Angewandte
Communications
Chemie
Table 1: Screening of dimerization conditions.
they are made from aromatic feedstocks in two
simple and general steps.
Based on our observation that secondary amines
were singularly effective in promoting these reac-
tions, and that chiral induction was observed when
using chiral amines (Table 1; Entries 4–6), we pro-
pose an iminium-mediated mechanism for this trans-
formation (Scheme 3). Thus, condensation of p-
quinol 1 with pyrrolidine would lead to iminium
ion 9. Oxa-Michael addition of a second molecule of
p-quinol 1 to intermediate 9 gives adduct 10, which
has an electron-rich diene and an electron-deficient
alkene in close proximity. An intramolecular [4+2]
cycloaddition, through either a concerted or stepwise
mechanism (Scheme 3; Pathway a or b), then forms
Entry Conditions
% Conversion[a](e.r.)[b]
2a
3a
1
2
3
4
5
6
4 (100 mol%, slow addition), DCE, 708C, 5 d
4 (30 mol%), CDCl3, 608C, 48 h
4 (30 mol%), CDCl3, 608C, 48 h then DBU, RT, 16 h
5 (30 mol%), CDCl3, 608C, 48 h
6 (30 mol%), CDCl3, 608C, 5 d
7 (30 mol%), 8 (60 mol%), CDCl3, 608C, 48 h
85
65
trace
10
trace
80
À
two new C C bonds to give 11, which upon hydro-
50 (41:59) 10 (nd)
lytic removal of pyrrolidine furnishes tetracycle 2.
The final oxa-Michael addition to give hexacycle 3
then occurs slowly in the presence of pyrrolidine, or
can be accelerated by the addition of the strong base
DBU. We considered two stereocontrol scenarios
that could account for the remarkable selectivity
observed for this domino reaction sequence
25 (67:33)
trace (89:11)
–
–
[a] Conversions were determined using 1H NMR spectroscopy. [b] Enantiomeric
ratios were determined using chiral-HPLC (Chiracel OD-H column). DCE=1,2-
dichloroethane, DBU=1,8-diazabicyclo(5.4.0)undec-7-ene.
reaction (Table 1; Entry 3). Given the complexity of the
transformation, we reasoned several mechanisms were pos-
sible, and therefore screened a number of catalysts and
promoters, spanning primary, secondary, and tertiary amines,
phosphines, bases, phosphoric acids, thioureas, and combina-
tions thereof (see the Supporting Information for complete
list of conditions). Of these, only secondary amines produced
dimers (2a or 3a), the yields of which dropped off signifi-
cantly when more sterically hindered amines were used
(Table 1; Entries 4–6). Indeed, whilst good enantioselectivity
could be obtained with highly hindered secondary amine 7
and co-catalyst 8 (Table 1; Entry 6),[8] the reaction afforded
a complex mixture with only trace quantities of dimer
obtained.
We synthesized a range of p-quinols 1a–h through
oxidative dearomatization of the corresponding 4-substituted
phenols, and subjected them to the dimerization conditions
(Scheme 2). In each case, by using chloroform as the solvent,
we were able to isolate tetracycles 2a–h in yields ranging from
47–58%, featuring a variety of alkyl and aryl substituents.
Performing the reaction again but adding DBU at the end, we
were able to isolate hexacycles 3a–h as the major products
instead, in yields ranging from 48–63%, thus providing easy
access to two polycyclic manifolds, with DBU differentiating
the outcome. The dimerizations were all performed in
standard glassware under an atmosphere of air.
(Scheme 3, kinetic models A and B). Firstly, given that
intermolecular oxa-Michael reactions are known to be
reversible,[10] the observed selectivity could be explained by
invoking the Curtin–Hammett principle,[11] wherein inter-
mediates 10 and 10’ are in rapid equilibrium and the [4+2]
cycloaddition is faster for intermediate 10 (Scheme 3, kinetic
model A). Alternatively, the initial oxa-Michael reaction may
exhibit high selectivity for the formation of ether 10 over 10’
(Scheme 3, kinetic model B).[12]
Density functional theory (DFT) calculations, at the
SMD[(CH2Cl)2]-M06-2X/Def2QZVP//M06-2X/6-31G* level
of theory, were undertaken to probe the reactivity and
selectivity of this process for methyl-substituted p-quinol 1a
(Scheme 4). This revealed that the reaction is likely not under
Curtin–Hammett control; the initial oxa-Michael reaction is
calculated to exhibit high selectivity for intermediate 10a
over 10a’ (DDG1° = 12.9 kcalmolÀ1) (Scheme 4). This is
principally due to steric factors and a favourable H-bonding
interaction between the incoming nucleophile and the
hydroxy group of the Michael acceptor, which can only be
achieved when the nucleophile approaches syn to the hydroxy
group (TS1; Scheme 4). The subsequent cycloaddition of ether
10a to afford tetracycle 11a is calculated to proceed via
a concerted, asynchronous (Dr= 34 pm), transition state
(DG2° = 28.8 kcalmolÀ1; Scheme 4). The initial Michael reac-
tion for the alternative stepwise mechanism (Scheme 3;
°
Attempted cross-dimerizations gave intractable mixtures
of all the expected products. p-Quinols with ortho and/or meta
substituents failed to produce dimers when subjected to our
conditions. The structure of each dimer was assigned using
extensive NMR spectroscopy, and crystal structures for both
a tetracycle and hexacycle (2a and 3 f, respectively) were
obtained (Scheme 2).[9] The complexity this collection of
polycyclic compounds exhibits, with seven or eight newly
formed contiguous stereogenic centres and numerous fused
and bridged (hetero)cycles, is truly remarkable given that
Pathway b) was found to have a higher barrier (DG3
=
30.6 kcalmolÀ1; Scheme 4). Thus, we propose that the pyrro-
lidine-mediated dimerization of p-quinols involves an initial
kinetically selective, though reversible, intermolecular oxa-
Michael addition followed by an irreversible intramolecular
Diels–Alder cycloaddition (Scheme 4; see the Supporting
Information for full computational details). If our mechanistic
proposal is correct, this work represents the first activation of
the p-quinol moiety by iminium catalysis for intermolecular
reactivity.[13] Given our clear demonstration of both the
2
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Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!
Green, Nicholas J.
