Generation of molecular diversity using a complexity-generating MCR-platform towards triazinane diones

Article abstract of DOI:10.1039/b807138a

Triazinane diones, readily generated by a recently reported multicomponent reaction, can be easily alkylated with various alkyl halides, allowing a wide variety of complexity-generating secondary reactions. Because of the high variability of the initial multicomponent reactions and the multiple possibilities for participation of substituents in the secondary reactions, a highly diverse set of complex products was obtained in short and efficient reaction sequences.

Full text of DOI:10.1039/b807138a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Generation of molecular diversity using a complexity-generating
MCR-platform towards triazinane diones†
Bas Groenendaal,a Eelco Ruijter,a Frans J. J. de Kanter,a Martin Lutz,b Anthony L. Spekb and
Romano V. A. Orru*a
Received 28th April 2008, Accepted 5th June 2008
First published as an Advance Article on the web 3rd July 2008
DOI: 10.1039/b807138a
Triazinane diones, readily generated by a recently reported multicomponent reaction, can be easily
alkylated with various alkyl halides, allowing a wide variety of complexity-generating secondary
reactions. Because of the high variability of the initial multicomponent reactions and the multiple
possibilities for participation of substituents in the secondary reactions, a highly diverse set of complex
products was obtained in short and efficient reaction sequences.
The MCR platform that we chose for this work is a one-
Introduction
pot synthetic protocol towards triazinane diones 1, a rather
unexplored class of heterocyclic scaffolds (Scheme 1).7,8 The four-
component reaction (4CR) combines phosphonate 2, nitriles 3,
aldehydes 4 and isocyanates 5 and proceeds with remarkable
efficiency and flexibility. Furthermore, subsequent alkylation of
5 proved successful and allows attachment of additional synthetic
handles.
Combination of this 4CR with additional complexity-
generating reactions, e.g., ring-closing metathesis (RCM),9 cy-
cloaddition reactions (Huisgen10 or Diels–Alder11), or isonitrile-
based MCRs (I-MCR)5 enables rapid access to highly com-
plex (poly)heterocyclic scaffolds with pharmaceutically interesting
cores.
Recent advances in genomics, proteomics, metabolomics, and
structural biology highlight a clear need for small molecules that
can modulate biological processes.1 Combinatorial synthesis is
undisputed as an enabling tool to access the required small-
molecule based compound collections. Although the benefit for
drug discovery seems obvious, the actual hit rates for new drug
candidates have decreased steadily over the past decade.2 It has
become clear that not only the number of molecules but also
the structural diversity and molecular complexity of the chosen
scaffolds are key issues to address in the design of a compound
library.3
Rapid generation of diverse sets of complex molecules can be
achieved by employing diversity-oriented synthetic strategies in
combination with complexity-generating reactions.4 Multicompo-
nent reactions (MCRs), which combine in one pot at least three
simple building blocks,5,6 provide a most powerful platform to
access diversity as well as complexity in a limited number of
reaction steps. Here we describe modular reaction sequences based
on our previously reported MCR chemistry7,8 in combination with
other common organic reactions or even with a second MCR.
Results and discussion
The triazinane dione 1a was chosen as the heterocyclic platform
and our attention initially focused on the combination with
additional MCRs. The isonitrile-based Ugi four-component (U-
4CR)5,6,12 and Passerini three-component (P-3CR)13 reactions,
widely used to generate complex peptide-like products, were
considered as candidate reactions to achieve fast complexity
generation. Thus, as described before,7 the 4CR of 2, 3a, 4a and
5a gave the triazinane dione 1a efficiently. The amide NH was
alkylated (NaH, tert-butyl 2-bromoacetate, DMF) to give tert-
butyl ester 6 in 75% yield. Subsequently, removal of the tert-
butyl group with TFA in CH2Cl2 afforded carboxylic acid 7 in
quantitative yield.
aDepartment of Chemistry and Pharmaceutical Sciences, Vrije Universiteit
Amsterdam, De Boelelaan 1083, 1081, HV, Amsterdam, The Netherlands.
E-mail: orru@few.vu.nl; Fax: +31 20 5987488; Tel: +31 20 5987447
bBijvoet Center for Biomolecular Research, Crystal and Structural Chem-
istry, Utrecht University, Padualaan 8, 3584, CH, Utrecht, The Netherlands
† Electronic supplementary information (ESI) available: 1H and 13C-NMR
spectra of all new compounds. CCDC reference number 686384. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b807138a
The acid 7 was employed in either an U-4CR or a P-3CR
(Scheme 2). The U-4CR was performed in MeOH at room
Scheme 1 4CR for triazinane diones as versatile platform for complexity generation.
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Scheme 2 Alkylation and then U-4CR or P-3CR reactions.
temperature using isobutyraldehyde, benzylamine or allylamine,
the triazinane dione acid 7 and tert-butyl isocyanide. This indeed
gave the expected peptide-derived triazinane diones 8a and 8b,
respectively, in reasonable to good isolated yields. The P-3CR of
isobutyraldehyde, acid 7 and tert-butyl isocyanide was performed
in CH2Cl2 at room temperature and afforded the corresponding
peptide-like 9 in 62% isolated yield. Thus, combination of our 4CR
and these isonitrile-based MCRs in a short synthetic sequence
(four steps) allows for rapid construction of rather complex,
peptide-functionalized heterocycles. Both the initial 4CR, which
generates the heterocyclic scaffold, as well as the U-4CR and the
P-3CR are easy to perform and compatible with a large variety
of differently functionalized inputs. This makes this four-step
sequence amenable for a combinatorial set-up to generate libraries
of peptidyl triazinane diones of type 8 or 9.
Next, our attention focused on the construction of highly func-
tionalized bi- or polycyclic ring systems. Combination of the initial
triazinane dione-generating 4CR with RCM or cycloaddition
reactions was envisioned as a powerful strategy to achieve this
goal. Thus, allylation of 1a to afford 10 and subsequent RCM
using the 2nd generation Grubbs’ catalyst14 in CH2Cl2 resulted in
the bicyclic triazinane dione 11 (64%, Scheme 3).
To further explore the potential of the triazinane dione scaffold
as a versatile platform for additional cyclization reactions, a
[2 + 3] Huisgen cycloaddition (click reaction)15,16 was considered.
Propargylation of the free NH in 1a (NaH, propargyl bromide,
DMF; Scheme 3) gave the desired product 12 in 60% isolated
yield. Then, the click reaction of 12 and readily available b-
glucosyl azide derivative 13 was performed in a H2O–t-BuOH–
MeCN mixture with CuSO4 and sodium ascorbate as the catalyst
Scheme 3 Alkylation and then RCM or click reactions.
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and co-catalyst, respectively.15 The cycloaddition product 14 was
obtained in a reasonable yield of 55%. Again, combination of our
initial 4CR for triazinane diones and these cyclization protocols
allow rapid complexity generation in a short synthetic sequence
(three steps). The RCM and the [2 + 3] Huisgen cycloaddition
are well established and robust reactions that are compatible
with a wide variety of different functionalities. This opens the
way for easy generation of diversified sets of xanthine-like17
annelated bicyclic cores 11 or non-natural nucleoside mimics of
type 14.18
Furthermore, a strategy based on the 4CR for triazinane
diones and an intramolecular Diels–Alder (IMDA) reaction was
envisioned to access the desired diversity and complexity of func-
tionalized polycyclic ring systems in a highly efficient manner.19
For this purpose, we decided to introduce the required dienophile
on a furan-functionalized triazinane dione (1b) platform. The
four-component synthesis of 1b proceeded smoothly following
the general procedure reported by us earlier.7 Next, reaction of 1b
with methyl E-4-bromo-2-butenoate in DMF after deprotonation
with NaH would lead to 15, which could then be subjected to
heating to give the IMDA product. However, the anticipated
IMDA reaction appears to proceed readily at room temperature
and occurs immediately after alkylation of 1b with the dienophile.
The intermediate alkylation product 15 was not observed. Thus,
the desired polycyclic IMDA product 16a is formed in a very
efficient one-pot domino process and could be isolated in 50%
yield (Scheme 4). The structure of 16a including the relative
stereochemistry is predicted by orbital symmetry considerations
and was unambiguously confirmed by NOESY and X-ray crystal
structure determination (Fig. 1).
Fig. 1 Displacement ellipsoid plot of racemic 16a, drawn at the 50% prob-
ability level, indicating the stereochemistry between hydrogens A1–A2,
A1–B, A2–C, B–C and C–D. Other hydrogen atoms are omitted for clarity.
between the corresponding hydrogens in 16a. Also, the coupling
constants of the various hydrogens in 16a (A1–B = 9.5 Hz; A2–
B = 7.3 Hz; B–C = 2.9 Hz; C–D = 4.8 Hz) are comparable
to those observed in 16b and 16c, indicating that the relative
stereochemistry of all three compounds is the same.
Thus, combination of our 4CR with an alkylation–IMDA
domino reaction yields a very efficient strategy to access highly
functionalized polycyclic cores in only two reaction steps.
Conclusions
In summary, the 4CR for triazinane diones provides a versatile
platform that can be applied in combination with additional
MCRs, RCM, [2 + 3] cycloaddition and IMDA reactions. This
results in very short reaction sequences (maximum of four) to gen-
erate both diversity and complexity. In some cases, diversification
is based solely on the N-alkyl functionality, while in other cases
various functional groups on the triazinane dione participate in
the secondary reactions, thus leading to increased scaffold diversi-
fication. Combination of both approaches leads to higher overall
diversity and therefore to a better coverage of chemical space. This
strategy will prove useful in the design of combinatorial libraries
based on highly functionalized heterocyclic small molecules.
Experimental
General information
Scheme 4 A domino alkylation–IMDA reaction.
All reactions were carried out under an inert atmosphere of dry ni-
trogen. THF was dried and distilled from sodium–benzophenone
prior to use, CH2Cl2 was dried and distilled from CaCl2 prior
to use. Other commercially available chemicals were used as
purchased. Thin layer chromatography (TLC) was performed
using aluminium TLC sheets (silica gel 60 F254) and compounds
were visualized using UV-detection (254 nm) and colouring with
an anisaldehyde solution (6 mL p-anisaldehyde, 7 mL acetic acid
and 7 mL sulfuric acid in 120 mL of EtOH) or a CER-MOP
solution (5 g molybdophosphoric acid, 2 g cerium(IV) sulfate and
16 mL sulfuric acid in 184 mL of H2O). Column chromatography
was performed using flash silica gel (40–63 lm) and mixtures of
Other furan-functionalized triazinane diones underwent similar
efficient spontaneous IMDA cyclization after alkylation with
methyl E-4-bromo-2-butenoate. Thus, alkylation of 1c, prepared
efficiently via the 4CR of 2, furonitrile 3b, piperonal 4b and 5a,
resulted in smooth in situ IMDA cyclization to give 16b in high
yield. Similarly, alkylation of 1d, prepared via the 4CR of 2, 3b,
4a and p-methoxyphenyl isocyanate 5b, afforded 16c (Scheme 5).
The structures of 16b and 16c were assigned on the basis of NOE
intensities between the hydrogens A1–A2, A1–B, A2–C and B–C
(Fig. 1), which have a similar build-up rate as the NOE intensities
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Scheme 5 Two more examples of the domino alkylation–IMDA reaction. PMP = p-methoxyphenyl.
cyclohexane and EtOAc. Melting points are uncorrected. Infrared
(IR) spectra were obtained from pure samples and wavelengths
128.3 (2C), 128.1, 127.5, 127.0 (2C), 126.4, 81.9, 81.2, 48.2, 27.9
(3C). HRMS (FAB) calculated for C35H34N3O4 (MH+) 560.2549,
found 560.2543. IR (neat): 2978 (w), 1713 (s), 1676 (s), 1493 (m),
1433 (s), 1321 (m), 1229 (m), 1148 (s), 752 (s), 692 (s).
1
(m) are reported in cm−1. H nuclear magnetic resonance (NMR)
spectra were recorded at 400.13 MHz or 250.13 MHz and 13C
NMR spectra at 100.61 MHz or 62.90 MHz with chemical shifts
(d) reported in ppm downfield from tetramethylsilane. HRMS-
FAB data were measured using a four sector mass spectro-
meter.
Triazinane dione acid 7
tert-Butyl ester 6 (900 mg, 1.6 mmol) was dissolved in CH2Cl2
(2 mL) and trifluoroacetic acid (2 mL) was added. This mixture
was stirred for 45 minutes after which the solvent and excess
trifluoroacetic acid were removed by evaporation under reduced
pressure. This afforded crude 7 as a white solid (806 mg, quant.)
without further purification being necessary. 1H NMR (250 MHz,
CDCl3): 7.61–7.57 (m, 2H), 7.40–7.11 (m, 18H), 6.76 (d, J =
16.0 Hz, 1H), 6.62 (d, J = 15.9 Hz, 1H), 4.20 (s, 2H). 13C NMR
(101 MHz, DMSO-d6): 169.5, 152.9, 152.2, 138.8, 138.5, 136.1,
135.5, 134.3, 130.1, 129.8, 129.6 (2C), 129.3, 129.3, 129.3 (2C),
129.0 (2C), 129.0 (2C), 128.9 (2C), 128.7, 128.4, 127.6, 127.6 (2C),
127.1, 125.8, 81.5, 47.8. HRMS (FAB) calculated for C31H26N3O4
(MH+) 504.1923, found 504.1916. IR (neat): 2818 (w), 2567 (w),
1784 (m), 1705 (s), 1636 (s), 1491 (m), 1460 (m), 1445 (s), 1334 (m),
1253 (m), 1213 (s), 1146 (s), 756 (s), 692 (s), 590 (s). Melting point:
181.3–181.9 ◦C (decomp.).
General procedure I: alkylation of triazinane diones
NaH (1.1 equivalent, 0.12 M) was added to a flame-dried Schlenk
vessel and dry DMF was added. This suspension was cooled
to 0 ◦C after which the triazinane dione (1.0 equivalent. 0.11
M) was added. The mixture was then stirred for 1.5 h at 0 ◦C
after which the appropriate allylic or propargylic bromide was
added (1.1 equivalent, 0.12 M). The reaction mixture was then
allowed to warm to room temperature overnight, after which the
reaction was worked up. DMF was removed by evaporation and
the crude material was dissolved in EtOAc. This organic fraction
was washed twice with water, then with brine, dried (Na2SO4),
filtrated and concentrated by evaporation of the solvent under
reduced pressure. The crude product was purified by column
chromatography (cyclohexane–EtOAc).
Ugi product 8a
tert-Butyl ester 6
Benzylamine (107 mg, 1.0 mmol) and isobutyraldehyde (72 mg,
1.0 mmol) were dissolved in MeOH (5 mL) containing Na2SO4
(500 mg). This mixture was stirred for 2 h at room temperature,
after which the acid 7 (252 mg, 0.5 mmol) was added. This mixture
was then stirred for an additional 30 minutes after which tert-
butyl isocyanide (42 mg, 0.5 mmol) was added. The reaction
was stirred overnight and then worked up by addition of H2O
(25 mL) and extraction with EtOAc (3 × 25 mL). The combined
organic fractions were washed with brine (25 mL), dried (Na2SO4),
Following general procedure I, reaction between triazinane dione
1a (1.00 g, 2.20 mmol) and tert-butyl 2-bromoacetate (340 mg,
2.40 mmol) followed by column chromatography (cyclohexane–
EtOAc = 2 : 1), afforded 6 (945 mg, 75%) as a white foam. 1H NMR
(400 MHz, CDCl3): 7.45–7.58 (m, 2H), 7.09–7.36 (m, 18H), 6.61 (s,
2H), 4.03 (s, 2H), 1.39 (s, 9H). 13C NMR (101 MHz, CDCl3): 167.7,
153.2, 152.5, 138.6, 138.2, 135.4, 135.1, 135.0, 129.9 (2C), 129.5,
129.2 (2C), 129.0, 128.9 (2C), 128.7 (2C), 128.7 (2C), 128.6 (2C),
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filtered and concentrated by evaporation of the solvent under
reduced pressure. The crude product was purified by column
chromatography (cyclohexane–EtOAc 4 : 1, gradient) affording 8a
(281 mg, 75%) as a white foam as a 1 : 1 mixture of diastereomers
and rotamers. NMR spectra were recorded at 403K to resolve
the rotamers, but this did not have a good resolving effect on the
NMR spectra. Therefore, quantification of the signals could not
Passerini product 9
To a suspension of isobutyraldehyde (54 mg, 0.75 mmol) and
7 (252 mg, 0.50 mmol) in CH2Cl2 (5 mL) was added tert-butyl
isocyanide (62 mg, 0.75 mmol). Within a minute the reaction
mixture became clear and it was then stirred overnight after which
the solvent was removed by evaporation under reduced pressure.
The crude product was purified by column chromatography
yielding 9 (203 mg, 62%) as a white foam as a 1 : 1 mixture of
diastereomers. Diastereomer a: 1H NMR (400 MHz, CDCl3): 7.62
(dd, J = 8.1, 1.9 Hz, 2H), 7.40–7.32 (m, 12H), 7.15–7.10 (m, 6H),
6.86 (d, J = 16.0 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.31 (s, 1H),
4.86 (d, J = 3.5 Hz, 1H), 4.16 (d, J = 16.2 Hz, 1H), 4.00 (d, J =
16.2 Hz, 1H), 2.34–2.27 (m, 1H), 1.37 (s, 9H), 0.89 (d, J = 7.6 Hz,
3H), 0.87 (d, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3):
168.0, 167.6, 153.8, 152.0, 138.2, 137.4, 135.1, 135.1, 134.7, 129.9,
129.3, 129.2 (2C), 129.0 (2C), 129.0 (2C), 128.9 (2C), 128.8 (2C),
128.7 (2C), 128.6 (2C), 128.4, 127.5, 127.1 (2C), 125.7, 81.6, 79.4,
1
be achieved. H NMR (400 MHz, DMSO-d6, 403 K): 7.64 (bs),
7.57 (bs), 7.47–7.46 (m), 7.40 (bs), 7.38 (bs), 7.34–7.11 (m), 6.90–
6.85 (m), 6.51 (d, J = 16.1 Hz), 6.40 (d, J = 15.6 Hz), 6.26 (d, J =
15.2 Hz), 6.23 (d, J = 16.0 Hz), 4.85 (bs), 4.81 (bs), 4.78 (bs),
4.74 (bs), 4.61 (bs), 4.57 (bs), 4.47 (bs), 4.44 (bs), 4.11 (bs),
2.27–2.22 (m, 1H), 1.18 (s), 1.09 (bs), 0.91 (d, J = 6.5 Hz),
0.88 (bs), 0.74 (d, J = 6.6 Hz), 0.65 (bs). 13C NMR (101 MHz,
DMSO-d6, 403 K): 168.5, 168.4, 167.8, 151.8, 151.8, 151.4, 151.4,
139.5, 139.5, 137.9, 137.9, 135.5, 135.4, 135.3, 135.2, 134.4, 129.5,
129.5, 128.3, 128.3, 128.0, 127.9, 127.8, 127.8, 127.8, 127.7, 127.1,
127.0, 126.9, 126.9, 126.8, 126.5, 126.5, 126.1, 125.7, 80.2, 80.1,
65.3, 49.8, 49.7, 47.7, 47.6, 27.6, 27.5, 27.2, 27.1, 18.3, 18.1, 18.0.
HRMS (FAB) calculated for C47H50N5O4 (MH+) 748.3863, found
748.3862. IR (neat): 3341 (w), 3065 (w), 2965 (w), 1717 (m), 1653
(s), 1491 (m), 1437 (s), 1302 (m), 1219 (m), 756 (m), 711 (m), 692 (s),
590 (m).
1
51.4, 48.1, 30.2, 28.3 (3C), 18.9, 16.5. Diastereomer b: H NMR
(250 MHz, CDCl3): 7.58–7.09 (m, 20H), 6.95 (d, J = 16.0 Hz, 1H),
6.81 (d, J = 15.9 Hz, 1H), 6.46 (s, 1H), 4.93 (d, J = 3.2 Hz, 1H), 4.12
(d, J = 16.6 Hz, 1H), 3.94 (d, J = 16.6 Hz, 1H), 2.48–2.35 (m, 1H)
1.15 (s, 9H), 0.99 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3):
168.0, 167.7, 153.7, 152.0, 138.2, 137.3, 135.1, 134.8, 134.4, 129.9,
129.2, 129.1 (2C), 129.0 (2C), 128.9 (2C), 128.8 (2C), 128.8 (2C),
128.6 (2C), 128.5 (2C), 128.4, 127.4, 127.2 (2C), 125.8, 81.6, 79.4,
51.4, 48.5, 30.1, 28.2 (3C), 19.1, 16.4. HRMS (FAB) calculated
for C40H43N4O5 (MH+) 659.3233, found 659.3237. IR (neat): 3349
(w), 2967 (w), 1716 (s), 1663 (s), 1437 (s), 1319 (m), 1192 (m), 756
(s), 692 (s), 588 (m).
Ugi product 8b
Allylamine (145 mg, 0.75 mmol) and isobutyraldehyde (53 mg,
0.75 mmol) were dissolved in MeOH (1 mL) containing Na2SO4
(50 mg). This mixture was stirred for 2 h at room temperature, after
which the acid 7 (180 mg, 0.38 mmol) was added. This mixture
was then stirred for an additional 30 minutes after which tert-
butyl isocyanide (32 mg, 0.38 mmol) was added. The reaction
was stirred overnight and then worked up by addition of H2O
(10 mL) and extraction with EtOAc (3 × 10 mL). The combined
organic fractions were washed with brine (30 mL), dried (Na2SO4),
filtered and concentrated by evaporation of the solvent under
reduced pressure. The crude product was purified by column
chromatography (cyclohexane–EtOAc 2 : 1, gradient) affording 8b
(112 mg, 43%) as a white foam as a 1 : 1 mixture of diastereomers
and rotamers. NMR spectra were recorded at 403 K to resolve
the rotamers, but this did not have a good resolving effect on the
NMR spectra. Therefore, quantification of the signals could not be
achieved. 1H NMR (400 MHz, DMSO-d6, 403 K): 7.68–7.65 (m),
7.52–7.39 (m), 7.33–7.28 (m), 7.24–7.16 (m), 7.08 (bs), 7.02 (bs),
6.89–6.87 (m), 6.53 (d, J = 16.1 Hz), 6.49 (d, J = 16.0 Hz), 6.32
(d, J = 16.0 Hz), 5.63 (bs), 5.09–5.04 (m), 4.93–4.86 (m), 4.66–
4.62 (m), 4.38 (d, J = 17.2 Hz), 4.29 (d, J = 17.0 Hz), 4.04 (s), 4.02
(s), 2.19–2.14 (m), 1.23 (s), 1.19 (bs), 0.90 (d, J = 6.4 Hz), 0.71
(d, J = 6.7 Hz), 0.69 (bs). 13C NMR (101 MHz, CDCl3): 169.6,
169.5, 168.9, 168.8, 153.3, 153.2, 152.7, 152.7, 138.3, 138.2, 135.8,
135.4, 135.4, 135.1, 134.9, 133.6, 133.2, 130.0, 129.3, 129.1, 129.1,
129.0, 128.9, 128.8, 128.7, 128.7, 128.7, 128.6, 128.6, 128.1, 128.0,
127.5, 127.4, 127.2, 127.1, 126.9, 126.9, 126.8, 117.1, 116.9, 116.8,
81.2, 81.1, 51.3, 51.2, 47.9, 47.8, 28.5, 28.2, 26.8, 26.6, 19.5, 19.5,
18.7. HRMS (FAB) calculated for C43H48N5O4 (MH+) 698.3706,
found 698.3702. IR (neat): 2924 (m), 2853 (w), 1751 (s), 1709 (m),
1672 (m), 143 (m), 1441 (m), 1367 (m), 1221 (s), 1037 (s), 912 (m),
731 (m), 694 (m), 596 (w).
N-Allyltriazinane dione 10
Following general procedure I, reaction between triazinane dione
1a (500 mg, 1.12 mmol) and allyl bromide (150 mg, 1.24 mmol)
followed by column chromatography (cyclohexane–EtOAc = 2 :
1), afforded 10 (267 mg, 49%) as a white foam. 1H NMR (400 MHz,
CDCl3): 7.57–7.55 (m, 2H), 7.38–7.06 (m, 18H), 6.61 (s, 2H), 5.96–
5.89 (m, 1H), 5.14 (ddt, J = 10.2, 1.4, 1.4 Hz, 1H), 5.05 (ddt, J =
17.1, 1.4, 1.4 Hz, 1H), 4.20 (ddt, J = 15.7, 5.2, 1.6 Hz, 1H), 3.98
(ddt, J = 15.6, 6.3, 1.3 Hz, 1H) 13C NMR (101 MHz, CDCl3):
153.4, 152.7, 138.7, 138.3, 135.5, 135.1, 135.0, 134.0, 129.6 (2C),
129.4, 129.2 (2C), 129.0, 128.9 (2C), 128.7 (2C), 128.6 (4C), 128.5
(2C), 128.1, 127.3, 127.0 (2C), 126.5, 117.2, 81.7, 49.0.
HRMS (FAB) calculated for C32H28N3O2 (MH+) 486.2182,
found 486.2176. IR (neat): 3061 (w), 1716 (s), 1670 (s), 1491 (m),
1420 (s), 1314 (m), 1281 (m), 754 (s), 692 (s), 588 (m).
RCM product 11
Grubbs’ 2nd generation catalyst (22 mg, 0.026 mmol) was added
to a solution of 10 (125 mg, 0.26 mmol) in CH2Cl2 (4.5 mL, dry)
and this mixture was heated to reflux for 2 h. Then the solvent
was removed by evaporation under reduced pressure. The crude
product was purified by column chromatography (cyclohexane–
EtOAc = 2 : 1) affording 11 (63 mg, 64%) as a grey solid. 1H NMR
(250 MHz, CDCl3): 7.49–7.28 (m, 13H), 7.15–7.12 (m, 2H), 6.25
(d, J = 6.3 Hz, 1H), 5.83 (d, J = 6.3 Hz, 1H), 4.77 (d, J = 16.2 Hz,
1H), 4.53 (d, J = 16.4 Hz, 1H). 13C NMR (101 MHz, CDCl3):
152.5, 150.6, 141.1, 137.5, 135.3, 130.2, 129.3 (2C), 129.0, 129.0
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(4C), 128.7 (2C), 128.7 (2C), 128.3, 128.2, 127.8, 125.6 (2C), 84.7,
54.0. HRMS (FAB) calculated for C24H20N3O2 (MH+) 382.1556,
found 382.1560. IR (neat): 3067 (w), 2872 (w), 1717 (s), 1684 (s),
1443 (s), 1319 (m), 1194 (w), 760 (m), 731 (m), 694 (m). Melting
point: 199.5–200.1 ◦C (decomp.).
135.0, 129.6 (2C), 129.4, 129.0 (2C), 128.8, 128.7 (2C), 128.7 (2C),
128.6 (2C), 128.5 (2C), 128.3 (2C), 128.1, 127.3, 127.1 (2C), 126.9,
122.7, 85.7, 81.8, 75.0, 72.6, 70.3, 67.5, 61.3, 41.0, 20.6, 20.4 (2C),
20.0. HRMS (FAB) calculated for C46H45N6O11 (MH+) 857.3146,
found 857.3146. IR (neat): 3350 (w), 3067 (w), 2967 (w), 2247 (w),
1713 (s), 1655 (s), 1493 (m), 1441 (s), 1304 (m), 1223 (m), 1186 (m),
909 (s), 727 (s), 692 (s), 646 (m), 690 (m), 519 (m).
N-Propargyltriazinane dione 12
Following general procedure I, reaction between triazinane dione
1a (500 mg, 1.12 mmol) and propargyl bromide (148 mg,
1.24 mmol) followed by column chromatography (cyclohexane–
EtOAc = 2 : 1), afforded 12 (326 mg, 60%) as a yellow foam.
1H NMR (250 MHz, CDCl3): 7.61–7.57 (m, 2H), 7.44–7.32 (m,
13H), 7.19–7.12 (m, 5H), 6.99 (d, J = 15.9 Hz, 1H), 6.82 (d, J =
16.0 Hz, 1H), 4.43 (dd, J = 17.5, 2.4 Hz, 1H), 3.96 (dd, J =
17.5, 2.4 Hz, 1H), 2.30 (t, J = 2.4 Hz, 1H). 13C NMR (63 MHz,
CDCl3): 153.0, 152.6, 138.4, 137.5, 135.3, 135.1, 134.5, 129.7, 129.4
(HSQC), 129.2 (2C), 129.1, 129.0 (2C), 129.0 (HSQC), 128.9 (2C),
128.8 (2C), 128.8 (2C), 128.6 (2C), 128.3, 127.3, 127.2 (2C), 126.1,
81.7, 79.8, 72.0, 35.4. HRMS (FAB) calculated for C32H26N3O2
(MH+) 484.2025, found 484.2032. IR (neat): 3287 (w), 3061 (w),
1713 (s), 1674 (s), 1491 (m), 1431 (s), 1310 (m), 1281 (m), 752 (s),
691 (s), 586 (m).
Diels–Alder product 16a
Following general procedure I, reaction between triazinane dione
1b (250 mg, 0.57 mmol) and methyl E-4-bromo-2-butenoate
(113 mg, 0.63 mmol) followed by column chromatography
(cyclohexane–EtOAc = 2 : 1), afforded 16a (144 mg, 47%) as
a yellow solid. 16a was crystallized by slow evaporation of an
EtOAc-solution. 1H NMR (400 MHz, CDCl3): 7.51–7.32 (m,
12H), 7.26–7.23 (m, 3H), 6.98 (d, J = 15.7 Hz, 1H), 6.61 (d,
J = 15.8 Hz, 1H), 6.10 (dd, J = 5.9, 1.6 Hz, 1H), 6.00 (d, J =
5.9 Hz, 1H), 5.33 (dd, J = 4.8, 1.6 Hz, 1H), 4.20 (dd, J = 11.3,
9.5 Hz, 1H), 3.75 (dd, J = 11.7, 7.3 Hz, 1H), 3.63 (s, 3H), 3.26
(dd, J = 4.8, 2.9 Hz, 1H), 2.61 (ddd, J = 9.4, 7.3, 2.9 Hz, 1H).
13C NMR (101 MHz, CDCl3): 170.8, 152.7, 150.5, 136.3, 135.3,
134.7, 133.8, 133.2, 133.0 (2C), 129.3 (4C), 129.1 (3C), 128.8 (2C),
128.5, 128.2, 127.2 (3C), 132.2, 98.8, 80.4, 77.1, 52.9, 52.2, 50.2,
42.7. HRMS (FAB) calculated for C32H28N3O5 (MH+) 534.2029,
found 534.2031.
Triazole 14
IR (neat): 3013 (w), 1717 (s), 1676 (s), 1449 (s), 1319 (m),
1213 (m), 754 (m), 694 (m). Melting point: 194.9–195.4 ◦C
(decomp.).
12 (100 mg, 0.21 mmol) and 13 (78 mg, 0.21 mmol) were added to a
mixture of H2O–t-BuOH (1 : 1, 400 ll : 400 ll). Sodium ascorbate
(17 mg, 0.084 mmol) and CuSO4·5H2O (10 mg, 0.042 mmol)
were added to the white suspension and this was stirred for
2.5 h. Then, acetonitrile (400 ll) was added and the mixture was
stirred overnight. An additional batch of sodium ascorbate and
CuSO4·5H2O were added to the clear yellow solution and the
mixture was stirred for another 2 h. The reaction was worked up by
adding H2O (10 mL) and extraction with CH2Cl2 (2 × 20 mL). The
combined organic fractions were dried (Na2SO4) and concentrated
by evaporation of the solvent under reduced pressure. The crude
product was purified by column chromatography (cyclohexane–
EtOAc = 2 : 1, gradient) affording 14 (99 mg, 55%) as a light
yellow sticky oil as a 1 : 1 mixture of diastereomers. Diastereomer
a: 1H NMR (400 MHz, CDCl3): 8.00 (s, 1H), 7.62–7.60 (m, 2H),
7.44–7.28 (m, 12H), 7.21–7.13 (m, 4H), 7.08–7.06 (m, 2H), 6.89 (d,
J = 16.0 Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H), 5.83–5.81 (m, 1H),
5.46–5.43 (m, 2H), 5.28–5.23 (m, 1H), 4.91 (d, J = 15.2 Hz, 1H),
4.69 (d, J = 15.0 Hz, 1H), 4.32 (dd, J = 12.6, 4.5 Hz, 1H), 4.26–
4.15 (m, 1H), 4.02–3.98 (m, 1H), 2.10 (s, 3H), 2.10 (s, 3H), 2.08
(s, 3H), 2.04 (s, 3H). 13C NMR (101 MHz, CDCl3): 170.4, 169.9,
169.1, 168.3, 153.2, 152.4, 144.8, 139.0, 138.1, 135.7, 135.3, 135.0,
129.6 (2C), 129.3, 129.1 (2C), 128.8, 128.7 (2C), 128.6 (4C), 128.4
(2C), 128.1, 128.1 (2C), 127.3, 127.1 (2C), 127.0, 123.2, 85.7, 81.7,
75.0, 72.5, 70.3, 67.5, 61.4, 41.0, 20.6, 20.4 (2C), 19.8. Diastereomer
b: 1H NMR (400 MHz, CDCl3): 7.89 (s, 1H), 7.63–7.56 (m, 2H),
7.44–7.28 (m, 12H), 7.21–7.20 (m, 4H), 7.15–7.08 (m, 2H), 6.96
(d, J = 16.0 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 5.85–5.82 (m,
1H), 5.46–5.42 (m, 2H), 5.27–5.24 (m, 1H), 4.82 (d, J = 15.2 Hz,
1H), 4.69 (d, J = 15.1 Hz, 1H), 4.32 (dd, J = 12.7, 4.7 Hz, 1H),
4.17–4.13 (m, 1H), 4.01–3.97 (m, 1H), 2.09 (s, 3H), 2.09 (s, 3H),
2.08 (s, 3H), 2.05 (s, 3H). 13C NMR (101 MHz, CDCl3): 170.4,
169.8, 169.1, 168.6, 153.4, 152.4, 144.7, 138.5, 138.1, 135.3, 135.3,
Crystallographic data for 16a
C32H27N3O5, Fw = 533.57, yellow plate, 0.36 × 0.36 × 0.12 mm3,
monoclinic, P21/c (no. 14), a = 9.8195(1), b = 25.2307(3), c =
◦
3
˚
˚
11.4069(2) A, b = 112.6460(5) , V = 2608.20(6) A , Z = 4, Dx =
1.359 g cm−3, l = 0.09 mm−1. 28707 Reflections were measured
on a Nonius Kappa CCD diffractometer with rotating anode
˚
(graphite monochromator, k = 0.71073 A) up to a resolution
−1
˚
of (sin h/k)max = 0.65 A at a temperature of 150 K. The
reflections were corrected for absorption and scaled on the basis
of multiple measured reflections with the program SORTAV20
(0.95–0.99 correction range). 5961 Reflections were unique (Rint
=
0.0497). The structure was solved with Direct Methods (program
SHELXS-9721) and refined with SHELXL-9721 against F2 of all
reflections. Non hydrogen atoms were refined with anisotropic
displacement parameters. All hydrogen atoms were located in
difference Fourier maps. Methyl and phenyl hydrogen atoms
were refined with a riding model; all other hydrogen atoms
were refined freely with isotropic displacement parameters. 398
Parameters were refined with no restraints. R1/wR2 [I > 2r(I)]:
0.0464/0.1247. R1/wR2 [all refl.]: 0.0716/0.1416. S = 1.085. The
maximum residual electron density peak has a height of 0.84 e
−3
˚
A
˚
and a distance of 2.34 A to the closest atom H33. Geometry
calculations and checking for higher symmetry was performed
with the PLATON program.22
Triazinane dione 1c
Triazinane dione 1c was prepared by the method reported by
Groenendaal et al.7 Reaction between diethyl methylphosphonate
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(730 mg, 5.0 mmol), furonitrile (510 mg, 5.5 mmol), piperonal
(826 mg, 5.5 mmol) and phenyl isocyanate (1.31 g, 11.0 mmol),
followed by column chromatography (cyclohexane–EtOAc 4 : 1)
afforded 1c (1.47 g, 61%) as a brown solid. 1H NMR (250 MHz,
CDCl3): 7.52–7.51 (m, 1H), 7.45–7.27 (m, 8H), 7.52–7.13 (m, 2H),
6.83 (d, J = 15.9 Hz, 1H), 6.76 (s, 3H), 6.46 (dd, J = 3.4, 0.8 Hz,
1H), 6.40 (dd, J = 3.4, 1.9 Hz, 1H), 6.11 (d, J = 15.8 Hz, 1H), 6.10
(s, 1H), 5.97 (s, 2H). 13C NMR (101 MHz, CDCl3): 152.7, 152.0,
151.7, 148.4, 148.1, 143.5, 136.8, 134.8, 133.4, 129.9 (2C), 129.1,
129.1 (2C), 128.7 (4C), 128.2, 128.1, 123.3, 122.4, 110.7, 110.0,
108.4, 105.8, 101.3, 71.0. HRMS (FAB) calculated for C28H22N3O5
(MH+) 480.1559, found 480.1562. IR (neat): 3160 (w), 3069 (w),
2899 (w), 1709 (s), 1667 (s), 1489 (m), 1444 (s), 1325 (m), 1251
(s), 1036 (s), 929 (m), 748 (m), 692 (s), 560 (s). Melting point:
205.8–206.4 ◦C (decomp.).
1319 (m), 1254 (m), 1036 (m), 912 (m), 760 (m), 729 (m), 696 (m).
Melting point: 161.8–162.5 ◦C (decomp.)
Diels–Alder product 16c
Following general procedure I, reaction between triazinane dione
1d (250 mg, 0.50 mmol) and methyl E-4-bromo-2-butenoate
(135 mg, 0.76 mmol) followed by column chromatography
(cyclohexane–EtOAc = 2 : 1), afforded 16c (125 mg, 67%, based on
recovered starting material) as a white solid. 1H NMR (400 MHz,
CDCl3): 7.47–7.37 (m, 6H), 7.13 (d, J = 8.9 Hz, 2H), 6.93 (d, J =
15.8 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 6.58 (d, J = 15.7 Hz,
1H), 6.11 (dd, J = 5.9, 1.6 Hz, 1H), 5.99 (d, J = 5.9 Hz, 1H),
5.33 (dd, J = 4.9, 1.6 Hz, 1H), 4.17 (dd, J = 11.2, 9.5 Hz, 1H),
3.80 (s, 3H), 3.77 (s, 3H), 3.73 (dd, J = 11.3, 7.5 Hz, 1H), 3.62
(s, 3H), 3.25 (dd, J = 4.8, 2.9 Hz, 1H), 2.56 (ddd, J = 9.5, 7.2,
2.8 Hz, 1H). 13C NMR (101 MHz, CDCl3): 170.7, 159.2, 159.0,
153.0, 150.7, 134.7, 133.8, 133.1, 132.7 (2C), 130.1 (3C), 129.2,
128.9 (3C), 128.8, 127.9, 127.1 (3C), 123.1, 114.0 (2C), 113.5 (2C),
98.4, 80.2, 55.3, 52.8, 52.0, 50.2, 42.4. HRMS (FAB) calculated
for C34H32N3O7 (MH+) 594.2240, found 594.2242. IR (neat): 2955
(w), 2837 (w), 1713 (s), 1676 (s), 1510 (s), 1456 (s), 1296 (m), 1248
(s), 1169 (m), 1032 (m), 829 (m), 731 (m). Melting point: 198.7–
199.3 ◦C (decomp.).
Triazinane dione 1d
Triazinane dione 1d was prepared by the method reported by
Groenendaal et al.7 Reaction between diethyl methylphosphonate
(730 mg, 5.0 mmol), furonitrile (510 mg, 5.5 mmol), benzaldehyde
(585 mg, 5.5 mmol) and p-methoxyphenyl isocyanate (1.64 g,
11.0 mmol), afforded 1d (1.30 g, 52%) as a light brown solid.
The crude product precipitated out of the reaction mixture after
evaporation of half of the solvent and addition of water (10 mL).
Subsequent washing of the crude product with cold Et2O gave 1d
Acknowledgements
1
as a light brown solid. H NMR (400 MHz, DMSO-d6): 9.16 (s,
We thank Dr Han Peeters (University of Amsterdam) for conduct-
ing HRMS measurements. This work was financially supported
by the EU and the Dutch Science Foundation (NWO/CERC3,
NWO/VICI). M.L. and A.L.S. thank the Council for Chemical
Sciences of the Netherlands Organization for Scientific Research
(NWO-CW) for financial support.
1H), 7.82 (dd, J = 1.6, 0.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 2H),
7.39–7.32 (m, 3H), 7.07 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.8 Hz,
2H), 6.95 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 15.9 Hz, 1H), 6.83 (d,
J = 9.0 Hz, 2H), 6.56 (dd, J = 3.3, 0.8 Hz, 1H), 6.49 (dd, J =
3.2, 1.8 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 3.77 (s, 3H), 3.70 (s,
3H). 13C NMR (101 MHz, DMSO-d6): 158.9, 158.7, 152.7, 152.4,
152.1, 144.3, 135.6, 133.1, 131.6 (2C), 130.8 (2C), 130.2, 129.1 (2C),
129.0, 128.7, 127.4 (2C), 126.6, 114.1 (4C), 111.1, 110.6, 71.0, 55.6,
55.5. HRMS (FAB) calculated for C29H26N3O5 (MH+) 496.1872,
found 496.1868. IR (neat): 3215 (w), 3065 (w), 2905 (w), 1717 (s),
1670 (s), 1508 (s), 1437 (m), 1296 (m), 1240 (s), 1028 (m), 826 (m),
743 (m), 554 (m). Melting point: 195.6–196.3 ◦C (decomp.).
Notes and references
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Diels–Alder product 16b
7 B. Groenendaal, D. Vugts, R. F. Schmitz, F. J. J. de Kanter, E. Ruijter,
M. B. Groen and R. V. A. Orru, J. Org. Chem., 2008, 73, 719.
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Following general procedure I, reaction between triazinane dione
1c (250 mg, 0.52 mmol) and methyl E-4-bromo-2-butenoate
(140 mg, 0.78 mmol) followed by column chromatography
(cyclohexane–EtOAc = 2 : 1), afforded 16b (150 mg, 81%, based
on recovered starting material) as an orange solid. 1H NMR
(400 MHz, CDCl3): 7.47–7.29 (m, 8H), 7.23–7.20 (m, 2H), 6.98
(d, J = 1.5 Hz, 1H), 6.93 (dd, J = 8.0, 1.5 Hz, 1H), 6.86 (d, J =
16.1 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.41 (d, J = 15.6 Hz, 1H),
6.09 (dd, J = 5.9, 1.6 Hz, 1H), 6.02 (s, 2H), 5.97 (d, J = 5.9 Hz,
1H), 5.32 (dd, J = 4.8, 1.5 Hz, 1H), 4.16 (dd, J = 11.3, 9.6 Hz,
1H), 3.72 (dd, J = 11.5, 7.4 Hz, 1H), 3.62 (s, 3H), 3.25 (dd, J =
4.8, 2.9 Hz, 1H), 2.58 (ddd, J = 9.8, 7.3, 2.8 Hz, 1H). 13C NMR
(101 MHz, CDCl3): 170.7, 152.6, 150.4, 148.6, 148.3, 136.2, 135.2,
133.7, 133.1, 132.4 (2C), 129.2 (4C), 128.9, 128.7 (4C), 128.4, 128.0,
122.6, 121.1, 108.6, 105.8, 101.4, 98.4, 80.2, 52.8, 52.0, 50.0, 42.6.
HRMS (FAB) calculated for C33H28N3O7 (MH+) 578.1972, found
578.1932. IR (neat): 2955 (w), 2899 (w), 1713 (s), 1676 (s), 1449 (s),
10 S. Dedola, S. A. Nepogodiev and R. A. Field, Org. Biomol. Chem.,
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15 B. L. Wilkinson, L. F. Bornaghi, S. A. Poulsen and T. A. Houston,
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This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3158–3165 | 3165
©