Evidence for Simultaneous Dearomatization of Two Aromatic Rings under Mild Conditions in Cu(I)-Catalyzed Direct Asymmetric Dearomatization of Pyridine

Article abstract of DOI:10.1021/jacs.0c04486

Bis(phosphine) copper hydride complexes are uniquely able to catalyze direct dearomatization of unactivated pyridines with carbon nucleophiles, but the mechanistic basis for this result has been unclear. Here we show that, contrary to our initial hypothes

Full text of DOI:10.1021/jacs.0c04486

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Article
Evidence for Simultaneous Dearomatization of Two
Aromatic Rings Under Mild Conditions in Cu(I)-
Catalyzed Direct Asymmetric Dearomatization of Pyridine
Michael W. Gribble, Richard Y. Liu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04486 • Publication Date (Web): 26 May 2020
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Evidence for Simultaneous Dearomatization of Two Aromatic Rings
Under Mild Conditions in Cu(I)-Catalyzed Direct Asymmetric
Dearomatization of Pyridine
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Michael W. Gribble, Jr.,* Richard Y. Liu,* and Stephen L. Buchwald.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United States.
ABSTRACT: Bis(phosphine) copper hydride complexes are
uniquely able to catalyze direct dearomatization of unactivated
pyridines with carbon nucleophiles, but the mechanistic basis for
this result has been unclear. Here we show that, contrary to our
initial hypotheses, the catalytic mechanism is monometallic and
proceeds via dearomative rearrangement of the phenethylcopper
nucleophile to a Cpara-metalated form prior to reaction at
heterocycle C4. Our studies support an unexpected heterocycle-
promoted pathway for this net 1,5-Cu-migration beginning with a
doubly dearomative imidoyl-Cu-ene reaction.
Kinetics,
substituent effects, computational modeling, and spectroscopic
studies support the involvement of this unusual process. In this
pathway, the CuL2 fragment subsequently mediates a stepwise
Cope rearrangement of the doubly dearomatized intermediate to
the give the C4-functionalized 1,4-dihydropyridine, lowering a
second barrier that would otherwise prohibit efficient asymmetric
catalysis.
Introduction
Dearomative addition reactions of carbon nucleophiles
(Figure 1, A-D)1 build up complexity starting from relatively
abundant heteroaromatic substrates and give access to
products spanning several oxidation states, including pyridines
and piperidines, the two most common heterocycles in FDA-
approved drugs.2 However, harsh reagents or reaction
conditions are typically required for direct organometallic
addition to pyridine (Figure 1, A),1c,3 and catalysis of such
reactions (Figure 1, C) was undocumented,4 to our knowledge,
until
2018.5-7
Broadly
useful
C–C-bond-forming
dearomatization methods have instead relied on stoichiometric
preactivation of the heterocycle (Figure 1, B) to achieve
efficient reaction under mild conditions.1 This powerful tactic
has been the subject of hundreds of methodological
contributions from numerous research groups,1c and there now
exist many options for effecting dearomatization with a
specific sense of regioselectivity (i.e., 1,4-addition or 1,2-
addition, Figure 1, B). However, these methods often require
installation or removal of activating groups or preparation of
non-commercial nucleophiles in separate operations, and thus
commit significant effort to non-strategic transformations.
Certain forms of stereocontrol have also been difficult to
achieve within this reactivity paradigm. In particular,
Figure 1. C–C-Bond-forming dearomatization of pyridine.
diastereofacial discrimination by nucleophiles approaching
pyridinium ions at C4 is challenging,8 and asymmetric
catalysis of 1,4-dearomatization9 remains rare1c despite
numerous successes realizing 1,2-selective variants.10
We recently described
transformation (Figure 1, C) that operates directly on pyridine
a new type of dearomative
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Our early observations suggested that two CuL2 fragments
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7
8
were likely involved in the dearomative addition step (Figure
2, A).4 However, the mechanistic investigations presented in
this article show that the major pathway exclusively involves
monometallic intermediates and entails dearomatization of the
phenethylcopper nucleophile (9a, Figure 2, A and B) prior to
its ultimate delivery to heterocycle C4 (see Figure 2, B, ii for
labeling conventions).
Based on pioneering work by
Schomaker,13 we initially thought that 9a might undergo
stepwise dearomative 1,5-Cu-migration (steps ii + iii, Figure
2, B, i) to give Cpara-metalated intermediate 13aa (after
coordination, step iv, Figure 2, B, i), which we hypothesized
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would generate 10aa through
a
polar isomerization
topologically equivalent to a 5,5-sigmatropic rearrangement
(step v, Figure 2, B, i). While our experiments support the
involvement of both 13aa and the 5,5-rearrangement in the
major pathway, they also indicate that the heterocycle must be
functioning as an electrophile in the most difficult step of the
phenethyl isomerization. In our revised pathway, doubly
dearomative imidoyl-Cu-ene reaction14 of 14aa (step iii,
Figure 2, B, ii) provides an unexpectedly facile pathway for
net 1,5-Cu-migration of the phenethyl group, with 13aa
forming via retro-ene reaction (step v, Figure 2, B, ii) of
transient 1,2-DHP 15aa. Notably, the retro-ene and 5,5-
rearrangement (steps v + vi, Figure 2, B, ii) can be viewed as a
stepwise Cope reaction in which 13aa is
a fleeting
intermediate. Cu(I)-mediation of this Cope rearrangement in a
two-step manner is critical for successful asymmetric catalysis
and results in the reaction’s dramatic intolerance of para-
substituted styrenes.
Background
At the outset, we imagined that Cu(I) might catalyze a new
dearomative transformation analogous to the recently reported
15
훼
1,2- -phenethylation of imines (Figure 3, A). However, we
expected that dearomative addition of an organocopper
nucleophile would require activation of the heterocycle by an
N-bound Lewis-acid, and we conjectured that the hydrosilane
reductants used in CuH-catalysis would be insufficiently
electrophilic for this purpose (we have subsequently proven
than the silane is not responsible for activation, vide infra).
Lewis-acid activation by Cu(I) was on the other hand
precedented,16 although addition via
intermediate seemed unlikely given that it would involve a
highly distorted metalacyclobutane-like transition state (TS14,2
a
monometallic
,
Figure 2. Mechanistic proposals for Cu-catalyzed direct
dearomatization.
Figure 3, B). Bimetallic carbonyl-addition mechanisms
(Figure 3, C-D)17 suggested that a more favorable transition
state (TS18,2, Figure 3, E) might be attainable with a second
CuL2 fragment bridging the nucleophile and heterocycle.
However, when we exposed pyridine to DMMS, styrene, and
precursors to [(S,S)-Ph-BPE]CuH, we indeed saw facile
catalytic dearomatization but obtained 1,4-DHP 7aa almost
exclusively (Figure 3, F).4 Although this regioselectivity was
incompatible with our mechanistic hypothesis, a study of
heterocycle reactivity trends nevertheless suggested that
activation by Cu(I) was important as expected; in particular,
C2-substitution on the heterocycle profoundly slowed the
reaction, even with groups (e.g., CF3)4,18 that increase the
intrinsic electrophilicity of the heterocycle but interfere with
coordination to bulky Lewis acids.
and generates the nucleophiles catalytically from olefin
precursors (6, Figure 1, D),4 making it even more efficient
than direct organometallic addition. The labile nature of the
N-silyl group11 incorporated into the product also obviates
separate protecting group manipulations. The reaction was
notable for being both highly enantio- and 1,4-selective, and it
gave 1,4-dihydropyridines (1,4-DHPs, i.e., anti-7, Figure 1, D)
with very high diastereoselectivity in all but a few cases.4
However, we did not have a clear mechanistic rationale for
these selectivity outcomes. The fundamental result that
pyridine reacts so readily under these conditions was also
surprising given that it is
a traditionally problematic
dearomatization substrate and far less intrinsically reactive
than the kinds of electrophiles typically used in CuH-catalyzed
hydrofunctionalization reactions (Figure 1, E).12
C4-selective addition with Cu(I)-activation of both reaction
partners was difficult to reconcile with monometallic (Figure
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to simple electronic perturbation of the arene given that the
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8
corresponding ortho-substituted styrenes are all excellent
dearomatization substrates (7ab, 7ad, 22ab, and 22ag, Table
1). Rather there must be a specific interaction, unique to the
dearomatization mechanism, affecting Cpara substituents and
one or more of the other reacting fragments. TS9,10 (Figure 4,
D) exhibits such an interaction: formation of a parallel-
휋
displacement -complex between 9 and the heterocycle would
project a para-group toward the bulky coordination sphere of
the CuL2 fragment bound at N1.
9
Despite its explanatory power, we had difficulty adopting
the bimetallic transition-state model upon learning that the
dearomatization is in fact highly selective for net retention of
the C훼 stereocenter in (S,S)S-9 (Table 2).4 We and others have
shown that hydrocupration is enantiodetermining in various
CuH-catalyzed reactions,21-23 which implies that the majority
of product is generated by stereospecific reaction of the major
phenethylcopper diastereomer with the electrophile. Thus,
major product C휶-(R)-anti-7 (Table 2) cannot be formed via
invertive attack by the nucleophile unless stereodetermination
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occurs in
a
fundamentally different manner in the
dearomatization (i.e., achieves net retention through invertive
preferential reaction of the minor phenethylcopper
diastereomer). At the same time, we were unaware of
precedent for models similar to TS9,10 (Figure 4, D) that might
yield stereoretention, which would require the CuL2 fragment
of the nucleophile to depart from the same face that the
electrophile approaches. Such models would not entail
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Figure 3. Cu-catalyzed direct dearomatization occurs with
regioselectivity opposite that predicted.
4, A) or closed bimetallic transition states (Figure 3, E).
However, open bimetallic transition states had structural
precedent. For example, Aggarwal’s 1,4-dearomatization of
pyridiniums with phenethylboronates8 occurs through an open
transition state (TS19,7, Figure 4, B) with invertive addition by
19a at C4, and our group has proposed a very similar mode of
attack (Figure 4, C) for stereoinvertive addition of
phenethylcopper nucleophiles to imines.15 Planarization of C
훼
휋
in Aggarwal’s reaction creates the potential for favorable
-
stacking19 between the phenyl and pyridinium rings (Figure 4,
B), leading to a preference for anti-selective addition, which
훼
avoids an otherwise disruptive clash between the C methyl
and the out-of-plane carbonyl group at C3.8 We realized that
we could explain one of the most surprising properties of the
휋
-
Cu-catalyzed dearomatization by invoking a similar
stacking interaction (see TS9,10, Figure 4, D). With the
휋
exception of those bearing strong -acceptor groups, styrenes
with substituents at Cpara have generally been among the best
substrates for the asymmetric olefin hydrofunctionalization
reactions our group had previously reported,20 including all
that use the catalyst system employed here. However, the
presence of para-F or para-OMe groups completely
suppressed catalytic dearomatization,4 while para-Me slowed
the reaction twentyfold and caused profound erosion of the
1,4-selectively (Table 1). These findings cannot be attributed
Figure 4. Development of an open bimetallic transition state
model.
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Table 1. The Styrene-Para-Group Effect.
Table 2. Representative Stereochemical Outcomes.
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orders if the resting state contained one catalyst species of
known composition in large excess over all others (i.e.,
contained a MACS, most abundant catalyst species). In that
case, the rate law would be determined by the linear sequence
of steps starting from the MACS and ending with the turnover-
limiting step (TLS).24 The dearomative step that consumes 9
(Table 2) was a likely TLS given its expected difficulty, and
Δ
the formation of 9 in in a facile, exergonic step (calculated
G‡ = 12.2 kcal/mol; calculated G = –11.2 kcal/mol for
styrene) thus suggested that the phenethylcopper nucleophile
should be a major component of the resting state. Hartwig’s
mechanistic studies of Cu-catalyzed hydroboration entailed
characterizing phenethylcopper complexes derived from
DTBM-SEGPHOS by 19F and 31P NMR spectroscopy and, in
the case of minor diastereomer (S)S-9cSEG (Figure 5, A), by X-
ray crystallographic analysis, showing these species to be
monometallic, Y-shaped complexes.22 We find that analogous
(S,S)-Ph-BPE complexes form as major hydrocupration
°
Δ
products
under
conditions
relevant
to
catalytic
(a) Reactions used (R,R)-Ph-BPE, (b) see supporting information
for details, (c) reactions used (S,S)-Ph-BPE.
dearomatization. Successively exposing THF-d8 solutions of
Cu(OAc)2 and (S,S)-Ph-BPE to DMMS and styrene-훼-13C
(Figure 5, B) gave mixtures containing three principal
phosphorus-containing species, as shown by 31P NMR
spectroscopy. One was free Ph-BPE, which resonated as a
sharp singlet with the expected shift at -60 °C; this signal
broadened at higher temperatures due to chemical exchange
with the other two components. These latter species were
clearly products of reaction with styrene, appearing as
doublets (Figure 5, C) having similar coupling constants
훼
planarization of C , and thus it seemed less assured that they
would permit 휋-stacking or incur a para-group clash. Further,
although the (anti):(syn) ratios we observed with substituted
heterocycles (Table 2) did not exhibit easily intuited
correlations with substituent properties, the selectivity trends
were clearly difficult to rationalize by analogy to the
stereochemical
model
for
dearomatization
with
phenethylboronates.
Highly
diastereoselective
phenethylboronate addition to pyridiniums requires a sterically
demanding out-of-plane carbonyl group at C3 (Figure 4, B);8
in contrast to that reaction, Cu-catalyzed dearomatization
occurred with excellent selectivity with small C3 substituents
like Me and MeO (12:1–30:1 dr; e.g., 7ca, Table 2)18 and gave
much lower dr’s with nicotinates and nicotinamides (e.g., 7ba,
Table 2). In fact, pyridazine, which lacks a C3 substituent
2
(2JP,C(S,S)S-9a = 22.5 Hz, JP,C(S,S)R-9a = 22.8 Hz).
Suggestively of the epimerization process described by
Hartwig for 9cSEG (Figure 5, A),22 the distribution of the
hydrocupration products greatly favored the major species
initially but approached an apparent equilibrium ratio < 1.8:1
over the course of four days. Confirming the minimal
connectivity in 9a (Figure 5, B), the benzylic 13C resonances
for the products were a pair of triplets (Figure 5, D) that
occurred in the same ratio as the 31P doublets and exhibited
≥
altogether, gave one of the highest dr’s we have observed (
28:1; 7ea, Table 2).
2
triplet couplings virtually identical to the JP,C values of the
Results and Discussion
respective corresponding 31P signals. We corroborated that the
species assigned as (S,S)S-9a and (S,S)R-9a (Figure 5, B)
were stereoisomers by introducing a much faster pathway for
attaining the apparent diastereomeric equilibrium. When the
Ph-BPE is enantiomerically pure, phenethylcopper
1. Identification of the catalyst resting state and observation of
kinetically controlled phenethylcopper dr during catalysis.
Reaction kinetics could confirm or invalidate bimetallic
pathways, provided that we knew the catalyst resting state.
We expected that the molecular formula for the turnover-
limiting transition state (TLTS) might be evident from kinetic
훼
diastereomers only interconvert by epimerization at C , via
훽
relatively slow -hydride-elimination/reinsertion. However,
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(A) Phenethylcopper intermediates in hydroboration - Hartwig
we have found that the species assigned as (S,S)S-9a and
(S,S)R-9a (Figure 5, B) undergo ligand exchange with free
Ph-BPE on the NMR timescale.18 The result of a heterochiral
F
1
2
3
4
5
6
7
8
O
F
F
Ar
P
Ar
(R)
(S)
Me
Me
O
O
slow
CuMe
Ar
⇌
ligand exchange reaction, e.g., (S,S)S-9a + (R,R)-Ph-BPE
(R,R)S-9a (S,S)-Ph-BPE, is rapid interconversion of
HBpin
C6D12
Cu[(S)-L2]
Cu[(S)-L2]
P
+
(S)R-9cSEG
(S)S-9cSEG
Ar
O
diastereomers by changing the configuration of the ancillary
ligand. Thus, conducting hydrocupration with racemic Ph-
BPE must immediately generate 9a (Figure 5, E) in its
equilibrium diastereomer ratio. In the event, hydrocupration
of styrene (6a) with racemic Ph-BPE gave [(R,R)R-9a +
(S,S)S-9a] and [(R,R)S-9a + (S,S)R-9a] in a static ratio of
1.43:1 (Figure 5, E) by the time of the first analysis, from
which we have calculated equilibrium constants of 0.699 and
0.489 for the respective processes in Figure 5, B and E.25 This
rapid equilibration method enabled us to study the relative
reactivity and selectivity of the individual phenethylcopper
diastereomers toward catalytic dearomatization (vide infra).
major
minor
23
[(S)-DTBM-SEGPHOS]CuMe
• observable by 19F, 31P NMR
• X-ray crystal structure obtained
of (S,S)-diastereomer
= [(S)-L2]CuMe
Ar = 3,5-(tBu)2-4-(MeO)Ph
9
(B) Hydrocupration of styrene--13
C
Cu(OAc)2
1. DMMS
10
11
12
(R)
H
KEQ
0.699
=
H
(S)
13C
0.11 mmol
0.12 M final
+
(13 equiv)
THF-d8, rt, 20 min
Me
Me
13C
H
2.
slow
Cu[(S,S)-L2]
Cu[(S,S)-L2]
(S,S)S-9a--13
(S,S)-Ph-BPE
= (S,S)-L2
1.06 equiv
13C
13
14
15
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17
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19
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(S,S)R-9a--13C
C
Ph
(12 equiv)
71% conversion to (S,S)S + (S,S)R
estimated from 31P NMR integrals
rt, 95 min
(C) 31P NMR of 9a--13C
(S,S)-L2
(D) 13C NMR of 9a--13
(S,S)S-9a
C
The phenethylcopper complexes (particularly the major
diastereomer) were indeed the MACS during dearomatization
of pyridine or 3-Ph-pyridine with styrene or 3-fluorostyrene.
Depending on the exact conditions, we estimated that total
phenethylcopper made up ca. 70–88% of all copper-containing
species (based on integration of the 31P NMR signals) after
hydrocupration conducted with excesses of styrene and
DMMS, and 75% (based on 19F integrals) to 90% (based on
31P integrals) of all copper-containing species after similar
hydrocupration of kinetics model substrate 3-fluorostyrene.26
Apart from a distribution of low-level species, some of which
formed in variable amounts and appeared to be decomposition
products of the phenethylcopper complexes, no other
observable copper compounds were present. Addition of 3-
Ph-pyridine to a hydrocupration mixture led to rapid catalytic
dearomatization (Figure 5, F) but did not generate any new
observable catalyst species or markedly alter the approximate
proportion of metal present as 9a (plotted using 31P-based
estimates in Figure 5, F, i). However, we did observe
mechanistically significant variation in the dr of 9a as the
catalytic reaction proceeded (figure 5, F, ii). This experiment
used 9a that had been aged in the absence of heterocycle for
>5 h (Figure 5, F), during which time extensive epimerization
occurred, giving an (R,R)R:(R,R)S ratio of 4:1 at the start of
the catalytic reaction. Over the first 30% conversion of 1d
(Figure 5, F), the (R,R)R:(R,R)S ratio increased to a maximum
of 45:1 before gradually declining again at higher conversion
(Figure 5, F, ii). Both phenethylcopper diastereomers present
when the heterocycle is added are consumed by the
dearomative addition step, leading to regeneration of [(R,R)-
Ph-BPE]CuH. Hydrocupration then regenerates (R,R)R-9a
with high kinetic selectivity in the presence of 1d (Figure 5,
F), which leads to subsequent catalytic recycling occurring
much faster than (R,R)R-9a epimerizes.27 This causes the
initial dramatic increase in the (R,R)R:(R,R)S ratio. The
catalyst dr gradually decreases at higher conversions because
epimerization of (R,R)R-9a (which has rate ~ k[(R,R)R-9a]28
under these conditions) becomes increasingly competitive with
turnover as the reactant required for dearomatization is
depleted. It is implied that the rate expression for the TLS of
the dearomatization has a nonzero kinetic order in at least one
of the substrates.
(S,S)R-9a
2JC,P
=
22.8 Hz
(S,S)R-9a
2JC,P
23.2 Hz
=
(S,S)S-9a
(E) Bimolecular equilibration via heterochiral ligand exchange
(R)
(R)
Me
Me
Ph
Ph
Cu[(R,R)-L2]
Cu[(S,S)-L2]
(S,S)R-9a
+
KEQ(bi)
= 0.489
[(R,R)-L2]CuH
+
(R,R)R-9a
styrene
fast
+
very fast
via
(S)
(S)
Ph
Ph
Me
Me
[(S,S)-L2]CuH
ligand
exchange
mixture
prepared from
0% ee Ph-BPE
Cu[(S,S)-L2]
(S,S)S-9a
Cu[(R,R)-L2]
(R,R)S-9a
(F) Monitoring the resting state in situ
Ph
Ph
Me
Ph
Me
Ph
8.6% Cu(OAc)2
13% (R,R)-L2
1d
Cu[(R,R)-L2]
N
Ph
DMMS (2.2 equiv)
THF-d8, rt
5 h equilibration
(R,R)R-9a
+ (R,R)S-9a
L2 = Ph-BPE
(0.23 mmol)
0 °C, inside
NMR probe
1.4
equiv
N
7da
SiMe(OMe)2
i. Phenethylcopper complexes are the MACS
estimated % of Cu present as 9a
Me
Ph
Me
Ph
Cu[(R,R)-L2]
(R,R)S-9a
Cu[(R,R)-L2]
(R,R)R-9a
% conversion of 3-Ph-Pyr
ii. (R,R)R:(R,R)S ratio is kinetically controlled during catalysis
phenethylcopper dr
(R,R)R-9a:(R,R)S-9a
% conversion of 3-Ph-Pyr
2. The dearomative addition step is stereoretentive.
Figure 5. Phenethylcopper complexes are the MACS during
dearomatization and exhibit mechanistically significant
stereochemical dynamics.
Mechanistic ramifications of the kinetically controlled
catalyst dr enabled us to demonstrate that the invertive
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nucleophilic approach trajectory in Figure 4, B and C, cannot selective for the major 1,4-DHP enantiomer. Conducting
1
2
3
4
5
6
7
8
be operative in Cu-catalyzed dearomatization, invalidating the
transition state model in Figure 4, D. For catalytic reactions
that continuously regenerate the major diastereomer of 9a
((R,R)R-9a + (S,S)S-9a if both Ph-BPE enantiomers are
dearomatization with 100% (R,R)-Ph-BPE under conditions
implied by the observed catalyst stereochemical dynamics to
increase the proportion of total product formed via (R,R)S-
932,33 significantly erodes the enantioselectivity and
diastereoselectivity of the catalytic reaction.18 Thus, only
(R,R)R-9 selectively generates the major 1,4-DHP product
enantiomer, and because these two species have the same
present; Figure 5, E) with high kinetic selectivity,
a
straightforward equilibrium calculation implies that
heterochiral ligand exchange (Figure 5, E) should generate
resting states containing 9a in a steady-state diastereomer ratio
governed by
훼
absolute configuration at C , the dearomative addition step
must itself be stereoretentive.
9
1
3. Dearomative addition involves a single CuL2 fragment:
Empirical determination of the molecular formula of the TLTS
for dearomatization of 3-phenylpyridine.
휓2 ― 휓 = 휙2 ― 휙
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1 ―
(
)
Keq(bi)
(eq 1),
We began kinetics studies with the model reaction in Figure
6, A, which had ideal properties for calorimetric reaction-
progress kinetics analysis.34 The near-perfect overlay of
rate/[Cu] (Figure 6, B) for two reactions differing only in
catalyst loading shows that the reaction is first-order in copper.
This implies that no additional equivalents of Cu are
incorporated into the catalyst during the sequence leading
from the MACS to the TLTS, and because the MACS is
monometallic, the TLTS can only contain one copper atom.
The general bimetallic mechanism in Figure 2, A cannot be
correct. Further, the linearity of the plots in Figure 6, C shows
that the reaction is first-order in one reactant and zero-order in
the others, and in that case, the invariance of the reaction rate
when [DMMS] and [3-F-styrene] are varied simultaneously
(Figure 6, C) implies that both have kinetic orders of zero.35
This means that no DMMS36 is incorporated into the TLTS,
and that no 3-fluorostyrene is incorporated beyond that already
present in 9h (Figure 6, A). It also means that the reaction is
first-order in heterocycle. With regard to stoichiometry, the
TLTS must be composed of one equivalent of the
phenethylcopper complex, and one equivalent of 3-
phenylpyridine (Figure 6, D).
휙
where is the mol fraction of Ph-BPE supplied as the major
enantiomer, Keq(bi) is the equilibrium constant (0.489) for
heterochiral ligand exchange, and 2 is the steady-state mol
fraction of 9a present as (R,R)S-9a + (S,S)R-9a (Figure 5,
E).29 Thus one can generate catalyst mixtures having very
different diastereomeric composition by varying the er of the
휓
ligand.
This enabled us to correlate the rate and
diastereoselectivity of the catalytic dearomatization with the
proportion of 9a (Figure 5, F) present as the minor
diastereomer.30,31 It became clear from those studies that
(R,R)S-9a undergoes dearomative addition to 3-
phenylpyridine at a comparable rate to (R,R)R-9a (Figure 5,
F), but with severely eroded anti-selectivity.18 Given that
catalytic dearomatization is highly anti-selective under typical
conditions, this implies that reaction via (R,R)S-9a is not
normally a major contributor to total product formation. It
also signals that simple substrate-controlled interactions are
not capable of explaining how diastereodetermination occurs
in the dearomative addition. Having established that both
diastereomers of 9 (Table 2) directly undergo dearomative
addition, it became possible to show that (R,R)S-9 is not
(A) Model reaction for kinetics analysis
F
F
Ph
Me
Ph
Cu(OAc)2
4.0-7.9 mol%
DMMS
F
F
2.4-3.8 equiv
1d
6h
N
(R)
(S)
Me
Me
+
+
[(S,S)-L2]CuH
THF, rt
25-30 min
L2 = Ph-BPE
1.2-2.7 equiv
1.0 mmol
0.25-0.34 M (total)
26 °C
(S,S)-L2
4.4-8.7 mol%
(1.1:1 L2:Cu)
rt, 90 min
Cu[(S,S)-L2]
Cu[(S,S)-L2]
(S,S)S-9h
N
(S,S)R-9h
7dh
calorimetry starts
SiMe(OMe)2
(B) Determination of the kinetic order in Cu(I)
(C) Kinetic orders in DMMS, 3-fluorostyrene, and heterocycle
rate
in s-1
first order in Cu
[Cu]
-1
rate
in Ms
zero order in DMMS
and 3-fluorostyrene
[Het] in M
[Het] in M
first order in Het
(D)i. Composition of the MACS
[(S,S)-L2]CuH
ii. Composition of the TLTS
Ph
Ph
[(S,S)-L2]CuH
DMMS
DMMS
F
N
F
N
6h
one equiv
8
1d
zero equiv
8
1d
one equiv
6h
one equiv
one equiv
zero equiv
one equiv
zero equiv
Figure 6. Determination of the molecular formula for the TLTS of dearomatization of 1d using reaction kinetics.
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4. The single-dearomatization pathway: Rearrangement of 9 to removed to give free 12a, which lies 17.3 kcal/mol above
a Cpara-metalated isomer and 5,5-rearrangement.
1
isomeric 9a (Figure 7, C). Given that the Cu–N dative bonds
in 13aa and 14aa should be comparably stabilizing, the fact
that heterocycle dissociation by 13aa is 10.7 kcal/mol more
endergonic than dissociation by 14aa (Figure 7, C) suggests
that secondary interactions between the 2,5-cyclohexadienyl
ring and the heterocycle are important to stabilizing 13aa.
The optimized structure for 13aa (Figure 8, A) supports this
interpretation: the two rings are arranged in the characteristic
geometry of a parallel-displacement 휋-stacking complex
(distance between centroids = 3.58 Å for 13aa versus 3.5 Å
for the parallel-displacement benzene dimer),39 permitting
Coulombic interactions between rings over a large area
(alignment of complementary charges is depicted with colored
circles in Figure 8, A). The structures of 13aa and 5,5-
rearrangement transition state [TS13,10]aa (Figure 8, B) closely
emulate the 휋-stacking interaction conjectured to exist within
bimetallic TS9,10 (Figure 8, B), although we note that
dearomatization via 13aa would result in the opposite
stereochemical outcome: In [TS13,10]aa (Figure 8, B), the CuL2
fragment of the nucleophile is present on the same face that
the electrophile approaches, leading to retention of
2
3
4
5
6
7
8
9
The reaction kinetics necessitated a major reappraisal of the
likely requirements for dearomative reactivity. Specifically,
we needed to formulate
a stereoelectronically feasible
mechanism by which a single CuL2 fragment simultaneously
activates the electrophile and nucleophile while mediating
transfer of the latter to a remote position on the heterocycle.
We additionally knew that this pathway needed to retain the
phenethylcopper C훼 stereocenter and generate 1,4-DHP’s with
robust anti-selectivity. It occurred to us that these conditions
could be fulfilled simultaneously only if the C4-C훼 bond-
forming event occurred from an isomerized form of the
phenethylcopper nucleophile. Schomaker has shown that
Cortho-halogenated phenethylcopper complexes (e.g., 9i,
Figure 7, A) undergo dearomative 1,3-Cu-migration en route
to halogen-rearrangement products (24, Figure 7, A).13
Successive 1,3-migrations starting from 9a (Figure 7, B)
would furnish 12a, whose dative complex (13aa), we
reasoned, might generate N-Cu-1,4-DHP 10aa through a polar
isomerization topologically equivalent to a 5,5-sigmatropic
rearrangement (henceforth ‘5,5-rearrangement’; Figure 7, B).
Modeling at the CPCM(THF)/BP86-D3(BJ)/6-311+G(d,p)–
SDD(Cu)//B3LYP/6-31G(d)–SDD(Cu)37 level of theory
located [TS13,10]aa 3.7 kcal/mol higher in energy than 13aa
and situated 13aa only 8.5 kcal/mol higher than the MACS
(Figure 7, C). It is noteworthy that 13aa is destabilized
relative to 14aa (Figure 7, C) by far less (+6.6 kcal/mol) than
the resonance energy of a phenyl ring (30-36 kcal/mol by
various estimates).38 A serious penalty for dearomatization of
the phenethyl group only becomes evident if the heterocycle is
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
훼
configuration at C .
5. An imidoyl-Cu-ene pathway for dearomatizing the
phenethylcopper nucleophile: Formulation and precedent.
Strong stabilization and a low barrier to [TS13,10]aa make
13aa a viable catalytic intermediate (Figure 7, C), but they
also make the computed PES for the single-dearomatization
mechanism inconsistent with the reaction kinetics. The most
challenging step in the pathway (Figure 7, C) is the initial
dearomative 1,3-Cu-migration, yielding predicted kinetic
Figure
7.
The
single-dearomatization
pathway:
Precedent
and
computed
energy
surface.
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Page 8 of 20
(A) Computed structures for 13aa and 5,5-rearrangement TS
5,5-rearrangement barrier (relative to the phenethylcopper)
1
2
3
4
5
6
7
8
and the 휎BM barrier would both need to significantly surpass
the 1,3-Cu-migration barrier for this substrate. As it is not
easily reconciled with empirical rate data, we consider the
single-dearomatization mechanism a problematic candidate for
being the general 1,4-selective pathway. However, our
modeling indicates that the intermediacy of 1,3-Cu-migration
product 11a en route to 13aa (Figure 7, B) should enable
formation of the 1,2-DHP regioisomer via an imidoyl-Cu-ene
reaction with pyridine (Figure 9, A and B). Although 1,2-
DHPs were formed in trace or undetectable quantities in the
majority of the dearomatization reactions we have
investigated, the single-dearomatization pathway is a plausible
source of the minor 1,2-addition products we have observed
with certain substrates.
Me
H
H
L2Cu
N
13aa
e-deficient
e-excessive
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
Me
H
L2Cu
N
H
Rearrangement of free 9a (Figure 7, B) is not the only way
[TS
]aa
13,10
to generate Cpara-metalated intermediates.
The
inconsistencies described above are eliminated if coordination
of the heterocycle occurs before the 1,5-Cu-migration process.
Brown’s C2-borylation of 3-haloheterocycles,14 which
(B) TS13,10 replicates key features of an earlier
transition-state model
→
CuL2
Me

involves a chair imidoyl-Cu-ene reaction (28 29, Figure 10,
H
A) suggests an alternative pathway to 13aa (Figure 8, A)
Me
H
involving
a
turnover-limiting polar reaction of the
H
H
compare to

phenethylcopper nucleophile with the heterocycle. That an
imidoyl-Cu-ene reaction might form the basis for a 1,4-
selective process is evident from the reaction of diallylcalcium
with pyridine,41 in which ene product 33 undergoes Cope
rearrangement to C4-functionalized 1,4-DHP 34 (Figure 10,
L2Cu
N
L2Cu
N
H
H
[TS ]aa
9,10
[TS
]aa
13,10
Figure 8: Models for Cpara-metalated intermediate 13aa and the
5,5-rearrangement transition state.
B).
Yang has provided evidence for electrophilic
dearomatization of phenethylcopper nucleophiles via an
orders of zero for all reaction components except Cu(I).
Further, heterocycle substituent effects on the rate of
dearomatization (Table 3) imply that the heterocycle is not
only present, but also behaving as an electrophile in the TLS:
electron-donor C3-substituents slow the reaction (compare 1f
to 1d and 1c to 1a, Table 3), whereas groups that stabilize
negative charge markedly accelerate it (compare 1a to 1d and
1d to 1g, Table 3).40 The single-dearomatization mechanism
would only predict the correct rate law and substituent effects
if the transition state for 5,5-rearrangement (corresponding to
[TS13,10]aa in Figure 7, C) were in general the true energy
maximum of the dearomatization PES, and this would require
dramatic changes to the energies in Figure 7. Further, the
(para-MsPh) group in 1g (Table 3) is sufficiently activating to
change the rate law, resulting in kinetic dependence on
DMMS in addition to 1g (vide infra), which implies that the
Table 3. Heterocycle Substituent Effects on the Rate of
Dearomatization.
(B) Transition-state model for
imidoyl-Cu-ene reaction of 11a
(A) Computed PES for 1,2-dearomatization via 1,3-Cu-migration
G°
(kcal/mol)
Me
H
H
H
L
Cu
N
+19.2
+22.3
CuL2
[TS
]a
Me
L
9,11
H
H
Me
H
[TS
]aa
27,2
N
CuL2
+11.2
+10.4
CuL2
11a
H
Me
H
L
Me
H
N
Cu
2aa
+0.9
Me
CuL2
L
0
9a
[TS
]aa
pyridine
27aa
27,2
Figure 9. The 1,3-Cu-migration product 11a in the single-dearomatization pathway is predicted to undergo facile 1,2- addition.
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Journal of the American Chemical Society
Cortho-cyanation with Consideration of how computational indices of aromaticity
imidoyl-Cu-ene reaction in
a
tosylcyanamides42 (Figure 10, C). Thus we investigated
whether phenethylcopper nucleophiles could engage in an
analogous imidoyl-Cu-ene reaction with pyridine
change as the ene reaction progresses affords a unique
perspective on the nature of the double-dearomatization event.
Figure 11, D, plots the NICS(0) indices44 (defined as the
negative of the magnetic shielding value calculated for a
virtual proton at the center of the ring in question) as functions
of the ene reaction coordinate for the pyridine ring (blue line),
phenyl ring (purple line), and pericyclic ring (i.e., the ring
defined by the bonds that are changing; green line). NICS(0)
values for the pyridine and phenyl rings initially indicate
strong aromaticity and decrease monotonically throughout the
reaction, entering a phase of particularly rapid dearomatization
near 40% extent-of-reaction. Both rings attain their maximum
rates of dearomatization at the transition state, showing that
the transformation as modeled is truly a simultaneous double-
dearomatization. The apparent aromaticity of the pericyclic
ring reaches its maximum value immediately after the
transition state and decreases thereafter. While the NICS(0)
value for this ring is not a pure measure of its aromatic
stabilization,44b the manner which it evolves nevertheless
suggests that the concerted double-dearomatization is
kinetically facilitated by transient formation of a new aromatic
orbital array that confers additional stabilization to the
transition state.
1
2
3
4
5
6
6. Computational investigation of the doubly dearomative ene:
PES, energy-decomposition analysis, and aromaticity as a
function of the reaction coordinate.
7
8
9
The hypothesized ene would have the remarkable property
of simultaneously dearomatizing two aromatic rings. Despite
this, our modeling identified a transition state ([TS14,15]aa,
Figure 11, A and B) for the ene only 25.8 kcal/mol above 9a
(Figure 11, A), which corresponds to a reaction rate significant
on the timescale of days at 298K. It is unintuitive that a
doubly dearomative transformation would occur at ambient
temperature in the absence of highly energetic reactants, but
our investigations provide some insight into why this reaction
should be feasible. We calculate a –28 kcal/mol free-energy
change for a hypothetical ene (eq 2, Figure 11, C) involving
similar changes in formally localized bonds but no
dearomatization. The amount of energy released in this step,
presumably due to replacement of C–N 휋- and Cu–C 휎-bonds
with stronger C–N and C–C 휎-bonds, is close to current
estimates for the aromatic stabilization energy of pyridine (30-
31 kcal/mol).38,43 Thus, coupling these bonding changes to
destruction of aromaticity could largely offset or
overcompensate the dearomative penalty for the heterocycle,
leaving a residual penalty for the doubly dearomative ene (eq
3, Figure 11, C) closer in magnitude to the aromatic
stabilization energy of just the phenyl ring. Accordingly, the
predicted barrier to 1,3-Cu-migration by 9a (+22.3 kcal/mol,
Figure 7, C), which dearomatizes only one ring but fails to
generate more favorable localized bonds, is only modestly
lower than the barrier to the doubly dearomative ene. Taking
the energy change of eq 2 as an estimate for the total energy
change not due to dearomatization in eq 3 (Figure 11, C)
enables estimation of the resonance energy lost in eq 3 as
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7. Retro-ene of the doubly dearomatized intermediate gives
13: Heterocycle promotion of the 1,5-Cu-migration.
We attempted to model a concerted Cope rearrangement of
15aa, which would give 10aa (Figure 11, E) analogously to
the presumptive mechanism of the rearrangements in Figure
10, B and C. However, the transition state we found
([TS15,13]aa, Figure 11, E) exhibits C2–Cortho cleavage, but
without inception of bonding between C4 and C훼. Instead, the
two dearomatized rings begin to reorient themselves parallel to
one another, and Cpara puckers out of the plane while
engaging Cu(I) in a new interaction, forming previously
identified 13aa (Figure 11, E). This step is thus just the
reverse of the imidoyl-Cu-ene reaction that would generate
doubly dearomatized intermediate 15aa from the Cpara-
metalated isomer of 14aa (Figure 11, E; the step is henceforth
referred to as the retro-ene). Viewed within the complete
ΔG°(푒푞 3) ― ΔG°(푒푞 2) = 48
larger than the overall thermodynamic penalty for the reaction
(+20 kcal/mol in the gas phase).
simply
kcal/mol, a value much
Figure 10. Precedent for 1,4-dearomatization via an imidoyl-Cu-ene reaction of the phenethylcopper intermediate.
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(D) Changes in in NICS(0) aromaticity indices in the ene
(A) Computed PES for the doubly dearomative ene
1
2
3
4
5
6
7
8
G°
Me
L
(kcal/mol)
N
+25.8
Me
Cu
L
Me
CuL2
Me
L
H
L
+23.3
N
N
N
Cu
L
Cu
H
H
H
Me
Me
L
L
N
L
CuL2
Cu
[TS
]aa
H
H
14,15
Me
14aa
[TS
]aa
15aa
NICS(0) pyridine
14,15
H2
15aa
L
N
9a
Cu
NICS(0) pyridine
H
transition
state
(-) NICS(0)
Aromaticity
Index (ppm)
+ pyridine
NICS(0) styrene
NICS(0) styrene
+1.9
L
9
NICS(0) pericyclic
NICS(0) pericyclic
0.0
14aa
reaction coordinate
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
(B) Transition state model for the ene
5
0
Me
L
N
Cu
H
GEOPT
L
STRUCT
[TS
]aa
14,15
extent of reaction (%)
-5
0
20
60
80
40
100
(C) Energy-decomposition analysis
Me
CuL2
Me
Me
Me
L
L
N
N
N
N
CuL2
Cu
Cu
H
H
H
(eq 3)
(eq 2)
H
G° = -28
kcal/mol
G° = 20
kcal/mol
(gas phase)
L
L
39
40
14aa
15aa
(gas phase)
break C– N -bond
break Cu– N dative bond
break Cu-C -bond
make C– C -bond
make Cu– N -bond
break C– N -bond
make C– C -bond
make Cu– N -bond
destroy aromaticity
break Cu– N dative bond
break Cu-C -bond
net destabilization (eq 2) comparable to -ASE of just one arene
G° (eq 1) close to ASE of pyridine
(E) Complete computed PES for the double-dearomatization pathway
Me
G°
(kcal/mol)
Me
Me
H
L
H
L
H
L
N
+25.8
Cu
+25.0
Cu
L
H
L2Cu
+23.3
N
R
N
H
H
CH2
H
L
L
H
Si
R
Cu
[TS
]aa
15,13
Me
H
Me
R
H
[TS
]aa
10,7
N
H
[TS
]aa
14,15
CuL2
H
+16.0
N
+13.3
L2Cu
[TS ]a
8,9
Me
H
L
L
[TS
]aa
13,10
Cu
+12.2
H
+8.5
Me
H
Me
H
H
H
9a
+ pyridine
H
Me
H
+1.9
L
L
+1.3
L2Cu
N
+1.1
L2Cu
N
Cu
13aa
15aa
0.0
Me
Me
Me
H
L
Cu
9a
N
H
H
+
R3Si
N
L2Cu
N
L
L2CuH
H
H
– 10.1
14aa
10aa
7aa
8
imidoyl-Cu-ene
Cu-promoted stepwise Cope

BM
hydrocupration
Figure
11.
The
double-dearomatization
pathway.
dearomatization PES (Figure 11, E), 13aa appears as an
intermediate in a stepwise Cope rearrangement (15aa
the double-dearomatization mechanism (+25.8 kcal/mol) is
slightly greater than the predicted barrier to 1,3-Cu-migration
by 9a (Figure 7, C), the rate law and substituent effects
support double-dearomatization being the major reaction
pathway. Given that heterocycle coordination to 9a is not
→ퟏퟑ퐚퐚
→ퟏퟎ퐚퐚
, Figure 11, E), while 15aa is a fleeting intermediate in
→ퟏퟓ퐚퐚→
a heterocycle-mediated net 1,5-Cu-migration (14aa
ퟏퟑ퐚퐚
, Figure 11, E). Although the predicted total barrier to
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Journal of the American Chemical Society
intrinsically favorable, the preference for generating 13aa this substrate. Figure 12 shows how strongly anion-stabilizing C3
1
2
3
4
5
6
7
8
substituents are expected to affect the energies of key
structures in the double-dearomatization PES. Because
→
→
→
→
→
way implies that the sequence 9a
14aa 15aa
13aa
(Figure 2, B, ii) is faster than 9a 11a 12a 13aa (Figure
2, B, i), which makes the ene/retro-ene sequence
→
a
Scheme 1. Simplified Catalytic Cycle for Rate-Law
Derivations.
heterocycle-promoted pathway for net 1,5-Cu-migration. The
ability of the heterocycle to couple dearomatization to
favorable changes in localized bonding and stabilize
dearomatized intermediates provides a plausible chemical
basis for this result.
8. The double-dearomatization mechanism correctly predicts
the rate law for dearomatization of 1d.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The double-dearomatization PES (Figure 11, E)
straightforwardly predicts the correct rate law and observed
resting state for dearomatization of 1d (Figure 6, A).45 The
stability of 9a (–1.9 kcal/mol) relative to dative complex 14aa
correctly implies that the latter should not be a significant
resting state component, and the relatively low barrier to
regeneration of 9a after the TLS implies that no 8 or 10aa
should be present during catalysis; i.e., 9a is required to be the
MACS. The simplified catalytic cycle in Scheme 1 can be
used for theoretical analysis of a generic reaction via the
double-dearomatization pathway because the ene/retro-
→
the doubly dearomative ene (14 15, Figure 12) and the ene
leading from 13 to 15 (i.e., the reverse of the retro-ene, Figure
12) both have nucleophilic addition character, anion-
stabilizing C3 groups must lower the barriers to both (i.e.,
decrease the energies of TS14,15 and TS15,13 relative to 9a;
Figure 12). Activating C3 groups also lower the energy of
doubly dearomatized intermediate 15 (Figure 12), which
contains a fully developed metalloenamine functional group.
These changes lower the rate-controlling barrier to
ene/5,5-rearrangement
indistinguishable from
sequence
unimolecular elementary step
10 in Scheme 1 and referred to as
is
kinetically
a
→
(modeled as 14
dearomative isomerization). Heterocycle binding to 9 is
expected to be much more facile than the other steps, making
⇌
9 + 1
14 a pseudoequilibrium (Scheme 1; refer to this
scheme for definition of all kinetic parameters). The PES
implies that dearomative isomerization should be the TLS, and
because 9 is the MACS, the rate law for the catalytic reaction
푘
dearomative isomerization (i.e., increase 푑). Our group’s
휎
earlier study of substituent effects on the rate of BM by Cu-
9 ⇄ 14 →10
can be determined from the sequence
1), thus
(Scheme
carboxylate complexes21 revealed marked slowing of that
reaction by groups that attenuate the nucleophilicity of the
carboxylate ligand, and we expect similar deceleration here
with substituents that attenuate the nucleophilicity of 10
푟푎푡푒≅ 푘 [ ] = 푘
14
[ ][ ] = 푘 [ ][ ]
9 Het Het Cu
푑K푒푞
(eq 4), in agreement with experiment.46
푑
eff
휎
(Figure 12). This implies an increase in the energy of BM
transition state TS10,7 relative to 10, whereas 10 itself should
be stabilized by the substituent much like 15 (Figure 12). If
the opposing effects on the dearomative isomerization and
BM steps are large enough, their barriers will become
comparable (i.e., 푑 and 푠 will have similar values). Because
9. Predicted saturation kinetics and altered resting state for
very electron-deficient heterocycles.
Highly reactive pyridines are among the best substrates for
asymmetric dearomatization and thus form an intrinsically
important heterocycle class. They also provide opportunities
for empirical study of proposed steps and intermediates that
occur after the TLS for 1d (Figure 6, A) and consequently
cannot be probed via kinetics or spectroscopy using that
휎
푘
푘
10aa is predicted to be very close in energy to 9a in the
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Page 12 of 20
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 12. Expected double-dearomatization PES for heterocycles with electron-withdrawing C3 substituents.
absence of
a
substituent (Figure 11, E), the double-
equivalents of DMMS used and [Het]0 is the initial heterocycle
concentration, one can write
dearomatization PES indicates that even modest additional
stabilization should render 10 isoenergetic with or potentially
more stable than 9 (Figure 12). Consequently, 10 (Figure 12)
must become a major component of the resting state if the
[
][ ][
DMMS Het Cu
]
퐴
푟푎푡푒
휎
barriers to dearomative isomerization and BM are similar.
Hydrocupration is expected to remain kinetically irrelevant,
however: this step cannot exhibit a (heterocycle) substituent
푘퐷 + 푘푠
(휒 ― 1)[
]
푘 ―푑
Het
0
=
[
] +
+
Het
(
)
(
)
푘퐷푘푠
푘퐷
푘퐷푘푠
휎
effect, and its barrier is already significantly below that of
BM (-2.7 kcal/mol) in the absence of a substituent (Figure 11,
E).
(eq 6).
Eq 6 provides a convenient graphical way to diagnose whether
the kinetics of a given dearomative reaction obey eq 5, and, if
so, to estimate rate constants for the kinetically relevant steps.
If the rate does obey eq 5, then plots of
using empirical rate and concentration data must be
linear functions of [Het] having slope N
Dearomatization of 1g (Figure 13, A) is faster than that of
any other pyridine we have studied (Table 3) and clearly obeys
a different rate law, making it an excellent model reaction for
testing these predictions. We have confirmed that this reaction
exhibits no kinetic dependence on 3-fluorostyrene. If this
result is stipulated, and no assumptions are made about the
([Het][DMMS][Cu
]/푟푎푡푒)
47
≅ (푘 + 푘 )/푘 푘
.
퐷 푠
퐷
푠
(
)
휒,[Het]0
Y
The Y-intercepts
of those plots must in turn
푘
푘 푘
relative values of
Scheme 1 must obey saturation rate law eq 5 (see the SI for
[Cu]
, 푠, and ―푑, then the catalytic cycle in
푑
(휒 ― 1)[
]
≅
0 having slope n
Het
constitute a linear function of
47
1/푘퐷
:
푘
푘
푑
derivation), in which
is defined as K푒푞 and
is the
퐴
퐷
푘 ―푑
1
total concentration of active catalyst species (note that the rate
law for 3-phenylpyridine is just an instance of eq 5 for which
(
)
휒,[ ] ≅
Het
(휒 ― 1)[ ] +
Het
Y
0
0
(
)
푘퐷
푘퐷푘푠
푘퐷
푘
푘
,
―푑<< 푠).
(eq 7)
Implication also goes in the other direction: given respective
푘 푘 [ ][
][
]
Het DMMS Cu
퐷
푠
퐴
([
kinetic orders of zero and one for [Sty] and [Cu], if plots of
푟푎푡푒 =
푘 [ ] + 푘 [
] + 푘
Het
DMMS
Het][DMMS][Cu]/푟푎푡푒)
퐷
푠
―푑
using actual rate and concentration
data are found to be linear functions of [Het], then the true rate
law must conform to an instance of eq 5. This is because, with
푘푑
푘 [ ][
][ ]
Het DMMS Cu
퐴
K푒푞
푠
푟푎푡푒 = 푘[Het][Cu]퐴
the exception of trivial examples like
=
푘푑
K푒푞
[
] + 푘 [
] + 푘
DMMS
Het
푠
―푑
푟푎푡푒 = 푘[DMMS][Cu]퐴
and
(which are themselves limiting
푟푎푡푒
[Het][DMMS][Cu]퐴
) by
(eq 5)
cases of eq 5), multiplying (1/
will only yield a linear function of [Het] if the denominator of
푟푎푡푒
푘푑
푘푠
The discussion of substituent effects implies that
and
is a linear function of [Het], and if [Het] and [DMMS]
both appear with exponents of one in the numerator of
Graphically determined linear parameters then indicate which
limiting case of eq is applicable. In particular,
straightforward algebraic manipulations (see the SI) show that
[DMMS] and [Het] must both appear with non-negligible
should be comparable for 1g (Figure 13, A), and thus its rate
law must correspond to an instance of eq 5 in which [Het] and
[DMMS] both appear with non-negligible coefficients in the
denominator. Taking advantage of the fact that [DMMS] is
linearly related to [Het] over the course of the reaction as
푟푎푡푒
.
5
[DMMS] = [Het] + (χ ― 1)[Het]
χ
0, where is the number of
(
)
푟푎푡푒
휒,[
]
Het
0
Y
coefficients in the denominator of
if
is found
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Journal of the American Chemical Society
by way of the Eyring relationship to the approximate energy
landscape in Figure 13, D. These energies are in excellent
qualitative agreement with how the double-dearomatization
PES is expected to change under the influence of an anion-
stabilizing C3 substituent (Figure 12). They also mirror the
prediction of Fig. 12 that 10gh should be a major resting state
component during dearomatization of 1g (Figure 13, D).
(휒 ― 1)[
]
for
0
Het
to be a (non-constant) linear function of
1
2
3
4
5
6
7
≠ N
n
which
.
([Het][DMMS][Cu]/푟푎푡푒)
Plots of
for three reactions
differing only in 휒 (Figure 13, C; the untransformed rate
curves are in Figure 13, B) were indeed linear except at very
high conversion, where the heatflow data became erratic. In
agreement with eq 6, the slopes of these lines are similar;
treating all slope estimates as resulting from identical
10. Observation of N-Cu-1,4-DHP intermediate 10gh.
Monitoring of the catalytic dearomatization of 1g (Figure
13, A) with 3-fluorostyrene-훼-13C by 13C, 31P, and 19F NMR
spectroscopy confirmed that a new major catalyst species was
present having the diagnostic 13C, 19F, and 31P NMR
resonances (Figure 13, E) expected for 10gh: in particular, its
13C (Figure 13, E, i) and 19F signals indicate the presence of a
fluorophenethyl group bound at C훼 to C rather than Cu.49
These signals were associated with a new 31P resonance
(Figure 13, E, ii), indicating the presence of a CuL2 fragment
(NB, neither these nor any analogous signals were evident for
a control reaction mixture prepared from 3-phenylpyridine).
The 13C, 19F, and 31P resonances assigned to 10gh (Figure 13,
E) were all relatively large near the start of the catalytic
reaction and simultaneously diminished as conversion of 1g
(Figure 13, A) increased. Phenethylcopper intermediate
8
9
푘 + 푘 /푘 푘 )≅47.8
measurements would yield an average (
Ms with standard deviation 1.88 (five measurements).
Further, the Y-intercepts of the lines in Figure 13, C (obtained
퐷
푠
퐷 푠
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(휒 ― 1)
by extrapolation) are monotonically increasing with
[Het]
2
0, as required by eq 7, and fit well enough to a line (R =
≅
푘
(푘 ―푑/푘퐷
0.97) to enable estimation of n 1/ 퐷 = 8.58 Ms and
푘 ) ≅
푠
2
18
0.345 M s from its slope and intercept, respectively.
The values of N and n are indeed very different, which
demonstrates that dearomatization of 1g (Figure 13, A) obeys
the saturation rate law predicted by the double-
dearomatization mechanism. This supports the catalytic cycle
having the form in Scheme 1. Equations for the linear
푘
parameters were solvable for estimates for
(0.117 M–1s–1),
퐷
–1 –1
(1.02•10–3s–1),48 which correspond
푘
푘
―푑
푠 (0.0255 M s ) and
SO2Me
(A) Calorimetric study of dearomatization with highly activated substrate 1g
F
F
Me
SO2Me
1g
Cu(OAc)2
DMMS
F
F
N
4.0 mol%
6h
(R)
(S)
0.52 mmol
in 1,4-dioxane
2.4-3.8 equiv
total
Me
Me
+
1.4 equiv
+
“[(R,R)-L2]CuH”
THF, rt
Cu[(R,R)-L2]
(R,R)S-9h
Cu[(R,R)-L2]
(R,R)-Ph-BPE
5.6 mol%
0.13 M final [Het]
N
total [Cu]
= 6.7 mM
L2 = Ph-BPE
7gh
5.0 mM final [Cu], 26 °C
(R,R)R-9h
SiMe(OMe)2
All stoichiometry values relative to 1a
calorimetry starts
(B) The rate depends on [DMMS], but with kinetic order <1
rate
(C) Demonstration that the rate law has the form of eq 4
[Het][DMMS][Cu]
in Ms-1
rate
[Het] in M
(D) Empirically determined PES predicts observable 10gh
(E) Observation of 10gh in the resting state
Me
L
L
13C
ii. 31P NMR
i. 13C NMR
G°
Me
H
Ar2
L
Ar1 = 4-MsPh
Ar2 = 3-F-Ph
Ar1
Cu
L
H
Ar2
kcal
mol
Cu
13C Me
G– d
= 21.5
kcal/mol
9h
13C Me
Ar1
N
Me
L
H
F
H
Si
N
F
Ar1
Ar1
Cu
R3
H
[TS10,7]gh
L
[TS14,15]gh
N
N
Gs
10gh
Ar2
CuL2
Me
Ar1
F
10gh
CuL2
= 19.6
°
Ga + Gd
=
kcal/mol
Me
L
13C
18.7 kcal/mol
Cu
N
H
Ar2
1g
+
L
9h
CuL2
0.0
Me
L
L
nd
– 2.8
Cu
H
9h Ar2
7gh
10gh
Figure 13: Saturation kinetics in the dearomatization of 1g imply an energy surface like that predicted for the double-dearomatization and
similarly imply that 10gh should be observable.
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9h, initially present in a much smaller amount than usual, should be stereospecific. Predicted energy differences for ax-
1
2
3
4
5
6
7
8
gradually increased in abundance at the expense of 10gh
(Figure 13, E), resuming its typical role as the MACS only at
very high conversion of 1g (Figure 13, A; the proportion of
observable phosphorus present as 9h + 10gh was conserved
throughout the catalytic reaction). This is precisely how the
distribution of catalyst species is expected to change
[TS14,15] and eq-[TS14,15] (analogs of the structures in Figure
14, A and B) for C6-attack on various C3-substituted
heterocycles known to give high diastereoselectivity were in
the range of 1.3–3.0 kcal/mol, which indicates that the double
dearomatization pathway should have a robust preference for
the observed anti-1,4-DHP. Further, because the ene, retro-
ene and 5,5-rearrangements are all suprafacial, the C훼
configuration of the phenethylcopper nucleophile is retained
throughout the remainder of the cycle.
휎
throughout the reaction if dearomative isomerization and BM
have similar barriers, as in Fig 12: the dearomative
isomerization becomes more nearly turnover-limiting as the
reaction proceeds because the concentration of 1g (Figure 13,
A) becomes very low, while the concentration of DMMS, used
in fivefold excess, remains relatively high. The predictive
power of the double-dearomatization mechanism thus enabled
us to confirm the involvement of 10 (Figure 12), show that 10
must be close in energy to 9 (Figure 12) as implied by our
modeling (Figure 11, E), calculate a rate constant and
9
12. Mechanistic basis for the styrene-para-group effect.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The double-dearomatization mechanism explains the severe
deterioration or failure of the asymmetric dearomatization
observed with para-substituted styrenes. The barrier to the
retro-ene step is low relative to intermediate 15aa (Figure 11,
E) but still very near the energy maximum of the PES.
Structural changes that destabilize the retro-ene transition state
(exemplified by [TS15,13]aa in Figure 11, E) are expected to
make it the TLTS, and if they do not commensurately stabilize
15, this will increase the total barrier to 1,4-dearomatization.
While the doubly dearomatized intermediate derived from
styrene permits close approach between Cu and Cpara (Figure
15, A), the presence of a para-Me or para-Ph would lead to
formation of a very sterically unfavorable Cu-Ctert bond in the
retro-ene step. In fact, the transition state we located for
rearrangement for 15ak (Figure 15, B) does not correspond to
휎
approximate activation barrier for BM (Figure 13, D), and
휎
corroborate our computational prediction that BM should be
significantly more challenging than hydrocupration.
11. The double-dearomatization mechanism predicts the
observed stereochemical outcomes.
The double-dearomatization model also predicts the correct
stereo- and regio-chemical outcomes. Unlike 11a (Figure 9,
A), 15aa (Figure 11, A) lacks a viable pathway to 1,2-DHP
2aa (Figure 9, A) and only generates stable species upon
rearomatizing the phenyl ring via reversion to 14aa or forward
reaction to 1,4-DHP 10aa (Figure 11, E). The PES in Figure
11, A and E, pertains to dearomatization via ene chair-
conformer ax-[TS14,15]aa (Figure 14, A) because our
calculations indicate that it is more favorable than its
equatorial-Me counterpart (ΔΔG‡ = –2.4 kcal/mol). Attaining
eq-[TS14,15]aa requires a serious clash between the Me group
and Ph-BPE (Figure 14, B), whereas ax-[TS14,15]aa projects
the methyl away from the phosphine. Two additional
diastereomeric chairs are possible for C3-substituted
heterocycles, but one (pro-syn-[TS14,15], Figure 14, C) causes
a clash between the equatorial C3 group and the approaching
phenyl ring, while the other (pro-anti-[TS14,15], Figure 14, D)
incurs no additional penalties. The only chair retro-ene
reaction available to pro-anti-15 generates 13 in the
conformer (pro-anti-13) leading to N-cuprated DHP anti-10
(Figure 14, D). At this point, stereorandomization prior to
formation of anti N-Si-1,4-DHP would require either
dissociation of heterocycle from 13 (+8.8 kcal/mol above
13aa, Figure 7, C) or 180° N–Cu rotation of 13; however, both
a
retro-ene reaction, but rather to a concerted Cope
rearrangement. The Cu-Cpara interaction is lost entirely in
[TS15,10]ak (Figure 15, B); it exhibits a Cu-Cpara distance
much longer (+1.2 Å) than that in [TS15,13]aa (Figure 15, A),
as is required to avoid clashes with Ph-BPE. We calculate that
the concerted Cope rearrangement of 15ak is 4.0 kcal/mol
more difficult than the retro-ene rearrangement of 15aa
(Figure 15, A), which is indeed enough to make the overall
1,4-dearomatization more challenging. The expected outcome
for a modest increase in the 1,4-dearomatization barrier is
erosion of enantioselectivity due to increased lifetime and
epimerization of the phenethylcopper (NB 4-phenylstyrene
gives virtually racemic 1,4-DHP product). Larger increases
are expected to cause 1,4-dearomatization to fail or cease to be
competitive with other processes. Thus, the ability of Cu to
provide a low-barrier stepwise alternative to the concerted
Cope appears to be critical for successful enantioselective
catalysis. For para-heteroatom-substituted styrenes, which
result in compete failure of the catalytic dearomatization,
additional factors may further affect the viability of the Cpara-
metalated intermediate (e.g., decomposition via elimination or
radical reactions).
휋
of these processes disrupt the -stacking interaction critical for
stabilizing 13, making them unfavorable relative to
13. Organocopper species that cannot generate Cpara-
regeneration of the phenethylcopper resting state via 5,5-
metalated
dearomatization: the case of 3-vinylfuran.
The double-dearomatization model predicts that conjugated
intermediates
undergo
1,2-selective
휎
rearrangement/ BM/hydrocupration (which occurs with a total
→
→
→
7aa + 8 9aa,
barrier of 7.5 kcal/mol for 13aa 10aa
Figure 11 E). As a result, the stepwise Cope/ BM sequence
휎
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Journal of the American Chemical Society
(A) The favored ene chair conformer displays the C-Me axially
(B) The equatorial-Me ene chair incurs a clash with the ligand
1
2
3
4
Me
H
eclipsed
L
L
N
N
Cu
L
Cu
L
H
Me
no clashes
with ligand
5
6
ax-[TS
]aa
eq-[TS
]aa
14,15
14,15
7
8
9
Me
CuL2
H
N
N
CuL2
H
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ax-[TS
]aa
eq-[TS
]aa
14,15
,ipso-(Z)-15aa
,ipso-(E)-15aa
14,15
C) The pro-syn ene chair
(D) The pro-anti ene chair avoids steric clashes, and subsequent steps stereospecifically generate anti-10
also results in a clash
R
R
H
H
Me
H
Me
H
Me
L
Me
(S)
Me
CuL2
H
N
H
L
Cu
N
N
H
Cu
L
H
H
R
Cm
L
H
L2Cu
N
N
L2Cu
clash
H
R
R
pro-syn-TS
14,15
pro-anti-15
pro-anti-TS
pro-anti-TS
(S)
Me
15,13
14,15
Me
Me
H
(S)
H
Me
Me
H
H
H
R
R
L2Cu
N
H
N
L2Cu
N
anti-10
H
L2Cu
N
CuL2
N
R
R
R
13,10
CuL2
pro-anti-13
syn-10
pro-anti-TS
Figure
14:
The
double-dearomatization
mechanism
predicts
the
correct
diastereo-
and
enantio-selectivity.
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(B) Para-phenyl is predicted to make the Cope concerted
(A) Transition state for the retro-ene showing Cpara-Cu bonding
1
CuL2
2
3
4
5
CuL2
CuL2
CuL2
N
H
N
N
N
N
N
CuL2
H
H
H
H
H
CuL2
H
Me
Me
H
Ph
Me
H
Me
H
Me
Ph
H
H
H
Ph
Me
H
H
[TS
]ak
10ak
15ak
13aa
H
15aa
15,10
[TS
]aa
15,13
6
7
8
9
CuL2
Ph
H
N
N
CuL2
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
H
Me
Me
[TS
]aa
[TS
]ak
15,13
15,10
(C) Furanethylcopper complex 9i prohibits the stepwise Cope and undergoes 1,2-dearomative addition exclusively
CuL2
CuL2
CuL2
N
N
N
H
O
H
N
L2Cu
H
N
14al
Me
H
Me
H
CuL2
Me
Me
H
O
O
Me
No possible
analog to 13
stepwise Cope
impossible
O
O
9l
H
H
H
N
H
10al
[TS
]al
15,10
15al
+ 5.6
G = 38.0
(B3LYP)
kcal/mol
(predicted)
CuL2
N
N
N
SiMe(OMe)2
O
Me
H
N
CuL2
CuL2
G = 8.0
CuL2
O
O
DMMS
(3 equiv.)
THF, rt
kcal/mol
(predicted)
Me
Me
Me
Me
O
O
H
H
H
H
H
11l
27al
5al
2al
2al
98% NMR yield
only regioisomer
H
Figure
15.
Mechanistic
basis
for
the
styrene-para-group
effect.
nucleophiles lacking the structural features required for
generating Cpara-metalated isomers should still undergo
dearomatization, albeit with complete reversal in
regioselectivity. This result is partially anticipated by the
work of Brown, et al. showing that allylcopper complexes
react with halopyridines and haloquinolines with exclusive
1,2-selelctivity (see e.g., Figure 10, A).14 The dearomatization
of -furanethylcopper complex 9l with pyridine is particularly
illuminating (Figure 15, C). Prior to formulating the new
mechanistic models described in this article, we expected 9l to
undergo 1,4-selective dearomatization analogously to
phenethylcopper nucleophiles. However, dearomatization of
9l via the ene/retro-ene pathway is impossible because the
furan ring lacks a para-carbon; in order to give 1,4-DHP, this
substrate would have to rearrange via the unfavorable
concerted Cope (Figure 15, C). Instead, 3-vinylfuran (6l),
undergoes catalytic dearomatization to give 1,2-DHP 5al
exclusively and in nearly quantitative yield (Figure 15, C).
Furan has a much lower aromatic stabilization energy (ca. 15
kcal/mol)43a than benzene; consistent with this, our
calculations indicate that dearomative 1,3-Cu-migration
should be much more facile for 9l (+5.6 kcal/mol, Figure 15,
C) than 9a (+22.3 kcal/mol, Figure 9, A). Further, we find
that 27al should have a low barrier (+8.0 kcal/mol relative to
9l) to forming 1,2-DHP 2al (Figure 15, C) via imidoyl-Cu-ene
reaction with pyridine (note: this is the same pathway that
would generate 1,2-DHP’s from phenethylcopper nucleophiles
in the single-dearomatization pathway, Figure 9).
Corroborating our preliminary expectations (Figure 3, B),
monometallic direct 1,2-addition of 9l (Figure 15, C,
+38.0 kcal/mol) does not appear to be a viable pathway for
generating the observed product.
Δ퐺 ‡
=
Conclusion
Our theoretical investigations have elucidated two possible
pathways for Cu-catalyzed asymmetric dearomatization of
unactivated heterocycles, both of which involve an unusual
5,5-rearrangement occurring within the dative complex of a
Cpara-metalated isomer of the phenethylcopper nucleophile.
The first pathway generates this intermediate via successive
1,3-Cu-migration steps, making it a plausible source of the
1,2-DHP products we observe in certain cases where 1,4-
dearomatization is particularly inefficient. However, our
theoretical analysis of this single-dearomatization pathway
yields an erroneous catalytic rate law and is inconsistent with
substituent effects and other reactivity trends indicating that
the heterocycle functions as an electrophile in the TLS of the
1,4-selective reaction. The double-dearomatization pathway
훼
훼
-
generates the Cpara-metalated intermediate through
turnover-limiting polar reaction of the phenethylcopper with
the heterocycle and is consequently consistent with all known
a
experimental properties of the catalytic reaction.
This
pathway is also notable for correctly predicting the regio-,
diastereo-, and enantio-selectivity of the catalytic reaction. It
is seemingly unintuitive that simultaneous dearomatization of
two arenes would be facile under such mild conditions.
However, this result is readily understood in terms of very
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Journal of the American Chemical Society
for the Synthesis of 4-Alkyl(aryl)pyridines. J. Org. Chem. 1982, 47,
4315-4319.
(4) Gribble, M. W. Jr.; Guo, S.; Buchwald, S. L. Asymmetric Cu-
Catalyzed 1,4-Dearomatization of Pyridines and Pyridazines Without
Preactivation of the Heterocycle or Nucleophile. J. Am. Chem.
Soc. 2018, 140, 5057-5060.
thermodynamically favorable bonding changes associated with
1
2
3
a generic imidoyl-Cu-ene reaction and plausible stabilization
of the transition state via transient formation of a new aromatic
orbital array. The new modes of reactivity documented in this
work illustrate how chiral Cu(I) complexes can facilitate
fundamental new catalytic transformations of a sort long
considered exceptionally challenging.
4
5
6
7
8
9
(5) Reports on catalyzed direct addition of hydride or silyl
nucleophiles to pyridine had appeared in preceding years and some
are conceptually related to the Cu-catalyzed asymmetric
dearomatization; the reaction with styrenes in Figure 1, D, can be
viewed formally as a diverted 1,4-hydrosilylation of pyridine in which
the hydride is intercepted by an olefin to generate a carbon-centered
nucleophile rather than undergoing attack at heterocycle C4. See (a)
Oshima, K.; Ohmura, T.; Suginome, M. Palladium-Catalyzed
Regioselective Silaboration of Pyridines Leading to the Synthesis of
Silylated Dihydropyridines. J. Am. Chem. Soc. 2011, 133, 7324-7327.
(b) Gutsulyak, D. V.; van der Est, A.; Nikonov, G. I. Facile Catalytic
Hydrosilylation of Pyridines. Angew. Chem. Int. Ed. 2011, 50, 1384-
1387. (c) Hill, M. S.; Kociok-Köhn, G.; MacDougall, D. J.; Mahon,
M. F.; Weetman, C. Magnesium Hydrides and the Dearomatisation of
Pyridine and Quinoline derivatives. Dalton Trans. 2011, 40, 12500-
12509. (d) Königs, C. D. F.; Klare, H. F. T.; Oestreich, M. Catalytic
1,4-Selective Hydrosilylation of Pyridines and Benzannulated
Congeners. Angew. Chem. Int. Ed. 2013, 52, 10076-10079. (e)
Dudnik, A. S.; Weidner, V. L.; Motta, A.; Delferro, M.; Marks, T. J.
Nat. Chem. 2014, 6, 1100-1107. (f) Gandhamsetty, N.; Park, S.;
Chang, S. Atom-Efficient Regioselective 1,2-Dearomatization of
Functionalized Pyridines by an Earth-Abundant Organolanthanide
Catalyst. J. Am. Chem. Soc. 2015, 137, 15176-15184. (g) Intemann,
J.; Bauer, H.; Pahl, J.; Maron, L.; Harder, S. Calcium Hydride
Catalyzed Highly 1,2-Selective Pyridine Hydrosilylation. Chem. Eur.
J. 2015, 21, 11452-11461. (h) Fan, X.; Zheng, J.; Li, Z. H.; Wang, H.
Organoborane Catalyzed Regioselective 1,4-Hydroboration of
Pyridines. J. Am. Chem. Soc. 2015, 137, 4916-4919. (i) Kaithal, A.;
Chatterjee, B.; Gunanathan, C. Ruthenium-Catalyzed Regioselective
1,4-Hydroboration of Pyridines. Org. Lett. 2016, 18, 3402-3405. (j)
Zhang, F.; Song, H.; Zhuang, X.; Tung, C-H.; Wang, W. Iron-
Catalyzed 1,2-Selective Hydroboration of N-Heteroarenes. J. Am.
Chem. Soc., 2017, 139, 17775-17778. (k) Yu, H-C.; Islam, S. M.;
Mankad, N. P. Cooperative Heterobimetallic Substrate Activation
Enhances Catalytic Activity and Amplifies Regioselectivity in 1,4-
Hydroboration of Pyridines. ACS Catal. 2020, 10, 3670-3675.
(6) You’s elegant work on hydrogenative C–C-bond-forming
dearomatization also addresses the challenges associated with
stoichiometric electrophilic preactivation, but these reactions are
distinct from catalyzed direct addition of carbon nucleophiles (Figure
1, C) in that they involve C–C-bond-forming nucleophilic addition
after dearomative semireduction of the heterocycle. See (a) Wang, S-
G.; Zhang, W.; You, S-L. Construction of Spiro-tetrahydroquinolines
ASSOCIATED CONTENT
Supporting Information
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Procedural information and characterization data (PDF)
Complete calorimetry data from
experiment (xlsx)
a representative kinetics
AUTHOR INFORMATION
Corresponding Author
*Michael W. Gribble, Jr. (mwgribblejr@gmail.com), * Richard
Y. Liu (ryl@mit.edu).
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The National Institutes of Health under award numbers
GM46059, GM122483, and R35-GM122483 supported research
reported in this publication. We thank Dr. Walt Massefski and Dr.
Bruce Adams for assistance with design of NMR experiments and
Dr. Sheng Guo (MIT) and Ms. Claudia Keller (Spirochem) for
sharing observations that ultimately proved to be mechanistically
significant; e.g., the regiochemical outcome of dearomatization
with 3-vinylfuran (SG). We thank Dr. Veronika Kottisch (MIT)
and Dr. Alex Schuppe (MIT) for assistance with preparation of
this manuscript, and Professor Donna Blackmond (TSRI) for
making us aware of reference 31b. We thank the National
Institutes of Health for a supplemental grant for the purchase of
supercritical fluid chromatography (SFC) equipment (GM058160-
17S1).
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(18) See the SI for details.
(19) π-stacking interactions have been invoked as critical
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additions. See ref. 1c and examples therein.
9
(10) For examples of catalytic asymmetric 1,2-selective
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12
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15
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23
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27
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29
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31
32
33
34
35
36
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41
42
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46
47
48
49
50
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54
55
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(23)
Although
not
primarily
concerned
with
hydrofunctionalization, Hoveyda’s study on the stereoselectivity of
Cu-catalyzed olefin carboborylation is highly pertinent to this
discussion: Lee, J.; Radomkit, S.; Torker, S.; del Pozo, J.; Hoveyda,
A. H. Mechanism-Based Enhancement of Scope and
Enantioselectivity for Reactions Involving a Copper-Substituted
Stereogenic Carbon Centre. Nat. Chem. 2018, 10, 99-108.
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Kinetics 40; Elsevier: Amsterdam, 2004, pp 227-239.
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and Dihydroquinolines. J. Org. Chem. 2020, 85, 5027-5037.
(25) Note that these pathways must have different equilibrium
constants in order to give the same equilibrium dr because they have
different molecularity. See the SI.
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S. L. Copper Hydride Catalyzed Hydroamination of Alkenes and
Alkynes Angew. Chem. Int. Ed. 2016, 55, 48-57. (b) Wang, H.;
(26) These estimates were made using parameter sets that had been
optimized for quantitative accuracy. Quantitation of 9h using 19F
NMR was based on the ratio of the integral for 9h to that of internal
4-fluoroanisole, whereas quantitation of 9a and 9h using 31P NMR
was based on comparison of the phenethylcopper integrals to the total
31P integral. Although 31P-based estimates were generally somewhat
higher, the discrepancy was not mechanistically significant, and only
31P-based estimates were suitable for stereochemical analysis of the
phenethylcopper (as in Figure 5, F).
(27) For a more detailed discussion of the mechanistic basis for this
phenomenon, see the SI.
(28) The rate of epimerization is actually a first order function of
the fractional distance from equilibrium, but when the fractional
distance from equilibrium is very large (i.e., the dr is very high), the
rate is well approximated by the equation given.
(29) This equation is derived in the SI and specifically pertains to
an idealized reaction in which the major phenethylcopper
diastereomer is continuously regenerated with perfect kinetic
selectivity. This scenario well approximates the reactions under study
because the hydrocupration step has very high kinetic selectivity.
(30) In section 3, we demonstrate that a single CuL2 fragment is
present in the dearomative addition transition state. If the addition
mechanism were bimetallic, as initially thought, then the differences
in rate and selectivity observed when both enantiomers of Ph-BPE are
present could be attributed to differences in reactivity or selectivity
for competing homo- and hetero-chiral bimetallic pathways: the latter
Buchwald,
S.
L.
Copper-Catalyzed,
Enantioselective
Hydrofunctionalization of Alkenes. In Organic Reactions; Denmark,
S. E., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2019; pp 121−205.
and refs. therein.
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shown in Figure 3, D is provided in the SI.
(16) For example, see Liu, R. Y.; Yang, Y.; Buchwald, S. L.
Regiodivergent and Diastereoselective CuH-Catalyzed Allylation of
Imines with Terminal Allenes. Angew. Chem. Int. Ed., 2016, 55,
14077-14080.
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are not possible when the Ph-BPE is enantiomerically pure.
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(39) Janowski, T.; Pulay, P. High Accuracy Benchmark
Calculations on the Benzene Dimer Potential Energy Surface. Chem.
Phys. Lett. 2007, 447, 27-32.
(40) For a more detailed discussion of the interpretation of the
substituent effects in Table 3, see Section 2.4 of the SI.
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L.; Okuda, J. Insertion of Pyridine into the Calcium Allyl Bond.
Angew. Chem. Int. Ed. 2010, 49, 7795-7798.
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Cyanation of Vinylarenes. ACS Catal. 2015, 5, 2944-2951. (b) Yang,
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Copper-Catalyzed Borylation/ortho-Cyanation Cascade. Angew.
Chem. Int. Ed. 2016, 55, 345-349.
However, because only one CuL2 fragment is present in the addition
step, the differences in rate and diastereoselectivity we observe can
only be due to differences in the intrinsic reactivity of the major and
minor phenethylcopper diastereomers.
1
2
3
4
5
6
7
8
(31) The phenomenon of a ligand’s enantiomeric composition
affecting the dr of the catalyst and consequently the
diastereoselectivity of the catalytic reaction is closely related to both
the Kagan model for nonlinear effects with catalysts bearing multiple
chiral spectator ligands and the ‘formal enantioselectivity refinement’
described by Jacobsen. (a) Girard, C.; Kagan, H. B. Nonlinear Effects
in Asymmetric Synthesis and Stereoselective Reactions: Ten Years of
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W.; Lee, N. H.; Jacobsen, E. N. Nonstereospecific Mechanisms in
Asymmetric Addition to Alkenes Result in Enantiodifferentiation
after the First Irreversible Step. J. Am. Chem. Soc. 1994, 116, 425-
426.
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43
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47
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(32) For example, if dearomatization is conducted with very low
catalyst loading, then formation of a resting state with high
phenethylcopper dr via catalytic recycling occurs while the reaction is
still at extremely low conversion. In that case, premature termination
of the reaction strictly lowers the amount of product formed via the
minor phenethylcopper by reducing the amount of product formed
during the phase of substantially eroded phenethylcopper dr that
occurs at high conversion. We find that this increases the ee and the
dr of the product. NB, reduced ee of product obtained upon complete
reaction cannot be attributed to configurational instability. See the SI
for more detail.
(33) Given that the TLS of the dearomatization has higher
molecularity than the epimerization step (which we show in section 3
is due to a kinetic order in 1d for dearomatization), running reactions
at higher concentration necessarily increases the kinetic preference for
dearomatization of (R,R)R-9 over epimerization of (R,R)R-9, and we
find that this markedly improves the enantioselectivity of the reaction.
See the SI for details. This result is in agreement with a mechanistic
postulate of ours in ref. 20b and conclusions discussed ref. 23.
(34) For discussion of the fundamentals of the reaction-progress
kinetics analysis methodology employed here, see (a) Blackmond, D.
G. Angew. Chem. Int. Ed. Reaction Progress Kinetic Analysis. 2005,
44, 4302-4320. (b) Blackmond, D. G. Kinetic Profiling of Catalytic
Organic Reactions as a Mechanistic Tool. J. Am. Chem. Soc. 2015,
137, 10852-10866.
(35) If, e.g., the kinetic order were one in DMMS, it would be zero
in styrene, and then the effect of varying [DMMS] and [3-F-styrene]
would be the same as if only [DMMS] were changed. The same
argument would apply, mutatis mutandis, if it were instead 3-F-
styrene that had a kinetic order of one. Consequently, simultaneous
variation of [DMMS] and [3-F-styrene] can only fail to affect the rate
if the kinetic orders are zero for both.
(36) DMMS could be incorporated into the TLS without there
being a kinetic dependence on [DMMS] if the heterocycle were
effectively saturated with DMMS at all relevant DMMS
concentrations, but we have confirmed spectroscopically that there is
negligible association between DMMS and pyridine in THF-d8,
making this situation untenable.
(43) (a) Cyrański, M. K. Energetic Aspects of Cyclic Pi-Electron
Delocalization:ꢀ Evaluation of the Methods of Estimating Aromatic
Stabilization Energies. Chem. Rev. 2005, 105, 3773-3811. (b) Fishtik,
I.; Grimme, S. Accurate Evaluation of the Resonance Energies of
Benzene and Pyridine via Cyclic Reference State. Phys. Chem. Chem.
Phys. 2012, 14, 15888-15896.
(44) (a) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jiao, H.;
Hommes, N. J. R. v. E. Nucleus-Independent Chemical Shifts. J. Am.
Chem. Soc. 1996, 118, 6317-6318. (b) Chen, Z.; Wannere, C. S.;
Corminboeuf, C.; Puchta, R.; Schleyer, P. v. R. Nucleus-Independent
Chemical Shifts (NICS) as an Aromaticity Criterion. Chem. Rev.
2005, 105, 3842-3888.
(45) Thorough derivations of the general rate law for the cycle in
Scheme 1 and kinetics equations 4-7 are provided in the SI.
(46) Interestingly, one can derive the correct rate law for
dearomatization of 1d without knowledge of the abundance of 9a
훽
relative to 8 or 10aa using instead the fact that the rate constant for
-
푘
hydride elimination must be comparable to or smaller than
for 3-
푑
phenylpyridine, which follows from the observation that the dr of 9a
is kinetically controlled during catalysis. See the SI.
(47) Relating linear parameters (N and n) determined graphically
([DMMS][Het][Cu])/푟푎푡푒
from plots of
to expressions in terms of
individual rates constants by way of eq 6 requires information about
the relationship between [Cu] and [Cu]A. The equations for N and n
≅
provided use the ‘approximately equals’ sign ( ) because we are
≅
employing the approximation that [Cu]
[Cu]A. Quantifying the
latter value with high precision would be logistically prohibitive and
푘
푘 푘
, 푠, and ―푑 of sufficiently
unnecessary for obtaining estimates of
퐷
high quality for our purposes. Our kinetics and spectroscopic studies
indicate that active catalyst species make up the large majority of
[Cu]
copper, with
퐴 = Q[Cu], where Q is constant over the course of a
reaction and invariant with respect to modest changes in reaction
≅
conditions. It is therefore justifiable to set [Cu] [Cu]A, although it
can be expected that this will result in each of the individual rate
constants being slightly underestimated.
(48) Details of these calculations are provided in the SI.
(49) A fuller explanation of the basis for this assignment is
provided in the SI.
(37) For a description of the computational methodology employed
in this article and relevant references, see the SI.
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