Synthesis of cyclopentadiene-fused chromanones via one-pot multicomponent reactions

Article abstract of DOI:10.1021/jo302790y

We have developed one-pot method for the synthesis of functionalized novel cyclopentadiene-fused chromanone scaffolds. A variety of 4-oxo-2,4- dihydrocyclopenta[c]chromene-1,2-dicarboxylates were obtained in moderate to good yields via condensation of 2-hydroxybenzaldehydes and ethyl acetoacetate with 1:1 acetylenecarboxylate-isocyanides in toluene. These reactions presumably proceed via reaction of the in situ generated 3-acetyl-2H-chromen-2-ones with acetylenecarboxylate-isocyanide zwitterionic intermediates through Michael addition/intramolecular cyclization and double [1,5] acyl shift rearrangement cascade.

Full text of DOI:10.1021/jo302790y

Article
pubs.acs.org/joc
Synthesis of Cyclopentadiene-Fused Chromanones via One-Pot
Multicomponent Reactions
Mehdi Ghandi,†,* Ali-Tabatabaei Ghomi,† and Maciej Kubicki‡
†School of Chemistry, College of Science, University of Tehran, P.O. Box 14155, Tehran 6455, Iran
‡Faculty of Chemistry, Adam Mickiewicz University in Poznan, Umultowska 89b, 61-614 Poznan, Poland
S
* Supporting Information
ABSTRACT: We have developed one-pot method for the
synthesis of functionalized novel cyclopentadiene-fused
chromanone scaffolds. A variety of 4-oxo-2,4-dihydro-
cyclopenta[c]chromene-1,2-dicarboxylates were obtained in
moderate to good yields via condensation of 2-hydroxyben-
zaldehydes and ethyl acetoacetate with 1:1 acetylenecarbox-
ylate−isocyanides in toluene. These reactions presumably
proceed via reaction of the in situ generated 3-acetyl-2H-
chromen-2-ones with acetylenecarboxylate−isocyanide zwit-
terionic intermediates through Michael addition/intramolecu-
lar cyclization and double [1,5] acyl shift rearrangement
cascade.
dihydrocoumarin system is widely distributed in nature, and
INTRODUCTION
■
some derivatives have been shown to exhibit pharmacological
activity.12 On the other hand, the hebertane sesquiterpene
hebertenolide, which contains a cyclopentane-fused chroma-
none, is a biologically active compound.13
The so-called multicomponent reactions (MCRs) are one-pot
processes in which at least three or more different simple
substrates react for the preparation of target materials.1 These
reactions, which have gained much attention during the past
years, are frequently occurring not through a single-step
procedure but rather by several sequential steps or multi-
component cascade or domino reactions.2 Simplicity, greater
efficiency, and atom economy with generation of molecular
complexity and diversity in the one-pot transformation are
some of the advantages of these reactions. As an important
subclass of MCRs, the isocyanide-based multicomponent
reactions (IMCRs) are processes in which an isocyanide is
used as one of the starting materials in order to obtain new
compounds.3 The pioneering work of Ugi describes the most
popular IMCR in which a carboxylic acid, a primary amine, an
aldehyde, and an isocyanide react in a one-pot manner to afford
an N-substituted acyl aminoamide containing four independ-
ently varying groups.4
In continuation of our investigation in searching for MCRs,14
we decided to explore the idea that trapping of acetylene-
carboxylate−isocyanide zwitterionic intermediates with 3-
acetyl-2H-chromen-2-ones might be hopeful in gaining access
to new types of chromanones, annulated-cyclopentadiene
moieties, via a three-component reaction. In addition, it
seemed intriguing to involve a domino process in this IMCR
by increasing the number of reactants if we could carry out the
in situ generation of 3-acetyl-2H-chromen-2-ones in the same
pot. Herein, we report the synthesis of novel 4-oxo-2,4-
dihydrocyclopenta[c]chromene-1,2-dicarboxylates via a one-
pot, four-component reaction of a variety of 2-hydroxybenzal-
dehydes with ethyl acetoacetate, acetylenedicarboxylates, and
cyclohexyl or tert-butyl isocyanides in toluene.
The reaction of isocyanides and acetylene compounds, first
described by Winterfeld in 1969, is perhaps the founding basis
for a large class of new, accessible scaffolds.5 This reaction
initially affords a zwitterionic adduct, which might undergo
cycloaddition to activated alkenes, leading to a variety of novel
highly substituted cyclopentadienoid systems.6
The abundance of naturally occurring chromene and
chromane derivatives, and their interesting physiological
properties have gained a vital place in the field of heterocyclic
chemistry.7 The chromanones are heterocycles with medicinal
properties.8 Chromone and coumarin derivatives have been
found to exhibit a broad range of biological activities such as
antiviral,9 antimicrobial,10 and antitumor ones.11 The 3,4-
RESULTS AND DISCUSSION
■
3-Acetyl-2H-chromen-2-one (1a) served for our early explora-
tion. Indeed, 2a was isolated as the sole reaction product upon
treatment of 1a with an equimolar amount of dimethyl
acetylenedicaboxylate (DMAD) and tert-butyl isocyanide
within 2 h, in refluxing toluene (Scheme 1).
Our later studies revealed that 2a could be synthesized in a
one-pot reaction if 1a prepared in situ from piperidine-
catalyzed condensation of salicylaldehyde (3a) with ethyl
Received: December 27, 2012
© XXXX American Chemical Society
A
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Scheme 1. Formation of 2a from Reaction of 1a with DMAD
and tert-Butyl Isocyanide
Table 2. Products 2m−x Obtained via One-Pot Reaction of
3a−d with DEAD and Isocyanides
entry
R1
R3
product
yield (%)
acetoacetate at reflux within 2 h was treated with equimolar
amounts of DMAD and tert-butyl isocyanide within 3 h under
reflux conditions (Scheme 2). Therefore, the implication of 3-
acetyl-2H-chromen-2-one (1a) in the initial reaction is
confirmed.
1
H
H
H
tert-butyl
2m
2n
2o
2p
2q
2r
72
73
50
77
72
62
55
56
50
55
57
54
2
cyclohexyl
3
tetramethylbutyl
tert-butyl
4
5-Br
5
5-Br
cyclohexyl
6
5-Br
tetramethylbutyl
tert-butyl
Scheme 2. One-Pot Synthesis of 2a
7
5-NO2
5-NO2
5-NO2
3-OMe
3-OMe
3-OMe
2s
8
cyclohexyl
2t
9
tetramethylbutyl
tert-butyl
2u
2v
2w
2x
10
11
12
cyclohexyl
tetramethylbutyl
for the proposed structure of 2q was finally obtained by single-
crystal X-ray-diffraction analysis (Figure 1).
Encouraged by this result, this new method was then applied
to a range of 2-hydroxybenzaldehydes 3a−d, tert-butyl,
cyclohexyl, or 1,1,3,3-tetramethylbutyl isocyanides and
DMAD (Table 1) or diethyl acetylenedicarboxylate (DEAD)
Table 1. Products 2a−l Obtained via One-Pot Reaction of
3a−d with DMAD and Isocyanides
entry
R1
R3
product
yield (%)
1
H
H
H
tert-butyl
2a
2b
2c
2d
2e
2f
73
75
65
74
75
64
58
54
52
59
63
53
Figure 1. X-ray crystal structure of compound 2q.16
2
cyclohexyl
3
tetramethylbutyl
tert-butyl
Although the precise mechanism is not known, a mechanistic
postulate as shown in Scheme 3 may be invoked to rationalize
the formation of 2a. It is conceivable that the zwitterionic
intermediate I, formed by the 1:1 interaction between the
isocyanide and acetylenedicarboxylate,15 attacks preferentially
the C-4 of 3-acetyl-2H-chromen-2-one (1a) leading to 1,7- or
1,5-dipolar intermediates II and III. The subsequently
generated IV upon ring closure is transformed into V via an
allowed [1,5] H shift. It is finally transformed into 2a,
presumably through two consecutive allowed [1,5] acyl shifts.
Generation of an extra conjugation between cyclopentadiene
ring and six-membered CO group seems to be the driving
force for these rearrangements.
As indicated in Tables 1 and 2, whereas unsubstituted
aldehydes (entries 1 to 3) or substituted with a modest
electron-withdrawing group (EWG) (entries 4−6) afford
products 2a−f and 2m−r in higher yields, those bearing a
strong EWG (entries 7−9) or a strong electron-donating group
(EDG) (entries 10−12) produce the corresponding products
2g−l and 2s−x in lower yields. This behavior is the result of a
4
5-Br
5
5-Br
cyclohexyl
6
5-Br
tetramethylbutyl
tert-butyl
7
5-NO2
5-NO2
5-NO2
3-OMe
3-OMe
3-OMe
2g
2h
2i
8
cyclohexyl
9
tetramethylbutyl
tert-butyl
10
11
12
2j
cyclohexyl
2k
2l
tetramethylbutyl
(Table 2) . The structures of 2a−p were deduced by elemental
analysis, MS, IR, and H and 13C NMR spectroscopy. For
1
example, part of the 1H NMR spectrum of dimethyl 2-acetyl-8-
bromo-3-(cyclohexylamino)-4-oxo-2,4-dihydrocyclopenta[c]-
chromene-1,2-dicarboxylate (2e) exhibited four singlets at δ
2.75 (3H), 3.74 (3H), 3.77 (3H), and 9.61 (1H) due to MeCO,
1
MeOCO, MeOCO, and NH, respectively. The H-decoupled
13C NMR revealed three characteristic signals at δ 195.7, 167.1,
and 165.0 due to three carbonyl groups. Unambiguous evidence
B
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Scheme 3. Mechanistic Rationalization for the Formation of Compound 2a
were purified and dried by following standard procedures unless
otherwise stated.
multistep reaction in which one step may be rate determining
for EWGs, but a different step may become rate limiting for
ERG substituents.17 Although substituted aldehyde with EWG
facilitates the formation rate of intermediates II and III via the
addition of zwitterionic intermediate I to the double bond of
1a, the subsequent cyclization step to iminocyclopentene IV
(Schemes 3) becomes rate limiting for this substitutent. In
contrast, the first step is expected to be rate limiting for
aldehyde bearing EDG. Therefore, obtaining lower yields of
2g−l and 2s−x in comparison to other products indicated in
Tables 1 and 2 is anticipated. On the other hand, the products
2m−x (Table 2) have generally been formed in lower yields in
comparison to those of 2a−l (Table 2), perhaps due to larger
steric effect of DEAD.
Overall, novel 4-oxo-2,4-dihydrocyclopenta[c]chromene-1,2-
dicarboxylates were obtained as the major products in moderate
to good yields. More importantly, doing the experiment in one-
pot reaction with four different simple substrates is of
fundamental importance due to the simplicity, greater efficiency
and atom economy with generation of molecular complexity
and diversity.
Synthesis of Dimethyl 3-(tert-Butylamino)-2-acetyl-5-
oxacyclopenta[a]naphthalen-4(2H)-one-1,2-dicarboxylate De-
rivatives 2a−x. General Procedure. To a stirring solution of
piperidine (0.17 g, 20 mol %) in toluene (20 mL) containing
́
molecular sieves 4 Å was added 2-hydroxybenzaldehyde derivatives
(3a−d) (1.0 mmol) and ethyl acetoacetate (1.0 mmol), and the
mixture was heated at reflux for 2 h. Acetylenedicarboxylate (1.0
mmol) and isocyanide (1.0 mmol) were then added, and the mixture
was heated at reflux for another 5 h. After completion as indicated by
TLC, the solvent was removed under reduced pressure and the residue
was purified by column chromatography (SiO2, eluent: 1:3 n-hexane/
EtOAc) to afford the products 2a−x.
Dimethyl 3-(tert-butylamino)-2-acetyl-5-oxacyclopenta[a]-
naphthalen-4(2H)-one-1,2-dicarboxylate (2a): yellow solid (301
mg, 73%); mp 140−142 °C; IR (KBr) νmax 3402, 1711, 1688, 1647,
1603 cm−1; δH (400 MHz, CDCl3) 1.66 (9H, s), 2.74 (3H, s), 3.74
(3H, s), 3.77(3H, s), 7.35−7.43 (2H, m), 7.66−7.89 (2H, m), 9.53
(1H, s) ppm; δC (100 MHz, CDCl3) 25.9, 30.6, 51.3, 52.3, 52.4, 96.2,
107.5, 121.5, 121.8, 125.4, 126.1, 128.7, 129.1, 146.0, 150.1, 155.3,
160.6, 165.0, 167.0, 195.0 ppm; m/z (EI, 70 eV) 413 (17, M+), 385
(25), 371 (60), 315 (100), 56 (55). Anal. Calcd for C22H23NO7: C,
63.91; H, 5.61; N, 3.39. Found: C, 63.79; H, 5.58; N, 3.33.
Dimethyl 2-acetyl-3-(cyclohexylamino)-5-oxacyclopenta[a]-
naphthalen-4(2H)-one-1,2-dicarboxylate (2b): orange solid (329
mg, 75%); mp 150−152 °C; IR (KBr) νmax 3408, 1711, 1673, 1638,
1603 cm−1; δH (400 MHz, CDCl3) 1.43−2.27 (10H, m), 2.75 (3H, s),
3.49−3.59 (1H, m), 3.74 (3H, s), 3.77 (3H, s), 7.35−7.43 (2H, m),
7.66−7.89 (2H, m), 9.63 (1H, s) ppm; δC (100 MHz, CDCl3) 23.7,
25.2, 26.3, 26.4, 30.0, 30.1, 51.4, 52.3, 52.4, 96.3, 107.5, 121.5, 121.8,
125.4, 126.1, 128.7, 129.1, 146.0, 150.1, 155.3, 160.6, 165.0, 167.0,
195.0 ppm; m/z (EI, 70 eV) 440 (15, M+ + 1), 411 (35), 397 (60),
315 (100), 56 (50). Anal. Calcd for C24H25NO7: C, 65.59; H, 5.73; N,
3.19. Found: C, 65.48; H, 5.78; N, 3.13.
Dimethyl 3-(2,4,4-trimethylpentan-2-ylamino)-2-acetyl-5-
oxacyclopenta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2c): or-
ange solid (304 mg, 65%); mp 151−152 °C; IR (KBr) νmax 3448,
1711, 1688, 1647, 1610 cm−1;δH (400 MHz, CDCl3) 1.06 (9H, S),
1.65 (6H, s), 1.78 (2H, s), 2.64 (3H), 3.74 (3H, s), 3.77 (3H, s),
7.35−7.43 (2H, m), 7.66−7.89 (2H, m), 9.53 (1H, s) ppm; δC (100
In conclusion, a number of 2-hydroxybenzaldehydes, ethyl
acetoacetate, acetylenecarboxylates, and isocyanides underwent
one-pot multicomponent reactions in toluene, affording the
desired products. These reactions were designed to obtain a
variety of biologically interesting cyclopentadiene-fused chro-
manones. These new structures broaden the scaffolds that are
accessible through Knoevenagel condensation−trans esterfica-
tion−Michael addition−intramolecular cyclization−acyl shift
rearrangement cascade and many of them may represent
interesting pharmacophores.
EXPERIMENTAL SECTION
■
General Information. 1HNMR, 13C NMR, MS, and elemental
analysis were measured with conventional spectrometers. All solvents
C
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The Journal of Organic Chemistry
Article
MHz, CDCl3) 25.9, 27.9, 31.0, 31.6, 31.7, 41.4, 52.3, 52.4, 53.4, 96.7,
107.5, 121.5, 121.8, 125.4, 126.1, 128.7, 129.1, 146.0, 150.1, 155.3,
160.6, 165.0, 167.0, 195.0 ppm; m/z (EI, 70 eV) 469 (12, M+),441
(32), 427 (55), 315 (100), 56 (55). Anal.Calcd for C26H31NO7: C,
66.51; H, 6.65; N, 2.98. Found: C, 66.48; H, 6.58; N, 3.03.
Dimethyl 3-(tert-butylamino)-2-acetyl-8-bromo-5-oxacyclo-
penta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2d): orange
solid (364 mg, 74%); mp 148−150 °C; IR (KBr) νmax 3412, 1712,
1701, 1688, 1623 cm−1; δH (400 MHz, CDCl3) 1.66 (9H, s), 2.74 (3H,
s), 3.74(3H, s), 3.77 (3H, s), 7.31 (1H, d, J 8.4 Hz), 7.70 (1H, dd, J =
8.4, 2.4 Hz), 8.01 (1H, d, J = 2.4 Hz), 9.60 (1H, s) ppm; δC (100
MHz, CDCl3) 25.9, 30.6, 53.4, 55.3, 59.1, 96.2, 107.5, 118.1, 118.7,
121.1(C1), 128.4, 129.1, 132.2, 146.0, 150.1, 155.3, 160.6, 165.0, 167.0,
195.0 ppm; m/z (EI, 70 eV) 494 (M+ + 2 [81Br], 8), 492(M+ [79Br],
8),463 (15), 394 (33), 363 (66), 57 (100). Anal. Calcd for
C22H22BrNO7: C, 53.67; H, 4.50; N, 2.85. Found: C, 53.58; H,
4.48; N, 2.83.
Dimethyl 2-acetyl-8-bromo-3-(cyclohexylamino)-5-oxacyclo-
penta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2e): orange solid
(388 mg, 75%); mp 153−155 °C; IR (KBr) νmax 3428, 1722, 1711,
1688, 1638 cm−1; δH (400 MHz, CDCl3) 1.43−2.27 (10H, m), 2.75
(3H, s), 3.55 (1H, m), 3.74 (3H, s), 3.77 (3H, s),7.31 (1H, d, J 8.4
Hz), 7.70 (1H, dd, J = 8.4, 2.4 Hz), 8.01 (1H, d, J = 2.4 Hz),9.61 (1H,
s) ppm; δC (100 MHz, CDCl3) 23.8, 25.2, 26.3, 26.4, 30.0, 30.1, 53.2,
55.3, 57.2, 96.3, 107.5, 118.1, 118.7, 121.1, 128.4, 129.1, 132.2, 146.0,
150.1, 155.3, 160.6, 165.0, 167.0, 195.6 ppm; m/z (EI, 70 eV) 519 (M+
+ 2 [81Br], 8), 517(M+ [79Br], 8),489 (19), 475 (23), 392(65),57
(100). Anal. Calcd for C24H24BrNO7: C, 55.61; H, 4.67; N, 2.70.
Found: C, 55.58; H, 4.68; N, 2.74.
Dimethyl 3-(2,4,4-trimethylpentan-2-ylamino)-2-acetyl-8-
bromo-5-oxacyclopenta[a]naphthalene-4(2H)-one-1,2-dicarboxy-
late (2f): orange solid (350 mg, 64%); mp 160−162 °C; IR (KBr) νmax
3458, 1732, 1721, 1688, 1640 cm−1; δH (400 MHz, CDCl3) 1.06 (9H,
s), 1.65 (6H, s), 1.78 (2H, s), 2.64 (3H, s), 3.84 (3H, s), 3.90(3H,
s),7.32 (1H, d, J 8.4 Hz), 7.70 (1H, dd, J = 8.4, 2.4 Hz), 8.01 (1H, d, J
= 2.4 Hz), 9.60 (1H, s) ppm; δC (100 MHz, CDCl3) 25.8, 27.9, 31.0,
31.6, 31.7, 42.4, 51.2, 53.5, 55.4, 96.4, 107.5, 118.1, 118.7, 121.1, 128.4,
129.1, 132.2, 146.1, 150.0, 155.3, 160.6, 165.0, 167.2, 195.5 ppm; m/z
(EI, 70 eV) 549 (M+ + 2 [81Br], 11), 547 (M+ [79Br], 11), 519 (22),
505 (53), 392(65), 57 (100). Anal. Calcd for C26H30BrNO7: C, 56.94;
H, 5.51; N, 2.55. Found: C, 56.97; H, 5.48; N, 2.54.
Dimethyl 3-(tert-butylamino)-2-acetyl-8-nitro-5-oxa-cyclopenta-
[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2g): yellow solid (265
mg, 58%); mp 158−160 °C; IR (KBr) νmax 3402, 1706, 1688,1622,
1603 cm−1; δH (400 MHz, CDCl3) 1.66 (9H, s), 2.64 (3H, s), 4.04
(3H, s), 4.07 (3H, s),7.55 (1H, d, J 9.6 Hz), 8.52−8.61 (2H, m), 10.22
(1H, s) ppm; δC (100 MHz, CDCl3) 25.9, 30.6, 53.4, 55.4, 59.1, 96.2,
107.5, 118.7, 121.1, 121.9, 125.4, 128.1, 144.0, 146.0, 153.1, 155.3,
160.6, 165.0, 167.0, 195.0 ppm; m/z (EI, 70 eV) 458(17, M+), 430
(25), 416 (55), 360 (100), 56 (100). Anal. Calcd for C22H22N2O9: C,
57.64; H, 4.84; N, 6.11. Found: C, 57.67; H, 4.82; N, 6.12.
Dimethyl 2-acetyl-3-(cyclohexylamino)-8-nitro-5-oxacyclopenta-
[a]naphthalen-4(2H)-one-1,2-dicarboxylate (3h): yellow solid (261
mg, 54%); mp 165−167 °C; IR (KBr) νmax 3418, 1711, 1701, 1638,
1603 cm−1; δH (400 MHz, CDCl3) 1.43−2.27 (10H, m), 2.75 (3H, s),
3.53 (1H, m), 4.04 (3H, s),4.07 (3H, s), 7.55(1H, d, J 9.6 Hz), 8.52−
8.61 (2H, m), 10.22 (1H, s), ppm; δC (100 MHz, CDCl3) 23.8, 25.2,
26.3, 26.4, 30.0, 30.1, 53.2, 55.3, 57.3, 93.2, 107.5, 118.7, 121.1, 121.9,
125.4, 128.1, 144.1, 146.1, 153.1, 155.3, 160.6, 165.1, 167.2, 195.5
ppm; m/z (EI, 70 eV) 484 (15, M+), 456 (28), 442 (55), 360 (100),
56 (59). Anal. Calcd for C24H24N2O9: C, 59.50; H, 4.99; N, 5.78.
Found: C, 59.48; H, 4.96; N, 5.75.
160.6, 165.1, 167.2, 195.4 ppm; m/z (EI, 70 eV) 514 (18, M+), 486
(45), 472 (65), 416 (100), 56 (55). Anal. Calcd for C26H30N2O9: C,
60.69; H, 5.88; N, 5.44; N, 5.78. Found: C, 60.65; H, 5.86; N, 5.48.
Dimethyl 3-(tert-butylamino)-2-acetyl-6-methoxy-5-oxacyclo-
penta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2j): yellow solid
(261 mg, 59%); mp 151 °C; IR (KBr) νmax 3402, 1711, 1701, 1647,
1610 cm−1; δH (400 MHz, CDCl3) 1.66 (9H, s), 2.64 (3H, s),3.74
(3H, s) 3.77 (3H, s), 4.00 (3H, s), 7.28 (1H, d, J 8.4 Hz), 7.71 (1H,
dd, J = 8.4, 2.4 Hz), 8.63 (1H, d, J = 2.4 Hz), 9.28 (1H, s) ppm; δC
(100 MHz, CDCl3) 25.9, 30.6, 52.3,52.7, 55.7, 59.1, 97.5, 107.5, 113.5,
119.1, 120.1, 125.4, 128.1, 142.1, 147.6, 148.0, 155.3, 160.6, 165.0,
167.0, 195.0 ppm; m/z (EI, 70 eV) 443 (14, M+), 401 (66), 371 (100),
315 (80),56 (55). Anal. Calcd for C23H25NO8: C, 62.30; H, 5.68; N,
3.16. Found: C, 62.27; H, 5.65; N, 3.13.
Dimethyl 2-acetyl-3-(cyclohexylamino)-6-methoxy-5-oxacyclo-
penta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2k): yellow solid
(295 mg, 63%); mp 149 °C; IR (KBr) νmax 3418, 1711, 1706, 1647,
1610 cm−1; δH (400 MHz, CDCl3) 1.43−2.27 (10H, m), 2.75 (3H, s),
3.53 (1H, m) 3.74(3H, s) 3.77 (3H, s), 4.02(3H, s), 7.27 (1H, d, J 8.4
Hz), 7.71 (1H, dd, J = 8.4, 2.4 Hz), 8.63 (1H, d, J = 2.4 Hz), 9.26 (1H,
s) ppm, δC (100 MHz, CDCl3) 23.7, 25.2, 26.3, 26.4, 30.0, 30.1, 52.3,
52.7, 55.7, 57.7, 97.2, 107.4, 113.5, 119.1, 120.1, 125.5, 128.1, 142.1,
147.0, 148.0, 155.4, 160.6, 165.1, 167.1, 195.1 ppm; m/z (EI, 70 eV)
469 (15, M+), 427 (50), 397 (100), 315 (90), 55 (55). Anal. Calcd for
C25H27NO8: C, 63.96; H, 5.80; N, 2.98%. Found: C, 63.89; H, 5.75; N,
3.02.
Dimethyl 3-(2,4,4-trimethylpentan-2-ylamino)-2-acetyl-6-me-
thoxy-5-oxacyclopenta[a]naphthalen-4(2H)-one-1,2-dicarboxylate
(2l): yellow solid (295 mg, 63%); mp 147−148 °C.IR (KBr) νmax 3428,
1712, 1706, 1647, 1610 cm−1; δH (400 MHz, CDCl3) 1.06 (9H, s),
1.65 (6H, s), 1.78 (2H, s), 2.64 (3H, s), 3.74(3H, s), 3.74 (3H, s),
4.03(3H, s), 7.27 (1H, d, J 8.4 Hz), 7.71 (1H, dd, J = 8.4, 2.4 Hz), 8.63
(1H, d, J = 2.4 Hz), 9.26 (1H, s) ppm; δC (100 MHz, CDCl3) 25.8,
27.8, 31.0, 31.6, 31.7, 45.0, 52.7, 53.5, 55.4, 54.7, 97.1, 107.4, 113.5,
119.2, 120.1, 125.5, 128.2, 142.2, 147.0, 148.0, 155.3, 160.6, 165.1,
167.2, 195.3 ppm; m/z (EI, 70 eV) 499 (15, M+), 471 (40), 427 (35),
315 (100), 57 (95). Anal. Calcd for C27H33NO8: C, 64.92; H, 6.66; N,
2.80. Found: C, 64.86; H, 6.68; N, 2.82.
Diethyl 3-(tert-butylamino)-2-acetyl-5-oxacyclopenta[a]-
naphthalen-4(2H)-one-1,2-dicarboxylate (2m): orange solid (317
mg, 72%); mp 145−147 °C; IR (KBr) νmax 3403, 1712, 1688, 1647,
1603 cm−1; δH (400 MHz, CDCl3) 1.17 (3H, t, J = 7.2 Hz), 1.30 (3H,
t, J = 7.2 Hz), 1.66 (9H, s), 2.74 (3H, s), 4.13−4.26 (4H, m), 7.35−
7.43 (2H, m), 7.66−7.89 (2H, m), 9.60 (1H, s) ppm; δC (100 MHz,
CDCl3) 13.9, 14.6, 25.9, 30.6, 51.3, 59.2, 61.4, 95.3, 107.3, 121.1,
121.6, 125.4, 126.1, 128.7, 129.1, 146.0, 150.1, 155.3, 160.6, 165.0,
167.1, 195.3 ppm; m/z (EI, 70 eV) 441 (17, M+), 385 (21), 371 (40),
315 (100), 56 (55). Anal. Calcd for C24H27NO7: C, 65.29; H, 6.16; N,
3.17. Found: C, 65.27; H, 6.12; N, 3.19.
Diethyl 2-acetyl-3-(cyclohexylamino)-5-oxacyclopenta[a]-
naphthalen-4(2H)-one-1,2-dicarboxylate (2n): orange solid (340
mg, 73%); mp148−150 °C; IR (KBr) νmax 3418, 1713, 1688, 1648,
1603 cm−1; δH (400 MHz, CDCl3) 1.17 (3H, t, J = 7.2 Hz), 1.30 (3H,
t, J = 7.2 Hz), 1.43−2.27 (10H, m), 2.75 (3H, s), 3.49−3.59 (1H, m,
CHN) 4.13−4.23 (4H, m), 7.35−7.43 (2H, m), 7.66−7.89 (2H, m),
9.60 (1H, s) ppm; δC (100 MHz, CDCl3) 13.9, 14.6, 23.7, 25.2, 26.3,
26.4, 30.0, 30.1, 51.4 (CHN, 59.2, 61.4, 95.1, 107.3, 121.1, 121.6,
125.4, 126.1, 128.7, 129.1, 146.1, 150.3, 155.1, 160.0, 165.1, 167.7,
195.1 ppm; m/z (EI, 70 eV) 467 (15, M+), 411 (28), 397 (65), 315
(100), 56 (55). Anal. Calcd for C26H29NO7: C, 66.80; H, 6.20; N,
3.00. Found: C, 66.72; H, 6.23; N, 3.02.
Diethyl 3-(2,4,4-trimethylpentan-2-ylamino)-2-acetyl-5-oxa-
cyclopenta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2O): orange
solid (248 mg, 50%); mp153−154 °C; IR (KBr) νmax 3449, 1710,
1700, 1647, 1610 cm−1; δH (400 MHz, CDCl3) 1.06 (9H, s), 1.17 (3H,
t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.65 (6H, s), 1.78 (2H, s), 2.74
(3H), 7.35−7.43 (2H, m), 7.66−7.89 (2H, m), 9.59 (1H, s) ppm; δC
(100 MHz, CDCl3) 13.9,14.6, 25.9, 27.9, 31.0, 31.6, 31.7, 41.5, 53.4,
59.2, 61.4, 95.2, 107.6, 121.1, 121.6, 125.4, 126.1, 128.7, 129.1, 146.8,
150.3, 155.2, 160.0, 165.2, 167.6, 195.2 ppm; m/z (EI, 70 eV) 498 (12,
Dimethyl 3-(2,4,4-trimethylpentan-2-ylamino)-2-acetyl-8-nitro-
5-oxacyclopenta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2i):
yellow solid (267 mg, 52%); mp 166−168 °C; IR (KBr) νmax 3428,
1721, 1706, 1647, 1610 cm−1; δH (400 MHz, CDCl3) 1.06 (9H, s),
1.65 (6H, s), 1.78 (2H, s), 2.64 (3H), 4.04 (3H, s), 4.07 (3H, s),
7.55(1H, d, J 9.6 Hz), 8.52−8.61 (2H, m), 10.22 (1H, s) ppm; δC (100
MHz, CDCl3) 25.9, 27.9, 31.0, 31.6, 31.7, 43.4, 51.2, 53.5, 55.4, 96.9.2,
107.6, 118.7, 121.1, 121.9, 125.4, 128.1, 144.1, 146.1, 153.1, 155.3,
D
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The Journal of Organic Chemistry
Article
M+ + 1), 427 (15), 343 (50), 315 (100), 57 (57). Anal. Calcd for
C28H35NO7: C, 67.59; H, 7.09; N, 2.81. Found: C, 67.64; H, 7.02; N,
2.82.
8.52−8.61 (2H, m), 10.39 (1H, s) ppm; δC (100 MHz, CDCl3) 13.9,
14.6, 25.9, 27.9, 31.0, 31.6, 31.7, 43.4, 51.2, 61.4, 63.3, 96.9, 107.6,
118.7, 121.1, 121.9, 125.4, 128.1, 144.1, 146.1, 153.1, 155.3, 160.6,
165.1, 167.1, 195.4 ppm; m/z (EI, 70 eV) 542 (11, M+), 472 (35), 440
(65), 313 (100), 56 (55). Anal. Calcd for C28H34N2O9: C, 61.98; H,
6.32; N, 5.19. Found: C, 62.02; H, 6.36; N, 5.15.
Diethyl 3-(tert-butylamino)-2-acetyl-6-methoxy-5-oxacyclo-
penta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2v): yellow solid
(259 mg, 55%); mp 153−155 °C; IR (KBr) νmax 3404, 1712, 1701,
1648, 1610 cm−1 ; δH (400 MHz, CDCl3) 1.17 (3H, t, J = 7.2 Hz),
1.30 (3H, t, J = 7.2 Hz), 1.66 (9H, s), 2.74 (3H, s), 3.93 (3H, s), 4.13−
4.26 (4H, m), 7.27 (1H, d, J 8.4 Hz), 7.71 (1H, dd, J = 8.4, 2.4 Hz),
8.63 (1H, d, J = 2.4 Hz), 9.28 (1H, s) ppm; δC (100 MHz, CDCl3)
13.9, 14.6, 25.9, 30.6, 55.7, 59.1, 61.4, 63.3, 97.5, 107.5, 113.5, 119.1,
120.1, 125.4, 128.1, 142.1, 147.0, 148.0, 155.3, 160.6, 165.0, 167.0,
195.0 ppm; m/z (EI, 70 eV) 471 (20, M+), 457 (56), 355 (67), 268
(100), 56 (55). Anal. Calcd for C25H29NO8: C, 63.68; H, 6.20; N,
2.97. Found: C, 63.75; H, 6.20; N, 3.02.
Diethyl 2-acetyl-3-(cyclohexylamino)-6-methoxy-5-oxacyclo-
penta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2w): yellow
solid (283 mg, 57%); mp 158−160 °C; IR (KBr) νmax 3420, 1712,
1706, 1657, 1610 cm−1 ; δH (400 MHz, CDCl3) 1.17 (3H, t, J = 7.2
Hz), 1.30 (3H, t, J = 7.2 Hz), 1.43−2.27 (10H, m), 2.75 (3H, s),
3.49−3.56 (1H, m), 3.93 (3H, s), 4.13−4.26 (4H, m), 7.27 (1H, d, J
8.4 Hz), 7.71 (1H, dd, J = 8.4, 2.4 Hz), 8.63 (1H, d, J = 2.4 Hz), 9.28
(1H, s) ppm; δC (100 MHz, CDCl3) 13.9, 14.6, 23.7, 25.1, 26.3, 26.4,
30.0, 30.1, 51.7, 55.7, 61.4, 63.3, 97.1, 107.4, 113.5, 119.1, 120.1, 125.5,
128.1, 142.1, 147.0, 148.0, 155.4, 160.6, 165.1, 167.1, 195.3 ppm; m/z
(EI, 70 eV) 497 (17, M+), 483 (50), 453 (25), 268 (100), 56 (55).
Anal. Calcd for C27H31NO8: C, 65.18; H, 6.28; N, 2.82. Found: C,
65.27; H, 6.27; N, 2.84.
Diethyl 3-(2,4,4-trimethylpentan-2-ylamino)-2-acetyl-6-me-
thoxy-5-oxacyclopenta[a]naphthalen-4(2H)-one-1,2-dicarboxylate
(2x): yellow solid (284 mg, 54%); mp 149−151 °C; IR (KBr) νmax
3429, 1714, 1705, 1648, 1610 cm−1; δH (400 MHz, CDCl3) 1.05 (9H,
s), 1.17 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.65 (6H, s), 1.78
(2H, s), 2.74 (3H, s), 3.93 (3H, s), 4.13−4.26 (4H, m), 7.27 (1H, d, J
8.4 Hz), 7.71 (1H, dd, J = 8.4, 2.4 Hz), 8.63 (1H, d, J = 2.4 Hz), 9.27
(1H, s) ppm; δC (100 MHz, CDCl3) 13.9, 14.6, 25.9, 27.9, 31.0, 31.6,
31.7, 45.0, 51.7, 55.7, 61.4, 63.3, 97.1, 107.4, 113.4, 119.2, 120.1, 125.5,
128.1, 142.2, 147.0, 148.0, 155.3, 160.2, 165.1, 167.3, 195.2 ppm; m/z
(EI, 70 eV) 527 (19, M+), 513 (34), 499 (45), 268 (100), 56 (55).
Anal. Calcd for C29H37NO8: C, 66.02; H, 7.07; N, 2.65. Found: C,
66.31; H, 7.15; N, 2.58.
Diethyl 3-(tert-butylamino)-2-acetyl-8-bromo-5-oxacyclopenta-
[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2P): orange solid (400
mg, 77%); mp 153−155 °C; IR (KBr) νmax 3413, 1712, 1701, 1688,
1633 cm−1; δH (400 MHz, CDCl3) 1.17 (3H, t, J = 7.2 Hz), 1.30 (3H,
t, J = 7.2 Hz), 1.66 (9H, s), 2.74 (3H, s), 4.13−4.26 (4H, m), 7.32
(1H, d, J 8.4 Hz), 7.70 (1H, dd, J = 8.4, 2.4 Hz), 8.01 (1H, d, J = 2.4
Hz), 9.60 (1H, s) ppm; δC (100 MHz, CDCl3) 13.9, 14.6, 25.9, 30.6,
51.3, 59.3, 61.4, 95.5, 107.4, 118.1, 118.7, 121.1, 128.5, 129.1, 132.2,
146.0, 150.0, 155.6, 160.3, 165.0, 167.1, 195.5 ppm; m/z (EI, 70 eV)
521 (M+ + 2 [81Br], 14), 519 (M + [79Br], 8), 505 (30), 433 (100),
417 (60), 55 (90). Anal. Calcd for C24H26BrNO7: C, 55.39; H, 5.04;
N, 2.69. Found: C, 55.43; H, 5.02; N, 2.72.
Diethyl 2-acetyl-8-bromo-3-(cyclohexylamino)-5-oxacyclopenta-
[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2q): orange solid (393
mg, 72%); mp 152−153 °C; IR (KBr) νmax 3429, 1724, 1712, 1688,
1647 cm−1; δH (400 MHz, CDCl3) 1.17 (3H, t, J = 7.2 Hz), 1.30 (3H,
t, J = 7.2 Hz), 1.43−2.27 (10H, m), 2.75 (3H, s), 3.49−3.56 (1H, m),
4.13−4.23 (4H, m), 7.31 (1H, d, J 8.4 Hz), 7.70 (1H, dd, J = 8.4, 2.4
Hz), 9.60 (1H, d, J = 2.4 Hz), 8.44 (1H, s) ppm; δC (100 MHz,
CDCl3) 13.9, 14.6, 23.7, 25.1, 26.3, 26.4, 30.0, 30.1, 51.4, 59.2, 61.4,
95.0, 107.4, 118.1, 118.7, 121.1, 128.4, 129.1, 132.2, 146.1, 150.0,
155.3, 160.6, 165.0, 167.0, 195.0 ppm; m/z (EI, 70 eV) 547 (M+ + 2
[81Br], 13), 545 (M+ [79Br], 13), 505 (25), 475 (63), 459 (100), 56
(55). Anal. Calcd for C26H28BrNO7: C, 57.15; H, 5.17; N, 2.56.
Found: C, 57.13; H, 5.12; N, 2.54.
Diethyl 3-(2,4,4-trimethylpentan-2-ylamino)-2-acetyl-8-bromo-
5-oxacyclopenta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2r):
orange solid (357 mg, 62%); mp 161−163 °C; IR (KBr) νmax 3459,
1742, 1721, 1688, 1640 cm−1; δH (400 MHz, CDCl3) 1.06 (9H, s),
1.17 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.65 (6H, s), 1.78
(2H, s), 2.74 (3H, s), 7.32 (1H, d, J 8.4 Hz), 7.70 (1H, dd, J = 8.4, 2.4
Hz), 9.59 (1H, d, J = 2.4 Hz), 8.45 (1H, s) ppm; δC (100 MHz,
CDCl3) 13.9, 14.6, 25.9, 27.9, 31.0, 31.6, 31.7, 41.4, 51.2, 59.2, 61.4,
95.3, 107.4, 118.1, 118.7, 121.1, 128.4, 129.1, 132.2, 146.1, 150.0,
155.3, 160.6, 165.0, 167.1, 195.3 ppm; m/z (EI, 70 eV) 577 (M+ + 2
[81Br], 16), 575 (M+ [79Br], 16), 505 (57), 475 (48), 388(100), 56
(45). Anal. Calcd for C28H34BrNO7: C, 58.34; H, 5.94; N, 2.43.
Found: C, 58.36; H, 5.96; N, 2.43.
Diethyl 3-(tert-butylamino)-2-acetyl-8-nitro-5-oxacyclopenta[a]-
naphthalen-4(2H)-one-1,2-dicarboxylate (2s): yellow solid (267 mg,
55%); mp 165 °C; IR (KBr) νmax 3404, 1710, 1698,1632, 1603 cm−1;
δH (400 MHz, CDCl3) 1.17 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2
Hz), 1.66 (9H, s), 2.74 (3H, s), 4.13−4.26(4H, m), 7.55(1H, d, J 9.6
Hz), 8.52−8.61 (2H, m), 10.38 (1H, s) ppm; δC (100 MHz, CDCl3)
13.9, 14.6, 25.9, 30.6, 51.1, 61.2, 63.3, 96.2, 107.5, 118.7, 121.1, 121.9,
125.4, 128.1, 144.0, 146.0, 153.1, 155.6, 160.6, 165.0, 167.0, 195.0
ppm; m/z (EI, 70 eV) 486 (19, M+), 444 (49), 416 (55), 384 (100),
56 (50). Anal. Calcd for C24H26N2O9: C, 59.25; H, 5.39; N, 5.76.
Found: C, 59.29; H, 5.36; N, 5.75%.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all compounds; X-ray data for
compound 2q (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ghandi@khayam.ut.ac.ir.
■
Diethyl 2-acetyl-3-(cyclohexylamino)-8-nitro-5-oxacyclopenta-
[a]naphthalen-4(2H)-one-1,2-dicarboxylate (3t): yellow solid (286
mg, 56%); mp 173−175 °C; IR (KBr) νmax 3420, 1712, 1701, 1638,
1603 cm−1 ; δH (400 MHz, CDCl3) 1.17 (3H, t, J = 7.2 Hz), 1.30 (3H,
t, J = 7.2 Hz), 1.43−2.27 (10H, m), 2.75 (3H, s), 3.49−3.56 (1H, m)
4.13−4.23 (4H, m), 7.55 (1H, d, J = 9.6 Hz), 8.52−8.61 (2H, m)
10.39 (1H, s) ppm; δC (100 MHz, CDCl3) 13.9, 14.6, 23.7, 25.1, 26.3,
26.4, 30.0, 30.1, 51.4, 61.3, 63.3, 96.2, 107.5, 118.7, 121.1, 121.9, 125.4,
128.1, 144.1, 146.1, 153.1, 155.3, 160.6, 165.1, 167.1, 195.6 ppm; m/z
(EI, 70 eV) 486 (12, M+), 442 (38), 410 (57), 313 (100), 56 (49).
Anal. Calcd for C26H28N2O9: C, 60.93; H, 5.51; N, 5.47. Found: C,
60.86; H, 5.50; N, 5.48.
Diethyl 3-(2,4,4-trimethylpentan-2-ylamino)-2-acetyl-8-nitro-5-
oxacyclopenta[a]naphthalen-4(2H)-one-1,2-dicarboxylate (2u):
yellow solid (271 mg, 50%); mp 163−165 °C; IR (KBr) νmax 3429,
1722, 1710, 1647, 1610 cm−1; δH (400 MHz, CDCl3) 1.05 (9H, s),
1.17 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.65 (6H, s), 1.78
(2H, s), 2.74 (3H, s), 4.13−4.26 (4H, m), 7.55(1H, d, J 9.6 Hz),
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the University of Tehran for financial support
of this research.
■
REFERENCES
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