Sonogashira coupling reactions of bromomaleimides: Route to alkyne/cis-alkene/alkyl maleimides: Synthesis of luffarin X and cacospongionolide C

Article abstract of DOI:10.1021/jo2021218

Palladium-catalyzed Sonogashira coupling reaction of bromomaleimides with a diverse range of terminal alkynes has been demonstrated to furnish the corresponding alkynylmaleimides in very good yields. This coupling reaction followed by selective reduction of the triple bond to single bond have been utilized as the decisive steps to accomplish the first total synthesis of natural products (±)-luffarin X and (±)-cacospongionolide C.

Full text of DOI:10.1021/jo2021218

Note
pubs.acs.org/joc
Sonogashira Coupling Reactions of Bromomaleimides: Route to
Alkyne/cis-Alkene/Alkyl Maleimides: Synthesis of Luffarin X and
Cacospongionolide C
Prashant S. Deore and Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
S
* Supporting Information
ABSTRACT: Palladium-catalyzed Sonogashira coupling re-
action of bromomaleimides with a diverse range of terminal
alkynes has been demonstrated to furnish the corresponding
alkynylmaleimides in very good yields. This coupling reaction
followed by selective reduction of the triple bond to single
bond have been utilized as the decisive steps to accomplish the first total synthesis of natural products ( )-luffarin X and
( )-cacospongionolide C.
reactions for the introduction of an alkyne segment.22−27 The
large number of alkyl- and dialkyl-substituted maleic
synthetic utility of this reaction has been demonstrated on a
Aanhydrides, the corresponding lactols and γ-lactones
broad assortment of vinylic, aromatic, and heteroaromatic
substrates to accomplish the effective synthesis of many exotic
bioactive natural and unnatural products.28−34 Although the
Sonogashira coupling with halomaleimides has not been
previously described, several palladium-catalyzed cross-coupling
reactions with them have been reported.35−37 In continuation
of our studies on carbon−carbon and carbon−heteroatom
coupling reactions,13,15,38−40 we realized that Sonogashira
coupling of bromomaleic anhydrides/bromomaleimides would
be useful to develop a new general route to alkyne/alkene/
alkyl-substituted maleic anhydrides and several analogous
natural products. In this context, we herein report our results
on the synthesis of a variety of alkylmaleimides/maleic
anhydrides and their applications in the synthesis of
( )-luffarin X and ( )-cacospongionolide C (Tables 1−5
and Scheme 1).
(butenolides), have been isolated as the natural products with
an array of promising bioactivities (Figure 1).1−7 Many new
The initially attempted Sonogashira coupling reaction of
reactive bromomaleic anhydride with 1-hexyne resulted in
decomposition. Relatively more stable corresponding multi-
functional halomaleimides 141 were therefore preferred as the
potential precursors for our systematic studies on Sonogashira
coupling reactions. As depicted in Table 1, the reaction
between bromomaleimide and 1-hexyne was performed
employing three different palladium catalysts in THF. Two of
these catalysts selectively furnished the desired coupled product
2b in ∼90% yields (entries 2 and 4). However, the
bromomethylmaleimide and dibromomaleimide under similar
set of reaction conditions failed to deliver the corresponding
desired mono/double coupling products, leading to decom-
position (entries 5−8). The corresponding chloromaleimide
and dichloromaleimide also failed to deliver the coupling
products and remained unreacted at room temperature, while
Figure 1. Naturally occurring butenolides.
routes have been devised in recent times to synthesize the
essential dialkyl-substituted maleic anhydrides8−12 and buteno-
lides.13−18 To the best of our knowledge, only a few practical
routes have been known for the synthesis of alkylmaleic
anhydrides.19−21 They have been based on condensation of
glyoxylic acid with aldehydes/esters bearing the active α-
hydrogens19 and also Heck reaction using palladium-catalyzed
dicarbonylation of terminal acetylenes with carbon monoxide.20
Our own recent approach based on isomaleimide intermediate
involves more synthetic steps.21 The Sonogashira coupling is
one of the most important carbon−carbon bond-forming
Received: October 13, 2011
Published: December 2, 2011
© 2011 American Chemical Society
739
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The Journal of Organic Chemistry
Note
Table 1. Sonogashira Coupling Reactions of Bromomaleimides and Chloromaleimides
entry
X
R3
catalyst
solvent
time (h)
% yield
a
1
2
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
H
Pd(PPh3)4
THF
THF
DMF
THF
THF
THF
THF
THF
THF
THF
6.0
1.0
1.0
1.0
6.0
6.0
6.0
6.0
6.0
6.0
NR
H
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(CH3CN)2
PdCl2(PPh3)2
PdCl2(CH3CN)2
PdCl2(PPh3)2
PdCl2(CH3CN)2
PdCl2(PPh3)2
PdCl2(PPh3)2
90
67
89
3
H
4
H
a
5
Me
Me
Br
Br
H
NR
a
6
NR
a
7
NR
a
8
NR
b
9
NR
b
10
Cl
NR
a
b
No reaction, decomposition after 24 h. No reaction from 25 to 65 °C.
Lindlar catalyst in methanol reduced both the triple bond and
internal double bond to provide alkylsuccinimide 5b in 74%
yield (entry 6). However the same reaction in methanol−
acetone (1:1) in the presence of quinoline (1.00 equiv)
selectively reduced only the carbon−carbon triple bond to the
single bond furnishing the alkylmaleimide 4b in 68% yield
(entry 8). The reaction of 2b in the presence of Lindlar catalyst
in solvent acetonitrile/acetone and quinoline (1.50 equiv)
yielded the desired monoreduction product cis-alkenylmalei-
mide 3b in 56/57% yields along with the ∼6% of 4b (entries 9
and 10). The reaction of imide 2b in the presence of Pd−C in
ethyl acetate provided completely reduced product 5b in 78%
yield (entry 5). The same reaction in methanol in the presence
of quinoline (1.50 equiv) was also selective and gave the
alkylmaleimide 4b in 63% yield (entry 7). Finally, as depicted in
Tables 4 and 5, the aliphatic alkyne-substituted maleimides
were selectively reduced to the corresponding cis-alkenylmalei-
mides in 61−66% yields and alkylmaleimides in 68−75% yields.
The cis-geometry of the products 3 was confirmed on the basis
of NOE studies and the comparison with reported data.4 Thus,
the present protocol provides a facile new route to both the
alkylmaleimides and the alkylmaleic anhydrides. Further
conversion of alkylmaleimides to the corresponding dialkylma-
leic anhydrides has been recently reported from our group.21
However the alkyne-substituted maleimides with aromatic rings
led to decomposition under present reduction conditions
(Tables 4 and 5, entry 5).
The terpenoids luffarin X and cacospongionolide C have
been isolated, respectively, from the marine sponge Luffariella
geometrica46 and Fasciospongia cavernosa.47 To date, no
synthesis of these natural products has been reported in the
literature. The present protocol was extended for the first
synthesis of the above-mentioned natural products. The
appropriate precursor 4h on base-catalyzed hydrolysis followed
by the acetic anhydride induced ring-closure provided the
corresponding alkylmaleic anhydride 6 in 62% yield41 (Scheme
1). The regioselective reduction of anhydride 6 was studied
using the five different reducing agents.48 In the sodium
borohydride reduction of unsymmetrical anhydride 6, boron
atom complexes with the unhindered carbonyl group and
delivers the hydride to the hindered carbonyl group to
exclusively yield the desired butenolide ( )-luffarin X (7) in
Scheme 1. Synthesis of Luffarin X and Cacospongionolide C
slowly undergoing decomposition under the reflux conditions
(entries 9 and 10). As described in Table 2, the reactions of
bromomaleimides with several aliphatic and aromatic alkynes
were performed in the presence of PdCl2(PPh3)2/CuI in THF,
and the desired products 2a−r were obtained in very good
yields (entries 1−18). We also obtained the coupling products
2b, 2k, and 2n from the corresponding iodomaleimide in
similar yields (Table 2, entries 19−21). In these multifunctional
maleimides 2a−r, a variety of chemoselective transformations
would be possible on carbon−carbon triple bond to obtain the
corresponding alkenyl/alkyl/acyl/1,2-dicarbonyl-substituted
maleimides/maleic anhydrides as potential building
blocks.42−45 As indicated in Table 3, chemoselective and
controlled hydrogenation of carbon−carbon triple bond in
product 2b was performed employing several catalysts. The
reduction of imide 2b in the presence of Wilkinson catalyst and
Pearlman catalyst were futile. While the former reaction did not
proceed at all, the latter resulted in decomposition (entries 1
and 3). As shown in entry 4, the transfer hydrogenation
conditions also resulted in decomposition. The selective
reduction of imide 2b in the presence of Lindlar catalyst was
feasible, and it was dependent on both the solvent used and the
presence/absence of quinoline.45 As described in entry 2, the
acetylene segment of imide 2b in the presence of Lindlar
catalyst in ethyl acetate did not undergo reduction and
remained unreacted. The reaction of 2b in the presence of
740
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Note
Table 2. Sonogashira Couplings of Bromomaleimides and Iodomaleimides: Synthesis of Alkynylmaleimides
entry
X
R1
R2
time (h)
2 (% yield)
1
2
3
4
5
6
7
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
C6H5
Si(Me)3
3.0
1.0
1.0
1.0
0.5
0.5
0.5
1.0
2.0
2.0
1.0
1.0
1.5
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.0
2a (52)
2b (90)
2c (90)
2d (93)
2e (93)
2f (95)
2g (95)
2h (56)
2i (67)
2j (63)
2k (75)
2l (78)
2m (67)
2n (72)
2o (91)
2p (86)
2q (81)
2r (74)
2b (86)
2k (77)
2n (69)
CH2(CH2)2CH3
CH2(CH2)4CH3
CH2(CH2)6CH3
CH2(CH2)11CH3
CH2(CH2)12CH3
CH2(CH2)13CH3
C14H29
a
8
9
10
11
12
13
14
15
16
17
18
19
20
21
CH2(CH2)7CH2OH
CH2(CH2)7COOH
C6H5
p-C6H4-CH3
o-C6H4-OCH3
p-C6H4-OCH3
CH2(CH2)2CH3
CH2(CH2)2CH3
C6H5
CH2C6H5
CH3
(CH2)2CO2CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
CH2(CH2)2CH3
CH2(CH2)2CH3
C6H5
I
I
p-C6H4-OCH3
a
C14H29: CH2CHCH3(CH2)3CHCH3(CH2)3CH(CH3)2 (diastereomeric mixture).
Table 3. Selective Hydrogenation of Alkynylmaleimides
% yield
entry
catalyst
reaction conditions
H2, DCM, reflux, 5 h
3b
4b
5b
a
1
2
3
4
Wilkinson
Lindlar
NR
a
H2, quinoline, EtOAc, 25 °C, 24 h
H2, MeOH, 25 °C, 5 h
TsNHNH2, DME
NR
b
Pearlman
D
b
D
aq NaOAc, reflux, 5 h
5
6
7
8
Pd−C
Lindlar
Pd−C
Lindlar
H2, EtOAc, 25 °C, 1 h
H2, MeOH, 25 °C, 5 h
H2, quinoline, MeOH, 25 °C, 1.5 h
H2, quinoline
78
74
63
68
MeOH + acetone (1:1), 25 °C, 6 h
H2, quinoline, CH3CN, 25 °C, 5 h
H2, quinoline, acetone, 25 °C, 5 h
9
Lindlar
Lindlar
56
57
6
6
10
a
b
No reaction. Decomposition.
86% yield. The reduction reactions of anhydride 6 with
NaBH(OAc)3 and Li(t-BuO)3AlH were less selective and
provided the column chromatographically separable mixture of
products 7 and 8 in 81/70% yields (7:8 = ∼1:3). The reduction
reactions of anhydride 6 with the NaB[CH(CH3)C2H5]3H and
DIBAL-H at −78 °C were also completely regioselective and
reduced the hindered carbonyl group to the corresponding
lactol to provide yet another desired natural product
( )-cacospongionolide C (8) in 73/74% yields, respectively.
Such compounds containing hemiketal/lactol/lactamol unit
display the ring−chain tautomerism and are prone to
racemize.39 The analytical and spectral data obtained for both
the natural products 7 and 8 were in complete agreement with
reported data.46,47 Thus, starting from imide 1 the natural
products 7 and 8 were obtained in five linear steps with 21%
and 18% overall yields, respectively.
741
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Note
Table 4. Stereoselective Reduction of Alkynylmaleimides
entry
R2
time (h)
3 (% yield)
a
1
2
3
CH2(CH2)2CH3
CH2(CH2)6CH3
CH2(CH2)12CH3
C14H29
5.0
5.0
3b (63)
a
3d (61)
5.0
3f (65)
3h (66)
b
4
5.0
c
5
C6H5
12.0
3k D
a
b
The products were contaminated with traces of overreduced products 4b and 4d. C14H29: CH2CHCH3(CH2)3CHCH3(CH2)3CH(CH3)2.
c
Decomposition.
Table 5. Synthesis of Alkylmaleimides
entry
R2
time (h)
4 (% yield)
1
2
CH2(CH2)2CH3
CH2(CH2)6CH3
CH2(CH2)12CH3
C14H29
6.0
5.0
4b (68)
4d (70)
4f (75)
4h (70)
3
a
6.5
4
6.5
b
5
C6H5
12.0
4k D
a
b
C14H29: CH2CHCH3(CH2)3CHCH3(CH2)3CH(CH3)2. Decomposition.
(0.55 mmol), triethylamine (0.077 mL, 0.55 mmol), and CuI (0.70
mg, 10 mol %) were added successively at 0 °C, and reaction mixture
was stirred at 25 °C under argon atmosphere. After completion of the
reaction (by TLC), ethyl acetate (10 mL) and water (5 mL) were
added to the reaction mixture. The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate (10 mL × 2). The
combined organic layer was washed with brine, dried over Na2SO4,
and concentrated in vacuo. The obtained residue was purified by silica
gel column chromatography using petroleum ether−ethyl acetate as an
eluent to furnish the desired coupling product 2. Alternatively, the
reaction mixture was filtered through a Celite, concentrated under
vacuum, and then directly subjected to silica gel column chromato-
graphic purification. All the reactions were performed using
bromomaleimides (100 mg) to obtain the desired products 2a−g,i−
r. For the preparation of natural products precursor 2h, the reaction
was performed on a 1 g scale of 3-bromo-1-(p-tolyl)-1H-pyrrole-2,5-
dione.
In summary, we have demonstrated a new general approach
to alkyne/alkene/alkyl substituted maleimides/anhydrides by
performing the palladium-catalyzed Sonogashira coupling
reactions on the multifunctional bromomaleimides with a
variety of terminal alkynes using CuI as the cocatalyst. The
present protocol has been utilized to accomplish the total
synthesis of natural products luffarin X and cacospongionolide
C. The present Sonogashira coupling reactions of bromoma-
leimides and the chemo- and regioselective reductions are of
general interest. We foresee their usefulness to obtain several
complex bioactive natural and unnatural products for SAR
studies.
EXPERIMENTAL SECTION
■
General Description. Melting points are uncorrected. The 1H
NMR spectra were recorded on 200 MHz, 400 MHz, and 500 MHz
NMR spectrometers using TMS as an internal standard. The 13C
NMR spectra were recorded on 200 (50 MHz), 400 (100 MHz), and
500 NMR spectrometer (125 MHz). Mass spectra were taken on an
MS-TOF mass spectrometer. HRMS were taken on ESI mass
spectrometer. The IR spectra were recorded on an FT-IR
spectrometer. Column chromatographic separations were carried out
on silica gel (60−120 and 200−400 mesh). Commercially available
Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(CH3CN)2, CuI, alkynes, Lindlar
catalyst (5 wt %), Pd on charcoal (10 wt %), synthetic quinoline,
NaBH4, NaBH(OAc)3, DIBAL-H, N-Selectride, and Super-Hydride
were used. The halomaleimides were prepared by using known
procedure.41 The required alkynes were also prepared by using known
procedure.49
1-(p-Tolyl)-3-((trimethylsilyl)ethynyl)-1H-pyrrole-2,5-dione
1
(2a): yellow solid (55 mg, 52%); mp 89−92 °C; H NMR (CDCl3,
200 MHz) δ 0.30 (s, 9H), 2.39 (s, 3H), 6.79 (s, 1H), 7.15−7.32 (m,
4H); 13C NMR (CDCl3, 50 MHz) δ 0.7, 21.1, 92.9, 115.2, 125.9,
128.5, 129.8, 130.4, 132.3, 138.1, 166.1, 169.0; ESIMS (m/z) 306 [M
+ Na]+, 322 [M + K]+; HRMS (ESI) calcd for C16H18NO2Si [M + H]+
284.1107, found 284.1110; IR (CHCl3) νmax 2311, 1713, 1393 cm−1.
3-(Hex-1-yn-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione (2b): yel-
low solid (90 mg, 90%); mp 93−94 °C; 1H NMR (CDCl3, 200
MHz) δ 0.94 (t, J = 8 Hz, 3H), 1.35−1.70 (m, 4H), 2.38 (s, 3H), 2.54
(t, J = 8 Hz, 2H), 6.67 (s, 1H), 7.15−7.30 (m, 4H); 13C NMR
(CDCl3, 50 MHz) δ 13.5, 19.9, 21.1, 22.0, 30.0, 70.9, 110.3, 125.9,
128.6, 129.7, 130.5, 131.5, 138.0, 166.6, 169.4; ESIMS (m/z) 290 [M
+ Na]+, 306 [M + K]+; HRMS (ESI) calcd for C17H18NO2 [M + H]+
268.1338, found 268.1339; IR (CHCl3) νmax 2230, 1721, 1715 cm−1.
3-(Oct-1-yn-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione (2c): yel-
General Procedure for Sonogashira Coupling Reaction of 3-
Bromo-1-(p-tolyl)-1H-pyrrole-2,5-dione. A round-bottom flask
was charged with PdCl2(PPh3)2 (13 mg, 5 mol %) and
bromomaleimide (100 mg, 0.37 mmol) in THF (7 mL). The alkyne
1
low solid (100 mg, 90%); mp 74−75 °C; H NMR (CDCl3, 200
MHz) δ 0.90 (t, J = 6 Hz, 3H), 1.20−1.52 (m, 6H), 1.60 (quintet, J =
742
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Note
8 Hz, 2H), 2.37 (s, 3H), 2.53 (t, J = 8 Hz, 2H), 6.67 (s, 1H), 7.10−
7.32 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.0, 20.2, 21.1, 22.4,
27.9, 28.5, 31.2, 70.9, 110.4, 126.0, 128.6, 129.7, 130.5, 131.5, 138.0,
166.6, 169.4; ESIMS (m/z) 366 [M + K + MeOH]+; HRMS (ESI)
calcd for C19H22NO2 [M + H]+ 296.1651, found 296.1649; IR
(CHCl3) νmax 2224, 1723, 1715 cm−1.
2359, 1721, 1715, 1697 cm−1. Anal. Calcd for C22H25NO4: C, 71.91;
H, 6.86; N, 3.81. Found: C, 71.65; H, 6.84; N, 3.76.
3-(Phenylethynyl)-1-(p-tolyl)-1H-pyrrole-2,5-dione (2k): yel-
1
low solid (81 mg, 75%); mp 138−139 °C; H NMR (CDCl3, 200
MHz) δ 2.39 (s, 3H), 6.82 (s, 1H), 7.15−7.33 (m, 4H), 7.33−7.52 (m,
3H), 7.62 (d, J = 6 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 21.1, 79.0,
106.8, 121.0, 126.0, 128.6, 129.8, 130.4, 130.7, 130.8, 132.4, 138.1,
166.3, 169.1; ESIMS (m/z) 342 [M + Na + MeOH]+; HRMS (ESI)
calcd for C19H14NO2 [M + H]+ 288.1025, found 288.1028; IR
(CHCl3) νmax 2212, 1717 cm−1.
3-(Dec-1-yn-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione (2d): yel-
1
low solid (113 mg, 93%); mp 52−53 °C; H NMR (CDCl3, 200
MHz) δ 0.88 (t, J = 6 Hz, 3H), 1.28 (br s, 8H), 1.35−1.53 (m, 2H),
1.64 (quintet, J = 6 Hz, 2H), 2.38 (s, 3H), 2.53 (t, J = 8 Hz, 2H), 6.67
(s, 1H), 7.13−7.30 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.1,
20.2, 21.1, 22.6, 27.9, 28.9, 29.0, 29.1, 31.8, 70.9, 110.4, 125.9, 128.6,
129.7, 130.5, 131.5, 138.0, 166.6, 169.4; ESIMS (m/z) 394 [M + K +
MeOH]+; HRMS (ESI) calcd for C21H26NO2 [M + H]+ 324.1964,
found 324.1975; IR (CHCl3) νmax 2225, 1724, 1715 cm−1.
1-(p-Tolyl)-3-(p-tolylethynyl)-1H-pyrrole-2,5-dione (2l): yel-
1
low solid (88 mg, 78%); mp 133−134 °C; H NMR (CDCl3, 200
MHz) δ 2.39 (s, 6H), 6.78 (s, 1H), 7.15−7.32 (m, 6H), 7.51 (d, J = 8
Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 21.1, 21.7, 78.8, 107.4, 117.9,
125.9, 128.6, 129.4, 129.7, 130.2, 130.8, 132.4, 138.0, 141.1, 166.4,
169.2; ESIMS (m/z) 356 [M + Na + MeOH]+; HRMS (ESI) calcd for
C20H16NO2 [M + H]+ 302.1181, found 302.1181; IR (CHCl3) νmax
2212, 1721, 1715 cm−1.
3-(Pentadec-1-yn-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione
1
(2e): yellow solid (137 mg, 93%); mp 59−60 °C; H NMR (CDCl3,
200 MHz) δ 0.87 (t, J = 6 Hz, 3H), 1.25 (br s, 18H), 1.30−1.50 (m,
2H), 1.64 (quintet, J = 8 Hz, 2H), 2.38 (s, 3H), 2.53 (t, J = 8 Hz, 2H),
6.67 (s, 1H), 7.13−7.30 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.1,
20.2, 21.1, 22.7, 28.0, 28.9, 29.0, 29.3, 29.4, 29.57, 29.61 (3 carbons),
31.9, 70.9, 110.4, 126.0, 128.6, 129.7, 130.5, 131.5, 138.0, 166.6, 169.5;
ESIMS (m/z) 426 [M + H + MeOH]+; HRMS (ESI) calcd for
C26H36NO2 [M + H]+ 394.2746, found 394.2737; IR (CHCl3) νmax
2218, 1721, 1713 cm−1.
3-((2-Methoxyphenyl)ethynyl)-1-(p-tolyl)-1H-pyrrole-2,5-
1
dione (2m): yellow solid (80 mg, 67%); mp 127−129 °C; H NMR
(CDCl3, 200 MHz) δ 2.40 (s, 3H), 3.94 (s, 3H), 6.82 (s, 1H), 6.94 (d,
J = 8 Hz, 1H), 6.99 (dt, J = 8 and 2 Hz, 1H), 7.20−7.32 (m, 4H), 7.43
(dt, J = 8 and 2 Hz, 1H), 7.57 (dd, J = 8 and 2 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) δ 21.1, 55.9, 83.1, 103.9, 110.3, 110.8, 120.6, 126.0,
128.6, 129.7, 130.1, 130.9, 132.2, 134.3, 138.0, 160.7, 166.4, 169.3;
ESIMS (m/z) 372 [M + Na + MeOH]+; HRMS (ESI) calcd for
C20H16NO3 [M + H]+ 318.1130, found 318.1119; IR (CHCl3) νmax
2359, 1717 cm−1.
3-(Hexadec-1-yn-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione (2f):
1
yellow solid (145 mg, 95%); mp 61−62 °C; H NMR (CDCl3, 200
MHz) δ 0.88 (t, J = 8 Hz, 3H), 1.26 (br s, 20H), 1.35−1.55 (m, 2H),
1.64 (quintet, J = 8 Hz, 2H), 2.38 (s, 3H), 2.53 (t, J = 8 Hz, 2H), 6.66
(s, 1H), 7.15−7.30 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.1,
20.2, 21.1, 22.7, 28.0, 28.9, 29.0, 29.3, 29.4, 29.6 (5 carbons), 31.9,
70.9, 110.4, 126.0, 128.6, 129.7, 130.5, 131.5, 138.0, 166.6, 169.5;
ESIMS (m/z) 440 [M + H+MeOH]+; HRMS (ESI) calcd for
C27H38NO2 [M + H]+ 408.2903, found 408.2899; IR (CHCl3) νmax
2224, 1718, 1608 cm−1.
3-((4-Methoxyphenyl)ethynyl)-1-(p-tolyl)-1H-pyrrole-2,5-
1
dione (2n): yellow solid (86 mg, 72%); mp 140−141 °C; H NMR
(CDCl3, 200 MHz) δ 2.39 (s, 3H), 3.85 (s, 3H), 6.75 (s, 1H), 6.87−
6.95 (m, 2H), 7.17−7.32 (m, 4H), 7.50−7.60 (m, 2H); 13C NMR
(CDCl3, 50 MHz) δ 21.1, 55.4, 78.8, 107.8, 113.0, 114.3, 126.0, 128.7,
129.4, 129.7, 131.0, 134.3, 138.0, 161.3, 166.5, 169.4; ESIMS (m/z)
372 [M + Na + MeOH]+; HRMS (ESI) calcd for C20H16NO3 [M +
H]+ 318.1130, found 318.1131; IR (CHCl3) νmax 2212, 1721, 1715
cm−1.
3-(Heptadec-1-yn-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione
1
(2g): yellow solid (150 mg, 95%); mp 65−66 °C; H NMR (CDCl3,
200 MHz) δ 0.88 (t, J = 6 Hz, 3H), 1.26 (br s, 22H), 1.30−1.52 (m,
2H), 1.64 (quintet, J = 8 Hz, 2H), 2.38 (s, 3H), 2.53 (t, J = 8 Hz, 2H),
6.66 (s, 1H), 7.15−7.30 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.1,
20.2, 21.1, 22.7, 28.0, 28.9, 29.0, 29.3, 29.4, 29.57, 29.63, 29.7 (4
carbons), 31.9, 70.9, 110.4, 126.0, 128.6, 129.7, 130.5, 131.5, 138.0,
166.6, 169.4; ESIMS (m/z) 444 [M + Na]+; HRMS (ESI) calcd for
C28H40NO2 [M + H]+ 422.3059, found 422.3078; IR (CHCl3) νmax
2361, 1717 cm−1.
3-(Hex-1-yn-1-yl)-1-phenyl-1H-pyrrole-2,5-dione (2o): yel-
low solid (91 mg, 91%); mp 67−68 °C; 1H NMR (CDCl3, 200
MHz) δ 0.95 (t, J = 8 Hz, 3H), 1.37−1.73 (m, 4H), 2.55 (t, J = 8 Hz,
2H), 6.68 (s, 1H), 7.30−7.53 (m, 5H); 13C NMR (CDCl3, 50 MHz) δ
13.5, 19.9, 22.0, 29.9, 70.8, 110.5, 126.0, 127.9, 129.1, 130.5, 131.3,
131.5, 166.5, 169.3; HRMS (ESI) calcd for C16H16NO2 [M + H]+
254.1181, found 254.1182; IR (CHCl3) νmax 2231, 1719 cm−1.
1-Benzyl-3-(hex-1-yn-1-yl)-1H-pyrrole-2,5-dione (2p): thick
1
1-(p-Tolyl)-3-(4,8,12-trimethyltridec-1-yn-1-yl)-1H-pyrrole-
2,5-dione (2h, diastereomeric mixture): thick oil (860 mg, 56%);
1H NMR (CDCl3, 200 MHz) δ 0.75−1.60 (m, 26H), 1.70−1.92 (m,
oil (86 mg, 86%); H NMR (CDCl3, 400 MHz) δ 0.93 (t, J = 8
Hz, 3H), 1.45 (sextet, J = 8 Hz, 2H), 1.60 (quintet, J = 8 Hz, 2H), 2.50
(t, J = 8 Hz, 2H), 4.67 (s, 2H), 6.53 (s, 1H), 7.20−7.40 (m, 5H); 13C
NMR (CDCl3, 100 MHz) δ 13.5, 19.8, 21.9, 29.9, 41.8, 70.9, 109.8,
127.8, 128.4, 128.6, 130.6, 131.4, 136.0, 167.4, 170.1; HRMS (ESI)
calcd for C17H18NO2 [M + H]+ 268.1338, found 268.1328; IR
(CHCl3) νmax 2228, 1773, 1714 cm−1.
1-Methyl-3-(phenylethynyl)-1H-pyrrole-2,5-dione (2q): yel-
low solid (90 mg, 81%); mp 74−75 °C; 1H NMR (CDCl3, 400
MHz) δ 3.07 (s, 3H), 6.70 (s, 1H), 7.35−7.48 (m, 3H), 7.59 (d, J = 8
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 24.3, 79.0, 106.3, 121.1,
128.6, 130.3, 130.8, 131.0, 132.4, 167.5, 170.3; HRMS (ESI) calcd for
C13H10NO2 [M + H]+ 212.0712, found 212.0711; IR (CHCl3) νmax
2200, 1775, 1713 cm−1.
Methyl 3-(3-(hex-1-yn-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyr-
rol-1-yl)propanoate (2r): thick oil (74 mg, 74%); 1H NMR
(CDCl3, 200 MHz) δ 0.94 (t, J = 8 Hz, 3H), 1.35−1.75 (m, 4H),
2.52 (t, J = 8 Hz, 2H), 2.64 (t, J = 8 Hz, 2H), 3.68 (s, 3H), 3.84 (t, J =
8 Hz, 2H), 6.54 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.5, 19.9,
22.0, 30.0, 32.6, 34.0, 51.9, 70.8, 110.0, 130.6, 131.6, 167.3, 170.0,
171.0; HRMS (ESI) calcd for C14H18NO4 [M + H]+ 264.1236, found
264.1238; IR (CHCl3) νmax 2220, 1775, 1734, 1716 cm−1.
1H), 2.25−2.65 (m, 2H), 2.39 (s, 3H), 6.67 (s, 1H), 7.15−7.33 (m,
4H); 13C NMR (CDCl3, 50 MHz) δ 19.5, 19.6, 21.1, 22.6, 22.7, 24.4,
24.7, 27.5, 27.6, 27.9, 32.5, 32.7, 36.5, 37.1, 37.2, 37.3, 39.3, 71.8,
109.5, 125.9, 128.6, 129.7, 130.3, 131.5, 137.9, 166.6, 169.4; ESIMS
(m/z) 430 [M + Na]+; HRMS (ESI) calcd for C27H38NO2 [M + H]+
408.2903, found 408.2903; IR (CHCl3) νmax 2220, 1721, 1606 cm−1.
3-(11-Hydroxyundec-1-yn-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-
1
dione (2i): yellow solid (89 mg, 67%); mp 70−72 °C; H NMR
(CDCl3, 200 MHz) δ 1.20−1.75 (m, 14H), 2.38 (s, 3H), 2.54 (t, J = 8
Hz, 2H), 3.64 (t, J = 6 Hz, 2H), 6.68 (s, 1H), 7.15−7.32 (m, 4H); 13C
NMR (CDCl3, 50 MHz) δ 20.2, 21.1, 25.6, 27.9, 28.8, 28.9, 29.28,
29.33, 32.7, 63.0, 70.9, 110.4, 126.0, 128.6, 129.7, 130.5, 131.5, 138.0,
166.6, 169.5; ESIMS (m/z) 376 [M + Na]+; HRMS (ESI) calcd for
C22H28NO3 [M + H]+ 354.2069, found 354.2066; IR (CHCl3) νmax
2359, 1721, 1715, 1697 cm−1.
11-(2,5-Dioxo-1-(p-tolyl)-2,5-dihydro-1H-pyrrol-3-yl)undec-
10-ynoic acid (2j): yellow solid (87 mg, 63%); mp 114−116 °C; 1H
NMR (CDCl3, 200 MHz) δ 1.20−1.75 (m, 12H), 2.35 (t, J = 8 Hz,
2H), 2.37 (s, 3H), 2.53 (t, J = 8 Hz, 2H), 6.67 (s, 1H), 7.12−7.31 (m,
4H); 13C NMR (CDCl3, 50 MHz) δ 20.2, 21.1, 24.6, 27.9, 28.7, 28.8,
28.9, 29.0, 33.9, 70.9, 110.3, 126.0, 128.6, 129.8, 130.6, 131.5, 138.0,
166.7, 169.5, 179.7; ESIMS (m/z) 390 [M + Na]+; IR (CHCl3) νmax
General Procedure for Hydrogenation of Alkynylmalei-
mides (2b,d,f,h) to Alkenylmaleimides (3b,d,f,h). To a solution
of alkynylmaleimide 2 (0.10 mmol) in CH3CN or acetone (2 mL)
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The Journal of Organic Chemistry
Note
were added quinoline (19.4 mg, 0.15 mmol) and Lindlar catalyst (10
mg, 5 wt %). The reaction mixture was then stirred at 25 °C under
balloon pressure hydrogen atmosphere for 5 h. The reaction mixture
was filtered through Celite, and the residue was washed with ethyl
acetate (20 mL). The resulting solution was concentrated in vacuo,
and the obtained residue was purified by silica gel flash column
chromatography using petroleum ether−ethyl acetate as an eluent to
yield the desired (Z)-alkene 3. All the reactions were performed using
alkynylmaleimides 2b,d,f,h (0.10 mmol) to obtain the desired products
3b,d,f,h.
and the residue was washed with ethyl acetate (20 mL). The resulting
solution was concentrated in vacuo, and the obtained residue was
purified by silica gel flash column chromatography using petroleum
ether−ethyl acetate as an eluent to yield the desired monoalkyl-
substituted maleimide 4. All of the reactions were performed using
alkynylmaleimides 2b,d,f (0.10 mmol) to obtain the desired products
4b,d,f. For the preparation of natural product precursor 4h the
reaction was performed using a 1.00 mmol scale of 2h.
3-Hexyl-1-(p-tolyl)-1H-pyrrole-2,5-dione (4b):.21 yellow solid
(19 mg, 68%); mp 70−72 °C; 1H NMR (CDCl3, 200 MHz) δ 0.90 (t,
J = 6 Hz, 3H), 1.25−1.52 (m, 6H), 1.65 (quintet, J = 6 Hz, 2H), 2.38
(s, 3H), 2.51 (dt, J = 8 and 2 Hz, 2H), 6.41 (t, J = 2 Hz, 1H), 7.15−
7.32 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.0, 21.1, 22.5, 25.5,
27.0, 28.9, 31.4, 125.9, 126.2, 128.9, 129.7, 137.7, 150.3, 169.9, 170.6;
ESIMS (m/z) 294 [M + Na]+; IR (CHCl3) νmax 1713, 1637 cm−1.
3-Decyl-1-(p-tolyl)-1H-pyrrole-2,5-dione (4d):.21 yellow solid
(23 mg, 70%); mp 60−61 °C; 1H NMR (CDCl3, 200 MHz) δ 0.87 (t,
J = 6 Hz, 3H), 1.26 (br s, 14H), 1.63 (quintet, J = 8 Hz, 2H), 2.36 (s,
3H), 2.49 (dt, J = 8 and 2 Hz, 2H), 6.40 (t, J = 2 Hz, 1H), 7.10−7.30
(m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.1, 21.1, 22.7, 25.5, 27.1,
29.21, 29.24, 29.27, 29.46, 29.54, 31.9, 125.9, 126.3, 129.0, 129.7,
137.7, 150.3, 169.9, 170.6; ESIMS (m/z) 350 [M + Na]+; IR (CHCl3)
νmax 1713, 1675 cm−1.
(Z)-3-(Hex-1-en-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione (3b):
1
yellow solid (17 mg, 63%); mp 81−83 °C; H NMR (CDCl3, 200
MHz) δ 0.97 (t, J = 8 Hz, 3H), 1.25−1.75 (m, 4H), 2.40 (s, 3H), 2.40
(t, J = 8 Hz, 2H), 6.30−6.50 (m, 2H), 6.57 (s, 1H), 7.17−7.35 (m,
4H); 1H NMR (benzene-d6, 400 MHz) δ 0.80 (t, J = 8 Hz, 3H), 1.05−
1.20 (m, 4H), 1.80−1.90 (m, 2H), 2.05 (s, 3H), 5.82 (dt, J = 12 and 8
Hz, 1H), 6.08 (s, 1H), 6.36 (d, J = 12 Hz, 1H), 6.98 (d, J = 8 Hz, 2H),
7.36 (d, J = 8 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 13.8, 21.1, 22.5,
30.5, 30.9, 115.5, 123.9, 125.9, 128.8, 129.7, 137.7, 140.7, 147.5, 170.4,
170.5; 13C NMR (benzene-d6, 125 MHz) δ 14.0, 20.9, 22.5, 30.4, 31.0,
115.9, 124.1, 125.9, 129.6, 130.0, 137.1, 140.3, 146.4, 169.8, 170.3;
ESIMS (m/z) 292 [M + Na]+; HRMS (ESI) calcd for C17H20NO2 [M
+ H]+ 270.1494, found 270.1507; IR (CHCl3) νmax 1777, 1714, 1620
cm−1.
3-Hexadecyl-1-(p-tolyl)-1H-pyrrole-2,5-dione (4f): yellow
1
solid (31 mg, 75%); mp 66−67 °C; H NMR (CDCl3, 200 MHz) δ
(Z)-3-(Dec-1-en-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione (3d):
1
0.87 (t, J = 8 Hz, 3H), 1.25 (br s, 26H), 1.63 (quintet, J = 8 Hz, 2H),
2.36 (s, 3H), 2.49 (dt, J = 8 and 2 Hz, 2H), 6.39 (t, J = 2 Hz, 1H),
7.15−7.30 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.1, 21.1, 22.7,
25.5, 27.1, 29.3, 29.4, 29.5, 29.7 (8 carbons), 31.9, 125.9, 126.3, 128.9,
129.7, 137.7, 150.3, 170.0, 170.5; ESIMS (m/z) 444 [M + H
+MeOH]+; HRMS (ESI) calcd for C27H42NO2 [M + H]+ 412.3216,
found 412.3213; IR (CHCl3) νmax 1713, 1635 cm−1.
yellow solid (20 mg, 61%); mp 77−78 °C; H NMR (CDCl3, 200
MHz) δ 0.82 (t, J = 8 Hz, 3H), 1.21 (br s, 10H), 1.40−1.60 (m, 2H),
2.20−2.40 (m, 2H), 2.31 (s, 3H), 6.20−6.40 (m, 2H), 6.48 (s, 1H),
7.10−7.25 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 14.1, 21.1, 22.6,
28.8, 29.2, 29.36, 29.42, 30.9, 31.8, 115.5, 124.0, 125.9, 128.8, 129.7,
137.8, 140.8, 147.6, 170.49, 170.54; ESIMS (m/z) 380 [M + Na +
MeOH]+; HRMS (ESI) calcd for C21H28NO2 [M + H]+ 326.2120,
found 326.2121; IR (CHCl3) νmax 1709, 1621 cm−1.
1-(p-Tolyl)-3-(4,8,12-trimethyltridecyl)-1H-pyrrole-2,5-dione
1
(4h, Diastereomeric Mixture): thick oil (290 mg, 70%); H NMR
(Z)-3-(Hexadec-1-en-1-yl)-1-(p-tolyl)-1H-pyrrole-2,5-dione
1
(CDCl3, 200 MHz) δ 0.80−0.93 (m, 12H), 0.95−1.75 (m, 19H), 2.36
(s, 3H), 2.48 (dt, J = 8 and 2 Hz, 2H), 6.40 (t, J = 2 Hz, 1H), 7.15−
7.30 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 19.5, 19.55, 19.64, 19.7,
21.1, 22.6, 22.7, 24.4, 24.7, 24.8, 25.8, 28.0, 32.5, 32.8, 36.55, 36.64,
37.2, 37.4, 39.3, 125.9, 126.3, 128.9, 129.7, 137.6, 150.3, 169.9, 170.6;
ESIMS (m/z) 434 [M + Na]+; HRMS (ESI) calcd for C27H42NO2 [M
+ H]+ 412.3216, found 412.3216; IR (CHCl3) νmax 1710, 1635 cm−1.
3-Hexyl-1-(p-tolyl)pyrrolidine-2,5-dione (5b). Method A.
To a solution of alkynylmaleimide 2b (27 mg, 0.10 mmol) in ethyl
acetate (2 mL) was added palladium on activated charcoal (5 mg, 10
wt %). The reaction mixture was stirred at 25 °C under balloon
pressure hydrogen atmosphere for 1 h. The reaction mixture was
filtered through Celite, and the residue was washed with ethyl acetate
(20 mL). The resulting solution was concentrated in vacuo, and the
obtained residue was purified by silica gel flash column chromatog-
raphy using petroleum ether−ethyl acetate (85:15) as an eluent to
yield 5b50 as a white solid (21 mg, 78% yield).
Method B. To a solution of alkynylmaleimide 2b (27 mg, 0.10
mmol) in methanol (2 mL) was added Lindlar catalyst (10 mg, 5 wt
%). The reaction mixture was stirred at 25 °C under balloon pressure
hydrogen atmosphere for 5 h. The reaction mixture was filtered
through Celite, and the residue was washed with ethyl acetate (20
mL). The resulting solution was concentrated in vacuo and the
obtained residue was purified by silica gel flash column chromatog-
raphy using petroleum ether−ethyl acetate (85:15) as an eluent to
yield 5b as a white solid (20 mg, 74% yield): mp 74−76 °C; 1H NMR
(CDCl3, 200 MHz) δ 0.90 (t, J = 6 Hz, 3H), 1.20−1.55 (m, 8H),
1.55−1.75 (m, 1H), 1.90−2.10 (m, 1H), 2.39 (s, 3H), 2.45−2.72 (m,
1H), 2.87−3.10 (m, 2H), 7.16 (d, J = 8 Hz, 2H), 7.28 (d, J = 8 Hz,
2H); 13C NMR (CDCl3, 50 MHz) δ 14.0, 21.1, 22.5, 26.5, 28.9, 31.4,
31.5, 34.4, 39.9, 126.2, 129.2, 129.7, 138.5, 175.8, 179.1; ESIMS (m/z)
296 [M + Na]+; IR (CHCl3) νmax 1705 cm−1.
(3f): yellow solid (27 mg, 65%); mp 76−77 °C; H NMR (CDCl3,
200 MHz) δ 0.88 (t, J = 6 Hz, 3H), 1.26 (br s, 22H), 1.45−1.65 (m,
2H), 2.30−2.45 (m, 2H), 2.38 (s, 3H), 6.27−6.45 (m, 2H), 6.55 (s,
1H), 7.17−7.32 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 21.1,
22.7, 28.8, 29.3, 29.4, 29.5, 29.6, 29.7 (5 carbons), 30.9, 31.9, 115.5,
124.0, 125.9, 128.8, 129.7, 137.8, 140.8, 147.6, 170.5, 170.6; ESIMS
(m/z) 464 [M + Na + MeOH]+; HRMS (ESI) calcd for C27H40NO2
[M + H]+ 410.3059, found 410.3052; IR (CHCl3) νmax 1712, 1625
cm−1.
(Z)-1-(p-Tolyl)-3-(4,8,12-trimethyltridec-1-en-1-yl)-1H-pyr-
role-2,5-dione (3h, diastereomeric mixture): thick oil (27 mg,
1
66%); H NMR (CDCl3, 400 MHz) δ 0.75−1.45 (m, 24H), 1.45−
1.60 (m, 1H), 1.65−1.75 (m, 1H), 2.15−2.30 (m, 1H), 2.30−2.40 (m,
2H), 2.38 (s, 3H), 6.35−6.48 (m, 2H), 6.57 (s, 1H), 7.20−7.30 (m,
4H); 13C NMR (CDCl3, 50 MHz) δ 14.1, 19.6, 19.7, 19.8, 21.1, 22.6,
22.7, 24.5, 24.8, 28.0, 29.4, 29.7, 31.9, 32.7, 33.3, 37.2, 37.4, 38.2, 38.3,
39.3, 116.1, 124.0, 125.9, 128.9, 129.7, 137.8, 140.8, 146.6, 170.5,
170.6; ESIMS (m/z) 464 [M + Na + MeOH]+; HRMS (ESI) calcd for
C27H40NO2 [M + H]+ 410.3059, found 410.3061; IR (CHCl3) νmax
1712, 1604 cm−1.
General Procedure for Hydrogenation of Alkynylmalei-
mides (2b,d,f,h) to Alkylmaleimides (4b,d,f,h). Method A. To
a solution of alkynylmaleimide 2 (0.10 mmol) in methanol (2 mL)
were added quinoline (19.4 mg, 0.15 mmol) and palladium on
activated charcoal (5 mg, 10 wt %). The reaction mixture was then
stirred at 25 °C under balloon pressure hydrogen atmosphere for 1.5
h. The reaction mixture was filtered through Celite, and the residue
was washed with ethyl acetate (20 mL). The resulting solution was
concentrated in vacuo, and the obtained residue was purified by silica
gel flash column chromatography using petroleum ether−ethyl acetate
as an eluent to yield the desired monoalkyl-substituted maleimide 4.
Method B. To a solution of alkynylmaleimide 2 (0.10 mmol) in
methanol (2 mL) plus acetone (2 mL) were added quinoline (13 mg,
0.10 mmol) and Lindlar catalyst (10 mg, 5 wt %). The reaction
mixture was then stirred at 25 °C under balloon pressure hydrogen
atmosphere for 6 h. The reaction mixture was filtered through Celite,
3-(4,8,12-Trimethyltridecyl)furan-2,5-dione (6, Diastereo-
meric Mixture). To a stirred solution of monoalkylmaleimide 4h
(1.20 g, 2.92 mmol) in THF (6 mL) was added 5% aq LiOH (3 mL)
solution in a dropwise manner. The reaction mixture was stirred at 25
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The Journal of Organic Chemistry
Note
°C for 48 h. The reaction mixture was acidified with 10% aq HCl (3
mL) and extracted with ethyl acetate (10 mL × 3). The combined
organic layer was washed with brine, dried over Na2SO4, and
concentrated in vacuo. The obtained residue without any further
purification was heated at 100 °C in acetic anhydride (10 mL) for 5 h.
The acetic anhydride was distilled off in vacuo, and the obtained
residue was purified by silica gel column chromatography using
petroleum ether−ethyl acetate (9:1) as an eluent to yield the desired
(2) Schobert, R.; Jagusch, C. J. Org. Chem. 2005, 70, 6129.
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references cited therein.
́
1
anhydride 6 as thick liquid (580 mg, 62% yield): H NMR (CDCl3,
200 MHz) δ 0.80−0.93 (m, 12H), 1.00−1.80 (m, 19H), 2.51 (dt, J = 8
and 2 Hz, 2H), 6.60 (t, J = 2 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ
19.4, 19.5, 19.6, 19.7, 22.6, 22.7, 24.4, 24.5, 24.8, 26.2, 28.0, 32.5, 32.7,
36.4, 36.5, 37.1, 37.15, 37.24, 37.29, 37.33, 39.3, 128.4, 153.8, 164.0,
165.9; ESIMS (m/z) 377 [M + Na + MeOH]+; HRMS (ESI) calcd for
C20H35O3 [M + H]+ 323.2586, found 323.2585; IR (CHCl3) νmax
1842, 1777, 1707, 1642 cm−1.
4-(4,8,12-Trimethyltridecyl)furan-2(5H)-one (Luffarin X, 7,
Diastereomeric Mixture). To a stirred solution of alkylmaleic
anhydride 6 (50 mg, 0.15 mmol) in dry THF (3 mL) at 0 °C was
added NaBH4 (6.84 mg, 0.18 mmol) in three equal portions over a
period of 10 min. The reaction mixture was allowed to reach room
temperature (25 °C) and further stirred for 2 h. It was then quenched
with dilute HCl (2 N, 3 mL) and extracted with ethyl acetate (5 mL ×
3). The combined organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The obtained residue was purified
by silica gel column chromatography using petroleum ether−ethyl
acetate (9:1) as an eluent to yield the desired product 746 as a thick oil
(13) Patel, R. M.; Puranik, V. G.; Argade, N. P. Org. Biomol. Chem.
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72, 1009.
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́
(19) Miles, W. H.; Yan, M. Tetrahedron Lett. 2010, 51, 1710 and
references cited therein.
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6923 and references cited therein.
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1
(41 mg, 86% yield): H NMR (CDCl3, 200 MHz) δ 0.80−0.95 (m,
12H), 1.00−1.75 (m, 19H), 2.40 (t, J = 8 Hz, 2H), 4.75 (d, J = 2 Hz,
2H), 5.85 (t, J = 2 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 19.4, 19.5,
19.6, 19.7, 22.6, 22.7, 24.4, 24.7, 27.9, 28.8, 32.5, 32.7, 36.5, 36.6, 37.1,
37.16, 37.19, 37.25, 37.29, 39.3, 73.0, 115.3, 170.6, 174.1; ESIMS (m/
z) 331 [M + Na]+; IR (CHCl3) νmax 1782, 1751, 1640 cm−1.
5-Hydroxy-4-(4,8,12-trimethyltridecyl)furan-2(5H)-one (Ca-
cospongionolide C, 8, Diastereomeric Mixture). To a stirred
solution of alkylmaleic anhydride 6 (50 mg, 0.15 mmol) in dry THF
(3 mL) at −20 °C was added DIBAL-H or N-Selectride (1 M in THF,
0.18 mL, 0.18 mmol) in a dropwise manner over 10 min. The reaction
mixture was stirred at −20 °C for 1 h and then at 25 °C for 1 h. It was
then quenched with water (3 mL) and extracted with ethyl acetate (5
mL × 3). The combined organic layer was washed with brine, dried
over Na2SO4, and concentrated in vacuo. The obtained residue was
purified by silica gel column chromatography using petroleum ether−
ethyl acetate (8:2) to give desired product 847 as a thick oil (37 mg,
16, 4467.
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references cited therein.
1
74%): H NMR (CDCl3, 200 MHz) δ 0.80−0.93 (m, 12H), 0.95−
1.75 (m, 19H), 2.20−2.60 (m, 2H), 5.39 (br s, 1H), 5.83 (s, 1H), 6.02
(s, 1H); 13C NMR (CDCl3, 50 MHz) δ 19.44, 19.50, 19.53, 19.6, 19.7,
22.6, 22.7, 24.2, 24.4, 24.8, 27.9, 28.0, 32.5, 32.8, 36.6, 36.7, 37.3, 37.4,
39.3, 99.2, 117.2, 170.4, 172.0; ESIMS (m/z) 347 [M + Na]+; IR
(CHCl3) νmax 3363, 1759, 1747, 1652 cm−1.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, 13C NMR, and DEPT spectra of compounds 2a−r,
3b,d,f,h, 4b,d,f,h, 5b, and 6−8 and NOE of 3b. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: np.argade@ncl.res.in
■
ACKNOWLEDGMENTS
■
(40) Kshirsagar, U. A.; Puranik, V. G.; Argade, N. P. J. Org. Chem.
2010, 75, 2702 and references cited therein.
(41) Sahoo, M. K.; Mhaske, S. B.; Argade, N. P. Synthesis 2003, 346
and references cited therein.
P.S.D. thanks CSIR, New Delhi, for the award of a research
fellowship. N.P.A. thanks the Department of Science and
Technology, New Delhi, for financial support.
(42) Braun, M.; Hohmann, A.; Rahematpura, J.; Buhne, C.; Grimme,
̈
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