Alkylation of amine 12a was performed by reductive
amination20 and by way of a silylamide intermediate.21
Hydrochloride 12a was treated with triethylamine and,
respectively, condensed with p-benzyloxybenzaldehyde and
tolualdehyde (90 mol %), in the presence of molecular sieves
to yield imines, which were reduced with sodium triacetoxy-
borohydride (150 mol %) in dichloroethane providing
secondary amines 13a and 14a, both in 87% yield. Ally-
lamine 15a and benzylamine 16c were, respectively, prepared
in 70% and 65% yields by a sequence featuring silylation
of amine 11a and 11c with N,O-bis(trimethylsilyl)acetamide
(BSA, 160 mol %), alkylation with allyl and benzyl bromide
(200 mol %), and treatment with propylenediamine to
scavenge excess alkyl halide.
With primary and secondary amino pyrroles in hand, we
explored diazepinone annulation. The Pictet-Spengler reaction
refers commonly to the condensation of a tryptamine analog
with an aldehyde or ketone to yield a ꢀ-carboline;22 however,
this intramolecular annulation via an imminium ion intermediate
has been accomplished with a variety of amines tethered to
electron-rich aromatic and heteroaromatic ring systems. Few
reports have, however, described Pictet-Spengler reactions with
pyrrole as the nucleophile.23–27 For example, pyrrolo[3,2-
e]pyrimidines were made from the Pictet-Spengler reactions
of ureidopyrroles and arylaldehydes.27
Figure 2. Diazepinones 1a-j (isolated yields) a. 1j was obtained
To explore the Pictet-Spengler cyclization for adding
substituents to the 5-position of the diazepinone ring, we
initially heated N-(phenyalaninyl)aminopyrrole 12a with a
set of aldehydes and TFA at 70 °C in toluene (condition A,
Figure 2). Analysis by LC-MS showed masses corresponding
to diazepinone 1 and starting material. Diazepinones 1a-j
were purified on silica gel and isolated as pure diastereomers
in 8-83% yields (Figure 2). Although the electron-rich
p-hydroxybenzaldehyde gave diazepinone 1f in 47% yield,
benzaldehyde and the electron-poor p-nitro- and p-bro-
mobenzaldehydes all reacted with aminoamidopyrrole 12a
to give 1a,d,e in 75-83% yields, suggesting that electron-
deficient iminium ions were more reactive in the cyclization.
Hexanal reacted to give diazepinone 1h in 22% yield,
accompanied by diazepinone 1j (8%) from a homoaldol
reaction prior to cyclization.28 On the contrary, iso-butyral-
dehyde gave diazepinone 1g in 72% yield.
as a side product from the synthesis of 1h as a single olefin isomer.
degassed solvent avoided oxidation to the corresponding 4,5-
unsaturated diazepinone, such as 17 (Figure 3), which formed
on air oxidation of 1g.29
Condition A (Figure 2) was also used to react N-
(isoleucinyl)aminopyrrole 12b with benzaldehyde and iso-
butyraldehyde to give diazepinones 1b and 1i in 72% and
64% yields, respectively. On the other hand, the less sterically
demanding N-(alaninyl)aminopyrrole 12c reacted with ben-
zaldehyde to give 1c in only 18% yield.
In the case of secondary amines, p-substituted benzy-
lamines and allylamine 13a-15a reacted with benzaldehyde
under condition B (excess aldehyde in toluene at reflux using
a Dean-Stark apparatus) to give diazepinones 1k-m in
62-90% yields, respectively (Figure 3). p-Benzyloxyben-
zylamine 13a reacted, respectively, with p-hydroxybenzal-
dehyde and iso-butyraldehyde to give diazepinone 1p in 42%
yield and diazepinone 1o in 40% yield, likely due to the
volatility of iso-butyraldehyde. Alaninylaminopyrrole 16c
also reacted with benzaldehyde to provide diazepinone 1n
in 45% yield.
Diastereoisomerically pure and enriched diazepinones
1 were, respectively, isolated after cyclization of primary
(12a-c) and secondary amines 13-16. The cis relative
stereochemistry of the major product was assigned based
on the observed nuclear Overhauser effect between the
signals for the C-5 and C-3 protons in the NOESY spectra
of 1a and the major diastereoisomer of diazepinone 1l.
With primary amino pyrroles 12, our best Pictet-Spengler
reaction yields and purity were obtained using the aldehyde
as the limiting reagent (90 mol %) with 12 (100 mol %) at
low concentration (0.01 M) in toluene. A sealed system and
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(21) Ando, W.; Tsumaki, H. Chem. Lett. 1981, 693.
(22) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797.
(23) Xiang, J.; Zheng, L.; Chen, F.; Dang, Q.; Bai, X. Org. Lett. 2007,
9, 765
(24) Rousseau, J.-F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731
(25) Raiman, M. V.; Pukin, A. V.; Tyvorskii, V. I.; De Kimpe, N.;
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(28) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
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(29) Diness, F.; Beyer, J.; Meldal, M. Chem.-Eur. J. 2006, 12, 8056.
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