An intramolecular inverse electron demand Diels-Alder approach to annulated α-carbolines

Article abstract of DOI:10.3762/bjoc.8.93

Intramolecular inverse electron demand cycloadditions of isatin-derived 1,2,4-triazines with acetylenic dienophiles tethered by amidations or transesterifications proceed in excellent yields to produce lactam- or lactone-fused α-carbolines. Beginning with various isatins and alkynyl dienophiles, a pilot-scale library of eighty-eight α-carbolines was prepared by using this robust methodology for biological evaluation.

Full text of DOI:10.3762/bjoc.8.93

An intramolecular inverse electron demand
Diels–Alder approach to annulated α-carbolines
Zhiyuan Ma, Feng Ni, Grace H. C. Woo, Sie-Mun Lo, Philip M. Roveto,
Scott E. Schaus and John K. Snyder*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 829–840.
Department of Chemistry and the Center for Chemical Methodology
and Library Development (CMLD-BU), Boston University, 590
Commonwealth Avenue, Boston, Massachusetts 02215
doi:10.3762/bjoc.8.93
Received: 10 February 2012
Accepted: 08 May 2012
Published: 06 June 2012
Email:
John K. Snyder* - jsnyder@bu.edu
This article is part of the Thematic Series "Recent developments in
chemical diversity".
* Corresponding author
Keywords:
Guest Editor: J. A. Porco Jr.
α-carboline; chemical diversity; inverse electron demand Diels–Alder;
isatin; pyrido[2,3-b]indole; 1,2,4-triazine
© 2012 Ma et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Intramolecular inverse electron demand cycloadditions of isatin-derived 1,2,4-triazines with acetylenic dienophiles tethered by
amidations or transesterifications proceed in excellent yields to produce lactam- or lactone-fused α-carbolines. Beginning with
various isatins and alkynyl dienophiles, a pilot-scale library of eighty-eight α-carbolines was prepared by using this robust method-
ology for biological evaluation.
Introduction
In comparison with the well-known β-carbolines, α-carboline indolo[2,3-b]quinoline class of heterocycles [8], has been
alkaloids are quite rare, and only a few natural products isolated shown to be a strong inhibitor of Plasmodium falciparum
to date contain this pyrido[2,3-b]indole (α-carboline, 1, growth [9]. 2-Amino-α-carbolines have also been identified as
Figure 1) core. The most prominent examples are grossularine-1 mutagens produced in the pyrolysis of proteins [10,11] as well
(2) and grossularine-2 (3), which are marine cytotoxic agents as the pyrolysis of tryptophan [12]. Isoeudistomin U, isolated
that were isolated from the tunicate Dendrodoa grossularia from the ascidian Lissoclinum fragile, was originally reported to
(Stylidae) [1,2], and desmethylgrossularine-1 from tunicate have an α-carboline skeleton [13], but this assignment was later
Polycarpa aurata [3]. Other natural α-carbolines include shown to be incorrect [14].
mescengricin (3), an inhibitor of L-glutamate excitotoxicity in
neutrons, isolated from Streptomyces griseoflavus [4], and Given their isomeric relationship to β-carbolines, α-carbolines
cryptotackieine (4) [5], also known as neocryptolepine [6], have, unsurprisingly, attracted attention from synthetic chemists
isolated from roots of the West African plant Cryptolepis for a long time [15], and more recently from medicinal chemists
sanguinolenta [7]. Cryptotackieine, a member of the [16]. Synthetic members of this class were shown to have a
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Beilstein J. Org. Chem. 2012, 8, 829–840.
Figure 1: Natural products with α-carboline subunits.
wide range of activities, including topoisomerase II inhibition hexanone, catalyzed by PPA, followed by dehydrogenation over
[17], and 4-amino-α-carbolines have also been shown to pos- Pd–C has also been reported for the preparation of the un-
sess anxiolytic properties by stabilization of the open chloride substituted α-carboline [48], but no other successful applica-
channel [18,19]. Relatively few patents have been granted on tions of this strategy have appeared in the literature.
the medicinal use of α-carbolines, particularly in comparison to
β-carbolines, with recent applications including use as antiviral A more common strategy to α-carbolines closes the pyridine
agents [20], inhibitors of ApoB-100-associated lipoprotein ring onto an existing indole framework. In general, applications
production for cholesterol lowering [21], and more recently, as of this construction sequence fall into two major camps, namely
inhibitors of CDK1 kinase as potential anticancer agents [22]. condensations routed through a 2-aminoindole synthon [49-56],
This later filing has triggered investigations into α-carbolines as and those targeting pyridine closures onto a 2-oxindole [57,58].
potential multikinase inhibitors [23].
In addition, intramolecular Hartwig–Buchwald cross-coupling
onto a 2-bromoindole, with formation of the pyridine was
Existing synthetic approaches to α-carbolines are numerous and reported by Dodd [59], and C–N bond closures in presumed
often independent of a specific target, but are instead method- nitrogen-radical processes have also been reported by Narasaka
ology oriented. Exceptions include those efforts to target the [60,61]. Electrocyclic ring closures forming the pyridine ring
grossularines [24-30] and the more popular cryptotackieine from 2-aminoindole-derived intermediates are also known
[31-35].
[62-64]. In addition, cycloadditions of 3-vinyl-7-azaindole have
also been used to close the pyridine ring [65], as have intramo-
The first reported synthesis of an α-carboline by Robinson in lecular dipolar cycloadditions of 2-azidoindole derivatives [66],
1924 [15,36] proceeded through the acid-catalyzed decomposi- and intramolecular cycloadditions of carbodiimides [67,68].
tion of 1-(2-pyridyl)benzotriazole, a modification of the
Graebe–Ullmann carbazole synthesis, which closes the indole We had envisioned that a library of annulated α-carboline struc-
ring. This procedure was improved upon and exploited for tures 6 could be prepared by the intramolecular inverse electron
decades [37-40]. Later, reversing the roles of the benzene and demand Diels–Alder reaction (IEDDA) of isatin-derived 1,2,4-
pyridine rings, with the former as the nucleophile and latter as triazines 7 with tethered electron-rich dienophiles (Scheme 1)
electrophile through the diazonium salt, led to improved yields [69]. Inverse electron demand Diels–Alder cycloadditions
in the indole ring closure [41], as did microwave promotion of employing electron-deficient heteroaromatic azadienes are well-
the original methodology [42]. Nitrene insertion chemistry of established for the synthesis of heterocyclic compounds, and
appropriately substituted 3-arylpyridines also found application have been previously applied to the synthesis of α-carbolines.
[43,44], and likewise falls into the category of indole ring Intramolecular IEDDA chemistry to prepare α-carbolines
closure onto an existing substituted pyridine, though in this case employing 2-N-(o-alkynylanilino)pyrimidine systems have been
with the formation of the C–N bond. More recently, the group successful in a limited number of examples [70,71]. Hoornaert
of Cuny has reported two strategies that exploit cross-couplings and co-workers have also employed pyrazinones as dienes in
to prepare anilinopyridines, with final indole ring closure occur- IEDDA reactions to prepare α-carbolines [72].
ring by either a second cross-coupling [45] or a photocycliza-
tion [46]. The former, sequential cross-coupling strategy closely Though the existing synthetic routes can readily produce
follows the previous work by Queguiner [47]. A Fischer indole various α-carbolines, the intramolecular IEDDA approach
synthesis route through the 2-pyridylhydrazone of cyclo- outlined in Scheme 1 has several advantages from the perspec-
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Beilstein J. Org. Chem. 2012, 8, 829–840.
Scheme 1: Retrosynthetic inverse electron Diels–Alder approach to α-carbolines.
tive of library synthesis. First, easy access exists to a wide was anticipated that an electron-withdrawing group R2, which
selection of commercially available or easily synthesized could also serve as a diversification point, would be needed on
starting materials, i.e., isatins, propargylic and homoprop- the indole nitrogen.
argylic amines and alcohols. Second, three easily modifiable
diversification sites, R1, R2 and R4, can be built into the core Results and Discussion
α-carboline structure. Furthermore, construction of the annu- Feasibility studies began with isatin-derived 1,2,4-triazine 9a
lated lactam or lactone as the fourth ring would be easily (9, R1 = H) [73,74], which was easily prepared by the conden-
accomplished by the IEDDA reactions, thereby adding two sation of isatin (10, R1= H) with ethyl oxaloamidrazonate
more diversification points in the form of R3 and the lactam/ [75-77] (11) in quantitative yield (Scheme 2). The first step in
lactone ring size. A particular goal in this work was to establish the cyclocondensation was accomplished by stirring in ethanol
the reaction chemistry and scope in order to build a library of at rt for 12 h and heating under reflux for 20 min, after which
α-carbolines for biological screening. The targeted α-carbolines the solvent was removed and the cyclocondensation completed
6 (X = O) are similar to those prepared by Dodd by a rather by heating under reflux in bromobenzene (bp 156 °C) for 24 h.
lengthy route, but with a transposed carbonyl group on the The two-step condensation with different solvents was needed
lactone ring [59].
to optimize the triazine formation. Sulfonylation of the indole
nitrogen also proceeded routinely to give triazine 8a (R1 = H,
One consideration in this design was the electron donation from R2 = p-Tol), and served two purposes. As noted, the reduction
the indole nitrogen into the isatin-derived triazine ring of 9, of electron donation from this nitrogen into the triazine ring was
which would result in an elevated LUMO of the triazinyl thought to be important for the subsequent cycloaddition to
azadiene, and thereby inhibit the desired cycloaddition. Thus, it proceed, as was shown to be correct in later studies. Further-
Scheme 2: Condensation of isatins with ethyl oxaloamidrazonate to form triazines.
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Beilstein J. Org. Chem. 2012, 8, 829–840.
Table 1: Preparation of N-protected isatin-derived 1,2,4-triazines 8.a
R2
R1 = H
R1 = Me
R1 = MeO
R1 = F
p-MePh
p-MeOPh
Ph
8a, 88%
8e, 90%
8i, 90%
8b, 92%
8f, 87%
8j, 88%
8c, 89%
8g, 84%
8k, 87%
8d, 85%
8h, 88%
8l, 91%
aIsolated yield over two steps (Scheme 2).
more, sulfonylation greatly improved the solubility of the protocols employed 1.2 equiv of Zr(Ot-Bu)4 [85]. Weinreb
triazines 8 in organic solvents in comparison to 9, which amidation with Al(Me)3 also gave excellent yields, but required
showed only limited solubility in dichloromethane, chloroform, the extra step of first mixing Al(Me)3 and the amine, then
THF, toluene, methanol and acetone. Starting with other cannulating this amine–AlMe3 complex into the triazine solu-
5-substituted isatin derivatives, analogous triazines were simi- tion in order to avoid ketonization of the ester [86]. Other Lewis
larly prepared in good yields (84–92%, Table 1). 5-Nitro- and acids, MgCl2, Mg(OTf)2, Zn(OTf)2, Yb(OTf)3 and Sc(OTf)3,
5-carboxamidoisatins also readily participated in the cyclocon- were not successful in catalyzing the amidation. Stoichiometric
densation with the oxaloamidrazonate 11 to form the corre- amounts of catalyst were required for the amidation, presum-
sponding triazines (9, R1 = NO2, CONH2), but due to the elec- ably due to the product itself sequestering the catalyst and
tron withdrawing nature of the isatin substituents, subsequent preventing efficient turnover.
sulfonylations were not successful (not shown).
Table 2: Lewis acid catalysis of amidation of triazine 8a.a
The intermolecular IEDDA reactions of 8a with various elec-
Entry
Catalyst
Loading (equiv) Solvent Yield (%)
tron-rich dienophiles, including ethyl ethynyl ether, the en-
amines (E)-1-N-propenylpyrrolidine, 1-pyrrolidino-1-cyclohex-
ene, and 2-(dimethylamino)imidazole [78-80], all of which have
been shown to react quite well with triazines or tetrazines in
intermolecular IEDDA cycloaditions, were investigated.
However, 8a showed no reactivity with any of these dienophiles
under any conditions, further confirming the importance of the
proposed intramolecular strategy for preparing α-carbolines.
1b
2
Al(Me)3
1.5
0.5
1.2
1.2
DCM
toluene
toluene
DCM
>95
60
Zr(Ot-Bu)4
Zr(Ot-Bu)4
Zr(Ot-Bu)4
3
90
4c
>95
aAll reactions were carried out at rt for 20 h unless otherwise noted;
isolated yield. bMix catalyst and amine, then transfer the mixture of the
amine–aluminum complex into a triazine solution by cannula.
cReaction time was 16 h.
Lewis acid catalyzed amidation of 8a with methyl propargyl
amine (12) gave the cycloaddition precursor 13a in excellent The intramolecular cycloaddition of 13a, the alkyne-tethered
yield when Al(Me)3 was used as catalyst (Scheme 3, Table 2) triazine, was studied under various conditions (Scheme 4,
[81-84]. However, the most convenient procedure for library Table 3). Ultimately, it was found that the IEDDA reaction
proceeded smoothly under microwave irradiation, in diglyme
(120 °C, 20 min; Table 3, entry 3) to give the γ-lactam annu-
lated α-carboline 14a in quantitative yield. The microwave reac-
tion conditions were preferred over the more traditional heating
(Table 3, entry 1) due to the shorter reaction time. Attempts to
lower the temperature and/or shorten the reaction time led to
lower yields (Table 3, entries 2, 4 and 5). Little reaction
occurred in toluene under microwave irradiation (Table 3, entry
6) unless silicon carbide chips were added as a microwave facil-
Scheme 3: Amidation of triazine ester 8a.
itator (Table 3, entry 7) [87].
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Beilstein J. Org. Chem. 2012, 8, 829–840.
then the reaction mixture was heated under reflux at 65 °C for
another 24 h to yield cycloadduct 14a. This one-pot procedure
gave a yield (89%) that was comparable to the overall yield
(94%) of the corresponding two-step sequence, with isolation of
the intermediate amide. Control experiments were carried out to
determine the possible catalytic role of Zr(Ot-Bu)4 in the
cycloaddition. In two side-by-side reactions, 13a, with and
without Zr(Ot-Bu)4 catalyst, was heated to 65 °C. The two reac-
tions required the same amount of time (24 h) to achieve
complete conversions, indicating that the presence of amidation
catalyst Zr(Ot-Bu)4 in the one-pot two-step sequence had no
effect on the cycloaddition of 13a. For the library synthesis, the
two-step sequence was adopted in order to isolate the triazine
intermediates 13, which can also serve as library members.
Scheme 4: Microwave-promoted IEDDA reaction of isatin derived
triazines.
Table 3: IEDDA reaction conditions of 13a to give cycloadduct 14a.a
Entry
Solvent
Temperature (°C) Time
Yield
1b
2
diglyme
diglyme
164
100
120
120
160
160
160
7 h
>95%
20 min 40%
20 min >95%
10 min 70%
10 min 85%
30 min trace
30 min 60%
With the two-step sequence optimized for the preparation of
14a, the scope of this chemistry was then probed with other
alkynyl amines. The amidations all proceeded in high yields
under the optimized conditions with Zr(Ot-Bu)4 as catalyst. The
cycloaddition precursors were then subjected to the optimized
microwave-promoted cycloadditions to give the final
cycloadducts 14 (Scheme 6 and Table 4).
3
diglyme
4
diglyme
5
diglyme
6
toluene
7c
toluene/Si–C
aIEDDA reactions were carried out under microwave irradiation unless
otherwise noted. All yields were determined by UPLC unless other-
wise noted. bHeating in oil bath. cSi–C chip was added to the reaction
under microwave irradiation. Isolated yield.
Tertiary propargyl amides 13a, 13d, and 13e with terminal
alkyne dienophiles all showed comparable reactivity (Table 4,
Upon further exploration of the reaction conditions, it was entry 1, 4, and 5), under the optimized cycloaddition conditions
discovered that the amidation/cycloaddition sequence could be (diglyme, microwave irradiation, 120 °C, 20 min), producing
accomplished in one pot (Scheme 5). The Zr(IV)-catalyzed the desired α-carbolines in excellent yields (96–98%). However,
amidation was thus accomplished in tetrahydrofuran (16 h, rt), propargyl amide 13f with the internal alkyne (Table 4, entry 6)
Scheme 5: One-pot amidation/cycloaddition of triazine ester 8a.
Scheme 6: Amidation/cycloaddition forming α-carbolines 14.
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Beilstein J. Org. Chem. 2012, 8, 829–840.
Table 4: Amidation-IEDDA sequence to α-carbolines 14 from triazine 8a.a
Entry
Amine
Cycloaddition precursor 13 (yield)
Cycloadduct 14 (yield)b
1
13a (98%)
14a (96%)
14b (83%)
2c
13b (90%)
13c (89%)
3d
14c (91%)
4
5
13d (96%)
13e (96%)
13f (95%)
14d (98%)
14e (97%)
6e
14f (93%)
7f
8
13g (93%)
13h (95%)
14g (95%)
no reaction
aAmidation reactions were carried out in DCM, with 1.2 equiv of amine and 1.2 equiv of Zr(Ot-Bu)4 at rt for 16 h, 0.25 M. IEDDA reactions were
carried out in diglyme under microwave irradiation at 120 °C for 20 min, unless otherwise noted. All IEDDA reaction concentrations were 0.1 M.
bIsolated yields. cIEDDA in DMF at 160 °C for 30 min. dIEDDA in diglyme at 160 °C for 30 min. eIEDDA in diglyme at 120 °C for 40 min, 0.1 M.
fIEDDA in diglyme at 160 °C for 30 min.
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Beilstein J. Org. Chem. 2012, 8, 829–840.
required a longer reaction time (40 min) for the cycloaddition to give the desired product 14c (91%; Table 4, entry 3), presum-
be completed to good yield (93%). Increasing the tether length ably aided by the Thorpe–Ingold effect [88-90].
between the alkyne group and the amide linkage also decreased
the reactivity (Table 4, entry 7). The cycloaddition of tertiary To confirm the importance of the electron-withdrawing group
propargyl amide 13g to produce the δ-lactam 14g required on the original indole nitrogen position, the reactivity of amide
higher temperatures (160 °C versus 120 °C) to proceed in high 9a (R1 = H) was also examined (Scheme 8). As expected, no
yield, still in 30 min.
cycloaddition was observed under any conditions, presumably
due to the greater electron donation from the indole nitrogen,
In contrast to the tertiary amides, the secondary amides 13b and which elevates the LUMO of the triazine ring, thereby
13c (Table 4, entry 2 and 3) showed no or very little reaction preventing the desired cycloaddition.
under the standard microwave conditions. The reason for this
lack of reactivity was thought to be strong intramolecular In addition to the amide linkage of the alkyne dienophiles,
hydrogen bonding, which inhibits the rotation of the alkyne transesterification of 8a with alkynyl alcohols led to tethered
group to the proper position for the cycloaddition to occur alkynyl esters as cycloaddition precursors 17a and 17b in good
(Scheme 7).
yields (Scheme 9). Various catalysts for the transesterification
reaction were screened. Boronic acid [91] and indium(III)
The NMR spectra also supported this hypothesis: While all iodide [92] yielded no transesterification product with propargyl
tertiary amides showed the presence of two rotamers in a 1:1 alcohol, while Ti(OiPr)4 [93] gave only a trace of the desired
ratio in CDCl3, the secondary amides 13b and 13c showed only product, with mostly detosylation resulting. Otera’s catalyst
a single rotamer in the NMR spectra. In the 1H NMR spectrum [94] proved to be optimal, giving cycloaddition precursors 17a
for 13b, a very slowly exchanging proton (48 h for complete and 17b in excellent yields (84% and 87%, respectively).
exchange) at δ 8.254 supported the presence of a single con-
formation with strong intramolecular hydrogen bonding. When Cycloaddition precursors 17a and 17b showed a much lower re-
the cycloaddition of 13b was run in DMF instead of diglyme activity in the cycloadditions in comparison to the amides 13.
(160 °C, 20 min), the cycloadditions proceeded in good yield to For ester 17a, after microwave irradiation at 160 °C for 2 h, the
give the desired cycloadduct 14b (83%; Table 4, entry 3). desired cycloadduct 17a with the annulated γ-lactone was
Presumably the significantly greater capabilities of DMF to produced in good yield (80%). In contrast, 17b, with the longer
accept hydrogen bonds in comparison to diglyme help to disrupt tether (n = 2) failed to produce the desired δ-lactone under any
the intramolecular hydrogen bonding and enable the cycloaddi- conditions. A sharp decrease in reactivity in intramolecular
tion to proceed. When 13c, with the gem dimethyl substituted IEDDA reactions of alkynes tethered to 1,2,4-triazines upon
propargylic carbon, was run in diglyme at a higher temperature progression from 5- to 6-membered ring annulations was previ-
(160 °C, 30 min), the cycloaddition proceeded in good yield to ously noted by Taylor [95-98], and has been ascribed to the
Scheme 7: Intramolecular hydrogen bonding prevents IEDDA cycloaddition of 14b.
Scheme 8: Preparation of unprotected triazine 15, and its lack of reactivity in cycloadditions.
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Beilstein J. Org. Chem. 2012, 8, 829–840.
Scheme 9: Transesterification and subsequent cycloaddition of 17a.
greater entropy loss for the larger rings [99]. Indeed, it has been Using this optimized two-step amidation-IEDDA reaction-
estimated that the effective molarity for 5-membered ring sequence methodology, an 88-membered pilot-scale library of
closures can be as high as 1,000-fold greater in comparison to α-carbolines was prepared by using triazine analogues 8 and
6-membered ring cyclizations [100].
alkynyl amines (Table 5). The crude library was analyzed by
Table 5: Library synthesis matrix.a
R1 = H
R2 (p-) → MeOPh MePh
R1 = Me
R1 = OMe
R1 = F
R3 ↓
Ph
MePh MeOPh
Ph
MeOPh
Ph
MeOPh MePh
Ph
100
100
97
100
94b
94b
100
100
100
50
100
77
100
100
98
50
66
90
90
72
100
99
100
100
98
85
100
100
100
100
100
100
100
40
100
97
98
90
85
95
97
80
93
96
100
100
100
100
100
100
100
100
100
100
95
100
100
100
100
100
100
100
100
100
100
100
65
–c
100
100
95
100
100
100
–c
92
56
100
–c
100
–c
100
94
100
100
100
–c
100
aUPLC yields against starting materials. bIsolated yields. cMembers were not prepared due to the limited amount of cyclohexyl propargylamine.
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Beilstein J. Org. Chem. 2012, 8, 829–840.
UPLC. The average yield of the library was 94%, with 90% of tography, Rf 0.68 (hexanes/EtOAc, 1:1) gave 8a (827 mg,
the library members produced in yields greater than 85%. 2.09 mmol, 88% yield) as a yellow solid: mp 145–146 °C; IR
Purification by LC–MS produced the final library.
(neat): 2982, 1742, 1379, 1191, 1180, 671, 579 cm−1; 1H NMR
(400 MHz, CDCl3) δ 1.54 (t, J = 7.0 Hz, 3H), 2.36 (s, 3H), 4.60
(q, J = 7.0 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.58 (ddd, J = 8.0,
Conclusion
Isatin-derived 1,2,4-triazines have proven to be excellent 7.4, 0.8 Hz, 1H), 7.83 (ddd, J = 8.6, 7.4, 1.0 Hz, 1H), 8.20 (d,
heteroaromatic azadienes for intramolecular inverse electron J = 8.4 Hz, 2H), 8.49 (ddd, J = 8.0, 0.8, 0.8 Hz, 1H), 8.52 (ddd,
demand Diels–Alder reactions with tethered alkynyl J = 8.6, 1.0, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.4,
dienophiles. These cycloadditions led to lactam-annulated 21.9, 63.1, 115.1, 118.9, 123.4, 125.8, 128.8 (2C), 130.1 (2C),
α-carbolines in excellent yields under microwave assistance. 133.7, 134.4, 140.5, 145.0, 146.8, 146.9, 152.6, 162.7;
The scope of the chemistry was probed by using various alkynyl HRMS–ESI (m/z): [M + Na]+ calcd for C19H16N4O4SNa,
amines and alkynyl alcohols, and by variation of the tether 419.0790; found, 419.0770 (100%).
length between the aminoalkyne and the triazine. The triazines
with ester linkages showed significantly less reactivity in General procedure C, amidation of 8 to amides 13: To a
cycloadditions compared to those with amide linkages. The solution of triazine 8 (1.0 equiv) and propargyl amine
longer tether length also led to a decrease in cycloaddition re- (1.2 equiv) in CH2Cl2 (0.25 M) was added Zr(Ot-Bu)4
activity. This chemistry was subsequently applied to a library (1.2 equiv) at rt. The reaction mixture was stirred at rt for 16 h,
synthesis, producing a focused library of eighty-eight members. then the mixture was diluted with CH2Cl2 (2 mL) and passed
Diversity was introduced by using a combination of various through an HM/HCl plug (hydro-matrix plug saturated with
substituted isatin-derived triazines, with various sulfonylations 0.1 M HCl aqueous solution) eluting with CH2Cl2. The filtrate
of the indole nitrogen, and propargyl amine derivatives as was dried over sodium sulfate, and then the solvent was
dienophiles.
removed in vacuo. The residue was purified by flash chroma-
tography to yield the desired amide 13.
Experimental
General procedure A, preparation of isatin-derived Representative example: N-Methyl-5-[(4-methylbenzene)sul-
triazines 9: Freshly prepared ethyl oxalamidrazonate (11) [76] fonyl]-N-(prop-2-yn-1-yl)-5H-[1,2,4]triazino[5,6-b]indole-3-
was dissolved in anhydrous EtOH (0.1 M) and the isatin carboxamide (13a). According to general procedure C, begin-
(1.0 equiv) was added at rt under stirring. The reaction mixture ning with 8a (80 mg, 0.20 mmol, 1.0 equiv) and N-methyl-
was stirred at rt for 12 h, and then heated under reflux for propargylamine (16.7 mg, 0.24 mmol, 1.2 equiv). Purification
20 min. After removal of the EtOH in vacuo, the residue was by flash chromatography, Rf 0.54 (DCM/EtOAc, 10:1, 83 mg,
dissolved in anhydrous bromobenzene (0.2 M) and refluxed for 0.19 mmol, 98% yield) gave 13a as a brown-orange oil: IR
24 h. After removal of the solvent in vacuo, the residue was (neat): 2933, 1655, 1370, 1192, 1178, 732, 666 cm−1; 1H NMR
dried by the addition and evaporation of toluene three times, (400 MHz, CDCl3) δ 2.31 (t, J = 2.4 Hz, 0.37H, minor rotamer),
and used directly in the next step without any further purifica- 2.34–2.36 (overlap, 3.63H), 3.12 (s, 1.89H, major rotamer),
tion.
3.31 (s, 1.11H, minor rotamer), 4.22 (d, J = 2.4 Hz, 0.74H,
minor rotamer), 4.52 (d, J = 2.4 Hz, 1.26H, major rotamer),
General procedure B, preparation of sulfonamides 8: The 7.29 (d, J = 8.6 Hz, 2H), 7.57 (dd, J = 8.0, 8.0 Hz, 1H), 7.81
isatin-derived triazine 9 was suspended in THF (0.25 M) and (dd, J = 8.2, 8.0 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1.24H, major
triethylamine (2.0 equiv) was added to the solution at rt. The rotamer), 8.12 (d, J = 8.6 Hz, 0.74H, minor rotamer), 8.44 (d,
reaction mixture was stirred at rt for 30 min until dissolution J = 8.0 Hz, 1H), 8.49 (d, J = 8.2 Hz, 1H); 13C NMR (75 MHz,
was completed, then the sulfonyl chloride (2.0 equiv) was CDCl3) δ 21.9, (33.2, 36.0, 1C), (36.6, 40.9, 1C), (73.1, 73.9,
added at rt, and the reaction mixture was stirred at rt for 7 h. 1C), (77.4, 77.9, 1C), 115.0, 119.1, 123.0, 125.8, 128.3 (2C),
After removal of the solvent in vacuo, the residue was purified 130.3 (2C), 133.3, 134.4, 139.9, 144.3, 146.8, 147.0, (156.6,
by flash chromatography to yield the desired sulfonylated 156.8, 1C), 164.6; HRMS–ESI (m/z): [M + Na]+ calculated for
triazine 8.
C21H17N5O3SNa, 442.0950; found, 442.0935 (100%).
Representative example: Ethyl 5-[(4-methylbenzene)sul- General procedure D, cycloaddition of 13 to 14: A solution
fonyl]-5H-[1,2,4]triazino[5,6-b]indole-3-carboxylate (8a). of the amide 13 in diglyme (0.1 M) was placed in a thick-walled
According to general procedures A and B, beginning with isatin microwave tube, and then the reaction mixture was subjected to
(350 mg, 2.38 mmol, 1.0 equiv) and p-toluenesulfonyl chloride microwave irradiation at 160 °C for 20 min under stirring,
(907 mg, 4.76 mmol, 2.0 equiv). Purification by flash chroma- unless otherwise noted. After the irradiation, the solvent was
837

Beilstein J. Org. Chem. 2012, 8, 829–840.
6. Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck, A.
Tetrahedron Lett. 1996, 37, 1703–1706.
removed in vacuo and the residue was purified by flash chroma-
tography to yield the cycloadducts 14.
doi:10.1016/0040-4039(96)00112-8
7. Alajarín, M.; Molina, P.; Vidal, A. J. Nat. Prod. 1997, 60, 747–748.
doi:10.1021/np970177f
Representative example: 13-Methyl-8-[(4-methylbenzene)sul-
fonyl]8,10,13-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-
1(16),2(7),3,5,9,11(15)-hexaen-12-one (14a). According to
general procedure D, beginning with 13a (30 mg, 0.071 mmol).
Purification by flash chromatography, Rf 0.17 (DCM:EtOAc,
2:1, 27 mg, 0.069 mmol, 96% yield) gave product 14a as a
white yellow solid: mp 271–272 °C; IR (neat): 3057, 2987,
1739, 1692, 1375, 1175, 667 cm−1; 1H NMR (400 MHz,
CDCl3) δ 2.28 (s, 3H), 3.26 (s, 3H), 4.40 (s, 2H), 7.20 (d, J =
8.4 Hz, 2H), 7.32 (dd, J = 8.0, 7.8 Hz, 1H), 7.51 (dd, J = 7.8,
7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 8.20 (d, J =
8.4 Hz, 2H), 8.42 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 21.8, 30.4, 49.7, 115.0, 120.3, 121.1, 121.7, 122.8,
123.9, 128.6 (2C), 129.3, 129.6 (2C), 130.6, 135.5, 138.8,
145.4, 147.7, 151.3, 166.3; HRMS–ESI (m/z) [M + Na]+ calcd
for C21H17N3O3SNa, 414.0888; found, 414.0873 (100%).
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[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-93-S1.pdf]
Acknowledgements
doi:10.1016/S0960-894X(01)80129-3
This work was supported by the National Institutes of Health
(P41 086180). We also thank UROP (Boston University) for
support of undergraduate researchers Sie-Mun Lo and Philip
Roveto, and the NSF for supporting the purchase of the NMR
(CHE 0619339) and HRMS (CHE 0443618) spectrometers. We
also thank Professor John Porco and Dr. Aaron Beeler (Boston
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