M. Nayak, S. Batra / Tetrahedron Letters 51 (2010) 510–516
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Scheme 3. Reagent and conditions: (i) MeOH, rt, 10 h or lW, 120 °C, 15 min; (ii) LiOH (5 equiv), THF–H2O (1:1, v/v), rt, 8 h or 20% TFA in CH2Cl2, rt, 2 h; (iii) EDC (1.1 equiv),
NMM (1.1 equiv), CH2Cl2, À10 °C to 0 °C, 1 h. For key to substitutions refer to Table 1.
utility for MCR.5 In continuation to that work, we have now devel-
oped the stereoselective synthesis of isonitriles from the Baylis–
Hillman adducts of acrylates. It occurred to us that such substi-
tuted isonitriles would be appropriate substrate for synthesis of
functionalized tetrazoles via a modified Ugi reaction which em-
ploys TMSN3 as the reactant in the place of acid. Because of the dis-
position of the functional group in the expected tetrazoles it was
envisaged that a subsequent intramolecular reaction may occur
in the same sequence to produce annulated tetrazoles in one-pot.
A survey of the literature revealed that analogous reactions
have been performed earlier. Hulme and co-workers disclosed
one-pot synthesis of tetrazole-fused ketopiperazine through Ugi
reaction and post-Ugi intramolecular cyclization.6 But the protocol
did not work well for yielding tetrazole-fused diazepinone. Later,
adopting an alternative strategy they synthesized tetrazole-fused
temperature. The reactions were complete within 10 h and the
products were isolated in good yields. Spectroscopically these
products were identified to be the tetrazoles 4(A–V) (Scheme 3, Ta-
ble 1). In no case we observed the formation of anticipated annu-
lated tetrazole-fused diazepinone. At this point we decided to
investigate a representative reaction under microwave heating
which may induce the post-Ugi cyclization in the same pot. There-
fore reactions were performed under the microwave heating at
120 °C for 15 min (Table 1, entries 21 and 22). Unfortunately, how-
ever, the products isolated from these reactions were identified as
the tetrazoles 4U and 4V, respectively.
In order to achieve the synthesis of the target compounds, in an
alternative protocol it was decided to initially hydrolyze the ester
group and then perform the coupling reaction. Consequently the
ester group in 4A–V was hydrolyzed either in the presence of LiOH
(for methyl or ethyl ester) or in the presence of TFA (for tert-butyl
ester) to obtain the corresponding acids 5A–V. Subsequent intra-
molecular amide coupling reaction in 5A–V in the presence of
EDC in NMM afforded the tetrazole-fused diazepinone 6A–V in
modest yields (Scheme 2). As evident from the Table 1 this reaction
sequence is versatile and works very well over a broad range of iso-
nitriles, benzaldehydes/heteroaldehydes, and primary aliphatic
amines. Replacing the aldehyde with ketone as shown for 4P (Ta-
ble 1, entry 16) does not affect the outcome of the result and the
expected tetrazole was formed in 80% yields. However use of ani-
lines in the place of the primary amine did not work and the forma-
tion of tetrazoles was not observed (Table 1, entries 23 and 24).
It is documented that in the presence of suitable base the exo-
cyclic double bond in cyclic compounds generated from the Baylis–
Hillman chemistry isomerizes to the endocyclic position.12 There-
fore, the reaction of 6A with DBU in acetonitrile was investigated.
However the reaction was unsuccessful and the starting material
was recovered unreacted.
azepinone by employing N-Boc-a-amino aldehyde as the aldehyde
component.7 However the products formed in the latter approach
were different from the compounds generated in their previous en-
deavor (Scheme 1). Umkehrer et al. disclosed one-pot synthesis of
tetrazolo-fused piperazines through Ugi reaction followed by
intramolecular cyclization.8 Kalinski et al. reported the synthesis
of 4,5-dihydrotetrazolo[1,5-a]quinoxalines through the combina-
tion of Ugi and SNAr reactions.9
This Letter essays the stereocontrolled synthesis of isonitriles
from the Baylis–Hillman adduct of acrylate, their use for the Ugi
reaction to obtain substituted tetrazoles, and modification of
generated tetrazoles to afford differently substituted tetrazole-
fused diazepinone system in good yields.
The investigation commenced by the synthesis of primary allyl
amines 1 from the Baylis–Hillman acetate of acrylates following
the reported procedure.10 Primary allyl amines were reacted with
formamide to furnish the N-formamides 2,11 which upon treat-
ment with POCl3 in the presence of Et3N in methylene chloride
at 0 °C for 2 h smoothly afforded the desired isonitriles 3 as E-iso-
mer only (Scheme 2). These isonitriles were found to be stable at
room temperature and showed up as trimer in the mass spectra.
With substituted isonitriles in hand, we conducted the Ugi reac-
tion of isonitriles with TMSN3, aliphatic primary amines, and
substituted benzaldehydes/heteroaldehydes in methanol at room
In summary, we have demonstrated the synthesis of the substi-
tuted allyl isonitriles from the primary allyl amines afforded from
the Baylis–Hillman adducts of acrylates for the first time. Further,
we have utilized these substituted isonitriles for obtaining tetra-
zole-fused diazepinones in good yields via Ugi/hydrolyze/couple
strategy.
Nayak, Maloy
