Lewis Acid Mediated Addition of Indoles and Alcohols to Tetronic Acid and Tetramic Acids

Article abstract of DOI:10.1055/s-0036-1588335

The electrophilic substitution of indoles with tetronic acid and N-acetyltetramic acid mediated by BF₃·OEt₂ was investigated. This strategy allowed for the preparation of nine indole-substituted furan-2-ones (indolyl-γ-lactones) and 3-pyrrolin-2-ones (indolyl-γ-lactams) and is more straightforward than previously reported synthetic methods. During the course of our investigation, we also discovered a facile synthesis of tetronates and a tetramate via a BF₃-mediated addition of alcohols to tetronic acid and N-acetyltetramic acid, respectively.

Full text of DOI:10.1055/s-0036-1588335

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
F. Banales Mejia et al.
Letter
Synlett
Lewis Acid Mediated Addition of Indoles and Alcohols to Tetronic
Acid and Tetramic Acids
R1
N
Fernando Banales Mejia
Megan M. Lafferty
Sophia J. Melvin
R1
N
HO
BF3•Et2O, 3 Å MS
CH2Cl2 or DCE or PhCl
R2
Nathanyal J. Truax
Maeve H. Kean
+
O
9 examples
(14–90% yield)
X
O
R2
X
H
X = O or NAc
Erin T. Pelkey*
R1 = H, Me
2 = H, 2-Me, 5-Br, 5-OMe
Department of Chemistry, Hobart and William Smith Colleges,
Geneva, NY, 14456, USA
R
pelkey@hws.edu
Received: 09.08.2016
Accepted after revision: 22.09.2016
Published online: 12.10.2016
Much less attention has been given to the correspond-
ing monocarbonyl γ-lactams (e.g., 3a)6 and γ-lactones (e.g.,
4a).7 To our knowledge, there is just one reported synthesis
of 3a. Prudhomme and co-workers studied the reduction of
1 with various reducing agents.6 Lactam 3a was the major
product when 1 was treated with LiAlH4. Baron and co-
workers reported the synthesis of furanone 4a via the
Dieckmann condensation of 3-acylindole 5.7 Given the lack
of synthetic methods, it is not surprising that neither the
biological activity nor the cycloaddition chemistry of 3 or 4
has ever been reported.
DOI: 10.1055/s-0036-1588335; Art ID: st-2016-r0520-l
Abstract The electrophilic substitution of indoles with tetronic acid
and N-acetyltetramic acid mediated by BF3·OEt2 was investigated. This
strategy allowed for the preparation of nine indole-substituted furan-2-
ones (indolyl-γ-lactones) and 3-pyrrolin-2-ones (indolyl-γ-lactams) and
is more straightforward than previously reported synthetic methods.
During the course of our investigation, we also discovered a facile syn-
thesis of tetronates and a tetramate via a BF3-mediated addition of al-
cohols to tetronic acid and N-acetyltetramic acid, respectively.
In continuation of our work aimed at the synthesis of
aryl-substituted 3-pyrrolin-2-ones8 and aryl-fused 3-pyr-
rolin-2-ones,9 we became interested in developing a new
approach to 3 and 4. We hypothesized that these materials
could be obtained directly by treating the corresponding te-
tramic acids and tetronic acids with indole nucleophiles in
the presence of a Lewis acid (Scheme 1). Lobo and Prabha-
kar and co-workers reported a single example of an indole
substitution reaction involving a tetramic acid and 2,2′-bi-
indole, which was mediated by BF3·OEt2.10–12 This transfor-
mation proceeds via a Lewis acid mediated addition–elimi-
nation of the hydroxy moiety of the tetramic acid with the
indole nucleophile.13 The use of tetramic acids and tetronic
acids as electrophiles would also further build on the work
of others who have investigated the electrophilic substitu-
tion of other 1,3-dicarbonyl electrophiles with indoles in
the presence of transition metals,14 Lewis acids,15 and Brøn-
sted acids.16
Key words lactams, lactones, indoles, heterocycles, cycloadditions
Indolylmaleimides (parent = 1)1,2 and indolylmaleic an-
hydrides (parent = 2)2 are heterocyclic molecules that have
interesting physical properties, reactivity, and utility in the
preparation of polycyclic heterocycles (Figure 1). Indolyl-
maleimides have been used as a structural platform to
study chemiluminescence and fluorescence.3 A bromo-sub-
stituted indolylmaleimide demonstrated antibacterial ac-
tivity,4 while chloro-substituted indolylmaleimides showed
anticancer activity.5 The Diels–Alder reactivity of 1 and 2
and substituted variants have been exploited in the prepa-
ration of a variety of biologically active heterocycles.1,2
well studied
few reports
H
N
H
N
We started this work by systematically studying the
BF3-mediated arylation of commercially available tetronic
acid (7) and N-methylindole (8b). We charged a 20 mL vial
fitted with a Teflon cap with a stir bar, 7, 8b, and a solvent.
BF3·OEt2 was then added, and the reaction mixtures were
either stirred at room temperature or heated at the speci-
fied temperatures as noted (Table 1). We estimated the rela-
O
O
O
X
X
1 X = NH indolylmaleimide
indolylmaleic anhydride
3a X = NH indolyl-γ-lactam
4a X = O
indolyl-γ-lactone
2 X = O
Figure 1 Structures of indolyl-substituted heterocycles
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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F. Banales Mejia et al.
Letter
Synlett
times. We briefly investigated the effect of leaving out the
molecular sieves (Table 1, entry 6), and we found a slight
erosion of the yield. This result surprised us as earlier ex-
periments in a related system suggested that molecular
sieves were necessary for an efficient reaction.11
previous methods
H
N
O
O
this work
N
H
We next explored the scope of the reaction using differ-
ent indole nucleophiles and using both tetronic acid (7) and
known N-acetyltetramic acid (6)19 as electrophiles (Scheme
2). To help with systematic comparisons, we chose to use
three different reaction conditions: (A) CH2Cl2, 40 °C, 4 h;
(B) DCE, 65 °C, time as noted; (C) PhCl, 65 °C, 30 min. With
tetronic acid (7) as the electrophile, good yields (>65% yield)
were obtained with N-methylindole (8b), 2-methylindole
(8e), and 5-bromoindole (8c). Lower yields were obtained
with indole (8a) and 5-methoxyindole (8d). We observed
that the choice of reaction conditions made a significant
difference in the yields with the latter two indole sub-
strates; DCE at 65 °C often proved to be better than CH2Cl2
at 40 °C.
1
H
N
H
N
LiAlH4
HO
ref. 6
Lewis acid
O
O
NaOMe
with 6 then
K2CO3, MeOH
X
X
ref. 7
3a X = NH
4a X = O
6 X = NAc
7 X = O
H
N
O
O
O
CO2Et
5
Scheme 1 Synthetic approaches to indolyl-substituted heterocycles
Table 1 Screen of Reaction Conditions
tive conversion of each reaction by analysis of the relative
integrations of the methylene protons in the crude 1H NMR
spectra (δ = 4.65 ppm for 7 vs. δ = 5.34 ppm for 4b in
DMSO-d6). In selected cases, we repeated the reaction con-
ditions two to four times and purified the reaction mix-
tures by flash chromatography to determine the isolated
yields.
Me
N
Me
N
BF3•OEt2
conditions
3 Å MS
HO
+
O
O
O
O
7
8b
4b
The indolylation reaction worked well and was amena-
ble to improvement (Table 1). Running the reaction in
CH2Cl2 for 30 minutes at room temperature led to a 42% rel-
ative conversion of starting material to product (Table 1, en-
try 1). The isolated yield using these reaction conditions
proved to be 38%, which indicates that the relative conver-
sion we determined using 1H NMR analysis of the crude
mixture is a good predictor of the efficacy of the reaction.
Running the reaction for longer periods of time (Table 1, en-
try 2) or at 40 °C (Table 1, entry 3) improved the relative
conversion to 84% and 73%, respectively. Running the reac-
tion at 40 °C for four hours (Table 1, entry 5) elevated the
relative conversion to 100%; these conditions then gave an
isolated yield of 77% (average of four runs).17,18 Running the
reaction in other chlorinated solvents at 65 °C, 1,2-dichlo-
roethane (DCE) and chlorobenzene (PhCl), also allowed for
full conversion (Table 1, entries 8 and 14). Isolated yields in
DCE and PhCl conditions were 90% and 87%, respectively. A
longer reaction time in PhCl led to a slight erosion in the
isolated yield (Table 1, entry 15). Non-chlorinated solvents,
tetrahydrofuran (THF) and toluene (PhMe), gave incomplete
conversions over the same range of temperatures and
Entry
Solvent
Temp (°C) Time (h) Conv. (%)a Isolated yield (%)b
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
r.t.
r.t.
40
40
40
40
40
65
40
40
65
40
65
65
65
0.5
4
42
84
73
86
100
–
38
–
3
0.5
2
–
4
–
5
4
77
71
–
6c
7
4
0.5
0.5
0.5
2
82
100
22
20
39
57
88
100
–
8
DCE
90
–
9
THF
10
11
12
13
14
15
THF
–
THF
0.5
0.5
0.5
0.5
2
–
PhMe
PhMe
PhCl
–
–
87
80
PhCl
a Determined by 1H NMR analysis of 4b/7 ratio (average of 2+ runs).
b 1.0 mmol scale (average of 2+ runs).
c No molecular sieves added.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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F. Banales Mejia et al.
Letter
Synlett
BF3•OEt2, 3 Å MS
CH2Cl2, 40 °C, 4 h
A conditions:
B conditions:
C conditions:
R1
N
BF3•OEt2, 3 Å MS
DCE, 65 °C, time as noted
a R1 = H; R2 = H
R1
N
b R1 = Me; R2 = H
c R1 = H; R2 = 5-Br
d R1 = H; R2 = 5-OMe
e R1 = H; R2 = 2-Me
HO
BF3•OEt2, 3 Å MS
PhCl, 65 °C, 30 min
R2
+
O
O
R2
X
X
8
7 X = O
4 X = O
6 X = NAc
9 X = NAc
Me
N
H
H
N
H
H
N
N
N
Me
Br
MeO
O
O
O
O
O
O
O
O
O
O
4a
4c
4e
4b
4d
(A: 18%)
(B, 0.5 h: 68%)
(C: 49%)
(A: 70%)
(A: 77%)
(A: 10%)
(B, 1 h: 38%)
(B, 0.5 h: 66%)
(C: 66%)
(B, 0.5 h: 90%)
(C: 87%)
(B, 0.5 h: 50%)
Me
N
H
N
H
H
N
H
N
N
Me
Br
Br
O
O
N
O
N
O
N
O
N
N
Ac
Ac
Ac
Ac
Ac
9a
9b
9c
9d
(A: 23%)
9e
(A: 12%)
(A: 66%)
(A: mixture)
(B, 1 h: mixture)
(A: 76%)
(B, 1 h: 14%)
(B, 1.5 h: 63%)
(B, 2 h: 63%)
Scheme 2 Reaction scope for Lewis acid mediated indole-substitution of tetronic acid (7) and tetramic acid (6)
Moving on to tetramic acid 6 as the electrophile, the re-
actions leading to 3-pyrrolin-2-ones 9 tended to be lower
yielding than the corresponding reactions with tetronic
acid (7) leading to furan-2-ones 4. For example, the yield
was 66% for the preparation of 9b compared to 77% for 4b
under the identical conditions (CH2Cl2, 40 °C, 4 h). Poten-
tially, the lower yields can be explained by the lower elec-
trophilicity of 6 and/or by the fact that the acetyl group has
the potential to partially fall off during the reaction. Analy-
sis of crude reaction mixtures did reveal that small
amounts of deprotected products 3 were being formed
(methylene protons δ = 4.5 ppm). Using 6 and indole (8a),
the highest yield obtained was just 14%. The reaction of 6
with 5-bromoindole (8c) led to an inseparable mixture of
materials that we believe to be indole substitution regioiso-
mers. Further regarding the reactions between 6 and 8c, we
consistently observed and were able to isolate a relatively
nonpolar byproduct. We will return to this result later in
the discussion.
ed 3-pyrrolin-2-ones 3 in moderate yields (53–56%). We did
not attempt to improve upon the reaction.
As mentioned earlier in the case of the reaction be-
tween 6 and 8c, we observed the formation of a nonpolar
byproduct. We determined that the byproduct was the
known methyl tetramate, N-acetyl-4-methoxy-3-pyrrolin-
2-one (10).20 This material was obtained in about ca. 10%
yield in this case21 and arose from the BF3-mediated addi-
tion of methanol to tetramic acid; methanol was intro-
duced to the reaction mixture as part of the workup. This
result struck us as having potential for providing a mild and
direct approach to alkyl tetronates and alkyl tetramates
from the corresponding tetronic acids and tetramic acids.
R1
N
R1
N
K2CO3
CH2Cl2/MeOH
R2
R2
O
O
N
We next pursued the synthesis of the N-unsubstituted
3-pyrrolin-ones 3 starting from the N-acetyl-3-pyrrolin-2-
ones 9 (Scheme 3). Treatment of 9 with K2CO3 in 1:1
CH2Cl2–MeOH smoothly gave the corresponding deprotect-
N
H
Ac
3a (54%)
3b (56%)
3e (53%)
9
Scheme 3 Deprotection of N-acetyltetramic acids
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
F. Banales Mejia et al.
Letter
Synlett
Table 2 Synthesis of Tetronates 10 and Tetramate 11
RO
HO
ROH, BF3•OEt2, 3 Å MS
O
O
X
X
6 X = NAc
7 X = O
10 X = NAc
11 X = O
Entry
Starting material
Solvent
Temp (°C)
Time (h)
R
Product
Yield (%)a
1
2
3
4
5
6
7
6
7
7
7
7
7
7b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCl
40
40
4
4
4
4
4
2
2
Me
Me
i-Pr
Bn
10
35
50
69
54
0
11a
11b
11c
11d
11d
11d
40
40
40
4-MeOC6H4
100
100
4-MeOC6H4
4-MeOC6H4
4
PhCl
17
a Isolated yield.
b Used 3.0 equiv of BF3·OEt2.
Examination of the literature revealed three common
methods for preparing alkyl tetramates from tetramic ac-
ids: treatment with diazomethane (to methyl tetronates);22
treatment with base followed by alkyl halides;23 and via the
Mitsunobu reaction.24 Similarly, there are three general
methods for preparing alkyl tetronates from tetronic acids:
treatment with diazomethane;25 treatment with base fol-
lowed by alkyl halides;26 and via the Mitsunobu reaction.27
There also is a report by Zimmer and co-workers of the use
of a Brønsted acid (H2SO4) to promote the condensation of
acids with tetronic acid (7).28 In their report, isopropyl alco-
hol gave the best yield (65%) of the corresponding tetronate
and benzyl alcohol gave the lowest yield (11%).
In conclusion, we have demonstrated a one-step trans-
formation of tetronic acids and tetramic acids into indolyl-
substituted furan-2-ones and 3-pyrrolin-2-ones, respec-
tively. During the course of our work, we also discovered a
facile transformation of tetronic acids and tetramic acids
into alkyl tetronates and alkyl tetramates. These two types
of reactions make use of a BF3-mediated substitution of the
latent ketone functionality of tetronic and tetramic acids by
indole and alcohol nucleophiles, respectively. This work
provides direct access to indolyl-γ-lactones, and indolyl-γ-
lactams, alkyl tetronates, and alkyl tetramates from readily
available starting materials, tetronic acids and tetramic ac-
ids.
We briefly investigated the use of BF3·OEt2 in the trans-
formation of tetramic acid (6) and tetronic acid (7) into al-
kyl tetramates and alkyl tetronates (Table 2). We chose to
run the reactions in CH2Cl2 at 40 °C for four hours. With te-
tramic acid (6) and methanol, we obtained a 35% yield of 10
(Table 2, entry 1). Higher yields of alkyl tetronates were ob-
tained with tetronic acid (7) and methanol (50%, Table 2,
entry 2), isopropanol (69%, Table 2, entry 3), and benzyl al-
cohol (54%, Table 2, entry 4). The result with benzyl alcohol
is a significant improvement over the literature yield with
H2SO4. On the other hand, the reaction failed with p-me-
thoxyphenol as the nucleophile under the standard reac-
tion conditions (CH2Cl2, 40 °C). When we ran the reaction in
PhCl at 100 °C, we did manage to obtain a 4% yield of the
desired aryl tetronate 11d (Table 2, entry 6). It is notable
that the preparation of 11d would not be possible using
standard alkylation or Mitsunobu conditions. Finally, the
yield of 11d was improved to 17% when the number of
equivalents of BF3·OEt2 was increased from 1.5 to 3.0 (Table
2, entry 7).
Acknowledgment
Financial support of this research from the NSF (RUI: 1362813), Ho-
bart and William Smith Colleges, Drs. Carey and Cohen (to MHK),
Dave and Brenda Rickey (to SJM), Dr. Edward Franks, and the Patchett
Family is gratefully acknowledged. We thank a referee bringing our
attention to additional references 14–16 involving 1,3-dicarbonyl
substrates.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588335.
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F. Banales Mejia et al.
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Synlett
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A reaction vial fitted with a septa-bonded cap was charged with
a stir bar, indole 8 (1.00 mmol or 1.20 mmol), tetronic acid (7,
1.00 mmol) or tetramic acid (6, 1.00 mmol), and anhydrous
solvent (10 mL) as noted. Neat BF3·OEt2 (185 μL, 1.50 mmol) was
added through the septum via syringe. The reaction vial was
heated to the specified temperature for the specified time and
then allowed to cool to r.t. MeOH (1 mL) was added to the reac-
tion mixture, and the solvent was removed in vacuo. The crude
materials obtained were purified by flash chromatography
(EtOAc–PE).
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.
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H), 5.34 (d, J = 1.6 Hz, 2 H), 3.86 (s, 3 H) ppm. 13C NMR (100
MHz, CDCl3): δ = 175.6, 158.7, 138.0, 130.2, 126.0, 123.8, 122.4,
120.5, 110.6, 107.5, 107.2, 71.5, 33.8. HMRS (ESI-FTICR): m/z
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