A multicomponent synthesis of triazinane diones

Article abstract of DOI:10.1021/jo701973d

(Chemical Equation Presented) An efficient, one-pot synthetic protocol toward triazinane diones, a rather unexplored class of heterocyclic scaffolds combining phosphonates, nitriles, aldehydes, and isocyanates is described. The optimization of the reactio

Full text of DOI:10.1021/jo701973d

SCHEME 1. Synthesis of Dihydropyrimidine-2-ones
A Multicomponent Synthesis of Triazinane
Diones
Bas Groenendaal, Danielle J. Vugts, Rob F. Schmitz,
Frans J. J. de Kanter, Eelco Ruijter, Marinus B. Groen, and
Romano V. A. Orru*
Department of Chemistry & Pharmaceutical Sciences, Vrije
UniVersiteit Amsterdam, De Boelelaan 1083, 1081 HV,
Amsterdam, The Netherlands
SCHEME 2. Formation of Noncyclized 6 and Triazinane
Dione 7a
orru@few.Vu.nl
ReceiVed September 7, 2007
An efficient, one-pot synthetic protocol toward triazinane
diones, a rather unexplored class of heterocyclic scaffolds
combining phosphonates, nitriles, aldehydes, and isocyanates
is described. The optimization of the reaction, synthesis of
a small library of different triazinane diones, as well as
alternative routes toward the triazinane dione scaffold are
discussed.
The thermodynamic driving force for a (concerted) aza-DA
reaction of such 1-azadienes is, compared to butadienes or
2-azadienes, much lower.5 Consequently, this results in a much
lower reactivity toward dienophiles. Therefore, Diels-Alder
reactions with 1-azadienes usually proceed sluggishly and are
of limited synthetic significance.6 During our initial studies, we
observed the formation of noncyclized 6 together with triazinane
dione 7a when diethyl methylphosphonate 1a, benzonitrile 2a,
4-methoxybenzaldehyde 3a, and PhNCO 4a were combined
(Scheme 2).4a The corresponding DHPM 5a was not formed in
this case. 6,6-Dialkyl/aryl-substituted triazinane diones such as
7 are a hitherto unexplored class of heterocyclic scaffolds and
only scattered reports exist on their synthesis.7 This led us to
examine the reaction pathway more closely in order to optimize
the MCR toward these highly interesting and novel cyclic urea
derivatives.
Most likely, triazinane dione 7a is formed via the pathway
depicted in Scheme 3. Deprotonation of the phosponate 1a with
n-BuLi and subsequent reaction with 2a yields the corresponding
intermediate ketimine. A subsequent Horner-Wadsworth-
Emmons reaction of this ketimine and 3a results in the formation
of the azadiene Ia. The isolation of the linear urea derivative 6
strongly supports a stepwise reaction mechanism, in which 6
Chemical space, defined as the total descriptor space including
all carbon-based molecules that in principle can be prepared,
contains more than 1060 small organic molecules.1 Only a very
limited number of these have been actually made by man and
explored for potential useful properties, like their biological
relevance. This continues to drive synthetic chemists to develop
novel reactions that can efficiently access unexplored regions
of chemical space. Especially appreciated are those methods
that allow the quick generation of scaffold diversity.2 Multi-
component reactions (MCRs) represent one of the most powerful
tools to easily access molecules showing both skeletal and
decoration diversity.3 As such, these reactions are also ideally
suited to uncover thus far unprecedented types of scaffolds.
Recently, we described a novel four-component reaction (4-
CR) that combines phosphonates 1, aldehydes 2, nitriles 3, and
isocyanates 4 to afford functionalized 3,4-dihydropyrimidine-
2-ones (DHPMs, 5) efficiently (Scheme 1).4 The MCR most
likely proceeds via 1-azadienes of type I that can undergo facile
aza-Diels-Alder (aza-DA) cycloaddition with isocyanates 4,
equipped with an electron-withdrawing substituent, to give
DHPMs of type 5.
(1) Dobson, M. Nature 2004, 32, 824.
(5) Jung, M. E.; Shapiro, J. J. J. Am. Chem. Soc. 1980, 102, 7862.
(6) Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56, 5259.
(7) (a) Etienne, A.; Bonte, B. Bull. Soc. Chim. Fr. 1975, 5-6, 1419. (b)
Etienne, A.; Lonchambon, G.; Giraudeau, P. Comptes Rendues 1977, 285,
321. (c) Vovk, M. V.; Dorokhov, V. I.; Zhitomir, S.-kh. IzV. Vyssh. Ucheb.
ZaVed. Khim. Khim. Tekhnol. 1992, 35, 28. (d) Vovk, M. V. Russ. J. Org.
Chem. 1996, 32, 767. (e) Nazarenko, K. G.; Shvidenko, K. V.; Pinchuk, A.
M.; Tolmachew, A. A. Monatsh. Chem. 2005, 136, 211.
(2) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46.
(3) (a) Do¨mling, A. Chem. ReV. 2006, 106, 17. (b) Zhu, J. Eur. J. Org.
Chem. 2003, 1133. (c) Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471.
(4) (a) Vugts, D. J.; Jansen, H.; Schmitz, R. F.; de Kanter, F. J. J.; Orru,
R. V. A. Chem. Commun. 2003, 2594. (b) Vugts, D. J.; Koningstein, M.
M.; Schmitz, R. F.; de Kanter, F. J. J.; Groen, M. B.; Orru, R. V. A. Chem.
Eur. J. 2006, 12, 7178.
10.1021/jo701973d CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/21/2007
J. Org. Chem. 2008, 73, 719-722
719

SCHEME 3. Mechanism for the Formation of Triazinane
Diones
TABLE 1. Optimization of the Formation of 7b
entry
equiv of 4a
reaction time
yield (%)
workupa
1
2
3
4
1.1
1.1
2.2
2.2
18 h
20
29
80
91
A
A
A
B
5 min
5 min
5 min
a Key: (A) After addition of Et2O, the reaction mixture was washed
with water and brine. Drying the organic phase and evaporation of the
solvents followed by column chromatography afforded pure 7b. (B) After
partial evaporation of the solvents, water was added to the reaction mixture.
The product precipitated, and after filtering and washing with cold Et2O,
pure 7b was obtained directly.
can be formed from an addition reaction of Ia to 4a followed
by a 1,3-H-shift. Moreover, formation of the triazinane dione
can be rationalized by the addition of a second equivalent of
4a followed by ring closure to afford the thermodynamically
favored six-membered cyclic urea derivative.
The moderate isolated yield of 7a encouraged us to further
optimize the reaction and explore the scope of this interesting
multicomponent procedure. For convenience, the combination
of 1a, 2a, benzaldehyde 3b, and 4a was employed to optimize
the reaction conditions toward the corresponding triazinane
dione 7b. As a starting point, the general conditions for the
efficient formation of the DHPM derivative 5b were chosen.4b
Not surprisingly, the standard conditions afforded mostly 5b,
and the desired triazinane dione 7b was observed in only 20%
yield (Table 1, entry 1). However, when product formation was
followed in time by HPLC analysis it became clear that the
formation of 7b was instantaneous. The conversion to 7b was
at its maximum only minutes after addition of 4a and decreased
slowly over time.
FIGURE 1. Range of differently substituted triazinane diones. PMP
) p-methoxyphenyl, PCP ) p-chlorophenyl.
compatible in this reaction. The reaction employing an isocy-
anate with an aliphatic R3 group is less efficient (7l, 13%).
Although the MCR proceeds smoothly using either an
optically pure nitrile, aldehyde, or isocyanate, the observed
diastereoselectivities are not very encouraging (7m-o). With
(S)-2-methylbutyronitrile, low stereoinduction is perhaps not
surprising considering the rather basic reaction conditions. On
the other hand, for the DHPM synthesis the use of the optically
pure (R)-myrtenal was relatively successful, and a de up to 85%
was observed.4b However, application of (R)-myrtenal did not
result in a diastereoselective formation of the corresponding
triazinane dione 7n. The best (albeit still moderate) diastereo-
selectivity was observed when (S)-R-methyl benzyl isocyanate
was combined with 1a, 2a, and 3a under the standardized
conditions for the formation of 7o (de ) 33%).
Thus, immediate workup after the addition of the final
isocyanate component already showed a significant improvement
of the yield of 7b (entry 2, 29%). The MCR was further
optimized by slight modification of the workup procedure and
using 2.2 equiv of isocyanate 4a. Addition of water during
workup caused precipitation of the product from the reaction
mixture, and 7b could simply be filtered off and washed with
diethyl ether to yield the pure product in 91% isolated yield
(entry 4).
As for the DHPM synthesis, the most limiting input in the
MCR for triazinane diones is, however, the phosphonate input.
From our earlier studies, it is known that only the use of diethyl
methylphosphonate or diethyl ethylphosphonate resulted in
efficient formation of the crucial 1-azadiene intermediate I.4b
Partly based on some literature precedents,8 some alternative
methods were investigated for the in situ generation of 1-aza-
dienes I and their subsequent trapping by PhNCO 4a. Attempts
With this optimized procedure in hand, the scope of the
reaction toward a range of differently substituted triazinane
diones was studied. As becomes clear from Figure 1, the reaction
is quite flexible and isolated yields of the corresponding
triazinane diones 7 are usually reasonable to good (25-91%).
Successful inputs include nitriles (2) and aldehydes (3) with
(hetero)aromatic and aliphatic substituents R1 and R2. For the
isocyanate input (4) benzylic and aromatic substituents R3 are
720 J. Org. Chem., Vol. 73, No. 2, 2008

SCHEME 4. Alternative Route toward Triazinane Diones
and addition of water (10 mL). In some cases, triazinane diones 7
either crystallized directly from this mixture or crystallized upon
standing overnight at 5 °C. Pure products were obtained by filtration
and washing of the residue with cold Et2O. In cases where triazinane
diones 7 did not crystallize from the reaction mixture, the products
were purified by flash chromatography or by recrystallization from
hexane/EtOAc. For compounds 7e,g-k, the products were co-
evaporated with Et2O and dried 48 h under vacuum (10-2 mbar) to
remove traces of solvents.
Triazinanedione 7a. Following the general procedure, reaction
between diethyl methylphosphonate (152 mg, 1.0 mmol), benzoni-
trile (113 mg, 1.1 mmol), p-methoxybenzaldehyde (150 mg, 1.1
mmol), and phenyl isocyanate (262 mg, 2.2 mmol) followed by
crystallization from hexane/EtOAc afforded 7a (340 mg, 71%) as
a white solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.59-7.57
(m, 2H), 7.39-7.33 (m, 7H), 7.30 (d, J ) 8.7 Hz, 1H), 7.20-7.11
(m, 7H), 6.91 (d, J ) 15.7 Hz, 1H), 6.89 (d, J ) 8.7 Hz, 1H), 6.39
(d, J ) 15.9 Hz, 2H). 6.16 (s, 1H), 3.83 (s, 3H); 13C NMR (101
MHz, CDCl3) δ (ppm) 160.3, 152.9, 152.5, 139.9, 137.7, 135.0,
132.4, 129.7 (2C), 129.5, 129.2 (2C), 128.9 (2C), 128.7 (2C), 128.6
(2C), 128.37 (2C), 128.35, 127.7, 127.6 (2C), 127.5, 125.6, 114.3
(2C), 75.8, 55.4; HRMS (FAB) calcd for C30H25N3O3 (MH+)
476.1974, found 476.1970; IR (KBr) 3435 (m), 3207 (w), 3090
(w), 1720 (s), 1680 (s), 1513 (m), 1435 (s), 1321 (m), 1256 (m),
741 (m), 694 (m), 592 (m), 536 (m); mp 177.4-178.4 °C.
starting from R,â-unsaturated aldehydes, like the addition of
appropriate Grignard reagents to nitriles or reduction of R,â-
unsaturated nitriles with DIBAL-H, were not successful and
gave mixtures of unidentified products. The only procedure that
indeed led to the formation of a triazinane dione is depicted in
Scheme 4a.
Triazinanedione 7b. Following the general procedure, reaction
between diethyl methylphosphonate (152 mg, 1.0 mmol), benzoni-
trile (113 mg, 1.1 mmol), benzaldehyde (117 mg, 1.1 mmol), and
phenyl isocyanate (262 mg, 2.2 mmol) afforded crude 7b. 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 7b (406 mg,
91%) as a white solid: 1H NMR (400 MHz, CDCl3) δ (ppm) 9.32
(s, 1H), 7.62-7.60 (m, 2H), 7.47-7.30 (m, 11H), 7.24-7.12 (m,
5H), 7.06-7.04 (m, 2H), 6.78 (d, J ) 16.0 Hz, 1H), 6.62 (d, J )
16.0 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ (ppm) 153.5,
152.9, 141.3, 138.9, 136.6, 136.1, 132.8, 130.7 (2C), 130.3 (2C),
129.8, 129.7 (2C), 129.7, 129.4, 129.4 (2C), 129.3 (2C), 129.2 (2C),
128.6, 128.6 (2C), 128.1, 127.8 (2C), 76.2; HRMS (FAB) calcd
for C29H23N3O2 (MH+) 446.1869, found 446.1872; IR (KBr) 3436
(m), 3208 (w), 3085 (w), 1721 (s), 1682 (s), 1493 (m), 1443 (s),
1330 (m), 752 (m), 694 (m), 596 (m), 535 (m); mp 169.0
-170.9 °C dec.
Triazinanedione 7p. Dry Et2O (2 mL) was cooled to -78 °C,
and MeLi (625 µL, 1.6 M in Et2O) was added. Cinnamonitrile (129
mg, 1.0 mmol) dissolved in dry Et2O (2 mL) was added dropwise
to this solution over a period of 30 min, and the mixture was then
stirred at -78 °C for 3 h and at room temperature for 1 h. Phenyl
isocyanate (217 µL, 2.0 mmol) was added, and after 5 min, the
reaction was worked up by addition of H2O (10 mL). Solid materials
were filtered off, washed with cold Et2O, dissolved in DCM, and
evaporated. Both the solid material and the Et2O wash contained
product, so they were purified together by column chromatography
(hexane/EtOAc 2:1) to afford 7p (115 mg, 30%) as a yellow solid:
1H NMR (400 MHz, CDCl3) δ 7.41-7.25 (m, 15H), 6.80 (d, J )
15.9 Hz, 1H)., 6.41 (d, J ) 15.9 Hz, 1H), 5.94 (s), 1.59 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 153.1, 152.4, 136.9, 135.2, 135.0,
130.1 (2C), 129.5, 129.3 (2C), 129.2 (2C), 128.9 (2C), 128.8 (2C),
128.7, 128.6, 128.3, 126.9 (2C), 70.6, 26.7; HRMS (EI, 70 eV)
calcd for C24H21N3O2 (M+) 383.1634, found 383.1632; IR (KBr)
3270 (w), 2925 (w), 1716 (s), 1674 (s), 1461(m), 1329 (m), 968
(w), 760 (m), 698 (m); mp 223.0-223.6 °C dec.
Thus, the reaction of R,â-unsaturated nitrile 2b with MeLi
and subsequent reaction with PhNCO 4a gave the corresponding
triazinane dione 7p, albeit in only 30% isolated yield.
Alternatively, efficient triazinane dione formation may occur
by trapping an intermediate imine, instead of a 1-azadiene, with
an appropriate isocyanate. Indeed, when MeLi was added to
nitrile 2c followed by the addition of PhNCO 4a the desired
product 7q was obtained, but again only in a disappointing 20%
yield (Scheme 4b). Since our MCR efficiently affords quite a
range of differently functionalized triazinane diones we did not
pursue further in this direction.
In conclusion, we have developed a flexible multicomponent
synthesis of a range of differently functionalized triazinane
diones. Our approach opens the way to more detailed studies
of the general and biological properties of these cyclic urea-
type scaffolds, which have hitherto remained unexplored. The
application of this scaffold in the synthesis of some unnatural
nucleoside analogues is currently under investigation in our
laboratories and will be reported in due course.
Experimental Section
General Procedure for the Synthesis of Triazinanediones. To
a solution of diethyl methylphosphonate (152 mg, 1.0 mmol) in
dry THF (5 mL) at -78 °C was added n-BuLi (1.2 mmol, 1.6 M
in hexanes), and this mixture was stirred for 1.5 h at this
temperature. The nitrile was added, and stirring was continued at
-78 °C for 45 min. Then the reaction mixture was warmed to
-40 °C, stirred for 1 h, and subsequently warmed to -5 °C and
stirred for 30 min. The aldehyde was then added, and the reaction
mixture was stirred at -5 °C for 30 min, warmed to room
temperature, and stirred for an additional 1.5 h. The isocyanate was
then added, and after 5 min, the reaction was worked up by
removing half of the solvent by evaporation under reduced pressure
(8) (a) Toye, T.; Ghosez, L. J. Am. Chem. Soc. 1975, 97, 2276. (b)
Blechert, S.; Wirth, T. Tetrahedron Lett. 1991, 32, 7237. (c) Langhals, H.;
Ruchardt, C. Chem. Ber. 1981, 114, 3831. (d) Babler, J. H.; Marcuccilli,
C. J. Tetrahedron Lett. 1987, 28, 4657. (e) Klein Gebbink, E. A.; Stork, G.
A.; Jansen, B. J. M.; de Groot, A. Tetrahedron 1999, 55, 11077. (f) Sulmon,
P.; De Kimpe, N.; Schamp, N. J. Chem. Soc., Chem. Commun. 1985, 11,
715.
Triazinanedione 7q. Dry Et2O (2 mL) was cooled to -78 °C,
and MeLi (625 µL, 1.6 M in Et2O) was added. Trimethylacetonitrile
(83 mg, 1.0 mmol) dissolved in dry Et2O (2 mL) was added
dropwise to this solution over a period of 30 min, and the mixture
was then stirred at -78 °C for 3 h and at room temperature for
1 h. Phenyl isocyanate (217 µL, 2.0 mmol) was added, and after 5
J. Org. Chem, Vol. 73, No. 2, 2008 721

min, the reaction was worked up by addition of H2O (10 mL). Solid
materials were filtered off, washed with cold Et2O, dissolved in
DCM, and evaporated. Both the solid material and the Et2O wash
contained product so they were purified together by column
chromatography (hexane/EtOAc 4:1) to afford 7q (67 mg, 20%)
as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.39-7.25 (m,
10H), 6.07 (s, 1H), 1.52 (s, 3H), 1.20 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 153.1, 152.0, 138.8, 135.1, 132.7, 130.9, 128.8 (2C),
128.7 (2C), 128.7, 128.5, 128.3, 125.1, 76.3, 44.1, 26.5 (3C), 24.8;
HRMS (EI, 70 eV) calcd for C20H23N3O2 (M+) 337.1790, found
337.1790; IR (KBr) 3206 (m), 3099 (m), 2978 (m), 1722 (s), 1677
(s), 1457 (s), 1325 (s), 769 (s), 700 (s), 589 (m), 562 (m); mp
219.2-220.2 °C dec.
Acknowledgment. We thank Dr. Marek Smoluch (Vrije
Universiteit Amsterdam) for conducting (HR)MS measurements.
This work was financially supported by the EU and the Dutch
Science Foundation (NWO/CERC3).
Supporting Information Available: Experimental procedures
1
and characterization data for compounds 7c-o and H and 13C
NMR spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO701973D
722 J. Org. Chem., Vol. 73, No. 2, 2008