G.A. Abeykoon, J.J. Sahn and S.F. Martin
Tetrahedron Letters 66 (2021) 152828
Scheme 1. MCAP approach to creating novel heterocycles exemplified by synthesis
of substituted triazolobenzodiazepine 2.
Fig. 1. Exemplary 1,4-benzodiazepine drugs AnexateÒ and ValiumÒ have structural
characteristics similar to the 1,2,3-triazolo-1,4-benzodiazepines 3 and 4.
congeners of 2 such as the substituted triazolobenzodiazepines 3
and 4 might exhibit interesting properties. For example, such com-
pounds have been reported to bind to cell surface GABA receptor/
chloride ion channel complex [9] and inhibit serine proteases [10].
Moreover, it is also notable that scaffolds like 3 and 4 comprise
medium-ring nitrogen heterocycles, which are underrepresented
among new chemical entities found in compound libraries used
for biological screening [11]. With this as background, we
embarked on a series of studies directed toward the synthesis of
several heterocyclic scaffolds related to 3 and 4 that were suitably
substituted for further derivatization [12]. Although other tria-
zolobenzodiazepines are known, compounds 3 and 4 represent
unique opportunities for lead discovery because they are the first
members of this class to possess functional handles that enable
diversification of substituents on both the triazole and the aryl
rings.
Scheme 2. Synthesis of triazolo-1,4-benzodiazepines.
reactions [6]. To exemplify possible ways in which different aryl
substituents may be introduced, Buchwald coupling of aryl bro-
mide 7b with morpholine gave 8 in 61% yield, and Suzuki coupling
of 7b with 3,4-methylenedioxyphenylboronic acid gave the biaryl
9 in 84% yield (Scheme 3). Other possibilities include conversion
of the aryl nitrile moiety in 7d,e into benzylic amines, aldehydes
or carboxylic acids, each of which can in turn be diversified further.
Demethylation of 7f would provide a phenol that can be alkylated.
Hence, there is considerable opportunity to generate collections of
novel compounds.
Inasmuch as there are only two points of diversification on
compounds like 7b–f, there are limitations to the regions of chem-
ical space that can be explored, so we turned our attention to ana-
logs of 3 having an additional functional handle (e.g., R1 = CH2OH,
CHO, CO2H, etc.) on the triazole ring. For example, a primary alco-
hol, R1 = CH2OH, could be modified by O-alkylation, a formyl group,
R1 = CHO, could be elaborated by reductive amination, and a car-
boxylic acid, R1 = CO2H, might be derivatized by amidation. Prepa-
ration of such compounds would simply require straightforward
modification of the reactions in Scheme 2.
To reduce this plan to practice, azidobenzaldehydes 6a–c were
reductively aminated with the hydrochloride salt of 4-aminobut-2-
yn-1-ol (10) [15] in the presence of Hünig’s base and NaBH(OAc)3,
and the intermediate amines were heated at 100 °C to induce the
azide-alkyne cycloaddition to furnish the triazolobenzodiazepines
11a–c in 71–86% overall yields (Scheme 4). Although derivatiza-
tion of the secondary amine group in 11a–c is a possibility, we
elected to protect the amine by reaction with (Boc)2O in the pres-
ence of Et3N to give the carbamates 12a–c (81–89%). The hydrox-
ymethyl group in 12a–c may now be elaborated by O-alkylations
to generate a set of ether analogs. To further increase the possibil-
ities for diversification, alcohols 12a-c were oxidized with IBX
using THF as a cosolvent to enhance the solubility of the alcohols
and provide the corresponding aldehydes 13a–c (84–91%)
[16,17]. Finally, Pinnick oxidation of 13a–c delivered the carboxylic
acids 14a–c in 62–70% yields [18,19]. We briefly explored several
methods (e.g., KMnO4 and TPAP/NMP) to directly oxidize 12a–c
to the acids 14a–c, but these procedures failed to give good yields.
Discussion and results
Our approach to access a series of 1,2,3-triazolo-1,4-benzodi-
azepines 3 (R1 = H) is related to the MCAP depicted in Scheme 1
and features the reductive amination of a series of 2-azidoben-
zaldehydes with a propargylamine followed by a Huisgen cycload-
dition (Scheme 2). The requisite 4- and 5-substituted (i.e., Br, CN,
OMe and CF3) 2-azidobenzaldehydes 6b–h were prepared in 47–
99% yield via the SNAr reaction of the corresponding 2-fluoroben-
zaldehydes 5b–h with sodium azide in DMSO [13], whereas 2-azi-
dobenzaldehyde (6a) was prepared via SNAr reaction of 2-
nitrobenzaldehyde with sodium azide in HMPA at room tempera-
ture (92%) (Scheme 2) [14]. Although reactions of 5b–f proceeded
well at 50 °C, poor yields were observed when the CF3-substituted
aldehydes 6g and 6f were prepared at 50 °C, so those reactions
were conducted at 0 °C. These reactions were readily scalable,
and the products could be easily purified via recrystallization from
i-PrOH. Reductive amination of 6a–h with propargylamine in the
presence of NaBH(OAc)3 followed by heating the intermediate
crude amine at 100 °C gave the 1,2,3-triazolo-1,4-benzodiazepines
7a–h, typically in good overall yields.
We have previously shown that the secondary amine in com-
pounds such as 7a–h can be further diversified by arylation, urea
formation, reductive N-alkylation, N-acylation, or sulfonylation
2
Abeykoon, Gayan A.
