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The Journal of Organic Chemistry
Page 2 of 11
Scheme 1. Summary of Aminolysis Behavior of Benzotri-
furanone (BTF)a
Chart 1. Benzoate ester derivatives and amines used in this
work.
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aminolysis product. For example, compound 1 (Scheme 1)
produced by aminolysis of BTF with one equivalent of amine
a will be denoted 1a, while 2 produced from BTF using two
equivalents of amine a will be denoted 2aa, and so on.
Benzoate Esters Used in this Work (Chart 1). BTF,11
BMF (2ꢀcoumaranone),11 and 4 (phloroglucinol triacetate)
were synthesized following literature precedent (see the SI for
details); BMP (3,4ꢀdihydrocoumarin) was purchased commerꢀ
cially. The synthesis of benzotripyranone BTP, a new comꢀ
pound, could be completed quantitatively through acidꢀ
catalyzed intramolecular transesterification of known triisoꢀ
propyl 3,3',3''ꢀ(2,4,6ꢀtrihydroxybenzeneꢀ1,3,5ꢀtriyl)tripropioꢀ
nate (which is available in six steps13 from 1,3,5ꢀ
trimethoxybenzene). Noted previously,11 attempts to prepare
BTF using “reversible” (e.g., Lewis and Brønsted acid cataꢀ
lyzed) lactonization conditions were plagued by the formation
of stable, partially cyclized intermediates. The observation
that BTP is formed quantitatively under the same conditions
speaks to its relative thermodynamic stability. The remaining
compounds shown in Chart 1, BDF and BDP, have been used
exclusively in calculations (vide infra).
aSummary of BTF aminolysis reactivity from ref. 10. Yields
shown are representative and determined from either 1H NMR
(1R, 2RR) or isolation (3RRR, 3R1R2R3).
We recently reported10 that benzotrifuranone (BTF)11
(Scheme 1), a C3hꢀsymmetrical trilactone, is unusually suited
for multifunctionalization through sequential aminolysis reacꢀ
tions. The platform affords rapid and efficient access to
monoꢀ (e.g., 1R), diꢀ (e.g., 2RR), and trifunctionalized (e.g.,
3RRR) targets provided routine control of temperature and
amine reagent stoichiometry, and lends itself to the oneꢀpot
synthesis of multifunctionalized phloroglucinol, 3 (e.g.,
3R1R2R3), from BTF in good yield (> 80%) and a single day.
General Aminolysis Behavior: BTF vs. BTP. BTP, like
BTF, forms a dilactone (5a) as the major product upon reacꢀ
tion with one equivalent of an aliphatic amine like benzylaꢀ
mine (a) (Scheme 2). The reaction, however, under conditions
identical to BTF aminolysis, is considerably slower and lower
yielding with respect to the monoaminolysis adduct (i.e., the
reaction is less selective). HPLC analysis (see Figure S1) of
the crude reaction after 2 h (at –41 °C in DMF), for example,
reveals a mixture of BTP (16%), 5a (70%), and 6aa (14%)
(and no detectable 7aaa). The conversion to 5a, nonetheless,
exceeds predictions given equivalent lactone reactivity (44%).
Similar results are found (not shown in Scheme 2) upon reacꢀ
tion of BTP with nꢀhepylamine (b) (where 5b is prepared in
71% isolated yield). Treatment of BTP with two equivalents
of a or b provides the corresponding monolactones (6aa and
6bb, respectively) in ~ 60% yield, again exceeding the 50%
predicted from equally reactive lactones. Phloroglucinol 7 can
be prepared essentially quantitatively with an excess of amine
(and warming to room temperature overnight) as shown
through the preparation of 7bbb (see the SI for details). These
synthetic experiments give the first indication that a simple
inductive argument is not sufficient to explain the high selecꢀ
tivity of BTF aminolysis.
We initially proposed a primarily electronic/inductive arguꢀ
ment (given the stepwise substituent changes occurring on the
central benzenoid ring) to rationalize the kinetic deactivation
observed upon successive aminolysis of BTF. In this paper,
we report a more comprehensive understanding of the aminolꢀ
ysis behavior of BTF through kinetics measurements, Xꢀray
crystal structure analysis, and quantum chemical calculations.
Included is comparison of BTF to various benzoate esters,
such as a ring expanded congener, benzotripyranone (BTP)
(Chart 1). Notably, our structureꢀproperty investigation exꢀ
poses a ring strain gradient as a component of the sequential
aminolysis behavior observed for BTF. While singular strain
elements are appreciated as useful promoters of chemical reacꢀ
tions,12 this study shows that energetically coupled strainꢀ
release events can afford stepwise reactivity and can serve as
the basis for sequential molecular functionalization.
RESULTS AND DISCUSSION
Numbering Convention. Throughout the paper, BTF and
BTP aminolysis products are first numbered based on their
parent structure. Letters after the numbers designate the numꢀ
ber, type, and sequence of amines (Chart 1) used to form the
Aminolysis Rate Constants: Determination and Caveats.
The aminolysis of simple phenyl acetates in polar aprotic
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