2b, 14 some involving aminofuran intermediates,9d, 15 but
they usually require two or more reaction steps. Sequential [4+1]-
[4+2] cycloadditions of isocyanides have not been reported until
now.
Introduction
Merging known transformations to form new cascade reactions
has been recognized as a challenging and powerful strategy in
15 synthesis.1 Especially, multicomponent tandem cycloadditions
are notably superior to stepwise procedures in terms of atom
efficiency and experimental simplicity.2
Furans, and particularly those containing electron-donating
groups, have been frequently employed as dienes in the Diels-
20 Alder reaction to afford substituted 7-oxabicyclo[2.2.1]heptanes,
which can be further transformed into a variety of molecular
Results and discussion
structures.3 In an important application, Padwa demonstrated that 55 We anticipated that readily accessible 2-oxo-4-arylbut-3-
2-aminofuran derivatives can undergo Diels-Alder reactions with
activated dienophiles as the key step in the synthesis of
25 substituted anilines4 and indoles.5 However, as a result of their
inherent instability, simple 2-aminofurans have proven to be
enoates16 could be suitable carbonyl substrates for this
transformation. Accordingly, we decided to verify if these
compounds would react with isocyanides to provide 2-
aminofuran intermediates 4, which could be trapped in situ with
elusive systems, difficult or impossible to synthesise or even trap 60 appropriate dienophiles. Thus, (E)-methyl 4-(4-methoxyphenyl)-
as in situ intermediates.6 This problem has been circumvented
2-oxobut-3-enoate (1b), cyclohexyl isocyanide (2a) and N-
phenylmaleimide (3a) were heated in toluene at 100 ºC (Scheme
1). Monitoring of the reaction by tlc showed the slow formation
of a new product. However, after several hours, the reaction
65 seemed to reach a steady state in which the starting material was
not further transformed into the product. Workup of the reaction
after 40 h, and purification by column chromatography led to the
isolation of a single identifiable product in a 20% yield, as well as
56% of unreacted ketoester 1b. Satisfactorily, we assigned the
7
7
either by using carbamate,5a,
amide5b,
or sulfonamide8
30 derivatives of 2-aminofuran, or by including electron-
withdrawing groups in the furanamine nucleus to enhance its
stability.9
On the other hand, isocyanides are known to give [4+1]
cycloadditions with α,β-unsaturated carbonylic compounds to
35 afford unsaturated N-substituted iminolactones10 and 2-
aminofurans.11 However, a recent report6a points out the difficulty
to isolate 2-aminofurans synthesised in this manner, due to its 70 structure of the new product to the expected 7-amino-1,3-
instability and its tendency to be quickly oxidized by triplet
oxygen.12
dioxoisoindoline-4-carboxylate (7b, Ar= 4-CH3OPh, R’= c-
C6H11, X= NPh).
40
We hypothesise that the high reactivity of 2-aminofurans could
be advantageously exploited to bring on subsequent synthetically
A plausible reaction mechanism is depicted in Scheme 1: the
α,β-unsaturated ketoester (1b) suffers a [4+1] cycloaddition with
useful reactions coupled in tandem. Hence, we anticipate that 2- 75 the isocyanide (2a). Subsequent [4+2] cycloaddition of the
aminofurans obtained by [4+1] cycloadditions of isocyanides and
electron deficient unsaturated carbonylic compounds may
resulting aminofuran intermediate (4) with N-phenylmaleimide
(3a, X= NPh) gives oxabicycle (5). This was not isolated, but the
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Organic & Biomolecular Chemistry
Page 2 of 10
oxygen bridge was opened in the reaction conditions and
polysubstituted aniline 7b was directly obtained after
aromatization.
View Article Online
DOI: 10.1039/C3OB41411F
Fig. 1 GS-MS chromatograms of aliquots of the reaction of 1a and 2a
taken at different times showing the transformation of intermediate 4a
into pyrrolone 10
5
Scheme 1 Proposed mechanism for the tandem cycloaddition
To evaluate if the formation of aniline 7 really occurs through
an aminofuran intermediate, an equimolar mixture of (E)-methyl
2-oxo-4-phenylbut-3-enoate (1a) and cyclohexyl isocyanide (2a)
was refluxed 35 hours in toluene. After workup, 5-hydroxy-2-
35
Electrophilic activation of carbonyl compounds by hydrogen
10b, 18
bond donors17 or Lewis acids
is known to catalyze [4+1]
and Diels-Alder cycloadditions, and in our case might also
facilitate the oxygen bridge opening and dehydration. Hence, we
investigated the effect of different organocatalysts and Lewis
10 pyrrolone 10 was obtained in a 13% yield as the only identifiable
product, besides a 45% of recovered starting material (Scheme 2).
This result is in agreement with Quai and co-workers, who have
reported an analogous pyrrolone from the reaction of cyclohexyl
isocyanide with 3-benzylidene-2,4-pentanedione.6a The formation
15 of this compound is attributed to the oxidation of an intermediate
2-aminofuran by triplet oxygen.12 In a separate experiment the
reaction was monitored at periodic intervals by GC-MS. The
resulting chromatograms showed the presence of a peak at 10.75
minutes, corresponding to pyrrolone 10, and a second peak at
20 10.82 minutes, having an associated mass spectrum compatible
with 2-aminofuran 4a (Scheme 2). As the reaction advanced, the
size of the peak corresponding to final compound 10
progressively increased, while the peak corresponding to
intermediate 4a decreased in a comparable way (Fig. 1). Also in
25 agreement with Quai’s observations, we were unable to isolate
aminofuran 4a. However, this experimental evidence suggests
that the desired intermediate aminofuran 4a is formed in the
reaction conditions,‡ though with a rather low reaction rate.
40 acids on the reaction of (E)-methyl 4-(4-methoxyphenyl)-2-
oxobut-3-enoate (1b), cyclohexyl isocyanide (2a) and N-
phenylmaleimide (3a). Furthermore, we explored the use of
thermal and microwave activation in different polar and non-
polar solvents (Table 1). In some cases shortening of the reaction
45 times was observed, but in most of them, no significant
improvements on the yields were obtained, and a considerable
fraction of the starting ketoester 1b was still recovered from the
reaction (Table 1, entries 1-23).
30
Scheme 2 Tandem [4+1] cycloaddition/oxidation
2
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Organic & Biomolecular Chemistry
23
24
25
26
In(OTf)3 5%
Y(OTf)3 5%
Y(OTf)3 5%
Y(OTf)3 5%
PhCl
PhCH3
PhCH3
120 ºC
rt
100 ºC
7 h
48 h
30
Table 1 Optimisation of the tandem synthesis of aniline 7b
NRa
Entry
1
2
3
4
5
6
7
8
Catalyst
-
Solvent Conditions Time Yield (%)
3Vhiew Article Online
50
35
THF
PhCH3
rt
24 h
40 h
2 h
30 h
3 h
NRa
20
23
30
17
15
18
31
6
9
10
12
6
PhCH3 mw, 100 ºC 8 min
DOI: 10.1039/C3OB41411F
-
-
100 ºC
a
b
NR = No reaction. ArTU = 1,3-bis(3,5-bis(trifluoromethyl)phenyl)
thiourea.
hydrolysis of the isocyanide occurs in these reaction conditions; the
5 reaction was stopped when the hydrolysis of the isocyanide was
complete; longer reaction times also gave no products.
decomposition of the starting materials to a complex mixture.
PhCH3 mw, 120 ºC
PhCH3 100 ºC
PhCH3 mw, 120 ºC
PhCH3 120 ºC
PhCH3 mw, 120 ºC
c
d
Ar2TUb 50%
Ar2TUb 50%
Sulfonamidec 15%
Sulfonamidec 10%
LiClO4 5%
AlCl3 5%
ZnCl2 5%
Zn(OTf)2 5%
(S,S)-N,N´-Bis(α-methyl)benzylsulfonamide.
Complete
24 h
2 h
e
Dec =
PhCH3
PhCH3
PhCH3
PhCH3
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
rt
12 h
12 h
12 h
12 h
12 h
12 h
10 min
9
10
11
Conversely, the use of only 5% molar Y(OTf)3 at 100 ºC
(Table 1, entries 25 and 26) results in very clean reactions, giving
10 aniline 7b in moderate yields and short reaction times. More
importantly, it is only in the presence of this catalyst that the
complete conversion of the starting ketoester 1b is achieved. In
these conditions tlc monitoring of the reactions evidences a rapid
formation of the intermediate aminofuran, and its slower
15 transformation into the final product. This observation suggests
that Y(OTf)3 catalyses the [4+1] cycloaddition of the isocyanide
(2a) and the ketoester (1b), but it has scarce or no influence on
the subsequent Diels-Alder reaction.
12 [Cu(OTf)]2·PhCH3 5% PhCH3
13
14
15
16
17
18
19
20
21
22
Cu(OTf)2 5%
Sc(OTf)3 5%
Sc(OTf)3 5%
Sc(OTf)3 5%
Sc(OTf)3 5%
Sc(OTf)3 5%
Sc(OTf)3 5%
Sc(OTf)3 5%
In(OTf)3 5%
In(OTf)3 5%
PhCH3
THF
NRa,d
NRa,d
NRa
Dece
NRa
15
THF mw , 100 ºC 10 min
CH3CN rt 12 h
CH3CN mw, 100 ºC 12 min
CH2Cl2
PhCH3
PhCl
PhCH3
PhCH3
rt
24 h
7 h
10 h
24 h
12 h
100 ºC
120 ºC
rt
17
NRa
15
100 ºC
Table 2 Three-component synthesis of anilinesa
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Page 4 of 10
CO2Me
O
Br
N
View Article Online
DOI: 10.1039/C3OB41411F
O
HN
7r (55%)f
a General procedure: To a solution of α-ketoester 1 (0.3 mmol) in dry toluene (1.2 mL), Y(OTf)3 (5% mol), isocyanide 2 (0.54 mmol) and dienophile 8
(0.36 mmol) were added. The resulting mixture was heated at 100 ºC under nitrogen atmosphere for 3 h, except otherwise stated. b Reaction time: 1 h.
c This product was obtained from a reaction carried out in toluene at 100 ºC during 30 h, using 50% 1,3-bis(3,5-bis(trifluoromethyl) phenyl)thiourea as
catalyst. d Obtained together with a 20% of 7g. e Obtained together with a 30% of 7h. f Reaction time: 6 h. g Reaction time: 15 h. h Reaction time: 30 h.
5
To study the scope of this reaction, we explored the use of
different α,β-unsaturated ketoesters, isocyanides and dienophiles.
The results are summarized in Table 2. The reaction tolerates
different substituents on the aromatic ring of the ketoester,
isocyanides and dienophiles, thus facilitating the synthesis of
10 diversely substituted anilines.
Surprisingly, when tert-butylisocyanide (2b) was used in the
optimised reaction conditions, unprotected anilines 7i-l (Table 2)
were obtained instead of the expected N-tert-butyl anilines 7e-h.
Conversely, when the time of the reactions between N-
15 phenylmaleimide (3a), tert-butylisocyanide (2b) and ketoesters
1a and 1d was reduced from 3 h to 1 h, it was possible to isolate
the corresponding N-tert-butyl anilines 7e,h in satisfactory yields
(Table 2). Also, when the multicomponent reaction was
performed in the presence of catalytic 1,3-bis(3,5-
20 bis(trifluoromethyl)phenyl)thiourea instead of Y(OTf)3, N-tert-
butyl anilines 7f,g were obtained (Table 2). These results suggest
that detertbutylation takes place, in the same pot, after the
multicomponent condensation, only in the presence of Y(OTf)3.
To confirm this idea, we performed separate experiments in
25 which N-tert-butyl anilines 7e,h were heated in toluene at 100 ºC
in the presence of 5% Y(OTf)3. Unprotected anilines 7i,l were
cleanly obtained in an almost quantitative yield, after two and
five hours, respectively (Scheme 3). When 7e,h were subjected to
similar reaction conditions in the absence of Y(OTf)3 the starting
30 material was recovered unchanged even after heating periods of
over 12 hours.
Scheme 3 Dealkylation of N-tert-butyl anilines
Although the use of tert-butylisocyanide as a convertible
35 isocyanide in Ugi-type reactions has been recently proposed for
the preparation of unprotected fused aminoimidazo[1,2-a]azines
and -azoles,19 an additional step is required for the removal of the
tert-butyl group. Furthermore, dealkylations of tert-butylanilines
usually require quite harsh acid conditions.20 However, in our
40 case, detertbutylation is readily performed in the same pot of the
MCR or in an independent step, under mild conditions in the
presence of catalytic Y(OTf)3. This process is probably facilitated
by the electron-withdrawing substituents present on the benzene
ring and by the neighbouring carbonyl group that might provide a
45 chelating anchor for the yttrium. To the best of our knowledge,
Lewis acids had not been previously reported to catalyse this type
of reaction. The possibility of obtaining unprotected anilines is
crucial for further functionality interconversion or cyclisation
leading to biologically relevant molecular scaffolds, such as
50 phenanthridines21 or carbazoles.22
To further study the utility of this new synthesis of anilines, we
explored the transformation of 2-(ortho-bromophenyl)aniline 7r
into pyrrolo[3,4-a]carbazole-1,3-dione 11. This type of structure
is present in analogues of granulatimide that show
55 antiproliferative activity related to inhibitory properties toward
Checkpoint
1
kinase (Chk1).23 Thus, copper catalyzed
intramolecular N-C coupling of 7r was efficiently achieved under
4
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Organic & Biomolecular Chemistry
microwave activation to afford carbazole 11 in high yield.
70 eV), Chemical Ionization (CI) with CH4, or ESI-FIA-TOF.
50 GC-MS conditions were as follows: injector temperature 250 ºC;
View Article Online
injection at 40 split ratio; capillary coluDmOnI: (1300.10m39x/C03O.2B541m4m11)F
Varian VF-5ms; carrier gas helium with a flow of 1 mL/min;
initial temperature 140°C, holding 2 min, ramping rate was
20°C/min by linear, up to 280°C, then 10°C/min up to a final
55 temperature of 310 ºC, holding 5 min; total time of the analysis
18.5 min.
General procedure for the tandem [4+1]/[4+2] cycloaddition.
Scheme 4 Synthesis of pyrrolo[3,4-a]carbazole-1,3-dione 11
To a solution of α-ketoester 1 (0.3 mmol) in dry toluene (1.2 mL),
yttrium trifluoromethanesulfonate (5% mol), isocyanide 2 (0.54
60 mmol) and dienophile 3 (0.36 mmol) were added under nitrogen
atmosphere. The resulting mixture was heated at 100 ºC under
nitrogen atmosphere for 1-3 h. The reaction was cooled to rt, 10%
HCl (5 mL) was added and the organic phase was extracted with
CH2Cl2, dried (Na2SO4) and concentrated. The residue was
65 purified by flash chromatography (silica gel, hexane-EtOAc
gradient), giving the corresponding aniline 7.
Conclusions
5
In conclusion, we have developed a convenient and highly
convergent one-pot synthesis of polysubstituted anilines. This
approach is based on the in situ trapping of elusive very reactive
2-aminofurans with dienophiles. The unprecedented tandem
combination of [4+1] cycloaddition, [4+2] cycloaddition, oxygen-
10 bridge opening and aromatisation affords anilines with diverse
substitution patterns that are difficult to synthesise by other ways.
Significantly, the overall transformation involves the formation of
three new C-C bonds. The use of Y(OTf)3 catalyst produces a
significant increase in the rate of the initial [4+1] cycloaddition,
15 leading to the rapid and clean synthesis of the final anilines. To
show the synthetic potential of this methodology, N-benzylaniline
7r was readily transformed into pyrrolo[3,4-a]carbazole-1,3-
dione 11. This tetracyclic compound is efficiently obtained in just
to steps from simple starting materials. Furthermore, by the use of
20 tert-butylisocyanide in the presence of Y(OTf)3 we were able to
obtain directly unprotected anilines with no need of additional
deprotection steps, thus establishing the basis for further
transformations. To the best of our knowledge, this is the first
example of a direct synthesis of unprotected anilines in just one
25 reaction step.
Synthesis of N-tert-butyl anilines 7f,g.
A solution of α-ketoester 1b or 1c (0.3 mmol), 1,3-bis(3,5-
bis(trifluoromethyl)phenyl)thiourea (0.15 mmol), isocyanide 2b
70 (0.45 mmol) and N-phenylmaleimide 3a (0.45 mmol) in dry
toluene (3 mL) was refluxed under nitrogen atmosphere for 30 h.
The reaction was cooled to rt, 10% HCl was added, and the
organic phase was extracted with CH2Cl2, dried (Na2SO4) and
concentrated. The residue was purified by flash chromatography
75 (silica gel, hexane-EtOAc gradient), giving the corresponding
anilines 7f or 7g.
Dealkylation of N-tert-butyl anilines 7e and 7h.
A solution of 7e or 7h (0.1 mmol) and Y(OTf)3 (5%) in dry
toluene (1 mL) was heated at 100 ºC under nitrogen atmosphere
80 for 1 or 5 h, respectively. The reaction was cooled to rt, H2O was
added and the organic phase was extracted with CH2Cl2, dried
(Na2SO4) and concentrated to give pure anilines 7i or 7l in
quantitative yield.
Experimental
General
Spectroscopic data
Methyl
All experiments were carried out in stoppered flasks using inert
atmosphere. Experiments under microwave irradiation were
85
7-(cyclohexylamino)-1,3-dioxo-2,6-
diphenylisoindoline-4-carboxylate (7a). (47%) obtained as a
30 performed in closed vials, using
a focused single-mode
yellow solid; mp 143-145 ºC; IR (cm-1) 3447, 2926, 2850, 1728,
microwave reactor CEM Discover BenchMate. Liquid reagents
were measured using positive-displacement micropipettes with
disposable tips and pistons. Thin layer chromatography was
performed on aluminium plates, using 254 nm UV light or a
35 mixture of p-anisaldehyde (2.5%), acetic acid (1%) and H2SO4
(3.4%) in 95% ethanol, as developer.
1
1704, 1610, 1206; H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H),
7.57 – 7.38 (m, 10H), 7.16 – 7.00 (bs, 1H), 3.95 (s, 3H), 2.82 –
90 2.68 (m, 1H), 1.70 – 0.76 (m, 10H); 13C NMR (101 MHz, CDCl3)
δ 169.4 (C), 165.8 (C), 164.6 (C), 148.0 (C), 139.8 (CH), 139.5
(C), 134.2 (C), 131.6 (C), 130.0 (C), 129.0 (CH), 128.6 (CH),
128.5 (CH), 128.2 (CH), 128.0 (CH), 126.7 (CH), 117.7 (C),
114.1 (C), 52.4 (CH3 and CH), 33.6 (CH2), 25.3 (CH2), 24.3
95 (CH2); MS (EI) m/z (%) 454 (M+·, 40), 410 (88), 379 (100), 361
(45), 307 (45); HRMS (EI) Calcd for C28H26N2O4: 454.1893.
Found: 454.1882.
Isocyanides,
phenylmaleimide,
maleimide,
maleic
N-methylmaleimide,
anhydride, (S,S)(N,N´)-Bis(α-
N-
methyl)benzylsulfonamide, Sc(OTf)3, In(OTf)3 and Y(OTf)3 were
40 purchased from commercial sources. α-Ketoesters 1a-i16 and 1,3-
bis(3,5-bis(trifluoromethyl)phenyl)thiourea24 were
according to the literature.
prepared
Methyl
7-(cyclohexylamino)-6-(4-methoxyphenyl)-1,3-
dioxo-2-phenylisoindoline-4-carboxylate (7b). (50%) obtained
100 as a yellow solid; mp 180-183 ºC dec; IR (cm-1) 2923, 1767,
1732, 1702, 1608, 1489, 1389, 1243; 1H NMR (400 MHz,
CDCl3) δ 7.74 (s, 1H), 7.56 – 7.33 (m, 7H), 7.10 – 7.01 (bs, 1H),
7.00 (d, J = 8.5 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 2.90 – 2.81
(m, 1H), 1.73 – 1.03 (m, 10H); 13C NMR (101 MHz, CDCl3) δ
Melting points are uncorrected. IR spectra were recorded as
KBr pellets. Proton and carbon-13 nuclear magnetic resonance
45 (1H NMR or 13C NMR) spectra were obtained on a 400 MHz or
500 MHz spectrometer. The assignments of signals in 13C NMR
were made using DEPT. Mass spectra (MS) and High Resolution
Mass Spectra (HRMS) were recorded using Electron Impact (EI,
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169.4 (C), 165.9 (C), 164.7 (C), 159.5 (C), 148.3 (C), 139.8
phenylisoindoline-4-carboxylate (7g). (50%) obtained as a
(CH), 134.3 (C), 131.6 (C), 131.6 (C), 129.7 (C), 129.6 (CH), 60 yellow solid; mp 198-200 ºC; IR (cm-1) 3428, 2963, 1771, 1689,
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129.0 (CH), 128.0 (CH), 126.7 (CH), 117.9 (C), 114.3 (C), 114.0
(CH), 55.4 (CH3), 52.4 (CH3), 52.3 (CH), 33.6 (CH2), 25.3 (CH2),
24.2 (CH2); MS (EI) m/z (%) 484 (M+·, 100), 441 (58), 413 (13);
HRMS (EI) Calcd for C29H28N2O5: 484.1998. Found: 484.2000.
1595, 1513, 1385, 1219, 805; 1H NMR (500DMOIH: 1z0,.1C0D39C/lC3)3OδB74.184111F
(s, 1H), 7.63 – 7.58 (m, 2H), 7.54 (t, J = 7.7 Hz, 2H), 7.50 – 7.40
(m, 3H), 7.16 (t, J = 8.6 Hz, 2H), 3.99 (s, 3H), 0.96 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ 168.8 (C), 165.9 (C), 164.2 (C), 164.0
5
Methyl 7-(cyclohexylamino)-6-(4-fluorophenyl)-1,3-dioxo- 65 (C), 161.5 (C), 149.4 (C), 141.4 (C), 138.6 (CH), 136.3 (C),
2-phenylisoindoline-4-carboxylate (7c). (35%) obtained as a
136.3 (C), 134.2 (CH), 131.4 (C), 131.2 (CH), 131.1 (CH), 129.1
(CH), 128.9 (C), 128.2 (CH), 128.0 (C), 126.7 (CH), 126.1 (CH),
122.4 (C), 121.7 (C), 115.9 (CH), 115.6 (C), 57.4 (C), 52.8
(CH3), 30.8 (CH3); MS (EI) m/z (%) 446 (M+·, 28), 431 (100),
yellow solid; mp 139-141 ºC; IR (cm-1) 2925, 1770, 1732, 1699,
1
10 1595, 1392, 1240, 1212; H NMR (400 MHz, CDCl3) δ 7.74 (s,
1H), 7.57 – 7.37 (m, 7H), 7.21 – 7.04 (m, 3H), 3.95 (s, 3H), 2.80
– 2.68 (m, 1H), 1.71 – 0.80 (m, 10H). 13C NMR (101 MHz, 70 390 (97), 359 (35); HRMS (EI) Calcd for C26H23FN2O4:
CDCl3) δ 169.3 (C), 165.7 (C), 164.5 (C), 163.8 (C), 161.3 (C),
148.1 (C), 139.9 (CH), 135.4 (C), 135.4 (C), 133.2 (C), 131.5
15 (C), 130.2 (CH), 130.2 (CH), 129.1 (CH), 128.1 (CH), 126.7
(CH), 117.9 (C), 115.8 (C), 115.6 (CH), 114.5 (C), 52.5 (CH3 and
446.1642. Found: 446.1645.
Methyl 7-(tert-butylamino)-6-(4-chlorophenyl)-1,3-dioxo-2-
phenylisoindoline-4-carboxylate (7h). (35%) obtained as a
yellow solid; mp 127-130 ºC dec; IR (cm-1) 3444, 1728, 1706,
1
CH), 33.6 (CH2), 25.2 (CH2), 24.3 (CH2); MS (EI) m/z (%) 472 75 1608, 1383, 1280, 1263, 1086; H NMR (500 MHz, CDCl3) δ
(M+·, 20), 429 (64), 340 (100), 267 (94), 239(49); HRMS (EI)
Calcd for C28H25FN2O4: 472.1798. Found: 472.1798.
7.81 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.53 (dt, J = 9.3, 1.8 Hz,
2H), 7.48 – 7.43 (m, 5H), 3.99 (s, 3H), 0.97 (s, 9H);13C NMR
(101 MHz, CDCl3) δ 168.8 (C), 165.8 (C), 164.2 (C), 149.3 (C),
141.2 (C), 138.7 (C), 138.5 (CH), 134.4 (C), 131.3 (C), 130.7
20
Methyl 6-(4-chlorophenyl)-7-(cyclohexylamino)-1,3-dioxo-
2-phenylisoindoline-4-carboxylate (7d). (51%) obtained as a
yellow solid; mp 172-174 ºC; IR (cm-1) 3435, 2930, 1766, 1699, 80 (CH), 129.1 (CH), 128.9 (CH), 128.3 (CH), 126.7 (CH), 122.4
1
1609, 1380, 1208, 1087; H NMR (500 MHz, CDCl3) δ 7.73 (s,
1H), 7.53 (t, J = 7.7 Hz, 2H), 7.46 – 7.42 (m, 4H), 7.41 (t, J = 7.2
(C), 121.8 (C), 57.5 (C), 52.8 (CH3), 30.8 (CH3); MS (EI) m/z
(%) 462 (M+·, 5), 447 (26), 406 (50), 375 (45), 148 (100); HRMS
(FAB) Calcd for C26H23ClN2O4: 462.1346. Found: 462.1344.
25 Hz, 3H), 7.09 (d, J = 9.5 Hz, 1H), 3.96 (s, 3H), 2.83 – 2.72 (m,
1H), 1.70 – 0.84 (m, 10H); 13C NMR (101 MHz, CDCl3) δ 169.2
Methyl
7-amino-1,3-dioxo-2,6-diphenylisoindoline-4-
(C), 165.7 (C), 164.4 (C), 148.0 (C), 139.8 (CH), 137.9 (C), 85 carboxylate (7i). (45%) obtained as a yellow solid; mp 112-114
134.3 (C), 133.0 (C), 131.5 (C), 130.2 (C), 129.8 (CH), 129.1
(CH), 128.8 (CH), 128.1 (CH), 126.7 (CH), 118.0 (C), 114.6 (C),
30 52.6 (CH), 52.5 (CH3), 33.5 (CH2), 25.3 (CH2), 24.2 (CH2); MS
(EI) m/z (%) 488 (M+·, 50), 445 (84), 267 (90), 200 (100); HRMS
(EI) Calcd for C28H25ClN2O4: 488.1503. Found: 488.1510.
ºC; IR (cm-1) 3479, 1770, 1772, 1621, 1503, 1385,1254, 1114,
754; 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.59 – 7.38 (m,
10H), 3.98 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.7 (C),
165.7 (C), 164.6 (C), 145.7 (C), 137.4 (CH), 135.6 (C), 133.2
90 (C), 131.6 (C), 130.1 (C), 129.5 (CH), 129.1 (CH), 128.9 (CH),
128.6 (CH), 128.6 (C), 128.0 (C), 126.7 (CH), 118.3 (C), 111.7
(C), 52.5 (CH3); MS (CI) m/z (%) 373 (M+1, 5), 341 (11), 111
(11), 55 (100); HRMS (ESI-FIA-TOF) Calcd for C22H16N2NaO4:
395.1003. Found: 395.1002.
Methyl
7-(tert-butylamino)-1,3-dioxo-2,6-
diphenylisoindoline-4-carboxylate (7e). (40%) obtained as a
35 yellow solid; mp 165-167 ºC; IR (cm-1) 3441, 1774, 1734, 1709,
1
1386, 1214, 1116, 741; H NMR (500 MHz, CDCl3) δ 7.83 (s,
1H), 7.61 (d, J = 7.3 Hz, 2H), 7.55 – 7.51 (m, 2H), 7.49 – 7.38
(m, 5H), 6.16 (bs, 1H), 3.99 (s, 3H), 0.96 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 168.9 (C), 165.9 (C), 164.3 (C), 149.5 (C), 142.2
40 (C), 140.3 (C), 138.7 (CH), 131.4 (C), 129.4 (CH), 129.1 (CH),
128.8 (C), 128.7 (CH), 128.3 (CH), 128.2 (CH), 126.7 (CH),
95
Methyl
7-amino-6-(4-methoxyphenyl)-1,3-dioxo-2-
phenylisoindoline-4-carboxylate (7j). (52%) obtained as a
yellow solid; mp 153-155 ºC; IR (cm-1) 3468, 1770, 1703, 1610,
1
1385, 1251, 1181, 755; H NMR (500 MHz, CDCl3) δ 7.84 (s,
1H), 7.52 (dt, J = 9.3, 1.8 Hz, 2H), 7.46 (dt, J = 8.4, 1.8 Hz, 2H),
122.0 (C), 121.2 (C), 57.2 (C), 52.7 (CH3), 30.7 (CH3); MS (CI) 100 7.44 – 7.40 (m, 3H), 7.09 – 7.05 (m, 2H), 6.00 (bs, 2H), 3.98 (s, ,
m/z (%) 429 (M+1, 8), 401 (14), 373 (91), 341 (100), 148 (12);
HRMS (ESI-FIA-TOF) Calcd for C26H26N2NaO4: 451.1634.
45 Found: 451.1628.
3H), 3.90 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.8 (C),
165.8 (C), 164.7 (C), 160.0 (C), 145.9 (C), 137.3 (CH), 133.1
(C), 131.6 (C), 129.9 (CH), 129.0 (CH), 128.0 (CH), 127.7 (C),
126.7 (CH), 118.3 (C), 114.9 (CH), 111.6 (C), 55.4 (CH3), 52.5
Methyl
7-(tert-butylamino)-6-(4-methoxyphenyl)-1,3-
dioxo-2-phenylisoindoline-4-carboxylate (7f). (56%) obtained 105 (CH3); MS (CI) m/z (%) 403 (M, 58), 371 (60), 337 (10), 192
as a yellow solid; mp 170-171 ºC; IR (cm-1) 3448, 1703, 1607,
1391, 1304, 1217; H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H),
(13), 61 (100); HRMS (ESI-FIA-TOF) Calcd for C23H18N2NaO5:
425.1110. Found: 425.1109.
1
50 7.64 – 7.36 (m, 7H), 6.98 (d, J = 8.7 Hz, 1H), 6.35 – 5.95 (bs,
Methyl
7-amino-6-(4-fluorophenyl)-1,3-dioxo-2-
1H), 3.97 (s, 3H), 3.88 (s, 3H), 0.98 (s, 9H). 13C NMR (101 MHz,
phenylisoindoline-4-carboxylate (7k). (16%) obtained as a
CDCl3) δ 168.9 (C), 166.0 (C), 164.4 (C), 159.7 (C), 149.6 (C), 110 yellow solid; mp 194-196 ºC; IR (cm-1) 2479, 3361, 1769, 1701,
142.3 (C), 138.5 (CH), 132.7 (C), 131.4 (C), 130.6 (CH), 129.1
(CH), 128.4 (C), 128.2 (CH), 126.7, (CH), 122.2 (C), 121.5 (C),
55 114.1 (CH), 57.3 (C), 55.4 (CH3), 52.7 (CH3), 30.8 (CH3); MS
(EI) m/z (%) 458 (M+·, 14), 443 (43), 402 (91), 197 (100); HRMS
(EI) Calcd for C27H26N2O5: 458.1842. Found: 458.1847.
1623, 1431, 1387, 1325, 849; 1H NMR (500 MHz, CDCl3) δ 7.84
(s, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.49 – 7.40 (m, 5H), 7.27 – 7.25
(t, J = 8.6 Hz, 2H), 5.79 (bs, 1H), 3.97 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 168.6 (C), 165.7 (C), 164.5 (C), 164.2 (C), 161.7
115 (C), 145.7 (C), 137.5 (CH), 132.1 (C), 131.6 (C), 131.5 (C),
131.5 (C), 130.6 (CH), 130.5 (C), 130.2 (C), 129.1 (CH), 128.1
Methyl 7-(tert-butylamino)-6-(4-fluorophenyl)-1,3-dioxo-2-
6
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Page 7 of 10
Organic & Biomolecular Chemistry
(CH), 126.7 (CH), 118.3 (C), 116.7 (CH), 116.5 (CH), 111.9 (C),
(CH3); MS (CI) m/z (%) 595 (M+1, 35), 463 (13), 174 (60), 69
52.5 (CH3); MS (CI) m/z (%) 391 (M+1, 92), 387 (33), 371 (28), 60 (100); HRMS (ESI-FIA-TOF) Calcd for C3V0Hiew23FArNtic2lNe OanOli4n:e
359 (100); HRMS (ESI-FIA-TOF) Calcd for C22H15FN2NaO4:
413.0898. Found: 413.0908.
517.1531. Found: 517.1534.
Methyl 7-(benzylamino)-6-(4-methoxyphenyl)-1,3-dioxo-2-
DOI: 10.1039/C3OB41411F
5
Methyl
7-amino-6-(4-chlorophenyl)-1,3-dioxo-2-
phenylisoindoline-4-carboxylate (7p). (59%) obtained as a
phenylisoindoline-4-carboxylate (7l). (20%) obtained as a
yellow solid; mp 118-120 ºC; IR (cm-1) 3428, 1703, 1607, 1496,
yellow solid; mp 136-138 ºC; IR (cm-1) 3437, 1771, 1698, 1620, 65 1385, 1258, 1116, 769, 740; H NMR (500 MHz, CDCl3) δ 7.78
1
1504, 1433, 1385, 1321, 1112, 750; 1H NMR (500 MHz, CDCl3)
(s, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.48 – 7.39 (m, 4H), 7.36 (d, J =
8.4 Hz, 2H), 7.30 – 7.20 (m, 3H), 7.05 (d, J = 7.1 Hz, 2H), 6.97
(t, J = 8.6 Hz, 2H), 4.00 (d, J = 5.4 Hz, 2H), 3.96 (s, 3H), 3.89 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 169.3 (C), 165.8 (C), 164.5
δ 7.84 (s, 1H), 7.57 – 7.49 (m, 4H), 7.48 – 7.37 (m, 5H), 5.92 (bs,
10 2H), 3.98 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 168.6 (C),
165.6 (C), 164.5 (C), 145.6 (C), 137.4 (CH), 135.1 (C), 134.0
(C), 131.8 (C), 131.5 (C), 130.4 (C), 130.0 (CH), 129.8 (CH), 70 (C), 159.6 (C), 148.4 (C), 140.2 (CH), 138.4 (C), 134.1 (C),
129.1 (CH), 128.1 (CH), 126.7 (CH), 118.4 (C), 112.0 (C), 52.5
(CH3); MS (CI) m/z (%) 407 (M+1, 76), 403 (13), 393 (17), 375
15 (100); HRMS (ESI-FIA-TOF) Calcd for C22H15ClN2NaO4:
429.0613. Found: 429.0613.
131.5 (C), 131.1 (C), 130.1 (CH), 129.5, 129.1 (CH), 128.6 (CH),
128.1 (CH), 127.5 (CH), 127.3 (CH), 126.7 (CH), 118.3 (C),
114.3 (C), 114.0 (CH), 55.4 (CH3), 52.5 (CH3), 49.9 (CH2); MS
(CI) m/z (%) 493 (M+1, 35), 461 (21), 403 (19), 389 (15), 371
Methyl
7-((2-(tert-butoxy)-2-oxoethyl)amino-6-(4- 75 (21), 349 (23), 347 (52), 192 (15), 87 (100); HRMS (ESI-FIA-
methoxyphenyl)-1,3-dioxo-2-phenylisoindoline-4-carboxylate
(7m). (20%) obtained as a yellow solid; mp 168-170 ºC; IR (cm-
20 1) 3326, 2981, 1725, 1696, 1637, 1530, 1466, 1416, 1367, 1241,
1213, 1163, 1042, 1021, 770; 1H NMR (400 MHz, CDCl3) δ 7.78
TOF) Calcd for C30H24N2NaO5: 515.1579. Found: 515.1577.
Methyl 7-(2,6-dimethylphenylamino)-6-(2-bromophenyl)-
1,3-dioxo-2-phenylisoindoline-4-carboxylate
(7q).
(65%
thermal) obtained as a yellow solid; mp 174-176 (dec.) ºC; IR
1
(s, 1H), 7.57 – 7.38 (m, 6H), 7.35 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 80 (cm-1) 3437, 1716, 1503; H NMR (500 MHz, CDCl3) δ 8.63 (s,
8.7 Hz, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.50 (d, J = 5.6 Hz, 2H),
1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 169.0 (C), 168.7 (C),
25 165.8 (C), 164.6 (C), 159.7 (C), 147.9 (C), 139.6 (CH), 133.9
(C), 131.6 (C), 130.6 (C), 130.1 (CH), 129.6, 129.0 (CH), 128.0
1H), 7.72 (s, 1H), 7.62 – 7.46 (m, 4H), 7.47 – 7.38 (m, 1H), 7.36
– 7.28 (m, 1H), 6.97 – 6.83 (m, 3H), 6.77 (t, J = 7.5 Hz, 1H), 6.71
(d, J = 7.5 Hz, 2H), 3.95 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 169.3 (C), 165.4 (C), 164.4 (C), 147.3
(CH), 126.8 (CH), 118.6 (C), 114.5 (C), 114.2 (CH), 82.3 (C), 85 (C), 141.1 (CH), 137.4 (C), 136.7 (C), 136.6 (C), 135.4 (C),
55.4 (CH3), 52.5 (CH3), 48.1 (CH2), 28.0 (CH3) MS (ESI-FIA-
TOF m/z (%) 539 (M+23, 100), 483 (25), 429 (15); HRMS (ESI-
30 FIA-TOF) Calcd for C29H29N2O7: 517.1966. Found: 517. 1969.
132.6 (C), 132.1 (CH), 131.5 (C), 130.6 (C), 130.3 (CH), 129.1
(CH), 129.0 (CH), 128.4 (CH), 128.2 (CH), 127.8 (CH), 126.8
(CH), 126.7 (CH), 126.3 (CH), 123.2 (C), 118.1 (C), 113.8 (C),
52.5 (CH3), 19.4 (CH3), 19.2 (CH3); MS (EI) m/z (%) 556 (M+·,
90 60), 554 (M+·, 60), 463 (49), 462 (47), 443 (100); HRMS (EI)
Calcd for C30H23BrN2O4: 554.0841. Found: 554.0840.
Methyl
7-((2,6-dimethylphenyl)amino)-6-(4-
methoxyphenyl)-1,3-dioxo-2-phenylisoindoline-4-carboxylate
(7n). (80%) obtained as a yellow solid; mp 174-175 ºC; IR (cm-1)
1
3443, 1763, 1698, 1608, 1504, 1396, 1323, 1248, 767; H NMR
Methyl
7-(benzylamino)-6-(2-bromophenyl)-1,3-dioxo-2-
35 (500 MHz, CDCl3) δ 8.85 (s, 1H), 7.80 (s, 1H), 7.58 – 7.49 (m,
3H), 7.43 (dd, J = 16.6, 9.6 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H),
6.81 – 6.75 (m, 1H), 6.72 (d, J = 7.4 Hz, 2H), 6.50 (d, J = 8.5 Hz, 95 1620; H NMR (500 MHz, CDCl3) δ 8.31 (s, NH), 7.62 (s, 1H),
phenylisoindoline-4-carboxylate (7r). (55%) obtained as a
yellow solid; mp 175-177 ºC; IR (cm-1) 3428, 2962, 1766, 1696,
1
2H), 5.17 – 5.16 (m, 1H), 3.98 (s, 3H), 3.71 (s, 3H), 2.09 (s, 6H);
13C NMR (126 MHz, CDCl3) δ 169.6 (C), 165.7 (C), 164.6 (C),
40 158.8 (C), 145.9 (C), 140.5 (CH), 136.6 (C), 134.1 (C), 133.5
(C), 131.6 (C), 129.6 (C), 129.1 (CH), 128.9 (CH), 128.1 (CH),
6.95-6.94 (m, 2H), 6.81-6.69 (m, 5H), 3.96 (s, 3H), 3.22 (s, 3H),
2.08 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 169.50 (C), 165.60 (C), 164.56 (C), 147.55 (C), 140.89
(CH), 140.03 (C), 137.97 (C), 132.69 (CH), 131.80 (CH), 131.62
128.1 (CH), 126.7 (CH), 126.3 (CH), 118.0 (C), 113.2 (C), 112.6 100 (C), 131.49 (C), 130.87 (C), 130.23 (CH), 129.21 (CH), 128.86
(CH), 55.4 (CH3), 52.5 (CH3), 19.0 (CH3); MS (CI) m/z (%) 507
(M+1, 79), 494 (15), 475 (25), 69 (100); HRMS (ESI-FIA-TOF)
45 Calcd for C31H26N2NaO5: 529.1724. Found: 529.1734.
(CH), 128.24 (CH), 127.82 (CH), 127.44 (CH), 127.39 (CH),
126.86 (CH), 124.65 (C), 117.12 (C), 113.32 (C), 52.61 (CH2),
49.03 (CH3); MS (EI) m/z (%) 542 (M+·, 15), 540 (M+·, 16), 461
(27), 429 (43), 383 (10), 91 (100); HRMS (EI) Calcd for
Methyl 7-((2,6-dimethylphenyl)amino)-6-(4-fluorophenyl)-
1,3-dioxo-2-phenylisoindoline-4-carboxylate
(7o).
(56%) 105 C29H21N2O4Br: 540.0685. Found: 540.0681.
obtained as a yellow solid; mp 158-160 ºC; IR (cm-1) 3317, 1765,
Methyl
7-(cyclohexylamino)-6-(4-methoxyphenyl)-2-
1
1729, 1620, 1591, 1501, 1385, 1349, 1326, 1217, 808, 771; H
50 NMR (500 MHz, CDCl3) δ 8.86 (s, 1H), 7.78 (s, 1H), 7.59 – 7.35
(m, 5H), 6.94 (dd, J = 8.3, 5.4 Hz, 2H), 6.83 (t, J = 7.5 Hz, 1H),
methyl-1,3-dioxoisoindoline-4-carboxylate
(7s).
(39%)
obtained as a yellow solid; mp 131-133 ºC; IR (cm-1) 3320, 2926,
1
2848, 1768, 1695, 1603, 1509; H NMR (500 MHz, CDCl3) δ
6.73 (d, J = 7.5 Hz, 2H), 6.66 (t, J = 8.6 Hz, 2H), 3.98 (s, 3H), 110 7.65 (s, 1H), 7.32 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H),
2.10 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 169.5 (C), 165.6 (C),
164.5 (C), 163.1 (C), 160.7 (C), 145.9 (C), 140.7 (CH), 136.4
55 (C), 134.2 (CH), 132.7 (C), 132.7 (C), 132.4 (C), 131.5 (C),
130.1 (C), 129.5 (CH), 129.4 (CH), 129.2 (CH), 129.1 (CH),
6.82 (d, J = 9.6 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.14 (s, 3H),
2.82-2.79 (m, 1H), 1.63-0.88 (m, 10H); 13C NMR (101 MHz,
CDCl3) δ 170.4 (C), 165.9 (C), 165.7 (C), 159.5 (C), 147.9 (C),
139.3 (CH), 134.1 (C), 131.7 (C), 130.4 (C), 129.6 (CH), 117.6
128.2 (CH), 128.0 (CH), 126.7 (CH), 126.7 (CH), 126.1 (CH), 115 (C), 115.2 (C), 114.0 (CH), 55.4 (CH3), 52.4 (CH3), 52.3 (CH),
118.0 (C), 114.1 (CH), 113.9 (CH), 113.3 (C), 52.6 (CH3), 19.0
33.6 (CH2), 25.3 (CH2), 24.3 (CH2), 23.8 (CH3); MS (EI) m/z (%)
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Organic & Biomolecular Chemistry
Page 8 of 10
1
423 (M+·, 20), 422 (72), 379 (100), 351 (27); HRMS (EI) Calcd
1687, 1605, 1512; H NMR (500 MHz, CDCl3) δ 7.72 (s, 1H),
for C24H26N2O5: 422.18417. Found: 454.1882.
60 7.70 (brs, 1H), 7.34 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H),
Methyl 6-(4-chlorophenyl)-7-(cyclohexylamino)-2-methyl-
1,3-dioxoisoindoline-4-carboxylate (7t). (40%) obtained as a
yellow solid; mp 139-144 ºC; IR (cm-1) 3321, 2931, 2852, 1766,
6.85 (d, J = 9.7 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H),V2ie.8w9Ar–tic2le.7O5nline
DOI: 10.1039/C3OB41411F
(m, 1H), 1.74 – 0.78 (m, 10H); 13C NMR (126 MHz, CDCl3) δ
169.9 (C), 165.4 (C), 165.2 (C), 159.5 (C), 148.4 (C), 139.9
(CH), 134.1 (C), 131.6 (C), 130.9 (C), 129.6 (CH), 117.6 (C),
5
1
1694, 1612, 1593, 1524; H NMR (500 MHz, CDCl3) δ 7.65 (s,
1H), 7.42 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.87 (d, J 65 115.4 (C), 114.0 (CH), 55.4 (CH3), 52.4 (CH), 33.6 (CH2), 25.3
= 9.9 Hz, 1H), 3.93 (s, 3H), 3.14 (s, 3H), 2.76 – 2.69 (m, 1H),
(CH2), 24.4 (CH2); MS (EI) m/z (%) 408 (M+·, 10), 365 (11), 204
(10), 167 (22), 149 (100); HRMS (EI) Calcd for C23H24N2O5:
408.1685. Found: 408.1685.
1.79 – 0.84 (m, 10H); 13C NMR (126 MHz, CDCl3) δ 170.2 (C),
10 165.6 (C), 165.5 (C), 147.6 (C), 139.3 (CH), 137.9 (C), 134.2
(C), 132.8 (C), 130.9 (C), 129.7 (CH), 128.8 (CH), 117.7 (C),
Methyl
6-(4-chlorophenyl)-7-(cyclohexylamino)-1,3-
115.5 (C), 52.6 (CH), 52.4 (CH3), 33.5 (CH2), 25.3 (CH2), 24.2 70 dioxoisoindoline-4-carboxylate (7y). (37%) obtained as
a
(CH2), 23.8 (CH3); MS (EI) m/z (%) 426 (M+·, 40), 383 (100),
355 (18), 347 (21), 321 (21); HRMS (EI) Calcd for
15 C23H23ClN2O4: 426.13463. Found: 426.1342.
yellow solid; mp 162-198 ºC; IR (cm-1) 3281, 2930, 2851, 1765,
1
1718, 1682, 1613, 1592 ; H NMR (500 MHz, CDCl3) δ 7.71 (s,
1H), 7.70 (brs, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 8.5 Hz,
2H), 6.90 (d, J = 9.6 Hz, 1H), 3.95 (s, 3H), 2.76-2.73 (m, 1H),
Methyl 7-(2,6-dimethylphenylamino)-2-methyl-1,3-dioxo-6-
o-tolylisoindoline-4-carboxylate (7u). (69%) obtained as a 75 1.65 – 0.89 (m, 10H); 13C NMR (101 MHz, CDCl3) δ 169.7 (C),
yellow solid; mp 178 ºC; IR (cm-1) 3434, 3279, 2950, 1758, 1690,
165.2 (C), 164.9 (C), 148.0 (C), 139.9 (CH), 137.8 (C), 134.3
(C), 132.8 (C), 131.4 (C), 129.7 (CH), 128.8 (CH), 117.7 (C),
115.6 (C), 52.7 (CH), 52.5 (CH3), 33.5 (CH2), 25.2 (CH2), 24.3
(CH2); MS (EI) m/z (%) 412 (M+·, 85), 397 (18), 369 (100), 340
1
1606, 1589; H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.59 (s,
20 1H), 6.96 – 6.88 (m, 2H), 6.79 – 6.65 (m, 5H), 3.94 (s, 3H), 3.19
(s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 170.3 (C), 165.8 (C), 165.5 (C), 147.2 (C), 139.6 80 (21); HRMS (EI) Calcd for C22H21ClN2O4: 412.1190. Found:
(CH), 137.2 (C), 136.3 (C), 135.8 (C), 135.7 (C), 135.2 (C),
133.9 (C), 130.9 (C), 129.4 (CH), 128.8 (CH), 128.0 (CH), 127.9
25 (CH), 127.6 (CH) 126.6 (CH), 124.9 (CH), 118.0 (C), 114.3 (C),
52.4 (CH3), 23.9 (CH3), 20.2 (CH3), 19.3 (CH3), 18.7 (CH3); MS
412.1176.
Methyl 7-(cyclohexylamino)-6-(4-fluorophenyl)-1,3-dioxo-
1,3-dihydroisobenzofuran-4-carboxylate (7z). (35%) obtained
as a yellow oil; IR (cm-1) 3437, 2940, 1706, 1634, 1523, 1384,
(EI) m/z (%) 428 (M+·, 76), 397 (16), 289 (18), 149 (23); HRMS 85 1255, 1212, 1098; 1H NMR (500 MHz, CDCl3) δ 7.91 – 7.83 (m,
(EI) Calcd for C26H24N2O4: 428.1736. Found: 428.1736.
Ethyl 7-(2,6-dimethylphenylamino)-2-methyl-1,3-dioxo-6-
30 phenylisoindoline-4-carboxylate (7v). (37%) obtained as a
1H), 7.71 – 7.63 (m, 1H), 7.42 – 7.31 (m, 1H), 7.17 (dt, J = 23.0,
8.6 Hz, 2H), 6.69 (d, J = 9.6 Hz, 1H), 3.97 (d, J = 0.9 Hz, 3H),
2.89 – 2.79 (m, 1H), 1.71 – 0.80 (m, 10H); 13C NMR (101 MHz,
CDCl3) δ 182.1 (C), 166.0 (C), 164.8 (C), 164.2 (C), 162.4 (C),
orange solid; mp 159-162 ºC; IR (cm-1) 3306, 2944, 1766, 1692,
1
1613; H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.71 (s, 1H), 90 161.5 (C), 159.2 (C), 148.5 (C), 147.2 (CH), 142.1 (CH), 134.4
7.01 – 6.90 (m, 5H), 6.75 – 6.62 (m, 3H), 4.42 (q, J = 7.1 Hz,
2H), 3.20 (s, 3H), 2.06 (s, 6H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR
35 (101 MHz, CDCl3) δ 170.7 (C), 165.8 (C), 165.1 (C), 145.5 (C),
140.2 (CH), 137.0 (C), 136.7 (C), 134.4 (C), 133.4 (C), 130.6
(C), 133.2 (C), 131.2 (CH), 131.1 (CH), 130.3 (CH), 130.2 (CH),
120.1 (CH), 118.0 (C), 116.5 (CH), 116.3 (CH), 116.0 (CH),
115.8 (CH), 114.2 (C), 77.2 (CH), 53.1 (CH3), 52.6 (CH3), 33.5
(CH2), 29.7 (CH2), 25.0 (CH2), 24.2 (CH2); MS (CI) m/z (%) 398
(C), 128.1 (CH), 127.8 (CH), 127.3 (CH), 127.1 (CH), 126.4 95 (M+1, 89), 378 (14), 366 (100), 316 (43), 284 (61), 149 (47);
(CH), 118.2 (C), 114.0 (C), 61.6 (CH2), 24.0 (CH3), 19.0 (CH3),
14.2 (CH3); MS (EI) m/z (%) 428 (M+·, 100), 427 (88), 335 (24),
40 275 (57); HRMS (EI) Calcd for C26H24N2O4: 428.1736. Found:
428.1733.
HRMS (ESI-FIA-TOF) Calcd for C22H20FNNaO5: 420.1209.
Found: 420.1218.
Methyl
7-((2,6-dimethylphenyl)amino)-6-(4-
methoxyphenyl)-1,3-dioxo-1,3-dihydroisobenzofuran-4-
Ethyl 7-(2,6-dimethylphenylamino)-6-(4-methoxyphenyl)- 100 carboxylate (7aa). (27%) obtained as a yellow solid; mp 178-180
2-methyl-1,3-dioxoiso indoline-4-carboxylate (7w). (65%)
ºC; IR (cm-1) 3433, 3327, 1838, 1769, 1727, 1609, 1500, 1429,
82, 1031, 908; H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 7.96
1
obtained as a orange solid; mp 153-155 ºC; IR (cm-1) 3299, 2986,
1
45 1757, 1693, 1605; H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H),
(s, 1H), 6.90 – 6.80 (m, 3H), 6.74 (d, J = 7.5 Hz, 2H), 6.51 (d, J =
7.69 (s, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 7.4 Hz, 2H),
8.6 Hz, 2H), 3.99 (s, 3H), 3.72 (s, 3H), 2.08 (s, 6H); 13C NMR
6.46 (d, J = 8.4 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.68 (s, 3H), 105 (101 MHz, CDCl3) δ 165.3 (C), 164.3 (C), 159.3 (C), 159.1 (C),
3.19 (s, 3H), 2.05 (s, 6H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 170.7 (C), 165.8 (C), 165.2 (C), 158.7 (C), 145.5
50 (C), 140.0 (CH), 136.8 (C), 134.3 (C), 133.1 (C), 130.3 (C),
129.3 (C), 129.0 (CH), 128.0 (CH), 126.2 (CH), 118.2 (C), 113.9
146.7 (C), 142.8 (CH), 135.8 (C), 134.2 (C), 134.1 (C), 129.4
(C), 128.9 (CH), 128.2 (CH), 128.2 (C), 126.9 (CH), 118.5 (C),
113.6 (C), 112.8 (CH), 55.3 (CH3), 52.6 (CH3), 18.9 (CH3); MS
(CI) m/z (%) 432 (M+1, 28), 400 (40), 177 (12), 61 (100); HRMS
(C), 112.6 (CH), 61.6 (CH3), 55.3 (CH2), 23.9 (CH3), 19.0 (CH3), 110 (ESI-FIA-TOF) Calcd for C25H22NO6: 432.1444. Found:
14.2 (CH3); MS (EI) m/z (%) 458 (M+·, 100), 413 (48), 385 (39),
351 (78); HRMS (EI) Calcd for C27H26N2O5: 458.1842. Found:
55 458.1849.
432.1442.
Reaction of 2-oxo-4-phenylbut-3-enoate (1a) and cyclohexyl
isocyanide (2a) under air.
Methyl
dioxoisoindoline-4-carboxylate (7x). (48%) obtained as
yellow solid; mp 145-160 ºC; IR (cm-1) 3436, 2928, 2849, 1773,
7-(cyclohexylamino)-6-(4-methoxyphenyl)-1,3-
A
solution
of
α-ketoester
1a
(0.5 mmol)
and
a
115 cyclohexylisocyanide 2a (0.88 mmol) in dry toluene (2 mL) was
heated at 100 ºC for 35 h. HCl 10 % was added and the organic
8
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Organic & Biomolecular Chemistry
decomposes under ambient conditions, especially in solution. Methyl 5-
phase was extracted with CH2Cl2, dried (Na2SO4) and
((2,6-dimethylphenyl)amino)-4-(4-methoxyphenyl)furan-2-
concentrated. The residue was purified by flash chromatography
(silica gel, hexane-EtOAc gradient), giving 10a (13%) and
recovered 1a (45%).
60 carboxylate. Obtained as a white solid; IR (cm-1) 3428, 1695, 1615,
View Article Online
1
DOI: 10.1039/C3OB41411F
1539, 1384, 1156; H NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 7.29 (d, J
= 8.7 Hz, 2H), 7.05 – 6.97 (m, 4H), 6.88 (d, J = 8.8 Hz, 2H), 5.95 (s, 1H),
3.82 (s, 6H), 2.21 (s, 6H); MS (CI) m/z (%) 352 (M+ +1, 100), 320 (19),
246 (35), 122 (10).
65 1. Z. Shi, P. Yu, T.-P. Loh and G. Zhong, Angew. Chem. Int. Ed., 2012,
51, 7861.
2. (a) A. G. Neo, J. Diaz, S. Marcaccini and C. F. Marcos, Org. Biomol.
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Jacobi von Wangelin, Org. Biomol. Chem., 2011, 9, 7224-7236; (c)
5
Methyl 1-cyclohexyl-2,5-dihydro-2-hydroxy-5-oxo-4-phenyl-
1H-pyrrole-2-carboxylate (10a). (13%) obtained as a white
solid; mp 121-123.5 ºC; IR (cm-1) 3423, 2936, 1755, 1673, 1366,
1
1278; H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 7.6, 1.8, 2H),
7.44-7.36 (m, 3H), 6.82 (s, 1H), 4.31 (bs, 1H), 3.84 (s, 3H), 3.55-
10 3-46 (m, 1H), 2.16 – 1.60 (m, 10H); 13C NMR (101 MHz, CDCl3)
δ 172.09 (C), 168.78 (C), 138.61 (C), 135.97 (CH), 130.36 (C),
129.38 (CH), 128.46 (CH), 127.65 (CH), 87.33 (C), 54.00 (CH),
53.20 (CH3), 30.31 (CH2), 30.03 (CH2), 26.25 (CH2), 25.32
(CH2); MS (EI) m/z (%) 315 (M+·, 7), 256 (69), 174 (82), 56
15 (100); HRMS (EI) Calcd for C18H21NO4: 315.1471. Found:
315.1470.
70
75
80
85
S. Barriga, P. Fuertes, C. F. Marcos and T. Torroba, J. Org. Chem.,
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A solution of aniline 7r (16 mg, 0.03 mmol), CuI (2 mg, 0.010
20 mmol, 35% mol), CsCO3 (19 mg, 0.06 mmol, 2 equiv) and L-
Boc-proline (2 mg, 0.009 mmol, 31% mol) in toluene (1 mL) was
heated 1 h at 130 ºC in microwave oven. The crude was filtered
through a short pad of SiO2 and washed with CH2Cl2. The
solvents were removed in the rotary evaporator to give 11 (94%)
25 obtained as a yellow solid; mp 226-228 ºC; IR (cm-1) 2923, 1762,
1702, 1493, 1269, 1170, 804; 1H NMR (500 MHz, CDCl3) δ 8.67
(s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.59 – 7.53 (m, 1H), 7.51 – 7.46
(m, 2H), 7.45 – 7.41 (m, 3H), 7.41 – 7.36 (m, 2H), 7.25 – 7.17
(m, 3H), 7.05 (d, J = 6.7 Hz, 2H), 6.40 (s, 2H), 4.05 (s, 3H); 13C
30 NMR (101 MHz, CDCl3) δ 167.56 (C), 166.57 (C), 165.80 (C),
143.34 (C), 137.65 (C), 137.48 (C), 131.75 (C), 130.15 (C),
129.19 (CH), 128.87 (CH), 128.29 (CH), 127.96 (C), 127.49
(CH), 127.13 (CH), 126.27 (CH), 126.22 (CH), 122.55 (C),
121.90 (CH), 121.40 (C), 121.21 (CH), 113.92 (C), 111.31 (CH),
35 53.17 (CH3), 50.48 (CH2); MS (CI) m/z (%) 461 (M+· + 1, 21),
429 (21), 339 (3), 199 (17), 91 (100); HRMS (EI) Calcd for
C29H20N2O4: 460.1423. Found: 460.1423.
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We thank financial support from Instituto de Salud Carlos III
40 (PI081234), Junta de Extremadura and FEDER.
Notes and references
a
Laboratorio de Química Orgánica y Bioorgánica (L.O.B.O.). Dept.
Química Orgánica e Inorgánica. Facultad de Veterinaria. Universidad de
Extremadura. 10071 Cáceres, Spain. E-mail: cfernan@unex.es
45 b HeteroBioLab. Dipartimento di Chimica Organica, Università di
Firenze. 50019 Sesto Fiorentino (FI), Italy.
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§ Stefano Marcaccini died on 1st October 2012. He will be sorely missed
by his friends and colleagues.
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† Electronic Supplementary Information (ESI) available: [details of any
50 supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
‡ When a reaction with (E)-methyl 4-(4-methoxyphenyl)-2-oxobut-3-
enoate (1b) and 2,6-dimethylphenyl isocyanide (2d) was carried out
under similar conditions,
a quick work-up and chromatographic
55 purification allowed the isolation of a small amount of methyl 5-((2,6-
dimethylphenyl)amino)-4-phenylfuran-2-carboxylate. This aminofuran
was identified by its mass and 1H-NMR spectra, although it rapidly
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