A versatile thiouronium-based solid-phase synthesis of 1,3,5-triazines

Article abstract of DOI:10.1002/chem.201102097

A thiouronium-based solidphase synthesis of a 1,3,5-triazine scaffold has been developed. The key feature of the synthesis is the use of a readily accessible solid-supported thiouronium salt as a primary precursor for the stepwise assembly of the 1,3,5-tri-azine substrate. The sulfur linker employed in the synthesis is stable under both acidic and basic conditions and is versatile enough to provide access to monocyclic, bicyclic, and spirocyclic compounds with the 1,3,5-triazine scaffold. By using this synthetic strategy, a representative set of 79 compounds containing the 1,3,5-triazine scaffold were prepared.

Full text of DOI:10.1002/chem.201102097

DOI: 10.1002/chem.201102097
A Versatile Thiouronium-Based Solid-Phase Synthesis of 1,3,5-Triazines
Kah Hoe Kong, Chong Kiat Tan, Xijie Lin, and Yulin Lam*[a]
Abstract: A thiouronium-based solid-
phase synthesis of a 1,3,5-triazine scaf-
fold has been developed. The key fea-
ture of the synthesis is the use of a
readily accessible solid-supported thio-
uronium salt as a primary precursor for
the stepwise assembly of the 1,3,5-tri-
ployed in the synthesis is stable under
both acidic and basic conditions and is
versatile enough to provide access to
monocyclic, bicyclic, and spirocyclic
compounds with the 1,3,5-triazine scaf-
fold. By using this synthetic strategy, a
representative set of 79 compounds
containing the 1,3,5-triazine scaffold
were prepared.
Keywords: microwave chemistry ·
nitrogen heterocycles · solid-phase
synthesis · thiouronium · triazines
ACHTUNGTRENNUNGazine substrate. The sulfur linker em-
Introduction
bonyl group on the triazine substrate to amino or phenoxy
functionalities results in triazines such as 3, which exhibits a
potential inhibitory effect on tumour-associated carbonic an-
hydrase,[9] and 4, a patented cardiovascular agent.[10] Despite
the broad spectrum of activities exhibited by compounds
containing the 1,3,5-triazine scaffold, a review of the litera-
ture suggests a lack of a common synthetic strategy for the
generation of these compounds. Earlier reported syntheses
of triazinediones, such as 1, 2a, and 2b, which use commer-
cially available isocyanates,[8b,11] suffer from several limita-
tions: First, the electrophilicity of isocyanates limits substitu-
ents at the N3 position of the triazine substrate to simple
alkyl, alkenyl, and aryl groups. Second, the toxicity and
moisture-sensitive nature of isocyanates create difficulties in
small-scale preparation. In addition, most of the syntheses
of 3 are based on the nucleophilic addition of cyanuric chlo-
ride, which can only accommodate amino substituents at the
2, 4, and 6 positions.[12] In continuation with our interest to
develop versatile strategies for the assembly of 1,3,5-triazine
substrates, we herein report the synthesis of these com-
pounds by using a simple solid-phase thiouronium salt. This
approach not only circumvents the problems associated with
the isocyanate-based triazine synthesis, it also enables the
compound to accommodate greater diversity at various posi-
tions of the triazine scaffold. It is gratifying to note that this
solid-phase approach is stable under both acidic and basic
cyclization conditions, thus enabling access to a spectrum of
monocyclic, bicyclic, and spirocyclic compounds with the
1,3,5-triazine scaffold.
1,3,5-Triazines constitute an important class of heterocycle
that have found applications as antimicrobial and antitumor
agents,[1] polymeric and supramolecular materials,[2] drug-de-
livery agents,[3] dyes,[4] and DNA-cleavage reagents.[5] For ex-
ample, bicyclic triazinedione 1 (Scheme 1) is a 5-HT2A-re-
ceptor antagonist that exhibits potential therapeutic activity
for the treatment of hypertension.[6] Compound 2a is a non-
peptidic prokineticin antagonist,[7] whereas analogues with
the general structure of 2b are a class of patented triazine-
dione that exhibit analgesic effects.[8] By changing the car-
Scheme 1. Examples of biologically active 1,3,5-triazines.
Results and Discussion
[a] K. H. Kong, C. K. Tan, X. Lin, Prof. Y. Lam
Department of Chemistry
National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6779-1691
Solution-phase synthesis: Prior to our solid-phase synthesis,
all the requisite reactions for the synthesis of the triazine
substrates were optimized through solution-phase synthesis.
Thiouronium salt 5 was obtained in quantitative yield by
treating benzyl bromide with thiourea in acetonitrile at
E-mail: chmlamyl@nus.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102097.
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Chem. Eur. J. 2012, 18, 1476 – 1486

FULL PAPER
room temperature (Scheme 2). The treatment of 5 with N-
methyl-N’-phenyl carbodiimide 7[13] in DMF at room tem-
perature gave the thiouronium biguanidine 8, which was dif-
73% yield (Scheme 3). To expand the scope of our thiouro-
nium approach further for the assembly of 1,3,5-triazine sub-
strates, 5 was treated with CDI under basic conditions in
Scheme 3. Safety-catch substitution of 11a. i) DMDO, acetone, ꢀ238C,
20 min; ii) BuNH2, RT, 1 h. DMDO=dimethyldioxirane.
THF to yield thiouronium azolide 12 in 93% yield
(Scheme 4). Subsequent treatment of 12 with benzylamine
under basic conditions gave the corresponding thiouronium
Scheme 2. Solution-phase synthesis of 9. i) CH3CN, RT, R1NH2, 3 h;
ii) TEA, the Mukaiyama reagent, DMF, RT, 1 h; iii) thiourea, CH3CN,
RT, 3 h; iv) the Mukaiyama reagent, TEA, CH3COOH, DMAP, DMF,
608C, 4 h. DMAP=4-dimethylaminopyridine, TEA=triethylamine.
ficult to purify. Thus, we decided not to isolate 8 and pro-
ceeded to perform a cyclization reaction mediated by using
the Mukaiyama reagent with acetic acid[14] in a one-pot reac-
tion, which gave 9a in 74% yield over two steps (Table 1,
entry 1). Next, we explored various cyclization conditions by
varying the reaction solvent, temperature, carboxylic acid,
and amine bases used. The results from the optimization ex-
periments indicated that when the R2 group is a methyl spe-
cies, the best yields were obtained when the reaction was
carried out in DMF and at a cyclization temperature of
608C (Table 1, entries 1 and 2). However, when the
R2COOH group was cinnamic acid, an increase in the cycli-
zation temperature to 1108C and a change of the base to
tributylamine was necessary to afford the corresponding tri-
azine 9 in moderate yields (Table 1, entries 7 and 8). Next, a
DMDO-mediated oxidation of 9a at ꢀ238C for 20 minutes
afforded the corresponding sulfone 10a. Because the sulfone
moiety is relatively labile, 10a was not isolated but immedi-
ately treated with n-butylamine to obtain triazine 11a in
Scheme 4. Solution-phase synthesis of 16a. i) CDI, TEA, THF, RT, 2 h;
ii) BnNH2, TEA, DMF, 808C, 30 min; iii) allylamine, DMF, TEA, 1.5 h,
408C; iv) DIEA, CDI, DMF, 1108C, 3 h; v) DMDO, acetone, RT, 5 min;
vi) BuNH2, DMF, 808C, 3 h. CDI=N,N’-carbonyldiimidazole, DIEA=
N,N-diisopropylethylamine.
urea 13a. The reaction proceeded most rapidly with excess
TEA in DMF at 808C (Table 2, entry 2) and gave 13a in
90% yield. When 12 was treated with amines with lower
boiling points, for example allylamine, a larger excess of the
amine and TEA were needed and the reaction was complet-
ed after 1.5 hours at 408C. The product 13b was obtained in
67% yield (Table 2, entry 6). Compound 13a was subse-
quently cyclized by using CDI[15] with excess DIEA in DMF
at 1108C to afford triazinedione 14a in 79% yield. Oxida-
tion of 14a by using DMDO at room temperature for 5 mi-
nutes gave sulfone 15a,[16] which was concentrated in vacuo
Table 1. Optimization of reaction conditions for the one-pot synthesis of
9 from 7.[a]
Entry
9
R1
R2
T
[8C]
Solvent
Base
Yield
[%]
1
2
3
4
9a
9b
9a
9b
Me
Bn
Me
Bn
Me
Me
Me
Me
60
60
RT
RT
DMF
DMF
CH2Cl2
CH2Cl2
TEA
TEA
TEA
TEA
74
68
30[b]
21[b]
Table 2. Optimization of reaction conditions for the synthesis of 13.
Entry Product Amine
(equiv)
Solvent
T
[8C]
TEA
[equiv]
Reaction time [h]
ACHTUNGTRENNUNG
(Yield [%])[a]
G
U
5
6
7
8
9c
9c
9c
9d
Bn
Bn
Bn
Me
60
DMF
DMF
DMF
DMF
TEA
TEA
Bu3N
Bu3N
24
40
50
57
1
2
3
4
5
6
13a
13a
13a
13a
13b
13b
Bn (2)
Bn (2)
Bn (2)
Bn (2)
allyl (4) DMF
allyl (4) DMF
DMF
DMF
DMF
THF
RT
80
RT
50
RT
40C
–
2
2
2
–
4
12 (–)
0.5 (90)
12 (23)[b]
12 (20)[b]
12 (21)[c]
1.5 (67)
110
110
110
[a] Yield of the isolated product. [b] Decomposition of 13a was observed.
[a] Reaction time=4 h. [b] Byproducts were observed.
[c] Incomplete reaction.
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Y. Lam et al.
and treated with a solution of butylamine in DMF at 808C
to afford 16a in 70% yield (over two steps). To demonstrate
the stability of 13a under acidic conditions, the compound
was subjected to an acid-catalyzed cyclization reaction with
either dimethoxypropane or trimethylorthoformate in DMF
to afford the corresponding triazine analogues 17 and 18 in
71 and 97% yields, respectively (Scheme 5). A DMDO-
Scheme 6. Solution-phase synthesis of bicyclic triazine 26. i) Mono Boc-
protected 1,3-diaminopropane 22a, TEA, DMF, 808C, 30 min; ii) N,N’-
thiocarbonyldiimidazole, DIEA, DMF, 608C, 36 h; iii) DIEA, CH3I, THF,
RT, 30 min; iv) phenol/TMSCl (3:1, m), CH2Cl2, RT, 1 h; v) DMDO,
CH2Cl2. Boc=tert-butyloxycarbonyl, TMS=trimethylsilyl.
Scheme 5. Solution-phase acid-catalyzed cyclization of 13a with orthofor-
mates and acetates. i) 2,2-Dimethoxypropane, TsOH (cat.), DMF, 808C,
3 h; ii) trimethylorthoformate, TsOH (cat.), DMF, 1108C, 4 h; iii) DM-
DO, CH2Cl2, RT, 15 min; iv) DMDO, CH2Cl2, ꢀ208C, 5 min. TsOH=
para-toluenesulfonic acid.
mediated safety-catch cleavage reaction of 18 gave triazine-
dione 19a cleanly and in near quantitative yield. Attempts
to isolate the triazine sulfone intermediate 20 for subse-
quent nucleophilic displacement with an amine yielded only
triazinediione 19a. This outcome indicated that 20 was too
unstable to be isolated in solution, and thus it was decided
to utilize solid-phase synthesis to prepare triazine analogue
21a because we reasoned that solid-supported sulfone 20
could probably be readily isolated through simple filtration.
For the final phase of our solution-phase synthesis, we treat-
ed thiouronium azolide 12 with mono Boc-protected 1,3-di-
Scheme 7. Liebeskind–Srogl coupling cleavage of 9a. i) [Pd2ACHTUNGTRENNUNG(dba)3] (6
mol%), Cy3P (24 mol%), CuTC (3 equiv), 4-methoxyphenylboronic acid
(2.2 equiv), THF, sealed tube microwave irradiation, 1358C, 45 min.
CuTC=copper(I) thiophene-2-carboxylate, Cy=cyclohexyl, dba=diben-
zylideneacetone.
boronic acid in THF under sealed-tube microwave condi-
tions at 1358C for 45 minutes to afford 29a in 70% yield.
Solid-phase synthesis: After the validation of our synthetic
strategies in solution, we proceeded to apply the analogous
conditions for the solid-phase synthesis of 1,3,5-triazine ana-
logues. The treatment of bromomethyl resin 30 with thio-
ACHTUNGTRENNUNG
aminopropane 22a[17] to afford urea 23 in 79% yield
(Scheme 6). Subsequent cyclization of 23 with N,N’-thiocar-
bonyldiimidazole under basic conditions furnished thione
24, which was S-methylated with iodomethane in one-pot re-
action to afford triazine 25 in 58% yield (over two steps).
Carbamate deprotection under neutral conditions by using
chlorotrimethylsilane in phenol released the free amine,
which underwent concomitant cyclization to provide bicyclic
triazine 26 in 70% yield. As a result of the poor solubility
of 26 in CH2Cl2, oxidation to the corresponding sulfone 27
was not possible. However, this problem could probably be
circumvented through the solid-phase synthesis of 27, which
would then permit the preparation of bicyclic triazines such
as 28a. In addition to the release of the triazine analogues
under the safety-catch conditions, a solution-phase study
was also carried out on 9a to establish the preliminary Lie-
beskind–Srogl coupling conditions (Scheme 7). We adapted
the microwave-cleavage conditions described by Kaval
AHCTUNGTREGuNNUN rea in DMF at 808C for 3 hours gave the solid-supported
thiouronium hydrobromide salt 31, which is amenable to
monitoring by IR (KBr) spectroscopic analysis for the ap-
pearance of the C=N stretch at n˜ =1647 cmꢀ1 (Scheme 8).
Resin 31 was treated with N-alkyl-N’-aryl carbodiimide in
DMF for 12 h, after which the corresponding carboxylic
acid, tertiary amine, and Mukaiyama reagent were added,
and the reaction mixture was heated at the optimized reac-
tion temperature (Table 1) to yield resin 32, which according
to IR spectroscopic analysis showed a C=N stretch at n˜ =
1628–1635 cmꢀ1. The treatment of resin 32 with DMDO at
ꢀ208C for 10 min gave resin 33. The respective amine was
introduced to the suspension, and the reaction mixture was
shaken at room temperature for 3 hours to yield 11. To dem-
onstrate the versatility of this strategy, a representative set
of 14 compounds were synthesized in overall yields of 12–
40% (Scheme 9). Resin 31 was also treated with CDI and
et al.[18] by treating 9a with 6 mol% [Pd
Cy3P, an excess of the CuI co-catalyst, and 4-methoxyphenyl
2ACHTUNGTRENUN(NG dba)3], 24 mol%
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Solid-Phase Synthesis of 1,3,5-Triazine Analogues
FULL PAPER
Scheme 8. Solid-phase synthesis of 11. i) Thiourea, DMF, 808C, 3 h; ii) N-
alkyl-N’-aryl carbodiimide, DMF, RT, 12 h; iii) R2COOH, Mukaiyama re-
agent, DMAP, tertiary amine, 608C or 1108C, 4 h; iv) DMDO, CH2Cl2,
ꢀ208C, 10 min; v) R3R4NH, CH2Cl2, RT, 3 h.
Scheme 10. Solid-phase synthesis of 2 and 16. i) Thiourea, DMF, 808C,
3 h; ii) CDI, TEA, THF, RT, 2 h; iii) R1NH2, TEA, DMF, 808C, 2 h;
iv) CDI, DIEA, DMF, 1108C, 3 h; v) R2NH2, THF, sealed-tube, micro-
wave irradiation, 1808C, 20 min, 13 bar; vi) DMDO, CH2Cl2, RT, 5 min;
vii) either R2NH2, DMF, 808C, 3 h or R2R3NH, DIEA, DMF, 808C, 3 h;
viii) PMBOH, DiAD, PPh3, THF, 08C!RT, 12 h; ix) DMDO, CH2Cl2,
RT, 10 min; x) ethylenediamine, THF, 508C, 12 h; xi) BnBr, DIEA, DMF,
608C, 5 h; xii) allylamine HCl salt, TEA, DMF, 508C, 12 h. PMBOH=4-
methoxybenzyl alcohol.
responding compound 16. However, this problem was even-
tually resolved by including excess DIEA (i.e., 5 equiv) in
the reaction mixture. Besides the safety-catch cleavage, we
also explored the microwave-assisted cleavage of resin 36 to
give 16 directly (Scheme 10). The results indicate that the
yields obtained from the microwave-assisted cleavage proce-
dure are significantly higher than those from the safety-
catch cleavage procedure (Scheme 11). This outcome is not
surprising because the microwave-assisted cleavage elimi-
nates the side reactions that arise from the hydrolysis of the
sulfone group, which could occur during the safety-catch
cleavage. Next, we sought to increase the diversity at the N1
position on resin 36 by using two different N-alkylation pro-
cedures. In the first approach, a base-promoted alkylation at
N1 with benzyl bromide and a subsequent safety-catch
cleavage reaction gave 2d in 37% overall yield. In the
Scheme 9. Library of compound 11.
TEA in THF at room temperature to afford the solid-sup-
ported thiouronium azolide 34, which in turn was treated
with a primary amine and TEA in DMF under the opti-
mized reaction conditions (Table 2) to yield resin 35. All the
solid-phase transformations were monitored by IR (KBr)
spectroscopic analysis (Scheme 10). Subsequent treatment of
resin 35 with CDI and DIEA at 1108C gave the solid-sup-
ported triazinedione 36, which could be oxidized with
DMDO to yield the solid-supported sulfone 37. The treat-
ment of resin 37 with the respective primary or secondary
amine provided compound 16. Initial attempts to cleave
resin 37 with secondary amines by using the same procedure
as that applied to the primary amines failed to yield the cor-
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Y. Lam et al.
Scheme 12. Solid-phase syntheses of 19, 21, 43, 45, and 47. i) 2,2-Dime-
thoxypropane, TsOH (cat.), DMF, 808C, 4 h; ii) DMDO, CH2Cl2, RT, 3 h;
iii) DMDO, CH2Cl2, ꢀ208C, 5 min; iv) R2NH2, DIEA, DMF, 808C, 12 h;
v) trimethylorthoformate, TsOH (cat.), DMF, 1108C, 4 h; vi) DMDO,
CH2Cl2, ꢀ208C, 10 min; vii) R2NH2, RT, 3 h (one-pot); viii) R2NH2,
DIEA, sealed tube, microwave irradiation, DMF, 1808C, 20 min; ix) 1,1-
dimethoxycyclohexane, TsOH (cat.), DMF, 1108C, 4 h.
Scheme 11. Library of compound 16. Percentage within parentheses indi-
cates overall yield. [a] Yield obtained through microwave-assisted cleav-
age. [b] Yield obtained through safety-catch cleavage.
amine that is used to cleave the substrate from the resin
under the microwave-assisted cleavage conditions.
To demonstrate the generality of this solid-phase method-
ology, the procedure was applied to the synthesis of various
analogues of 19, 21, 43, 45, and 47 (Scheme 13). To extend
the solid-phase synthetic procedure to the preparation of bi-
cyclic triazines, resin 34 was treated with the mono Boc-pro-
tected diamine 22 to yield resin 48, which was then cyclized
with N,N’-thiocarbonyldiimidazole to afford resin 49
(Scheme 14). Subsequent S-methylation and deprotection of
the Boc group gave the solid-supported free amine 51. We
reasoned that the macro environment on the solid support
may be different from that in solution and, thus, resin 51
was treated with DIEA for one hour to complete the base-
promoted intramolecular cyclization reaction to furnish bi-
cyclic triazine 52. Resin 52 was subjected to either the
sealed-tube microwave cleavage with amines to yield bicy-
clic triazine 28 or to the DMDO-mediated hydrolysis to give
bicyclic triazinedione 53. Because DMF is known to under-
go thermal degradation[20] at high temperatures to give di-
methylamine and carbon monoxide (caution: hazardous de-
composition materials), it was possible to harness the dime-
thylamine generated in situ to cleave resin 52 to yield ana-
logues of 28, which contain a N,N-dimethyl substituent at
the point of cleavage. By using this synthetic methodology, a
representative set of 16 analogues of 28 and 53 were pre-
second approach, application of the Mitsunobu N-alkylation
procedure[19] on resin 36 yielded resin 38a, which was
cleaved under the safety-catch cleavage conditions to pro-
vide triazine 2c in 33% overall yield. Compared to an earli-
er reported synthesis of 2c,[7,8b] this solid-phase strategy pro-
vides a more efficient synthesis of 2c. By subjecting resin 35
to an acid-catalyzed cyclization reaction with various or-
thoacetates and acetals, the corresponding solid-supported
triazines 40, 42, and 44 were obtained (Scheme 12), which
could be released from the resin by using either oxidative
activation of the sulphide linker or the sealed-tube micro-
wave-assisted cleavage procedure with primary amines to
give triazines 19, 21, 43, 45, and 47, respectively. Attempts
to apply the microwave-assisted cleavage conditions on
resins 40 and 44 failed to yield the corresponding triazine
product. This outcome led us to conclude that the latter
cleavage conditions could not be used in the presence of an
ꢀ
acidic N H proton on the triazine substrate. This behavior
could be attributed to the stabilization of the sulphide imini-
um bond through back donation of the neighboring lone
pair of electrons on the a-nitrogen into the p* orbital of the
sulphide iminium bond. This back donation stabilizes the
sulphide iminium bond against nucleophilic attack by the
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Chem. Eur. J. 2012, 18, 1476 – 1486

Solid-Phase Synthesis of 1,3,5-Triazine Analogues
FULL PAPER
was demonstrated by using
either the safety-catch or micro-
wave-assisted cleavage proce-
dures of the triazine derivatives
from the solid support. The Lie-
beskind–Srogl coupling condi-
tions were also applied to the
traceless cleavage of the tri-
AHCTUNGTREGaNNNU zine derivatives.
Experimental Section
General procedures: Bromomethyl
resin was purchased from Tianjin
Nankai Hecheng Science and Technol-
ogy Co. (100–200 mesh, 1.5 mmolgꢀ1
,
1% divinylbenzene cross-linking). All
other chemical reagents were pur-
chased from Aldrich, Merck, Lancas-
ter, or Fluka and were used without
further purification. DMDO in anhy-
drous acetone was prepared according
to a reported procedure and its con-
centration was determined prior to
usage.[21] Solid-phase, room-tempera-
ture reactions were agitated on a flask
shaker SF1 (Stuart Scientific). Micro-
wave reactions were carried out using
the Biotage Initiator microwave syn-
thesizer. Analytical TLC was carried
out on precoated plates (Merck silica
gel 60, F254) and visualized with UV
light or stained with iodine or Dragen-
dorff–Munier. Column chromatograph
was performed on silica gel (Merck,
Scheme 13. Library of compounds 19, 21, 43, 45, and 47. Percentage within parentheses indicates overall yield.
[a] Yield obtained through safety-catch cleavage. [b] Yield obtained through microwave-assisted cleavage.
1
70—230 mesh). H and 13C NMR spec-
tra were measured on a Bruker DPX
300 or DPX 500 Fourier Transform
spectrometer. Chemical shifts were re-
ported in d (ppm) relative to the resid-
pared (Scheme 15). As the feasibility of the safety-catch and
microwave-assisted cleavage procedures had been demon-
strated for the solid-phase synthesis of triazines, we proceed-
ed to apply the Liebeskind–Srogl coupling cleavage condi-
tions that had been established earlier in solution on resins
32, 40, and 42 (Scheme 16). This approach gave the corre-
sponding triazine products in moderate overall yields
(Scheme 17). It is worth noting that the use of (biphenyl-4-
yl)vinyl boronic acid in the Liebeskind–Srogl coupling cleav-
age gave significantly lower yields. This outcome is probably
as a result of the steric hindrance of the bulky (biphenyl-4-
yl)vinyl group, which hinders the adoption of the cis confor-
mation between the triazine and alkenyl moieties during the
reductive elimination step.
ual undeuterated solvent, which was used as an internal reference. The
signals observed were described as: s (singlet), d (doublet), t (triplet), or
m (multiplet). The number of protons (n) for a given resonance was indi-
cated as nH. All IR spectra were recorded on a Bio-Rad FTS 165 spec-
trometer. Mass spectra were performed on Finnigan MAT 95/XL-T spec-
trometer under electron impact (EI), electrospray ionization (ESI), or
fast-atom bombardment (FAB) techniques.
Solution-phase synthesis of 2-benzylisothiourea hydrobromide salt 5:
ThioACTHNUTRGNEuNUG rea (1.52 g, 20.0 mmol) dissolved in anhydrous acetonitrile (50 mL)
was treated with benzyl bromide (2.55 mL, 15.0 mmol), and the reaction
mixture was stirred at room temperature for 3 h. The white crystalline
solid, which precipitated in a quantitative amount, was filtered and used
1
without further purification. H NMR: (300 MHz, [D6]DMSO, 258C): d=
9.17 (s, 4H; C=NH2), 7.44–7.29 (m, 5H; ArH), 4.56 ppm (s, 2H;
ArCH2S); 13C NMR (75 MHz, [D6]DMSO, 258C): d=169.0, 135.0, 128.9,
128.7, 127.9, 34.2 ppm; HRMS (ESI): m/z calcd for C8H11N2S+: 167.0637
[M+H]+; found: 167.0643.
General solution-phase synthesis of N-alkyl-N’-aryl thiourea 6: The re-
spective primary amine (12.0 mmol) was added to a solution of phenyl
isothiocyanate (1.30 mL, 12.0 mmol) in anhydrous acetonitrile (120 mL),
and the reaction mixture was stirred at room temperature for 3 h. After-
ward, the reaction mixture was concentrated in vacuo to yield a white
solid. The crude product was washed with cold diethyl ether and filtered
to yield a white solid as 6, which was used in subsequent reactions with-
out further purification.
Conclusion
We have described the use of the solid-supported thiouroni-
um hydrobromide salt 31 as a primary precursor for the
solid-phase synthesis of a broad spectrum of 1,3,5-triazine
derivatives. In the process, the versatility of this approach
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Y. Lam et al.
Scheme 16. Liebeskind–Srogl coupling cleavage of resins 32, 40, and 42.
i) [Pd2ACTHNUGTRNE(UNG dba)3] (3 mol%), Cy3P (24 mol%), CuTC (3 equiv), respective
boronic acid (2.2 equiv), THF, sealed tube, microwave irradiation, 1358C,
45 min.
Scheme 14. Solid-phase synthesis of bicyclic triazines 28 and 53. i) Mono
Boc-protected diamine 22, TEA, DMF, 808C, 30 min; ii) N,N’-thiocarbo-
nyldiimidazole, DIEA, DMF, 608C, 36 h; iii) DIEA, CH3I, THF, RT, 1 h;
iv) phenol/TMSCl (3:1, m), CH2Cl2, RT, 1 h; v) DIEA, THF, RT, 1 h;
vi) DMDO, CH2Cl2, ꢀ208C, 15 min; vii) DMF/H2O (1:5), RT, 2 h;
viii) R1R2NH, DMF, sealed tube, microwave irradiation, 1908C, 20 min,
7–13 bar; ix) DMF, sealed tube, microwave irradiation, 2508C, 14–16 bar,
20 min.
Scheme 17. Library of triazines 29, 54, and 55. Percentage within paren-
theses indicates overall yield.
4 h (Table 1). Thereafter, the reaction mixture was added to brine
(50 mL) and extracted with diethyl ether (3ꢁ20 mL). The combined or-
ganic extracts were dried over MgSO4 and concentrated to yield a yel-
lowish syrup, which was purified by column chromatography to yield 9.
Solution-phase synthesis of (E)-N-butyl-5,6-dimethyl-4-(phenylimino)-
4,5-dihydro-1,3,5-triazin-2-amine (11a): DMDO (0.08m, 2.5 mL) was
added to a chilled solution (ꢀ238C) of 9a (32 mg, 0.1 mmol) in acetone
(4 mL). The reaction mixture was stirred at ꢀ238C for 20 min. Butyla-
mine (50 mL, 0.5 mmol) was added and the reaction mixture was allowed
to warm slowly to room temperature. After 1 h, the reaction was concen-
trated to yield a crude product, which was redissolved in CH2Cl2 (30 mL)
and extracted with aqueous CuSO4 (1m, 10 mL). The combined organic
phases were dried over MgSO4 and concentrated to yield a crude prod-
uct, which was purified by column chromatography with acetone/hexane
(1:4) as the eluent to afford 11a as a clear syrup (73% yield).
Scheme 15. Library of bicyclic triazines 28 and 53. Percentage within pa-
rentheses indicates overall yield.
General procedure for the one-pot solution-phase synthesis of 9: Phenyl-
thiourea (1.2 mmol), the Mukaiyama reagent (0.307 g, 1.2 mmol), and
TEA (0.836 mL, 6 mmol) were dissolved in anhydrous DMF (12 mL).
The solution was allowed to stir for 1 h at room temperature to afford
the corresponding carbodiimide (TLC monitoring). Compound 5
(0.247 g, 1 mmol) was added to the solution of carbodiimide in DMF, and
the reaction mixture was stirred at room temperature for 12 h to afford
an orange solution containing 8. The corresponding carboxylic acid
(1.2 mmol), the Mukaiyama reagent (0.307 g, 1.2 mmol), tertiary amine
(1.2 mmol), and DMAP (24.4 mg, 0.2 mmol) were added, and the reac-
tion mixture was heated to either 608C (R2 =Me) or 1108C (R2 ¼Me) for
Synthesis of benzyl N’-1H-imidazole-1-carbonyl carbamimidothioate
(12): Triethylamine (2.80 mL, 20.0 mmol) and CDI (3.243 g, 20.0 mmol)
were added to a solution of 5 (3.70 g, 15.0 mmol) in anhydrous THF
(50 mL) in a N2 atmosphere. Upon addition of CDI, a white suspension
formed and the reaction mixture was stirred at room temperature for 2 h.
Purification by column chromatography with EtOAc/acetone/hexane
(1:1:1) as the eluent afforded 12 as a white solid (3.600 g, 13.9 mmol,
1482
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1476 – 1486

Solid-Phase Synthesis of 1,3,5-Triazine Analogues
FULL PAPER
93% yield). 1H NMR: (300 MHz, CDCl3, 258C): d=9.42 (s, br, 1H;
NH), 8.25 (s, 1H; N=CH), 7.50 (s, 1H; N=CH), 7.49–6.95 (m, 5H; ArH),
6.95 (s, 1H; N=CH), 4.35 ppm (s, 1H; ArCH2); 13C NMR (75 MHz,
CDCl3, 258C): d=175.7, 155.3, 137.4, 135.8, 129.7, 128.8, 128.6, 127.8,
117.1, 35.2 ppm; HRMS (EI): m/z calcd for C12H12N4OS+: 260.0732 [M]+;
found: 260.0733.
127.43, 50.9, 35.5 ppm; HRMS (ESI): m/z calcd for C17H15N3NaOS+:
332.0828 [M+Na]+; found: 332.0839.
Synthesis of 3-benzyl-6-(benzylthio)-4,4-dimethyl-3,4-dihydro-1,3,5-tri-
ACHUTNGRENaNUG zin-2AHCTUNGTRENN(GUN 1H)-one (18): Compound 13a (2.39 g, 8 mmol), 2,2-dimethoxypro-
pane (9.84 mL, 80 mmol), and para-toluenesulfonic acid monohydrate
(0.304 g, 1.6 mmol) were dissolved in DMF (50 mL), and the reaction
mixture was stirred at 808C for 3 h. Purification by column chromatogra-
phy with acetone/hexane (1:3) as the eluent afforded 18 as a white solid
(2.64 g, 97% yield). 1H NMR: (300 MHz, CDCl3, 258C): d=9.51 (s, 1H;
NH), 7.24–7.09 (m, 10H; ArH), 4.53 (s, 2H; ArCH2), 4.07 (s, 2H;
ArCH2), 1.28 ppm (s, 6H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=
153.3, 149.8, 138.9, 137.2, 129.0, 128.2, 128.2, 127.3, 127.1, 126.8, 76.2,
45.3, 34.3, 28.0 ppm; HRMS (ESI): m/z calcd for C19H21N3NaOS+:
362.1298 [M+Na]+; found: 362.1300.
Synthesis of benzyl N’-benzylcarbamoylcarbamimidothioate (13a): Com-
pound 12 (2.861 g, 11 mmol), benzylamine (2.04 mL, 16.5 mmol), and
triethylamine (3.02 mL, 22 mmol) were dissolved in DMF (50 mL) under
N2 and stirred at 808C for 30 min. Thereafter, the reaction mixture was
concentrated and purified by column chromatography with acetone/
hexane (1:2) as the eluent to afford 13a as a clear syrup (2.9601 g,
9.9 mmol, 90% yield). 1H NMR: (300 MHz, CDCl3, 258C): d=7.23–7.14
(m, 10H; ArH), 4.31 (d, J=6.3 Hz, 2H; ArCH2NH) 4.13 ppm (s, 2H;
ArCH2); 13C NMR (75 MHz, CDCl3, 258C; mixture of tautomers): d=
169.3, 167.8, 163.2, 162.3, 138.6, 136.7, 128.5, 128.2, 128.1, 127.0, 126.9,
126.7, 43.6, 34.3 ppm; HRMS (ESI): m/z calcd for C16H18N3OS+:
300.1165 [M]+; found: 300.1172.
Synthesis of 1-benzyl-6,6-dimethyl-1,3,5-triazinane-2,4-dione (19a): Com-
pound 18 (0.339 g, 1 mmol) was stirred in CH2Cl2 (5 mL) before the addi-
tion of DMDO (25 mL, 0.08m). The reaction mixture was stirred at room
temperature for 15 min. Removal of the solvent in vacuo afforded 19a as
a white solid in quantitative yield (0.231 g, 0.99 mmol).
Synthesis of (E)-benzyl N’-allylcarbamoylcarbamimidothioate (13b): Al-
lylamine hydrochloride (0.21 g, 2.25 mmol) was dissolved in DMF
(10 mL) and Amberlyst A21 (1.5 g) was added to the reaction mixture,
which was shaken at room temperature for 30 min and then transferred
to a 25 mL round-bottom flask. Triethylamine (0.309 mL, 2.25 mmol) and
12 (0.146 g, 0.56 mmol) were added and the reaction mixture was stirred
under N2 at 408C for 1.5 h. Thereafter, the reaction mixture was
quenched with brine (50 mL) and extracted with diethyl ether (3ꢁ
20 mL). The combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo to yield a clear syrup, which was purified by
column chromatography (EtOAc/hexane=1:3) to give 13b as a pungent
clear syrup (94 mg, 67% yield). 1H NMR: (300 MHz, CDCl3, 258C): d=
7.27–7.16 (m, 5H; ArH), 5.77 (m, 1H; NHCH2CHCH2), 5.44 (s, 1H;
NH), 5.12 (dd, J=17.2, 1.4 Hz, 1H; NHCH2CHCH2), 5.03 (dd, J=10.2,
1.4 Hz, 1H; NHCH2CHCH2), 4.16 (s, 2H; ArCH2), 3.76 ppm (t, J=
5.5 Hz, 1H; NHCH2CHCH2); 13C NMR (75 MHz, CDCl3, 258C): d=
168.2, 162.7, 134.7, 128.7, 128.5, 127.3, 115.6, 42.3, 34.6 ppm; HRMS (EI):
m/z calcd for C12H15N3OS+: 249.0936 [M]+; found: 249.0936.
General procedure for the solution-phase synthesis of 22a: Compoun-
d 22a was synthesized according to a procedure reported by Jensen and
co-workers.[17b]
Synthesis of tert-butyl 3-{3-[amino(benzylthio)methylene]ureido}propyl-
carbamate (23): Anhydrous DMF (100 mL), tert-butyl 3-aminopropylcar-
bamate 22a (3.831 g, 22 mmol), and triethylamine (3.08 mL, 22.0 mmol)
were added to 12 (2.861 g, 11.0 mmol) under N2, and the reaction mixture
was stirred at 808C for 30 min. Thereafter, the reaction mixture was dis-
solved in brine (250 mL) and extracted with diethyl ether (3ꢁ100 mL).
The combined organic extracts were dried over MgSO4 and concentrated
in vacuo to yield a clear syrup, which was purified by column chromatog-
raphy with acetone/hexane (1:2) as the eluent to obtain 23 as a clear
syrup (3.18 g, 79% yield).
Synthesis of tert-butyl 3-[4-(benzylthio)-2-oxo-6-thioxo-5,6-dihydro-1,3,5-
triazin-1ACTHNUTRGNEU(GN 2H)-yl]propylcarbamate (24): N,N’-Thiocarbonyldiimidazole
(2.138 g, 12.0 mmol) and DIEA (2.09 mL, 12.0 mmol) were added to 23
(2.93 g, 8.0 mmol) in anhydrous DMF solvent under N2, and the reaction
mixture was stirred at 608C for 36 h. The resultant yellow–red solution
was adsorbed directly onto a small amount of silica gel, concentrated in
vacuo to yield a slurry, and purified by flash column chromatography
with CH2Cl2/EtOAc (7:1) as the eluent to yield a yellowish solid as 24
(2.27 g, 70% yield). Various attempts to purify 24 failed to yield a suffi-
ciently pure product for NMR characterization. HRMS (ESI): m/z calcd
for C18H23N4O3S2ꢀ: 407.1217 [MꢀH]ꢀ; found: 407.1208. Subsequent opti-
mization reactions involved a one-pot S-methylation reaction of 24 to
give 25 in 58% overall yield.
Synthesis of 3-benzyl-6-(benzylthio)-1,3,5-triazine-2,4ACTHNUTRGNEUGN(1H,3H)-dione
(14a): Compound 13a (0.300 g, 1 mmol), DIEA ( 0.348 mL, 2 mmol), and
CDI ( 0.324 g, 2 mmol) were dissolved in DMF (10 mL), and the reaction
mixture was stirred at 1108C for 3 h. The reaction mixture turned gradu-
ally from colorless to pale red. After 3 h, the reaction mixture was con-
centrated in vacuo to yield a white residue, which was purified by column
chromatography with acetone/CH2Cl2 (1:1) as the eluent to yield 14a as a
white solid (0.253 g, 79% yield). 1H NMR: (300 MHz, (CD3)2CO, 258C):
d=7.47–7.24 (m, 10H; ArH), 4.99 (s, 2H; ArCH2), 4.46 ppm (s, 2H;
ArCH2); 13C NMR (75 MHz, (CD3)2CO, 258C): d=167.8, 151.4, 151.3,
137.0, 136.3, 129.1, 128.4, 128.2, 128.1, 127.4, 127.2, 43.9, 33.9 ppm;
HRMS (ESI): m/z calcd for C17H14N3O2Sꢀ: 324.0812 [MꢀH]ꢀ; found:
324. 0807.
Synthesis of tert-butyl 3-[4-(benzylthio)-6-(methylthio)-2-oxo-1,3,5-tri-
A
E
(25):
Methyl
iodide
(1.87 mL,
30.0 mmol), DIEA (5.22 mL, 30.0 mmol), and 24 (2.44 g, 6 mmol) were
added to anhydrous THF (60 mL). The reaction mixture turned from
dark red to light red upon the addition of methyl iodide and was stirred
for 30 min at room temperature. Upon completion of the reaction, the re-
action mixture appeared as a red solution with a yellowish precipitate.
The reaction mixture was concentrated to dryness and purified by
column chromatography with acetone/hexane (1:1) as the eluent to
obtain 25 (2.00 g, 79% yield).
Synthesis of 3-benzyl-6-(butylamino)-1,3,5-triazine-2,4ACTHNUTRGNEUGN(1H,3H)-dione
(16a): DMDO (0.08m, 10 mL) was added to a solution of 14a (0.130 g,
0.4 mmol) in acetone (10 mL), and the reaction mixture was stirred at
room temperature for 5 min to yield 15a. Afterward, the reaction mix-
ture was concentrated in vacuo to yield a white solid, which was redis-
solved in DMF (5 mL). Butylamine (0.197 mL, 2 mmol) was added to the
reaction mixture, which was stirred at 808C for a further 3 h. Thereafter,
the reaction mixture was concentrated in vacuo, adsorbed onto silica gel,
and purified by column chromatography with acetone/hexane (5:2) as the
eluent to yield 16a as a white solid (76 mg, 70% yield).
Synthesis
of
2-(benzylthio)-6,7,8,9-tetrahydropyrimidoACHTUNGTRENNUNG[1,2-a]-
AHCTUNGTERG[NNUN 1,3,5]triazin-4-one (26): The deprotection procedure was adopted from a
procedure reported by Merrifield and co-workers.[22] TMSCl (13.73 mL,
108 mmol) and phenol (29.86 g, 317 mmol) were added to a solution of
25 (2.12 g, 5 mmol) in anhydrous CH2Cl2 (97 mL) under N2, and the reac-
tion mixture was stirred at room temperature for 1 h. Thereafter, the re-
sultant mixture, which appeared as a clear syrup, was adsorbed onto
silica gel, concentrated in vacuo to dryness, loaded onto a silica column,
and purified by column chromatography with EtOAc/hexane (1:1) as the
eluent to elute out the TMSCl/phenol mixture before switching to 2-
propanol/acetone (1:1) with 1% TEA as the eluent to obtain product 26
as a yellowish solid (0.959 g, 70% yield).
Synthesis of 1-benzyl-4-(benzylthio)-1,3,5-triazin-2ACTHNUTRGNEU(GN 1H)-one (17): Com-
pound 13a (2.392 g, 8 mmol), trimethylorthoformate (8.75 mL, 80 mmol),
and para-toluenesulfonic acid monohydrate (0.3044 g, 1.6 mmol) were
dissolved in DMF (50 mL) and stirred at 1108C for 4 h. Purification by
column chromatography with acetone/hexane (1:2) as the eluent afforded
17 as a white solid (1.75 g, 71% yield). 1H NMR: (300 MHz, CDCl3,
258C): d=8.01 (s, 1H; =CH), 7.36–7.27 (m, 10H; ArH), 4.97 (s, 2H;
ArCH2), 4.35 ppm (s, 2H; ArCH2); 13C NMR (75 MHz, CDCl3, 258C):
d=182.9, 156.4, 151.8, 135.8, 133.8, 129.1, 129.0, 128.7, 128.5, 128.3,
Chem. Eur. J. 2012, 18, 1476 – 1486
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1483

Y. Lam et al.
Solution-phase Liebeskind–Srogl coupling for the synthesis of 29a: THF
(3 mL) was charged into a microwave vessel and degassed with argon for
2 min. Compound 9a (0.161 g, 0.5 mmol), [Pd2ACHTNUTRGNE(UNG dba)3] (13.7 mg,
0.015 mmol), CuTC (0.285 g, 1.5 mmol), and the 4-methoxyboronic acid
(0.173 g, 1.15 mmol) were added into the microwave vessel under N2. The
reaction mixture was subjected to microwave irradiation at 1358C for
45 min. The reaction mixture was filtered through a plug of silica gel to
remove the palladium. The filtrate was concentrated to dryness and puri-
fied by column chromatography with EtOAc/hexane (1: 2) as the eluent
to afford 29a (0.107 g, 70% yield).
General procedure for the synthesis of resin 36: Resin 35 (3.5 mmol),
CDI (1.701 g, 10.5 mmol) and DIEA (1.82 mL, 10.5 mmol) were added to
DMF (35 mL) under N2. The reaction mixture was stirred at 1108C for
3 h. Afterward, the resin was filtered; washed thoroughly with DMF (3ꢁ
50 mL), acetone (3ꢁ50 mL), EtOAc (3ꢁ50 mL), CH2Cl2 (3ꢁ50 mL), and
THF (3ꢁ50 mL); and dried for 3 h in a vacuum oven at 408C. IR (KBr):
n˜ =1739 (C=O stretch), 1685 cmꢀ1 (C=N stretch).
General procedure for the synthesis of resin 37: Resin 36 (0.5 mmol) was
swollen in CH2Cl2 at room temperature for 10 min. Thereafter, DMDO
(0.08m, 15.6 mL) was added to the reaction mixture, which was stirred at
room temperature for 5 min. The resin was filtered and dried for 3 h in a
vacuum oven at 408C. IR (KBr): n˜ =1735 (C=O stretch), 1681 cmꢀ1 (C=
N stretch).
General procedure for the synthesis of resin-bound thiouronium hydro-
bromide salt 31: Thiourea (12.0 mmol) was added to a suspension of bro-
momethyl resin 30 (loading=1.5 mmolgꢀ1
, 5.33 g, 8 mol) in DMF
(80 mL) under N2, and the reaction mixture was stirred at 808C for 12 h.
Afterward, the resin was washed with DMF (3ꢁ50 mL), ethanol (3ꢁ
50 mL), acetone (3ꢁ50 mL), EtOAc (3ꢁ50 mL), THF (3ꢁ50 mL),
CH2Cl2 (3ꢁ50 mL), and diethyl ether (3ꢁ50 mL). The resin was dried at
458C under vacuum for 3 h. IR (KBr): n˜ =1647 cmꢀ1 (C=N stretch).
General procedure for the synthesis of 16 with primary amine and resin
37: Resin 37 (0.5 mmol) was swollen in DMF (5 mL) under N2 for
10 min. The corresponding primary amine (2.5 mmol) was added to the
reaction mixture, which was stirred at 808C for 3 h. Afterward, the resin
was filtered and washed thoroughly with DMF (2ꢁ10 mL). The filtrate
and combined washings were concentrated in vacuo and purified by
column chromatography (please refer to the Supporting Information for
the eluent used) to yield 16.
General procedure for the synthesis of resin 32: The respective thiourea
6
(1.2 mmol, 1.2 equiv), the Mukaiyama reagent (0.307 g, 1.2 mmol,
1.2 equiv), and TEA (0.836 mL, 6 mmol, 6 equiv) were dissolved in anhy-
drous DMF (12 mL). The solution was stirred for 1 h at room tempera-
ture to afford the corresponding carbodiimide. Resin 31 (1 mmol) was
added to the solution of carbodiimide under N2, and the reaction mixture
was shaken at room temperature for 12 h to afford an orange suspension.
Afterward, the corresponding carboxylic acid (1.2 mmol), the Mukaiyama
reagent (0.307 g, 1.2 mmol, 1.2 equiv), tertiary amine (1.2 equiv), and
DMAP (24.4 mg, 0.2 mmol, 0.2 equiv) were added. The suspension was
stirred at either 608C (R2 =Me) or 1108C (R2 >Me) for 4 h to yield a
dark-orange/red suspension. Thereafter, the resin was washed with DMF
(3ꢁ20 mL), ethanol (3ꢁ20 mL), acetone (3ꢁ20 mL), EtOAc (3ꢁ20 mL),
THF (3ꢁ20 mL), CH2Cl2 (3ꢁ20 mL), and diethyl ether (3ꢁ20 mL). The
isolated resin was dried at 458C under vacuum for 3 h. IR (KBr): n˜ =
1628–1635 cmꢀ1 (C=N stretch).
General procedure for the synthesis of 16 with secondary amine and
resin 37: Resin 37 (0.5 mmol) was swollen in DMF (5 mL) under N2 for
10 min. The corresponding secondary amine (2.5 mmol) and DIEA
(0.435 mL, 2.5 mmol) were added to the reaction mixture, which was
stirred at 808C for 3 h. Afterward, the resin was filtered and washed thor-
oughly with DMF (2ꢁ10 mL). The filtrate and combined washings were
concentrated in vacuo and purified by column chromatography (please
refer to the Supporting Information for the eluent used) to yield 16.
General procedure for the synthesis of 16 by using microwave-assisted
cleavage: Resin 36 (0.5 mmol) and anhydrous THF (5 mL) were placed
in a 5 mL microwave vessel and the resin was allowed to swell in THF
for 10 min. The corresponding primary amine (2.5 mmol) was added to
the reaction mixture, which was microwave irradiated at 1808C for
20 min at a pressure of 13 bar. Afterward, the reaction mixture was fil-
tered and washed with THF (2ꢁ10 mL). The filtrate and combined wash-
ings were concentrated in vacuo and washed with diethyl ether and ace-
tonitrile to yield 16. If the impurities could not be washed off, the crude
product was purified by column chromatography.
General procedure for the synthesis of resin 33: Resin 32 (1 mmol) was
added to CH2Cl2 (25 mL) and the suspension was left to swell at ꢀ208C
for 20 min before DMDO (0.08m, 25 mL) was added. Afterward, the sus-
pension was stirred at ꢀ208C for 10 min during which the resin turned
from dark red to light orange. The resin was filtered and dried at 458C
under vacuum for 3 h to give resin 33. IR (KBr): n˜ =1628 cmꢀ1 (C=N
stretch).
General procedure for the Mitsunobu N-alkylation of resin 36 to give
resin 38a: Resin 36 (3.22 mmol) was allowed to swell in anhydrous THF
(48 mL) for 10 min. Afterward, PPh3 (1.52 g, 5.79 mmol) and 4-methoxy-
benzyl alcohol (0.679 mL, 5.47 mmol) were added. The reaction mixture
was placed in an ice bath before adding diisopropyl azodicarboxylate
(0.951 mL, 4.83 mmol) dropwise to the reaction mixture, which was
shaken at room temperature for 12 h. The resin was filtered; washed
thoroughly with DMF (3ꢁ50 mL), acetone (3ꢁ50 mL), EtOAc (3ꢁ
50 mL), CH2Cl2 (3ꢁ50 mL), and THF (3ꢁ50 mL); and dried for 3 h in a
vacuum oven at 408C. IR (KBr): n˜ =1735 (C=O stretch), 1681 cmꢀ1 (C=
N stretch).
General procedure for the solid-phase synthesis of 11 from resin 33:
Resin 33 (0.5 mmol) added to the respective amine (2.5 mmol) in CH2Cl2
(5 mL), and the suspension was shaken at room temperature for 3 h. Af-
terward, the resin was removed by filtration and washed with CH2Cl2 (2ꢁ
10 mL). The combined filtrate and washings were concentrated in vacuo
to yield crude 11, which was dissolved in CH2Cl2 (30 mL) and extracted
with aqueous CuSO4 (1m, 1ꢁ10 mL) solution. The organic phase was
dried over MgSO4 and concentrated in vacuo to yield a syrup, which was
purified by column chromatography (please refer to the Supporting In-
formation for the eluent used).
General procedure for the N-alkylation of resin 36 by using alkyl bro-
mide to yield resin 38b: Resin 36 (1 mmol) was allowed to swell in anhy-
drous DMF (10 mL) for 10 min and benzyl bromide (0.594 g, 5 mmol)
and DIEA (0.870 mL, 5 mmol) were added. The reaction mixture was
stirred at 608C for 5 h and turned orange red. Thereafter, the resin was
filtered; washed thoroughly with DMF (3ꢁ20 mL), acetone (3ꢁ20 mL),
EtOAc (3ꢁ20 mL), CH2Cl2 (3ꢁ20 mL), and THF (3ꢁ20 mL); and dried
for 3 h in a vacuum oven at 408C. IR (KBr): n˜ =1735 (C=O stretch),
1681 cmꢀ1 (C=N stretch).
Synthesis of 1H-imidazole-1-carbonyl carbamimidothioate resin 34:
Resin 31 (5.681 g, 7.5 mmol), triethylamine (1.51 mL, 11.0 mmol), and
N,N’-carbonyldiimidazole (1.784 g, 11.0 mmol) were added to anhydrous
THF (100 mL) under N2, and the reaction mixture was shaken at room
temperature for 2 h. Afterward, the resin was filtered; washed thoroughly
with DMF (3ꢁ100 mL), ethanol (3ꢁ100 mL), acetone (3ꢁ100 mL), ethyl
acetate (100 mL x 3), and THF (3ꢁ100 mL); and dried for 3 h in a
vacuum oven at 408C. IR (KBr): n˜ =1734 (C=O stretch), 1681 cmꢀ1 (C=
N stretch).
General procedure for the synthesis of resin 39: The corresponding resin
38 (1 mmol) was allowed to swell in CH2Cl2 (10 mL) for 10 min and
DMDO (0.08m, 25 mL) was added. The reaction mixture was stirred for
10 min to allow 38 to fully oxidize to resin 39 before the resin was filtered
and dried for 3 h in a vacuum oven at 408C. IR (KBr): n˜ =1734 (C=O
stretch), 1682 cmꢀ1 (C=N stretch).
General procedure for the synthesis of resin 35: Resin 34 (2.65 g,
3.50 mmol), triethylamine (0.96 mL, 7 mmol), and the respective primary
amine (5.25 mmol) were added to DMF (30 mL) under N2, and the reac-
tion mixture was stirred at 808C for 2 h. Afterward, the resin was fil-
tered; washed thoroughly with DMF (3ꢁ50 mL), acetone (3ꢁ50 mL),
EtOAc (3ꢁ50 mL), CH2Cl2 (3ꢁ50 mL), and THF (3ꢁ50 mL); and dried
for 3 h in a vacuum oven at 408C. IR (KBr): n˜ =1637 (C=O stretch),
1596 cmꢀ1 (C=N stretch).
Procedure for the synthesis of 2c: Resin 39a (1.198 mmol) was allowed
to swell in anhydrous THF (10 mL) for 10 min and ethylenediamine
1484
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1476 – 1486

Solid-Phase Synthesis of 1,3,5-Triazine Analogues
FULL PAPER
(0.433 mL, 5.4 mmol) was added. The reaction mixture was stirred at
508C for 12 h to yield a white precipitate. Thereafter, the resin was fil-
tered and washed thoroughly with THF (2ꢁ10 mL). The filtrate and
combined washing were concentrated in vacuo to yield a translucent resi-
due, which was redissolved in EtOAc (50 mL) and extracted with de-ion-
ised water (2ꢁ20 mL). The organic phase was dried over Na2SO4 and
concentrated to yield a yellow syrup, which was purified by using prepa-
rative reverse-phase HLPC 0–100%, 0–35 min (H2O/acetonitrile) to yield
2c as a clear syrup (overall yield: 33%). 1H NMR: (500 MHz, CD3OD,
258C): d=7.28–6.83 (m, 8H; ArH), 5.05 (s, 2H; ArCH2N), 4.96 (s, 2H;
ArCH2N), 3.71 (s, 3H; ArOCH3), 3.64 (t, J=5.5 Hz, 2H;
NHCH2CH2NH2), 3.12 (t, J=5.6 Hz, 2H; NCH2CH2NH2), 2.56 (q, J=
7.5 Hz, 2H; ArCH2CH3), 1.16 ppm (t, J=7.5 Hz, 3H; ArCH2CH3);
13C NMR (75 MHz, CD3OD, 258C): d=160.7, 157.1, 156.6, 152.5, 144.8,
135.4, 129.3, 129.0, 128.7, 127.5, 115.1, 55.6, 46.2, 45.9, 40.4, 40.3, 29.4,
16.1 ppm; HRMS (ESI): m/z calcd for C22H28N5O3+: 410.2187 [M+H]+;
found: 410.2190.
General procedure for the solid-phase synthesis of 21: Resin 41
(0.5 mmol) was added to DMF (15 mL) together with diisopropylethyla-
mine (0.44 mL, 2.5 mmol) and the respective amine (2.5 mmol). The reac-
tion mixture was stirred at 808C for 12 h. The resin was filtered and
washed with DMF (3ꢁ20 mL). The combined filtrate and washings were
concentrated to dryness and purified by column chromatography using
EtOH/CH2Cl2 (1:10) with 1% glacial acetic acid as the eluent. It should
be noted that azeotropic removal of the acetic acid additive is necessary
to afford purified 21.
General procedure for the solid-phase synthesis of 43 by using micro-
wave-assisted cleavage: Resin 42 (0.5 mmol), diisopropylethylamine
(0.44 mL, 2.5 mmol), and the respective amine (2.5 mmol) were added to
DMF (12 mL) in a microwave vessel and sealed. The mixture was micro-
wave irradiated at 1808C for 20 min. The resin was filtered and washed
with DMF (3ꢁ20 mL). The filtrate was concentrated to dryness and puri-
fied by column chromatography with acetone/hexane (1:3) with 1% gla-
cial acetic acid as the eluent. It should be noted that azeotropic removal
of acetic acid additive was necessary to afford purified 43.
Procedure for the synthesis of 2d: Resin 39b (0.701 g, 0.760 mmol) was
allowed to swell in anhydrous DMF (10 mL) for 10 min and allylamine
hydrochloride salt (0.355 g, 3.8 mmol) and TEA (1.04 mL, 7.6 mmol)
were added. The reaction mixture was stirred at 508C for 12 h. There-
after, the resin was filtered and washed thoroughly with DMF (2ꢁ
10 mL). The filtrate and combined washing were concentrated in vacuo
and purified by column chromatography using EtOAc/acetone/hexane
(1:1:2) as the eluent to yield 2d as a clear syrup (overall yield: 37%).
1H NMR: (300 MHz, CDCl3, 258C): d=7.43–7.18 (m, 10H; ArH), 6.37
(br, 1H; NH), 5.64 (m, 1H; NCH2CHCH2), 5.12 (s, 2H; ArCH2N), 5.04
(s, 2H; ArCH2N), 4.91 (d, J=10.3 Hz, 1Hcis; NCH2CHCH2), 4.79 (d, J=
General procedure for the solid-phase synthesis of 43 by using the safety-
catch methodology: Resin 42 (0.5 mmol) was stirred in CH2Cl2 (15.6 mL)
at ꢀ208C for 10 min. Thereafter, DMDO (0.08m, 15.6 mL) was added to
the reaction mixture, which stirred at ꢀ208C for 10 min. Thereafter, the
corresponding amine (1.25 mmol) was added to the reaction mixture,
which was stirred at room temperature for a further 3 h. The resin was
filtered and washed with CH2Cl2 (3ꢁ20 mL). The filtrate was concentrat-
ed to dryness and purified by column chromatography using acetone/
hexane (1:3) with 1% glacial acetic acid as the eluent. It should be noted
that azeotropic removal of acetic acid additive was necessary to afford
purified 43.
17.1 Hz, 1Htrans
;
NCH2CHCH2), 3.90 ppm (t, J=5.2 Hz, 2H;
HNCH2CHCH2); 13C NMR (75 MHz, CDCl3, 258C): d=154.9, 153.8,
151.4, 136.7, 134.1, 132.7, 129.0, 128.5, 128.2, 128.2, 127.4, 126.5, 116.3,
45.4, 45.2, 43.8 ppm; HRMS (ESI): m/z calcd for C20H20N4O2Na+:
317.1478 [M+Na]+; found: 371.1485.
General procedure for the solid-phase synthesis of 45: Resin 44
(0.5 mmol) was swollen in CH2Cl2 (8 mL) for 30 min and DMDO
(15.7 mL, 0.08m) was added. The reaction mixture was stirred at room
temperature for 3 h. Filtration of the mixture followed by solvent remov-
al in vacuo afforded 45 directly.
General procedure for the synthesis of resin 40: Resin 35 (3.5 mmol),
2,2-dimethoxypropane (4.30 mL, 35.0 mmol), and para-toluenesulfonic
acid monohydrate (0.133 g, 0.7 mmol) were added to anhydrous DMF
(15 mL) under N2. The reaction mixture was stirred at 808C for 4 h. The
resin was washed with DMF (3ꢁ20 mL), acetone (3ꢁ20 mL), EtOAc
(3ꢁ20 mL), CH2Cl2 (3ꢁ20 mL), THF (3ꢁ20 mL), and diethyl ether (3ꢁ
20 mL) and dried under vacuum overnight. IR (KBr): n˜ =1676 (C=O
stretch), 1645 cmꢀ1 (C=N stretch).
General procedure for the solid-phase synthesis of 47: Resin 44
(0.7 mmol) was swollen in CH2Cl2 (8 mL) at ꢀ208C for 20 min and
DMDO (25 mL, 0.08m) was added. The reaction mixture was stirred at
ꢀ208C for 10 min. The resin was quickly filtered, washed with EtOAc
(3ꢁ20 mL), and dried under vacuum for 4 h to obtain resin 46. IR (KBr):
n˜ =1735 (C=O stretch), 1698 cmꢀ1 (C=N stretch). Resin 46 (0.5 mmol)
was added to DMF (15 mL) together with DIEA (0.44 mL, 2.5 mmol)
and the corresponding amine (2.5 mmol). The reaction mixture was
stirred at 808C for 12 h. The resin was filtered and washed with DMF
(3ꢁ20 mL). The filtrate was concentrated to dryness and purified by
column chromatography with EtOH/CH2Cl2 (1:20) with 1% glacial acetic
acid as the eluent. It should be noted that azeotropic removal of acetic
acid additive was necessary to afford purified 47.
General procedure for the synthesis of resin 41: Resin 40 (0.7 mmol) was
swollen in CH2Cl2 (8 mL) at ꢀ208C for 20 min and DMDO (25 mL,
0.08m) was added. The resin mixture was stirred at ꢀ208C for 5 min. The
resin was quickly filtered, washed with EtOAc (3ꢁ20 mL), and dried
under vacuum for 4 h. IR (KBr): n˜ =1699 cmꢀ1 (C=O stretch and C=N
stretch).
General procedure for the synthesis of resin 42: Resin 35 (3.5 mmol), tri-
methyl orthoformate (4.20 mL, 35.0 mmol) and para-toluenesulfonic acid
monohydrate (0.133 g, 0.7 mmol) were added to anhydrous DMF
(15 mL) under N2. The reaction mixture was stirred at 1108C for 4 h. The
resin was washed with DMF (3ꢁ20 mL), acetone (3ꢁ20 mL), EtOAc
(3ꢁ20 mL), CH2Cl2 (3ꢁ20 mL), THF (3ꢁ20 mL), and diethyl ether (3ꢁ
20 mL) and dried under vacuum overnight. IR (KBr): n˜ =1702 (C=O
stretch), 1596 cmꢀ1 (C=N stretch).
General procedure for the synthesis of resin 48: Compound 22
(14.4 mmol) and triethylamine (2 mL, 14.4 mmol) were added to resin 34
(7 mmol) in anhydrous DMF (70 mL) under N2. The reaction mixture
was stirred at 808C for 30 min. Thereafter, the resin was washed with
DMF (3ꢁ50 mL), acetone (3ꢁ50 mL), ethyl acetate (3ꢁ20 mL), CH2Cl2
(3ꢁ20 mL), THF (3ꢁ20 mL), and diethyl ether (3ꢁ20 mL). The resin
was dried under vacuum for 3 h. IR (KBr): n˜ =1686 (C=O stretch),
1601 cmꢀ1 (C=N stretch).
General procedure for the synthesis of resin 44: Resin 35 (3.5 mmol),
1,1-dimethoxycyclohexane (5.30 mL, 35.0 mmol) and para-toluenesulfon-
ic acid monohydrate (0.133 g, 0.7 mmol) were added to anhydrous DMF
(15 mL) under N2. The reaction mixture was stirred at 1108C for 4 h. The
resin was washed with DMF (3ꢁ20 mL), acetone (3ꢁ20 mL), EtOAc
(3ꢁ20 mL), CH2Cl2 (3ꢁ20 mL), THF (3ꢁ20 mL), and diethyl ether (3ꢁ
20 mL) and dried under vacuum overnight. IR (KBr): n˜ =1672 (C=O
stretch), 1654 cmꢀ1 (C=N stretch).
General procedure for the synthesis of resin 49: DIEA (1.73 mL,
10.5 mmol), N,N’-thiocarbonyldiimidazole (1.86 g, 10.5 mmol), and resin
48 (7 mmol) were added to anhydrous DMF (70 mL) under N2. The reac-
tion mixture was stirred at 608C for 36 h. Afterward, the resin was
washed with DMF (3ꢁ50 mL), acetone (3ꢁ50 mL), EtOAc (3ꢁ50 mL),
CH2Cl2 (3ꢁ50 mL), THF (3ꢁ50 mL), and diethyl ether (3ꢁ50 mL). The
resin was dried under vacuum for 3 h. IR (KBr): n˜ =1710 cmꢀ1 (C=O
stretch).
General procedure for the solid-phase synthesis of 19: Resin 40
(0.5 mmol) was swollen in CH2Cl2 (8 mL) for 30 min and DMDO
(15.7 mL, 0.08m) was added. The reaction mixture was stirred at room
temperature for 3 h. Filtration of the reaction mixture followed by sol-
vent removal in vacuo afforded 19 directly.
General procedure for the synthesis of resin 50: Methyl iodide (1.85 mL,
30 mmol), DIEA (5.2 mL, 30 mmol), and resin 49 (6 mmol) were added
to THF (60 mL), and the reaction mixture was shaken at room tempera-
ture for 1 h. Afterward, the resin was washed with DMF (3ꢁ50 mL), ace-
tone (3ꢁ50 mL), EtOAc (3ꢁ50 mL), CH2Cl2 (3ꢁ50 mL), THF (3ꢁ
Chem. Eur. J. 2012, 18, 1476 – 1486
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1485

Y. Lam et al.
50 mL), and diethyl ether (3ꢁ50 mL). The resin was dried under vacuum
Paquin, S. Raeppel, S. Leit, F. Gaudette, N. Zhou, O. Moradei, O.
Saavedra, N. Bernstein, F. Raeppel, G. Bouchain, S. Frechette, S. H.
Woo, A. Vaisburg, M. Fournel, A. Kalita, M.-F. RobeRT, A. Lu, M.-
C. Trachy-Bourget, P. T. Yan, J. Liu, J. Rahil, A. R. MacLeod, J. M.
Besterman, Z. Li, D. Delorme, Bioorg. Med. Chem. Lett. 2008, 18,
1067–1071; d) M. Zheng, C. Xu, J. Ma, Y. Sun, F. Du, H. Liu, L.
Lin, C. Li, J. Ding, K. Chen, H. Jiang, Bioorg. Med. Chem. 2007, 15,
1815–1827; e) S. Mandal, G. Berube, E. Asselin, I. Mohammad, V. J.
Richardson, A. Gupta, S. K. Pramanik, A. L. Williams, S. K.
Mandal, Bioorg. Med. Chem. Lett. 2007, 17, 4955–4960.
[2] a) T. Seki, Y. Yagai, T. Karatsu, A. Kitamura, J. Org. Chem. 2008,
73, 3328–3335; b) G. M. Whitesides, E. E. Simanek, J. P. Mathias,
C. T. Seto, D. Chin, M. Mammen, D. M. Gordon, Acc. Chem. Res.
1995, 28, 37–44; c) J. A. Zerkowski, C. T. Seto, G. M. Whitesides, J.
Am. Chem. Soc. 1992, 114, 5473–5475.
[3] J. Lim, E. E. Simanek, Org. Lett. 2008, 10, 201–204.
[4] S.-I. Um, Y. Kang, J.-K. Lee, Dyes Pigm. 2007, 75, 681–686.
[5] J. Chen, X. Wang, Y. Shao, J. Zhu, Y. Zhu, Y. Li, Q. Xu, Z. Guo,
Inorg. Chem. 2007, 46, 3306–3312.
[6] D. Pawlak, M. Adamkiewicz, J. Malyszko, A. takada, M. Mysliwiec,
W. Buczko, J. Cardiovasc. Pharmacol. 1998, 32, 266–273.
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Schultz, Patent WO2006104713, 2006.
for 3 h at 508C. IR (KBr): n˜ =1710 cmꢀ1 (C=O stretch).
General procedure for the synthesis of resin 51: TMSCl (13.7 mL,
10.8 mmol) and phenol (29.8 g, 31.7 mmol) were added to resin 50
(5.00 mmol) in anhydrous CH2Cl2 (97.0 mL) under N2, and the reaction
mixture was shaken at room temperature for 1 h. Afterward, the resin
was washed with DMF (3ꢁ30 mL), acetone (3ꢁ30 mL), EtOAc (3ꢁ
30 mL), CH2Cl2 (3ꢁ30 mL), THF (3ꢁ30 mL), and diethyl ether (3ꢁ
30 mL). The resin was dried under vacuum at 508C for 3 h. IR (KBr):
n˜ =1684 cmꢀ1 (C=O stretch).
General procedure for the synthesis of resin 52: DIEA (8 mmol,
1.39 mL) was added to resin 51 (4 mmol) in anhydrous THF (40 mL)
under N2. The reaction mixture was shaken at room temperature for 1 h.
Afterward, the resin was filtered and washed with DMF (3ꢁ50 mL), ace-
tone (3ꢁ50 mL), ethyl acetate (3ꢁ50 mL), CH2Cl2 (3ꢁ50 mL), THF (3ꢁ
50 mL), and diethyl ether (3ꢁ50 mL). The resin was dried under vacuum
at 508C for 3 h. IR (KBr): n˜ =1685 (C=O stretch), 1598 cmꢀ1 (C=N
stretch).
General procedure for the microwave-assisted synthesis of 2-
(alkylamino)bicycloACHTUNGTRENNUNG[1,3,5]triazin-4-one (28ai–28aiv, 28bi–28biv, and
28ci–28ciii) from resin 52: Resin 52 (1 mmol) and the respective amine
(10 mmol) were added to DMF (5 mL) in a 5 mL microwave vessel. The
microwave vessel was sealed and subjected to microwave irradiation at
1908C for 20 min (pressure=7–13 bar). Afterward, the reaction mixture
was filtered and the resin washed with DMF (2ꢁ10 mL). The filtrate and
combined washings were concentrated in vacuo to yield a yellow/brown
residue, which was purified by column chromatography.
[8] a) E. D. Brown, Eur. Pat. Appl. EP 300756, 1979; b) G. Balboni, I.
Lazzari, C. Trapella, L. Negri, R. Lattanzi, E. Giannini, A. Nicotra,
P. Melchiorri, S. Visentin, C. D. Nuccio, S. Salvadori, J. Med. Chem.
2008, 51, 7635–7639.
[9] V. Garaj, L. Puccetti, G. Fasolis, J.-Y. Winum, J.-L. Montero, A.
Scozzafava, D. Vullo, A. Innocenti, C. T. Supuran, Bioorg. Med.
Chem. Lett. 2005, 15, 3102–3108.
General procedure for
the
solid-phase
synthesis
of
2-
(dimethylamino)bicycloACHTUNGTRENNUNG[1,3,5]triazin-4-one (28av, 28bv, and 28civ) from
resin 52: Anhydrous DMF (5 mL) was added to resin 52 (1 mmol) in a
5 mL microwave vessel. The microwave vessel was sealed and microwave
irradiated at 2508C for 20 min (pressure=14–16 bar). Afterward, the re-
action mixture was filtered and washed with DMF (2ꢁ10 mL). The com-
bined filtrate and washings were concentrated in vacuo to yield a yellow
solid, which was purified by column chromatography (please refer to the
Supporting Information for the eluent used).
[10] R. B. Hargreaves, B. J. McLoughlin, S. D. Mills, US Pat. 5332737,
1990.
[11] a) J. L. Ralbovsky, J. G. Lisko, J. M. Palmer, J. Mabus, K. M. Cheva-
lier, M. J. Schulz, A. B. Dyatkin, T. A. Miskowski, S. J. Coats, P.
Hornby, W. He, Bioorg. Med. Chem. Lett. 2009, 19, 2661–2663;
b) K.-H. Kong, C.-K. Tan, Y. Lam, J. Comb. Chem. 2009, 11, 1050–
1060; c) A. Gopalsamy, H. Yang, J. Comb. Chem. 2001, 3, 278–283;
d) Y. P. Yu, J. M. Ostresh, R. A. Houghten, J. Comb. Chem. 2004, 6,
83–85; e) Y. P. Yu, J. M. Ostresh, R. A. Houghten, Tetrahedron
2002, 58, 3349–3353.
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Org. Lett. 2003, 5, 117–120; b) S. M. Khersonsky, Y.-T. Chang, J.
Comb. Chem. 2004, 6, 474–477; c) G. Blotny, Tetrahedron 2006, 62,
9507–9522.
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576.
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[16] The transformation of 15a was monitored by using TLC and nomi-
nal mass-spectrometric analysis as a result of the labile nature of
15a.
[17] a) D. M. Kneeland, K. Ariga, V. M. Lynch, C. Y. Huang, E. V.
Anslyn, J. Am. Chem. Soc. 1993, 115, 10042–10055; b) K. B. Jensen,
T. M. Braxmeier, M. Demarcus, J. G. Frey, J. D. Kilburn, Chem. Eur.
J. 2002, 8, 1300–1309.
General procedure for the solid-phase synthesis of bicycloACTHNUTRGNE[NUG 1,3,5]triazine-
2,4-dione 53 from resin 52: Resin 52 (1 mmol) was swollen in CH2Cl2
(25 mL) at ꢀ208C for 10 min. Afterward, DMDO (0.08m, 25 mL) was
added and the reaction mixture was stirred for another 15 min. There-
after, a mixture of DMF/H2O (1:5, 20 mL) was added and the reaction
mixture was stirred at room temperature for 2 h to generate a pale-
brown solid, which was filtered and washed with MeOH to yield a white
solid.
General procedure for the solid-phase Liebeskind–Srogl coupling for the
synthesis of 29, 54, and 55: THF (3 mL) was charged into a microwave
vessel and degassed with argon for 2 min. Resin 32, 40, or 42 (0.5 mmol),
[Pd2ACHTUNGTRENNUNG(dba)3] (13.7 mg, 0.015 mmol), CuTC (0.285 g, 1.5 mmol), and the re-
spective boronic acid (1.15 mmol) were added to the microwave vessel
under N2. The reaction mixture was subjected to microwave irradiation
at 1358C for 45 min. The reaction mixture was filtered through a plug of
silica gel to remove the palladium. The filtrate was concentrated to dry-
ness and purified by column chromatography (please refer to the Sup-
porting Information for the eluent used) to afford 29, 54, or 55.
[18] N. Kaval, B. K. Singh, D. S. Ermolat’ev, S. Claerhout, V. S. Parmar, J.
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Acknowledgements
The authors thank A*Star for the funding provided (BMRC grant R-
143–000–348–305).
[20] J. Juillard, Pure Appl. Chem. 1977, 49, 885–892.
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Chang, N. R. Kallenbach, Bioorg. Med. Chem. Lett. 2008, 18, 1308–
1311; b) K. Srinivas, U. Srinivas, K. Bhanuprakash, K. Harakishore,
U. S. N. Murthy, V. J. Rao, J. Med. Chem. 2006, 41, 1240–1246; c) I.
Received: July 8, 2011
Revised: September 9, 2011
Published online: December 27, 2011
1486
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1476 – 1486