Scandium triflate-catalyzed nucleophilic additions to indolylmethyl Meldrum's acid derivatives via a gramine-type fragmentation: Synthesis of substituted indolemethanes

Article abstract of DOI:10.1021/jo4017524

Treatment of indolylmethyl Meldrum's acids with catalytic scandium triflate and a variety of nucleophiles results in the nucleophilic displacement of the Meldrum's acid moiety via a gramine-type fragmentation. The reaction is useful for the generation of

Full text of DOI:10.1021/jo4017524

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Note
Scandium Triflate Catalyzed Nucleophilic Additions to
Indolylmethyl Meldrum’s Acid Derivatives via a Gramine-
type Fragmentation: Synthesis of Subsituted Indolemethanes.
Erin L. Armstrong, Huck K. Grover, and Michael Andre Kerr
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4017524 • Publication Date (Web): 25 Sep 2013
Downloaded from http://pubs.acs.org on September 26, 2013
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Scandium Triflate Catalyzed Nucleophilic Additions to Indolylmethyl Meldrum’s Acid Derivatives via a
Gramine-type Fragmentation: Synthesis of Subsituted Indolemethanes
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Erin L. Armstrong, Huck K. Grover, and Michael A. Kerr*
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Department of Chemistry, The University of Western Ontario, London, Ontario, Canada, N6A 5B7
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*makerr@uwo.ca
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RECEIVED DATE (will be automatically inserted after manuscript is accepted).
O
O
R
R
Sc(OTf)3 10 mol%
50 oC MeCN
Nu
NuH
O
O
N
H
N
H
Treatment of indolylmethyl Meldrum’s acids with catalytic scandium triflate and a variety of nucleophiles results in the
nucleophilic displacement of the Meldrum’s acid moiety via a gramine-type fragmentation. The reaction is useful for the generation
of heterocyclic compounds of significant molecular complexity.
The indolemethane moiety is abundant in a variety of marine and terrestrial natural products and has been shown to possess
important biological activities such as: antiviral, haemolytic, cytotoxic, insecticidal, antithrombotic, anti-carcinogenic and can also
act as enzymatic inhibitory agents.1 The unique structural frameworks of three different marine isolated indolemethane natural
products are shown in Figure 1.2 Due to the indole skeleton and the large array of biological activities that these molecules exhibit it
is not unexpected that research and development towards the synthesis of indolemethanes and related compounds are of ongoing
interest in the scientific community.3
H
N
NH
NH
NH
O
N
H
N
H
N
H
N
H
1,1,3-tris(3-indolyl)butane
Vibrindole A
Trisindoline
Figure 1: Indolemethane Natural Products
Scheme 1: Use of Meldrum’s Acid as a Leaving Group in Nucleophilic Additions
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Our interest in the synthesis4 and reactivity5 of indole molecules along with their synthetic utility towards alkaloid total synthesis6
was a vital factor in our decision to pursue a project devoted to the synthesis of indolemethanes. Inspired by the innovative work of
the Fillion group7 in the area of Meldrum’s acid chemistry8 it became apparent that we may be able to apply a similar strategy to
indole-substituted Meldrum’s acid molecules 3a in order to access a variety of indolemethane adducts 4 (scheme 1). The Fillion
method employed relatively harsh Lewis acids (Me3Al or AlCl3) which would surely destroy the electron-rich indole.9 Herein we
present a complementary method which provides access to a variety of functionalized indolemethanes.10
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Table 1. Optimization of Indole Addition
O
O
NH
Lewis Acid
O
Solvent
O
N
H
N
H
N
H
3a
5
4a
Entry
Indole
(equiv)
Catalyst
(mole %)
Solvent / Temp.
(o C)
Time
(hr)
Yield
(%)
Catalyst comparison
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2
3
4
1.1
1.1
1.1
1.1
Cu(OTf)2 (20 %)
Zn(NTf2)2 (20 %)
Yb(OTf)3 (20 %)
Sc(OTf)3 (20 %)
CH3CN / rt
CH3CN / rt
CH3CN / rt
CH3CN / rt
48 hr
48 hr
48 hr
48 hr
no rxn
no rxn
41 %a
58 %a
Reaction stoichiometry
5
6
7
8
9
1.5
2
Sc(OTf)3 (20 %)
Sc(OTf)3 (20 %)
Sc(OTf)3 (20 %)
Sc(OTf)3 (10 %)
Sc(OTf)3 (10 %)
CH3CN / rt
CH3CN / rt
CH3CN / rt
CH3CN / rt
CH3CN / rt
48 hr
48 hr
48 hr
48 hr
48 hr
60 %
95 %
quant.
95 %
quant.
3
2
3
Reaction temperature
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14
3
Sc(OTf)3 (10 %)
Sc(OTf)3 (10 %)
Sc(OTf)3 (10 %)
Sc(OTf)3 (10 %)
Sc(OTf)3 (10 %)
CH3CN / 100 oC
CH3CN / 100 oC
CH3CN / 50 oC
CH3CN / 50 oC
CH3CN / 50 oC
1 hr
1 hr
3 hr
3 hr
3 hr
decomp
decomp
quant.
73 %
2
2
1.1
1.5
quant.
Solvent comparison
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16
17
18
19
1.5
1.5
1.5
1.5
1.5
Sc(OTf)3 (10 %)
Sc(OTf)3 (10 %)
Sc(OTf)3 (10 %)
Sc(OTf)3 (10 %)
No catalyst
Benzene / 50 oC
THF / 50 oC
3 hr
3 hr
3 hr
3 hr
3 hr
73 %
79 %
CH2Cl2 / reflux
DMF / 50 oC
CH3CN / 50 oC
quant.
no rxnb
no rxnb
a Incomplete reaction based on recovery of starting material 3a.
b Higher temperatures and indole loadings were examined with no success.
To test our hypothesis 3a was prepared by a literature procedure,11 and subjected to a variety of reaction conditions in the
presence of nucleophilic indole (Table 1). Initial attempts to optimize this transformation were performed in acetonitrile while
varying the catalyst (entry 1-4). To our delight we found both Yb(OTf)3, and Sc(OTf)3 promoted the formation of di-indolemethane
4a in moderate yield, while at the sacrifice of the indole nucleophile due to what was suspected to be Lewis acid catalyzed
oligomerization. While both catalysts allowed for product formation, scandium triflate was ultimately chosen as the desired catalyst.
In order to overcome the decomposition of the indole nucleophile, we next examined the effect of indole stoichiometry and catalyst
loading (entry 5-9). Gratifyingly, we discovered that using 3 equivalents of indole with 10 mol % catalyst (entry 9) led to the
desired product in quantitative yield. It should be noted that lower catalyst loadings (5 mol %) were performed, however reactions
times dramatically increased while yields deceased.
Having achieved significant progress in optimization of this transformation, we then set forth to perform a temperature study in
hopes of lowering both the overall reaction time and the number of equivalents of indole required (entry 10-14). The best reaction
o
conditions were determined to be 1.5 equivalents of indole at 50 C (entry 14). The increase in temperature and lowering of indole
excess allowed for a quantitative product conversion in only 3 hours marking a significant decrease in reaction time with no effect
on overall yield.
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Finally, a selection of solvents was tested in order to identify alternative reaction media in the event of solubility issues in future
applications (entry 15-19). With the use of dichloromethane as the solvent we were pleased to see the reaction proceeded to
completion in quantitative yield, while both benzene and tetrahydrofuran afforded the product in lower yields. Not unexpectedly,
the use of a polar aprotic solvent (DMF) lead to no reaction, a result that could be explained by deactivation of the oxophilic catalyst
through the oxygen of the solvent.12
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9
Scheme 2: Attempted synthesis of mixed indole methanes
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O
O
Sc(OTf)3
10 mol%
NH
NMe
NMe
N
Me
O
MeCN
O
N
H
N
H
N
Me
N
H
6
3a
50 o
rt
C
4b: 38%
4c: 25%
4a: 25%
4b:
4c:
4a:
39%
27%
9%
-10 o C
4b: 12%
4c: trace
4a: trace
With efficient conditions established we then set out to examine the possibility of accessing dissymmetrical di-indolemethanes.
Scheme 2 summarizes our results for the addition of N-methylindole to Meldrum’s acid derivative 3a. Under standard reaction
conditions we were able to isolate the mixed di-indolemethane 4b in a 41 % yield after column chromatography; however both 4c
and 4a were also isolated in smaller quantities. Compound 4c is the result of addition of N-methylindole 6 to 4b with the expulsion
of indole itself (5). The addition of 5 to 3a or 4b produces 4a. To selectively promote the formation of only 4b the reaction
o
o
temperature was lowered from 50 C to rt and again to -10 C. By lowering the temperature we were successfully able to suppress
access to compounds 4a and 4c however at the consequence of unacceptable yields and impractical reaction times.
Scheme 3: Nucleophile Scope
O
O
Nu
Sc(OTf)3 10 mol%
50 oC MeCN
O
NuH
O
N
H
N
H
3a
4a, b, d - h
O2N
NH
NMe
NMe
N
H
N
H
N
H
4d
: 55%
4a
: 100%
4b
: 38%
O
O
S
N
Bn
N
H
N
H
N
H
4f
4g
: 68%
: 98%
4e: 54%
N
H
4h: 95%
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With standard reaction conditions in hand we set out to survey a range of nucleophiles which would efficiently undergo this
transformation. Initial attempts at varying the indole N-position (4b) and the benzenoid portion (4d) of the nucleophile allowed
access to dissymmetric di-indolemethanes in moderate isolated yields, however other cross over products were also isolated
(scheme 3). Interestingly when N-benzyl skatole was subjected to the reaction conditions indolemethane 4e was isolated as the sole
identifiable product (albeit in modest yield). With difficulty achieving high yields of the dissymmetric di-indolemethane, we turned
our attention to the use of alternative nucleophiles for the formation of substituted indolemethane molecules. It was suspected and
ultimately realized that soft nucleophiles would perform best for this transformation. Thiophenol and allyltrimethylsilane lead to a
near quantitative yield of 4f and 4h respectively.The electron rich aromatic ring of 1,3-dimethoxybenzene lead to a moderate yield
of 4g, with a minimal amount of the alternative regioisomer. A variety of other nucleophiles where attempted including alkyl thiols,
styrene, and morpholine, however all lead to quick decomposition of the Meldrum`s acid starting material
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We next set out to explore the role of the electrophile in the reaction. A library of electrophiles was prepared (scheme 4) using a
modification of the Oikawa procedure.9 All Meldrum’s acid derivatives (3a -g) were synthesized in moderate to excellent yields.
Scheme 4: Synthesis of Electrophiles
O
O
R2
O
O
O
O
5 mol % L-Proline
CH3CN
O
R2
H
N
R
O
O
N
R
5
7
8
3a - g
O
Br
MeO2C
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
H
3d: 79%
3a: 87%
3b: 70%
3c: 81%
O
O
O
O
O
O
8
O
O
O
O
O
O
N
Me
N
H
N
H
3e: 83%
3f: 67%
3g: 98%
With a variety of Meldrum’s acid derivatives 3 in hand, we were able to explore the reactivity of these substrates towards indole
(5) (Scheme 5). Interestingly when the R-group in 3 was aryl, the nature of the substitution on the aryl ring did not seem to greatly
affect the product yield. However, it should be noted that p-cyano and p-nitro derivatives failed to produce significant yields of
products. Notably di-indolemethane product formation was achieved readily when non-aromatic substitution was placed on the
Meldrum’s acid derivative, as both ethyl and nonane substituted electrophiles gave the desired product in 73 % (4l) and 79 % (4m)
respectively. Reaction of Meldrum’s acid derivative 3e with N-methyl indole as the nucleophile gave compound 4c in 79% yield.
The reduced yield when compared to 4a is consistent with our previous observations in which the unprotected indole behaved better
as a nucleophile when compared to N-methyl indole.5a
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Scheme 5: Electrophile Substrate Scope
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9
O
O
NH
R
R
Sc(OTf)3 10 mol%
50 oC MeCN
O
O
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N
H
N
H
N
H
3a - g
5
4a, i - m
O
Br
NH
NH
NH
N
H
N
H
N
H
4a: 100%
4i: 86%
4j: 83%
MeO2C
NH
NH
NH
8
N
H
N
H
N
H
4k: 84%
4l: 73%
4m: 79%
NMe
Note: N-methyl indole used as
the nucleophile in reaction with 3e
N
Me
4c
: 79%
A simple proposed mechanism of this transformation is shown in Scheme 6. Coordination of the Lewis acid to the carbonyl
oxygen in 3 allows for the Meldrum’s acid moiety to become a better leaving group in a presumed gramine style fragmentation of 9.
The putative iminium ion 10 is may subsequently undergo reaction with a variety of nucleophiles leading to adduct 4.
Scheme 6: Proposed Mechanism
LA
O
O
O
O
R
R
Lewis acid
O
O
O
O
N
N
H
H
3
9
R
Nu
H
N
Nu
HN
R
10
4
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In conclusion we have developed an expedient and efficient method for the synthesis of indolemethane derivatives. The one pot
gramine-type fragmentation/nucleophilic trapping has been shown to be versatile with a variety of nucleophiles and should be
applicable to the synthesis of a variety of interesting natural and unnatural products.
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Experimental Section
9
General Information. All solvents for routine isolation of products and chromatography were reagent grade. Flash chromatography
was performed using silica gel (230−400 mesh) with indicated solvents. All reactions were monitored by thin-layer chromatography
on 0.25 mm silica plates (60F-254) visualizing with UV light and developed using acidic anisaldehyde. 1H, 19F, and 13C NMR
spectra were recorded either on a 400 MHz or on a 600 MHz NMR spectrometer. Chemical shifts, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of protons. HRMS were measured with
electron impact (EI) ionization and quadrupolar mass analyzer.
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General Experimental Procedure for the Synthesis of Substituted Indolemethanes 4a-m.
To a solution of Meldrum’s acid derivative (3) (1.0 equiv) in anhydrous MeCN was added nucleophile (1.5 equiv). The solution was
stirred under argon for 20 minutes. Scandium triflate (10 mol %) was added and the reaction mixture was stirred at 50° C until
complete (as determined by TLC analysis). The reaction was quenched with sodium bicarbonate and extracted with EtOAc (3
times). The organic layers were then combined and dried with magnesium sulfate. Following filtration, the solvent was removed
under reduced pressure and the crude mixture purified by flash chromatography (EtOAc/hexanes) to yield the desired products 4a-
m.
3,3'-(Phenylmethylene)bis(1H-indole) (4a). Reagents employed: 5-((1H-indol-3-yl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (3a) (0.100 g, 0.286 mmol), indole (0.050 g, 0.430 mmol), scandium triflate (0.014 g, 0.0284 mmol), 5 mL anhydrous MeCN
at 50 °C, for 3 hours: yield 100 % (92 mg) as a pink foam; Rf= 0.30, 30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ = 7.72
(s, 2H), 7.44-7.15 (m, 11H), 7.05 (dt, J= 6.7, 2.6 Hz, 2H), 6.57 (s, 2H), 5.91 (s, 1H); 13C NMR (100 MHz, CDCl3) δ= 143.9,
136.56, 128.6, 128.1, 126.9, 126.1, 123.6, 121.8, 119.8, 119.5, 119.1, 111.0, 40.1; IR (thin film) 3414, 1635, 1492, 1455, 1417,
1336, 1216, 1092, 743, 700, 667, 596; HRMS (EI) calculated for C23H18N2 322.1470, found 322.1461.
3-((1H-Indol-3-yl)(phenyl)methyl)-1-methyl-1H-indole (4b). Reagents employed: 5-((1H-indol-3-yl)(phenyl)methyl)-2,2-dimethyl-
1,3-dioxane-4,6-dione (3a) (0.100 g, 0.286 mmol), N-methyl indole (0.0563 g, 0.429 mmol), scandium triflate (0.014 g, 0.0286
mmol), 10 mL anhydrous MeCN at 50 °C, for 3 hours: yield 38 % (37 mg) as a pink foam; Rf= 0.20, 30% EtOAc in hexanes; 1H
NMR (400 MHz, CDCl3) δ = 7.90 (s, 1H) 7.41-7.34 (m, 5H), 7.30-7.26 (m, 3H), 7.23-7.16 (m, 3H), 7.03-6.98 (m, 2H), 6.67 (s, 1H),
6.51 (s, 1H), 5.89 (s, 1H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ= 144.2, 137.4, 136.6, 128.7, 128.2, 128.1, 127.4, 127.0,
126.1, 123.6, 121.9, 121.4, 120.0, 119.9, 119.8, 119.2, 118.6, 118.1, 110.9, 106.0, 40.11, 32.6; IR (thin film) 3413, 3055, 2928,
1600, 1482, 1455, 1419, 1371, 1329, 1217, 1153, 1091, 1050, 1028, 741, 703; HRMS (EI) calculated for C24H20N2 336.1626 found
336.1627.
3,3'-(Phenylmethylene)bis(1-methyl-1H-indole) (4c). Reagents employed: 5-((1H-indol-3-yl)(phenyl)methyl)-2,2-dimethyl-1,3-
dioxane-4,6-dione (3a) (0.100 g, 0.286 mmol), N-methyl indole (0.0563 g, 0.429 mmol ), scandium triflate (0.014 g, 0.0286 mmol),
10 mL anhydrous MeCN at 50 °C, for 3 hours: yield 25 % (25 mg) as a red foam; Rf= 0.56, 30% EtOAc in hexanes; 1H NMR (400
MHz, CDCl3) δ = 7.40-7.34 (m, 4H), 7.31-7.25 (m, 4H), 7.23-7.19 (m, 3H), 7.02-6.98 (m, 2H), 6.53 (s,2H), 5.89 (s, 1H), 3.69 (s,
6H); 13C NMR (100 MHz, CDCl3) δ = 144.4, 137.4, 128.7, 128.3, 128.2, 127.4, 125.9, 121.4, 120.0, 118.6, 118.2, 109.0, 40.1, 32.7;
IR (thin film) 3446, 3055, 2930, 2360, 2340, 1635, 1549, 1472, 1423, 1370, 1327, 1224, 1153, 1011, 739, 762, 667, 576, 539;
HRMS (EI) calculated for C25H22N2 350.1783 found 350.1784.
3-((1H-Indol-3-yl)(phenyl)methyl)-5-nitro-1H-indole (4d). Reagents employed: 5-((1H-indol-3-yl)(phenyl)methyl)-2,2-dimethyl-
1,3-dioxane-4,6-dione (3a) (0.100 g, 0.286 mmol), 1-methyl-5-nitro-1H-indole (76 mg, 0.430 mmol), scandium triflate (0.014 g,
0.0286 mmol), 5 mL anhydrous MeCN at 50 °C, for 3 hours: yield 55% (60 mg), as an orange foam; Rf= 0.24, 30% EtOAc in
hexanes; 1H NMR (400 MHz, CDCl3) δ= 8.35 (s, 1H), 8.10, (dd, J= 9.5, 2.1 Hz, 1H), 8.03 (s, 1H), 7.39-7.28 (m, 7H), 7.23-7.17 (m,
2H), 7.02 (t, J= 7.3 Hz, 1H), 6.7 (s, 1H), 6.65 (s, 1H), 5.91 (s, 1H), 3.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 143.2, 140.1,
136.7, 131.2, 129.7, 128.5, 128.4, 126.7, 126.6, 126.5, 123.4, 122.1, 121.1, 119.7, 119.4, 118.9, 117.3, 117.2, 111.2, 111.1, 39.9,
33.1; IR (thin film) 3419, 2923, 2361, 1617, 1512, 1485, 1455, 1392, 1331, 1094, 1033, 742, 707; HRMS (EI) calculated for
C24H19N3O2 381.1477 found 381.1478.
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2-((1H-Indol-3-yl)(phenyl)methyl)-1-benzyl-3-methyl-1H-indole (4e). Reagents employed: 5-((1H-indol-3-yl)(phenyl)methyl)-2,2-
dimethyl-1,3-dioxane-4,6-dione (3a) (0.100 g, 0.286 mmol), 1-benzyl-3-methyl-1H-indole (0.095g, 0.4293 mmol ), scandium
triflate (0.014 g, 0.0286 mmol), 5 mL anhydrous MeCN at 50 °C, for 3 hours: yield 54% (66 mg), as a purple foam; Rf= 0.43, 30%
EtOAc in hexanes;1H NMR (400 MHz, CDCl3) δ= 7.86 (s, 1H), 7.62 (dd, J= 7.4, 1.6 Hz, 1H) 7.34 (d, J= 8.1 Hz, 1H), 7.30-7.26 (m,
7H), 7.24-7.15 (m, 6H), 7.05-6.98 (m, 3H), 6.52 (s, 1H), 5.89 (s, 1H), 5.27 (q, J=17.2 Hz, 2H), 1.85 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 141.4, 138.3, 136.6, 136.5, 136.3, 129.1, 128.7,128.6, 128.3, 127.1, 127.0, 126.4, 126.0, 124.0, 122.2, 122.1, 121.4,
119.5, 119.4, 118.8, 118.3, 117.0, 111.0, 109.3, 109.0, 46.8, 40.17; IR (thin film) 3852, 3820, 3743, 3648, 3413, 357, 2999, 2360,
2340, 1733, 1683, 1652, 1558, 1540, 1465, 1456, 1418, 1353, 1070, 1029, 741, 699; HRMS (EI) calculated for C31H26N2 426.2096
found 426.2104.
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3-(Phenyl(phenylthio)methyl)-1H-indole (4f). Reagents employed: 5-((1H-indol-3-yl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-
4,6-dione (3a) (0.100 g, 0.286 mmol), benzenethiol (0.047g, 0.429 mmol), scandium triflate (0.014 g, 0.0286 mmol), 5 mL
anhydrous MeCN at 50 °C, for 3 hours: yield 98% (88 mg), as a yellow foam; Rf= 0.58, 30% EtOAc in hexanes; 1H NMR (400
MHz, CDCl3) δ=7.86 (s, 1H), 7.54 (d, J= 8.2 Hz, 1H), 7.38 (d, J= 8.9 Hz, 2H), 7.23-6.96 (m, 12H), 5.72 (s, 1H); 13C NMR (100
MHz, CDCl3) δ = 141.2, 136.7, 136.6, 130.2, 128.6, 128.4, 127.1, 126.3, 126.2, 123.8, 128.3, 122.3, 119.6, 116.2, 111.2, 49.7
(missing 1 carbon presumably due to overlap); IR (thin film) 3853, 3750, 3675, 3628, 3420, 3056, 2924, 2360, 1716, 1616, 1581,
1479, 1455, 1437, 1417, 1353, 1337, 1223, 1177, 1124, 1089, 1073, 1025, 740, 697, 473; HRMS (EI) calculated for C21H17NS
314.1009 found 314.1009 (M - H).
3-((2,4-Dimethoxyphenyl)(phenyl)methyl)-1H-indole (4g). Reagents employed: 5-((1H-indol-3-yl)(phenyl)methyl)-2,2-dimethyl-
1,3-dioxane-4,6-dione (3a) (0.100 g, 0.286 mmol), 1,3-dimethoxybenzene (0.059 g 0.429 mmol), scandium triflate (0.014 g, 0.0286
mmol), 5 mL anhydrous MeCN at 50 °C, for 3 hours: yield 68% (67 mg), as a pink foam; Rf= 0.63, 30% EtOAc in hexanes; 1H
NMR (400 MHz, CDCl3) δ= 7.89 (s, 1H), 7.34 (d, J= 8.3 Hz, 1H), 7.29-7.15 (m, 6H), 7.00 (dt, J= 7.5, 1.08 Hz, 2H), 6.91 (d, J= 2.4
Hz, 1H), 6.54 (q, J= 1.2 Hz, 1H), 6.51 (d, J= 2.4 Hz, 1H), 6.37 (dd, J= 8.4, 2.8 Hz, 1H), 6.00 (s, 1H), 3.79 (s, 3H), 3.75 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ= 159.2, 157.8, 144.3, 136.7, 130.2, 128.9, 127.9, 127.1, 125.8, 124.9, 123.9, 121.9, 120.1, 120.0, 119.2,
110.9, 103.8, 98.5, 55.6, 55.2, 40.6; IR (thin film) 3418, 2931, 2361, 1771, 1733, 1669, 1652, 1609, 1586, 1558, 1503, 1456, 1436,
1417, 1291, 1258, 1207, 1175, 1156, 1114, 1033, 924, 833, 742, 700; HRMS (EI) calculated for C23H21NO2 343.1572, found
343.1576.
3-(1-Phenylbut-3-en-1-yl)-1H-indole (4h). Reagents employed: 5-((1H-indol-3-yl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (3a) (0.100 g, 0.286 mmol), allyltrimethylsilane (0.049g 0.429 mmol), scandium triflate (0.014 g, 0.0286 mmol), 5 mL
anhydrous MeCN at 50 °C, for 3 hours: yield 95% (67 mg), as a grey foam; Rf= 0.63, 30% EtOAc in hexanes; 1H NMR (400 MHz,
CDCl3) δ= 7.79 (s, 1H), 7.34 (d, J= 8.1 Hz, 1H), 7.23-7.12 (m, 5H), 7.11- 7.03 (m, 2H), 6.93 (dt, J= 8.1, 1.1 Hz, 2H), 5.79-5.66 (m,
1H), 4.98 (dq, J= 10.2, 1.9 Hz, 1H), 4.88 (dq, J= 10.2, 1.1 Hz, 1H), 4.19 (t, J= 7.63, 1H), 2.98-2.88 (m, 1H), 2.81-2.72 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ= 144.7, 137.3, 136.4, 128.2, 127.9, 126.9, 126.0, 121.9, 121.2, 119.6, 119.5, 119.2, 115.9, 110.9, 42.9,
40.5; IR (thin film) 3419, 3058, 3025, 2974, 2924, 2859, 1638, 1600, 1490, 1455, 1417, 1337, 1222, 1096, 1074, 1011, 993, 912,
741, 700, 583, 474; HRMS (EI) calculated for C18H17N 247.1361 found 247.1368.
3,3'-((4-Methoxyphenyl)methylene)bis(1H-indole) (4i). Reagents employed: 5-((1H-indol-3-yl)(4-methoxyphenyl)methyl)-2,2-
dimethyl-1,3-dioxane-4,6-dione (3b) (0.040 g, 0.105 mmol), indole (0.0185 g, 0.158 mmol), scandium triflate (0.005 g, 0.0105
mmol), anhydrous MeCN at 50 °C, for 3 hours: yield 86% (32 mg) as an orange foam; Rf= 0.38, 30% EtOAc in hexanes; 1H NMR
(400 MHz, CDCl3) δ= 7.86 (s, 2H), 7.39 (d, J=9.3 Hz, 2H), 7.34 (d, J= 9.3 Hz, 2H), 7.27-7.24 (m, 2H), 7.17 (t, J= 7.8 Hz, 2H), 7.01
(t, J= 7.4 Hz, 2H), 6.82 (d, J= 8.6 Hz, 2H), 6.64 (s, 2H), 5.85 (s, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ= 157.9, 136.7,
136.2, 129.6, 127.1, 123.5, 121.9, 120.0, 119.9, 119.2, 113.6, 110.0, 55.2, 39.2; IR (thin film) 3411, 2925, 2360, 2340, 1652, 1558,
1507, 1456, 1418, 1338, 1243, 1173, 1032, 742, 667; HRMS (EI) calculated for C24H20N2O 352.1576 found 352.1580.
3,3'-((4-Bromophenyl)methylene)bis(1H-indole) (4j). Reagents employed: 5-((4-bromophenyl)(1H-indol-3-yl)methyl)-2,2-
dimethyl-1,3-dioxane-4,6-dione (3c) (0.050 g, 0.116 mmol), indole (0.0205 g, 0.175 mmol), scandium triflate (0.006 g, 0.0122
mmol), anhydrous MeCN at 50 °C, for 3 hours: yield 83% (39 mg) as a red foam; Rf= 0.41, 30% EtOAc in hexanes; 1H NMR (400
MHz, CDCl3) δ= 7.93 (s, 2H), 7.39-7.34 (m, 6H), 7.22-7.20 (m, 4H), 7.02 (t, J= 7.9 Hz, 2H), 6.64 (s, 2H), 5.85 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ= 143.1, 136.6, 131.3, 130.5, 126.8, 123.6, 122.1, 119.8, 119.3, 119.1, 111.5, 111.1, 39.7; IR (thin film) 3852,
3748, 3648, 3410, 2922, 2210, 1652, 1558, 1540, 1485, 1456, 1418, 1338, 1216, 1223, 1093, 1009, 743; HRMS (EI) calculated for
C23H17BrN2 400.0575 found 400.0569.
Methyl 4-(di(1H-indol-3-yl)methyl)benzoate (4k). Reagents employed: methyl 4-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)(1H-
indol-3-yl)methyl)benzoate (3d) (0.050 g, 0.122 mmol), indole (0.0216 g, 0.184 mmol), scandium triflate (0.006 g, 0.0122 mmol),
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anhydrous MeCN at 50 °C, for 3 hours: yield 84% (39 mg) as a red foam; Rf= 0.41, 30% EtOAc in hexanes; 1H NMR (400 MHz,
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CDCl3) δ = 7.99 (s, 2H), 7.96 (d, J= 7.9, 2H), 7.43-7.35 (m, 7H), 7.18 (t, J= 8.0 Hz, 2H), 7.01 (t, J= 7.7 Hz, 2H), 6.67 (s, 2H), 3.89
(s, 3H); 13C NMR (100 MHz, CDCl3) δ=167.3, 149.6, 136.7, 129.7, 128.8, 128.2, 126.9, 123.7, 122.1, 119.8, 119.4, 118.8, 111.2,
52.6, 40.3; IR (thin film) 3405, 2923, 2852, 2285, 1719, 1609, 1457, 1435, 1376, 113, 1018, 724; HRMS (EI) calculated for
C25H20N2O2 380.1525 found 380.1530.
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3,3'-(Propane-1,1-diyl)bis(1H-indole) (4l). Reagents employed: 5-(1-(1H-indol-3-yl)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(3f) (0.050 g, 0.166 mmol), indole (0.0292 g, 0.249 mmol), scandium triflate (0.008 g, 0.0166 mmol), anhydrous MeCN at 50 °C,
for 3 hours: yield 73% (33 mg) as a clear red oil; Rf= 0.36, 30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ = 7.83 (s, 2H),
7.82 (d, J= 8.0 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 7.17 (dt, J= 7.4, 1.2 Hz, 2H), 7.06 (dt, J= 7.5, 1.0 Hz, 2H), 6.96 (d, J= 2.3 Hz, 2H),
4.40 (t, J= 7.0, 1H), 2.27-2.12 (m, 2H), 1.03 (t, J= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ= 136.5, 127.2, 121.7, 121.4, 120.2,
119.7, 118.9, 111.0, 35.8, 26.7,13.1; IR (thin film) 3412, 3054, 2957, 2926, 2869, 1616, 1455, 1485, 1418, 1337, 1218, 1093, 1010,
742, 581, 494; HRMS (EI) calculated for C19H18N2 274.1470, found 274.1472.
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3,3'-(Decane-1,1-diyl)bis(1H-indole) (4m). Reagents employed: 5-(1-(1H-indol-3-yl)decyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(3g) (0.050 g, 0.125 mmol), indole (0.0220 g, 0.188 mmol), scandium triflate (0.006 g, 0.0122mmol), anhydrous MeCN at 50 °C,
for 3 hours: yield 79% (37 mg) as a black oil; Rf= 0.56, 30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ= 7.91 (s, 2H), 7.61
(d, J= 8.1 Hz, 2H), 7.33 (d, J= 8.1 Hz, 2H), 7.15 (dt, J= 7.2, 1.2 Hz, 3H), 7.03 (dt, J= 7.5, 1.0 Hz, 3H), 7.00 (d, J= 2.0 Hz, 2H), 4.47
(t, J= 7.5 Hz, 1H), 2.25-2.15 (m, 2H), 1.45-1.15 (m, 12H), 0.87 (t, J= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ= 136.5, 127.1,
121.7, 121.3, 120.6, 119.7, 118.9, 111.0, 35.8, 33.9, 31.8, 29.8, 29.7, 29.3, 28.3, 22.6, 20.8, 14.1; IR (thin film) 38.52, 3749, 3674,
3412, 2923, 2852, 2361, 1733, 1699, 1652,1616, 1456, 1418, 1337, 1069, 1032, 740, 533, 521; HRMS (EI) calculated for C26H32N2
372.2565, found 372.2577.
General Experimental Procedure for the Synthesis of Electrophiles 3a-g. Indole (1.0 equiv) and aldehyde (2.0 equiv) were
added to a solution of Meldrum’s acid (1.0 equiv) in anhydrous MeCN. The mixture was stirred for 10 minutes then L-proline (5
mol %) was added. The reaction was allowed to stir at room temperature until complete (as determined by TLC analysis). Water
was then added and the organic layer was extracted with EtOAc (3 times). The organic layers were then combined and dried with
magnesium sulfate. Following filtration, the solvent was removed under reduced pressure and the crude mixture purified by flash
chromatography (EtOAc/hexanes) to yield the desired products 3a-g.
5-((1H-Indol-3-yl)(phenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3a). Reagents employed: indole (5.00 g, 42.7 mmol),
benzaldehyde (9.05 g, 85.4 mmol), Meldrum’s acid (6.15 g, 42.7 mmol), L-proline (0.246 g, 2.13 mmol), anhydrous MeCN at room
temperature, for 24 hours: yield 83% (12.38 g), as a pink powder; Rf= 0.20, 30% EtOAc in hexanes. Spectral analysis matched
known literature compound.9
5-((1H-Indol-3-yl)(4-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3b). Reagents employed: indole (0.081 g, 0.694
mmol), 4-methoxybenzaldehyde (0.189 g, 1.388 mmol), Meldrum’s acid (0.100 g, 0.694 mmol), L-proline (0.0204 g, 0.035 mmol),
anhydrous MeCN, at room temperature, for 24 hours: yield 70% (184 mg), as a light orange foam; Rf= 0.11, 30% EtOAc in
hexanes; 1H NMR (400 MHz, CDCl3) δ = 8.23 (s, 1H), 7.41 (d, J= 7.7 Hz, 1H), 7.35-7.31 (m, 4H), 7.18 (dt, J= 6.7, 1.1, 1H), 7.06
(dt, J= 7.72, 1.2, 1H), 6.82-6.78 (m, 2H), 5.6 (d, J= 2.4, 1H), 4.29 (d, J= 2.63, 1H), 3.76 (s, 3H), 1.69 (s, 3H), 1.43 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ= 165.7, 164.7, 158.5, 135.8, 131.7, 130.2, 126.8, 123.7, 122.1, 119.5, 118.9, 115.2, 113.6, 111.1, 105.1, 55.1,
51.9, 41.1, 28.1, 27.8; IR (thin film) 3416, 3003, 2932, 2837, 1779, 1743, 1610, 1511, 1458, 1383, 1297, 1249, 1205, 1179, 1094,
1011, 902, 833, 747; HRMS (EI) calculated for C22H21NO5 379.1420 found 379.1410.
5-((4-Bromophenyl)(1H-indol-3-yl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3c). Reagents employed: indole (0.163 g, 1.388
mmol), p-bromobenzaldehyde (0.514 g, 2.775 mmol), Meldrum’s acid (0.200 g, 1.388 mmol), L-proline (0.008 g, 0.069 mmol),
anhydrous MeCN at room temperature for 24 hours: yield 81 % (478 mg), as a light yellow foam; Rf= 0.20, 30% EtOAc in
hexanes; 1H NMR (400 MHz, CDCl3) δ= 8.18 (s, 1H), 7.41-7.32 (m, 5H), 7.31-7.25 m, 2H), 7.19 (t, J= 7.7 Hz, 1H), 7.07 (t, J= 8.0
Hz, 1H), 5.62 (d, J= 2.5 Hz, 1H), 4.27 (d, J= 2.1 Hz, 1H), 1.74 (s, 3H), 1.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ= 165.2, 164.4,
138.8, 135.8, 131.4, 130.9, 126.8, 123.9, 122.5, 121.1, 119.9, 118.9, 114.5, 111.2, 105.2, 51.8, 40.5, 28.2, 27.7; IR (thin film) 3852,
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3784, 3648, 3419, 3003, 2923, 2360, 2340, 1741, 1699, 1652, 1558, 1488, 1457, 1394, 1297, 1204, 1074, 1010, 903, 745, 667;
HRMS (EI) calculated for C21H18BrNO4 427.0419 found 427.0411.
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Methyl 4-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)(1H-indol-3 yl)methyl)benzoate (3d). indole (0.163 g, 1.388 mmol), methyl-4
formylbenzoate (0.456 g, 2.775 mmol), Meldrum’s acid (0.200 g, 1.388 mol), L-proline (0.008 g, 0.070 mmol), anhydrous MeCN at
room temperature, for 24 hours: yield 79% (0.445 g), as an orange foam; Rf= 0.21, 30% EtOAc in hexanes; 1H NMR (400 MHz,
CDCl3) δ= 8.31 (s, 1H), 7.90 (d, J= 8.3 Hz, 2H), 7.47 (d, J= 8.2 Hz, 2H), 7.49-7.30 (m, 3H), 7.19 (t, J= 7.7 Hz, 1H), 7.06 (t, J= 7.0
Hz, 1H), 5.71 (d, J= 2.0 Hz, 1H), 4.33 (d, J= 2.4 Hz, 1H), 3.88 (s, 3H), 1.74 (s, 3H), 1.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ=
166.9, 165.1, 164.4, 145.3, 135.7, 129.6, 128.8, 128.7, 126.8, 124.2, 122.4, 119.6, 118.9, 114.1, 111.2, 105.2, 52.1, 51.7, 40.9, 28.1,
27.7; IR (thin film) 3408, 3002, 2951, 1779, 1744, 1719, 1610, 1574, 1458, 1435, 1383, 1286, 1199, 1112, 1064, 1019, 905, 749;
HRMS (ESI) calculated for C23H21NO6 430.1266 found 430.1267 (M + Na+).
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2,2-Dimethyl-5-((1-methyl-1H-indol-3-yl)(phenyl)methyl)-1,3-dioxane-4,6-dione (3e). N-methylindole (0.930 g, 7.091 mmol),
benzaldehyde (1.505 g, 14.182 mmol), Meldrum’s acid (1.022 g, 7.091 mmol), L-proline (0.040 g, 0.355 mmol), anhydrous MeCN
at room temperature, for 24 hours: yield 83% (2.13 g), as a light pink foam; Rf= 0.24, 30% EtOAc in hexanes; 1H NMR (400 MHz,
CDCl3) δ= 7.45-7.39 (m, 3H), 7.28-7.19 (m, 6H), 7.04 (dt, J= 7.6, 1.4 Hz, 1H), 5.63 (d, J= 2.3 Hz, 1H), 4.28 (d, J= 2.7 Hz, 1H),
3.75 (s, 3H), 1.68 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ= 165.4, 164.6, 140.0, 136.5, 128.9, 128.8, 128.3, 127.4,
127.0, 121.8, 119.1, 118.9, 109.1, 105.0, 52.0, 41.2, 39.4, 32.8, 28.1, 27.8; IR (thin film) 3465, 3003, 2942, 1780, 1747, 1652,
1615, 1473, 1382, 1295, 1076, 1014, 898, 745, 719; HRMS (EI) calculated for C22H21NO4 363.1471 found 363.1473.
5-(1-(1H-indol-3-yl)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3f). Reagents employed: indole (0.163 g, 1.388 mmol), propanal
(0.161 g, 2.775 mmol), Meldrum’s acid (0.200 g, 1.388 mmol), L-proline (0.008 g, 0.069 mmol), anhydrous MeCN at room
temperature, for 24 hours: yield 67% (280 mg), as a yellow foam; Rf= 0.22, 30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ
= 8.30 (s, 1H), 7.68 (d, J= 8.2 Hz, 1H), 7.34 (d, J= 8.2 Hz, 1H), 7.21-7.10 (m, 3H), 4.11-4.04 (m, 1H), 3.79 (d, J= 2.9 Hz, 1H), 2.34-
2.25 (m, 1H), 2.12-2.04 (m, 1H), 1.61 (s, 3H), 1.19 (s, 3H), 0.99 (t, J= 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ= 165.9, 165.7,
135.6, 127.0, 123.4, 122.1, 119.7, 118.9, 114.7, 111.0, 105.2, 50.6, 38.8, 28.0, 27.9, 26.6, 12.8; IR (thin film) 3411, 2967, 2874,
2360, 2339, 1739, 1618, 1457, 1382, 1293, 1241, 1204, 1095, 1000, 745; HRMS (EI) calculated for C17H19NO4 301.1314 found
301.1317.
5-(1-(1H-indol-3-yl)decyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3g). Reagents employed: indole (0.163 g, 1.388 mmol), decanal
(0.434 g, 2.775 mmol), Meldrum’s acid (0.200 g, 1.388 mmol), L-proline (0.008 g, 0.007 mmol), anhydrous MeCN, yield 98% (543
mg), as a clear red oil; Rf= 0.27, 30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ = 8.37 (s, 1H), 7.70 (d, J= 7.7 Hz, 1H),
7.33 (d, J= 7.4 Hz, 1H), 7.21-7.11 (m, 3H), 4.21-4.14 (m, 1H), 3.79 (d, J= 3.0 Hz, 1H), 2.29-2.25 (m, 1H), 2.09-1.99 (m, 1H), 1.61
(s, 3H), 1.37-1.23 (m, 14H), 1.20 (s, 3H), 0.89 (t, J= 6.71, 3H); 13C NMR (100 MHz, CDCl3) δ=165.8, 165.6, 135.6, 126.9, 123.4,
122.1, 119.7, 119.0, 114.9, 111.0, 105.1, 50.9, 41.8, 37.0, 33.5, 31.8, 29.5, 29.4, 29.2, 28.2, 28.0, 27.9, 22.6, 14.0; IR (thin film)
3412, 3057, 2924, 2854, 1740, 1619, 1457, 1425, 1392, 1384, 1293, 1247, 1205, 1124, 1095, 907, 897, 743, 765, 646, 599, 515;
HRMS (EI) calculated for C24H33NO4 399.2410, found 399.2425.
Acknowledgments. We thank the Natural Sciences and Engineering Research Council of Canada for generous funding of this
research. We are grateful to Mr. Doug Hairsine of the Western University Mass Spectrometry facility for performing MS analyses.
Supporting Information Available: 1H NMR and 13C NMR spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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T. S. Kam in Alkaloids, Chemical and Biological Perspectives (E.: S. W. Pelletier), Pergamon, Amsterdam, 1999, Vol. 4.
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6 For selected total synthesis see: (a) Karadoelian, A.; Kerr, M., A. Angew. Chem. Int. Ed. 2010, 49, 1133. (b) Lebold, T., P.; Kerr, M., A. Org. Lett. 2008, 10, 997. (c)
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8 Selected recent advances in Meldrum’s acid shemistry: (a) Janikowska, K.; Makowiec, S.; Rachoń, J. Helv. Chim. Acta 2013, 96, 978. (b) Allen, J., C.; Kociok-Kohn,
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9 The Fillion conditions reported in reference 7a were employed in the present system. Extensive decomposition with a trace amount of product was obtained.
10 This work is complementary to the work of Bhuyan who report a similar reaction using barbituric acid derivatives. See: Deb, L; Bhuyan, P.J. Synthesis 2008, 18,
2891.
11 Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978, 20, 1759-1762.
12 We have observed the deactivation of such catalysts by DMF previously. See: England, D.B; Kuss, T.D.O. Keddy, R.G.; Kerr, M.A. J. Org. Chem. 2001, 66, 4704.
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