Asymmetric Cu-Catalyzed 1,4-Dearomatization of pyridines and pyridazines without preactivation of the heterocycle or nucleophile

Article abstract of DOI:10.1021/jacs.8b02568

We show that a chiral copper hydride (CuH) complex catalyzes C-C bond-forming dearomatization of pyridines and pyridazines at room temperature. The catalytic reaction operates directly on free heterocycles and generates the nucleophiles in situ, eliminati

Full text of DOI:10.1021/jacs.8b02568

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Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and
Pyridazines without Preactivation of the Heterocycle or Nucleophile
Michael W. Gribble, Sheng Guo, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02568 • Publication Date (Web): 02 Apr 2018
Downloaded from http://pubs.acs.org on April 3, 2018
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Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and
Pyridazines without Preactivation of the Heterocycle or Nucleophile
Michael W. Gribble Jr,† Sheng Guo,† and Stephen L. Buchwald*
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Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
dine rather than on stoichiometrically activated derivaꢀ
ABSTRACT: We show that a chiral copper hydride
(CuH) complex catalyzes CꢀC bondꢀforming dearomatiꢀ
zation of pyridines and pyridazines at room temperature.
tives,8aꢀj but there are no reactions of this type that
achieve either CꢀC bondꢀformation or asymmetric inꢀ
duction. In this report, we show that a chiral copper
The catalytic reaction operates directly on free heterocyꢀ
complex catalyzes C–C bondꢀforming dearomatization
under mild conditions without requiring activation of the
cles and generates the nucleophiles in situ, eliminating
the need for stoichiometric preactivation of either reacꢀ
heterocycle, preꢀformation of the nucleophile, or protectꢀ
tion partner; further, it is one of very few methods availꢀ
ing group manipulations (Figure 1, D). Moreover, the
able for the enantioselective 1,4ꢀdearomatization of hetꢀ
reaction is a very rare example of highly enantioselecꢀ
eroarenes. Combining the dearomatization with facile
tive catalytic 1,4ꢀdearomatization,
derivatization steps enables oneꢀpot syntheses of enantiꢀ
oenriched pyridines and piperidines.
Dearomatization of electronꢀdeficient heteroarenes
with carbon nucleophiles is an essential transformation
for the synthesis of pyridines and piperidines, which are
the two most common azaheterocycles in FDAꢀapproved
smallꢀmolecule drugs.1,2aꢀe However, direct dearomative
addition to pyridine generally requires harsh condiꢀ
tions2c,3b and has limited compatibility with complex,
functionalized molecules.
Most C–C bondꢀforming
pyridine dearomatizations employ activated substrates
generated through stoichiometric functionalization of the
heterocyclic nitrogen with strong electrophiles.2ꢀ7 While
useful, this approach has a number of limitations. For
instance, many methods require preꢀsynthesis of the acꢀ
tivated heterocycle2c or prior formation of nucleophile,
and separate deprotection steps are commonly required
to cleave the activating group from the dihydropyridine
(DHP) product. Further, whereas numerous methods
exist for asymmetric 1,2ꢀdearomatization,4aꢀe achieving
stereocontrol in 1,4ꢀselective variants has proven much
more challenging. The latter transformation is seldom
possible without auxiliaries or preꢀformed chiral nucleoꢀ
philes (Figure 1, A and B);5,6aꢀc asymmetric catalysis of
pyridine 1,4ꢀdearomatization7aꢀc was unknown until very
2c
recently,
and highly enantioselective catalytic reacꢀ
tions (Figure 1, C)7bꢀd are currently only possible with a
narrow set of multiply activated cationic substrates. A
number of catalyzed additions of hydride or silyl nucleꢀ
ophiles have been reported that operate directly on pyriꢀ
Figure 1. Methods for stereocontrolled 1,4ꢀ
dearomatization; (A) with chiral auxiliaries; (B) with chiral
nucleophiles; (C) using asymmetric catalysis; (D) this
work: asymmetric direct catalytic dearomatization.
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it succeeds with a broad selection of substituted pyriꢀ
of enantioenriched piperidines also proved to be
straightforward: adding NaHB(OAc)3 to crude DHPs
provided good yields of piperidines (generically, 4; Taꢀ
ble 1, B) in a oneꢀpot operation14 that could be conductꢀ
ed on gramꢀscale without appreciable loss of yield or
selectivity (4p; Table 1, B).
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dines and pyridazines, and it generates DHPs that can be
converted to enantioenriched pyridines or piperidines in
the same pot.
The dearomatization/reoxidation protocol succeeded
with pyridines, pyridazines, and a variety of C3ꢀ
substituted derivatives thereof. The enantioselectivity
obtained with pyridazines (3g-k; Table 1, A) was conꢀ
sistently excellent and insensitive to the presence of
electronꢀdonor groups; in contrast, the ee’s obtained with
pyridines were moderately depressed by electronꢀ
releasing groups (e.g., 3d; Table 1, A) and enhanced by
9
We hypothesized that pyridine could be activated toꢀ
ward nucleophilic dearomatization in an asymmetric
hydrofunctionalization reaction,9,10 thereby permitting
direct dearomatization of the heterocycle while replacing
preꢀformed nucleophiles with abundant olefin precurꢀ
sors. Subjecting a mixture of pyridine and styrene to
(PhꢀBPE)CuH, prepared as before (eq 1),11,12 gave 97%
conversion (1H NMR) to a mixture of dihydropyridines
strongly biased in favor of the 1,4ꢀadduct 1a (22:1 averꢀ
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aryl and
ꢀ ꢀacceptor substituents (3e, 4s-u; Table 1, A
and B). Substituted pyridines were also viable subꢀ
strates for dearomatization/reduction, and stereochemiꢀ
cal analysis of products 4s-u (Table 1, B) revealed that
both transformations exert control over the endocyclic
stereocenters they respectively generate, leading to mixꢀ
tures of diastereomeric piperidines having a major bias
for the 4 (a,s) diastereomers [see inset in Table 1, B for
explanation of nomenclature]. The major diastereomers
were isolable in stereochemically pure form,
3c
age 1,4:1,2). Treating crude DHPs with O2 provided
efficient rearomatization and enabled a oneꢀpot synthesis
of functionalized pyridines (generically, 3; Table 1, A).
Chiral analysis of pyridine 3a (90% ee) indicated that
the dearomatization had occurred with high enantioseꢀ
lectivity and that the aerobic rearomatization was stereoꢀ
specific.13 Applying the dearomatization to the synthesis
Table 1: Asymmetric Dearomative Syntheses of Functionalized Pyridines (A) and Piperidines (B).
aReactions used 1 mmol 2, 2 equiv olefin except where noted; see SI for details; O2 was used for 3b-k.; dyields and ee’s
b
c
e
f
g
are averages for two runs except where noted; reaction used 4.0% Cu(OAc)2, 4.4% PhꢀBPE; one measurement; used 0.5
mmol 2; hused 1.5 equiv olefin; iused 1.1 equiv olefin; jee determination used the NꢀBOC derivative.
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and thus the dearomatization/reduction protocol enabled
Nꢀcuprated DHP intermediate could then furnish product
IV and the regenerated catalyst via ꢃꢀbond metathesis
with the silane (step iv), similarly to transmetalation
processes implicated in other catalytic hydrofunctionaliꢀ
zations.12,18ꢀ19 We are currently undertaking a detailed
mechanistic investigation directed at elucidating how
activation and addition occur in this reaction.
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selective preparation of piperidines containing three conꢀ
tiguous stereocenters starting from prochiral substrates.
Our work with this series provided key insights into the
stereochemical properties of the asymmetric dearomatiꢀ
zation. Singleꢀcrystal Xꢀray diffraction analysis of
4s(a,s)•HCl revealed its absolute configuration,15,16 makꢀ
ing it clear that dearomative addition is retentive with
respect to the benzylic stereocenter set during hydrocuꢀ
pration and selective for (Cꢁ ,C4)ꢀanti DHPs, whereas
the reduction is selective for (C3,C4)ꢀsyn piperidines.
The basis for antiꢀselective dearomative addition is unꢀ
clear at present, but it appears to be general.15,17 Notably,
retention of the phenethylcopper stereocenter contrasts
with the clean inversion Aggarwal observed in the addiꢀ
tion of chiral phenethylboronates to acylpyridiniums
(Figure 1, B);5 our result is mechanistically interesting
given that the organocopper nucleophiles involved here
do undergo invertive addition in other transforꢀ
mations.12c
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Figure 2.
Dearomatization.
Plausible Mechanism for the Direct
In summary, we have demonstrated that pyridine and
pyridazine undergo direct asymmetric dearomatization
in the presence of a chiral CuH catalyst. This unique
reaction eliminates the need for extraneous activation
and nucleophileꢀformation steps, and it permits oneꢀpot
syntheses of highly enantioenriched C4ꢀfunctionalized
heterocycles. We expect that our ongoing mechanistic
investigations will shed light on the unusual reactivity
trends we observe and aid in the discovery of more genꢀ
eral dearomative transformations.
Unlike C3 substituents, groups at C4 are only accomꢀ
modated in special cases (as in 4r; Table 1, B), and subꢀ
stitution at C2 is not tolerated even for substituents that
increase the intrinsic electrophilicity of the free heteroꢀ
cycle (e.g., CF3, CO2Me). Further, examples 3i-k (Table
1, A) show that organocopper nucleophiles preferentially
add para to the less hindered nitrogen even when this
entails attack on the more encumbered and more elecꢀ
tronꢀrich of the two activated sites. These observations
concerning C2 substitution can be readily rationalized if
one invokes coordination of the heterocycle to a stericalꢀ
ly demanding Lewis acid (e.g., Cu) in the dearomative
addition step.
ASSOCIATED CONTENT
Supporting Information. The supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures and characterization data for all
compounds (PDF, CIF)
The dearomatization is compatible with various aryl
alkene substituents, but certain trends involving this reꢀ
actant were very surprising. Dearomatization exhibits
useful levels of selectivity for a variety of olefin ꢂ subꢀ
stituents (3b, 3k, 4q; Table 1, A and B), and ortho subꢀ
stitution is broadly tolerated (3c, 4l-n; Table 1, A and B).
But surprisingly, when groups such as F, Me and OMe
are present at the para position of the styrene, they comꢀ
pletely suppress dearomatization. This observation runs
counter to all our previous experience with styrene hyꢀ
drofunctionalization12aꢀe and leads us to propose that
para substituents incur a destabilizing interaction unique
to the dearomative addition transition state. Consistent
with this, we observed some sensitivity to the steric deꢀ
mand of the meta substituent; thus, 3ꢀmethylstyrene is
problematic for pyridine but not pyridazine (3g, 3h; Taꢀ
ble 1), while metaꢀhalides are tolerated with both (3g, 3i,
4o-p; Table 1, A and B).
PDF
CIF
AUTHOR INFORMATION
Corresponding Author
*Email: sbuchwal@mit.edu
Author Contribution
†These authors contributed equally.
Notes
No competing financial interests have been declared
Figure 2 illustrates one plausible mechanism for the
Cuꢀcatalyzed direct dearomatization. Activation of the
heterocycle occurs through formation of dative complex
I (step i), which undergoes dearomatization with an orꢀ
ganocopper nucleophile (II) (step ii).12a,18 The resulting
ACKNOWLEDGMENT
The National Institutes of Health under award numbers
GM46059, GM122483, and R35ꢀGM122483 supported
research reported in this publication. We thank Richard Liu
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(e) Dudnik, A. S.; Weidner, V. L.; Motta, A.; Delferro, M.; Marks, T.
and Andy Thomas (MIT) for advice on the preparation of
this manuscript, Charlene Tsay (MIT) for Xꢀray crystalloꢀ
graphic analysis, Bruce Adams (MIT) for assistance with
NMR structureꢀdetermination, and the National Institutes
of Health for a supplemental grant for the purchase of suꢀ
percritical fluid chromatography (SFC) equipment
(GM058160ꢀ17S1).
J. Nat. Chem. 2014, 6, 1100ꢀ1107. (f) Gandhamsetty, N.; Park, S.;
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(9) Kanai has suggested that hydrometallation and dearomative adꢀ
dition steps occur in the mechanism of Coꢀcatalyzed CꢀH functionaliꢀ
zation of pyridine, although they do not describe observing the DHP;
rather, they suggest that (presumably fast) rearomatization is intrinsic
to the catalytic cycle. Andou, T.; Saga, Y.; Komai, H.; Matsunaga,
S.; Kanai, M. Angew. Chem. Int. Ed. 2013, 52, 3213ꢀ3216.
(10) After our work was completed, a paper appeared by Yu, showꢀ
ing that phenethylcopper species generated in asymmetric hydrocuꢀ
pration effect reductive ortho CꢀHꢀfunctionalization of quinoline Nꢀ
oxides, probably via an initially dearomative mechanism. Yu, S.;
Sang, H. L.; Ge, S. Angew. Chem. Int. Ed. 2017, 56, 15896ꢀ15900.
(11) For detailed information about the safe handling of diꢀ
methoxy(methyl)silane (DMMS), see the Supporting Information.
(12) See, e.g., (a) Bandar, J. S.; Pirnot, M. T.; Buchwald, S. L. J.
Am. Chem. Soc. 2015, 137, 14812ꢀ14818. (b) Wang, YꢀM.; Buchꢀ
wald, S. L. J. Am. Chem. Soc. 2016, 138, 5024ꢀ5027. (c) Yang, Y.;
Perry, I. B.; Buchwald, S. L. J. Am. Chem. Soc. 2016, 138, 9787ꢀ
9790. (d) Gribble, M. W., Jr.; Pirnot, M. T.; Bandar, J. S.; Liu, R. Y.;
Buchwald, S. L. J. Am. Chem. Soc., 2017, 139, 2192ꢀ2195. (e) Zhou,
Y.; Bandar, J. S.; Buchwald, S. L. J. Am. Chem. Soc. 2017, 139,
8126ꢀ8129.
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1
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