Catalytic asymmetric addition of Grignard reagents to alkenyl-substituted aromatic N-heterocycles

Article abstract of DOI:10.1126/science.aaf1983

Catalytic asymmetric conjugate addition reactions represent a powerful strategy to access chiral molecules in contemporary organic synthesis. However, their applicability to conjugated alkenyl-N-heteroaromatic compounds, of particular interest in medicinal chemistry, has lagged behind applications to other substrates.We report a highly enantioselective and chemoselective catalytic transformation of a wide range of b-substituted conjugated alkenyl-N-heteroaromatics to their corresponding chiral alkylated products.This operationally simple methodology can introduce linear, branched, and cyclic alkyl chains, as well as a phenyl group, at the β-carbon position.The key to this success was enhancement of the reactivity of alkenyl-heteroaromatic substrates via Lewis acid activation, in combination with the use of readily available and highly reactive Grignard reagents and a copper catalyst coordinated by a chiral chelating diphosphine ligand.

Full text of DOI:10.1126/science.aaf1983

RESEARCH
◥
temporal resolution of the terahertz-driven streak
camera could also be used to characterize electron
microbunching in free-electron lasers, supple-
menting terahertz-based diagnostics for the x-
ray output (39, 40). The demonstrated concept is
scalable to higher terahertz frequencies and mul-
tiple stages, offering the potential for cascaded
compression into the subfemtosecond regime or
direct injection into a single optical cycle of a
laser-field accelerator (12). This may, in the long
run, lead to isolated attosecond electron pulses
for recording dynamic changes of electron dis-
tribution in complex systems, including biological
molecules and solid-state nanostructures.
REPORTS
ORGANIC CHEMISTRY
Catalytic asymmetric addition of
Grignard reagents to alkenyl-substituted
aromatic N-heterocycles
Ravindra P. Jumde, Francesco Lanza, Marieke J. Veenstra, Syuzanna R. Harutyunyan*
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Catalytic asymmetric conjugate addition reactions represent a powerful strategy to access
chiral molecules in contemporary organic synthesis. However, their applicability to conjugated
alkenyl-N-heteroaromatic compounds, of particular interest in medicinal chemistry, has
lagged behind applications to other substrates. We report a highly enantioselective and
chemoselective catalytic transformation of a wide range of b-substituted conjugated
alkenyl-N-heteroaromatics to their corresponding chiral alkylated products.This operationally
simple methodology can introduce linear, branched, and cyclic alkyl chains, as well as
a phenyl group, at the b-carbon position. The key to this success was enhancement of the
reactivity of alkenyl-heteroaromatic substrates via Lewis acid activation, in combination with
the use of readily available and highly reactive Grignard reagents and a copper catalyst
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sions of such transformations were feasible. It
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Rh-catalyzed addition of an organometallic re-
agent to alkenyl-substituted heteroaromatic com-
pounds—namely arylation with an arylboronic
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chiral products with high yields and enantio-
selectivities (16–19).
The limited number of reports on transition
metal–catalyzed asymmetric conjugate addi-
tion of nucleophiles to b-substituted alkenyl-
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metal–catalyzed arylations, is in striking contrast
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catalytic asymmetric alkylations, arylations, alky-
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T
half of all APIs are chiral (1). Because the two
enantiomers of a chiral drug can exhibit mark-
edly different bioactivity, any new chiral API must
be produced as a single enantiomer. Catalytic
asymmetric carbon-carbon (C-C) bond formation
represents the most straightforward and atom-
efficient strategy for the construction of organic
chiral molecules (2–4). Organometallic reagents
are used in a substantial fraction of the C-C bond–
forming reactions used to construct API molecules
(5–7). The conjugate addition of organometallic
reagents to electron-deficient substrates (Michael
acceptors) has proven to be a powerful method for
creating new C-C bonds in a catalytic asymmetric
manner for more than 20 years (7–12). In this
context, the catalytic asymmetric addition of orga-
nometallics to conjugated alkenyl-heteroaromatic
compounds represents an attractive strategy to
access valuable chiral heterocyclic aromatic com-
pounds in enantiopure form. Addition of carbon
nucleophiles to conjugated vinyl-substituted he-
teroaromatic compounds, leading mainly to achiral
molecules, is well known (13, 14). In contrast,
there are only a handful of reports of nucleophilic
additions to b-substituted analogs, in particular
when organometallics are considered.
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ACKNOWLEDGMENTS
This work was supported by the European Research Council and
the Munich-Centre for Advanced Photonics. We thank D. Frischke
for preparing ultrathin aluminum foils. The authors declare no
competing financial interests.
An early attempt at such a catalytic asymmetric
reaction, reported in 1998, was the nickel-catalyzed
addition of Grignard reagents to substituted 4-(1-
alkenyl)pyridines (15). Although the reaction did
We decided to explore the addition of Grignard
reagents to b-substituted conjugated alkenyl-
heteroaromatic compounds. Inexpensive and
readily available Grignard reagents are some of
the most commonly used organometallics in
synthetic chemistry (20), especially in copper-
catalyzed asymmetric conjugate addition to a
variety of Michael acceptors (9–12). We reasoned
SUPPLEMENTARY MATERIALS
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Materials and Methods
Fig. S1
References (41–43)
Stratingh Institute for Chemistry, 9747 AG Groningen,
Netherlands.
*Corresponding author. Email: s.harutyunyan@rug.nl
4 December 2015; accepted 2 March 2016
10.1126/science.aae0003
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that the high reactivity of Grignard reagents
might be able to overcome the low reactivity of
the b-substituted alkenyl heteroaromatics, and
thus provide a solution to this long-standing
challenge.
relative to typical Michael acceptors. Chiral
ferrocenyl diphosphine ligand L1 (Fig. 1A) did
not improve the results.
conversion of 1a was observed when EtMgBr
was used as nucleophile in toluene at −78°C, in
the presence of CuBr·SMe2 and BF3·OEt2 as LA.
However, the addition of chiral ligand L1 led to
the desired product 2a with 59% isolated yield
and 87% enantioselectivity. The effect of different
LAs on the activation of 1a was studied next;
TiCl4, trimethylsilyl chloride (TMSCl), MgBr2, and
trimethylsilyl trifluoromethanesulfonate (TMSOTf)
were examined, but none performed better than
BF3·OEt2 (table S1).
Having established the optimal LA for the ac-
tivation of 1a toward EtMgBr, we assessed the
effect of the chiral ligand and different solvents
(Fig. 1A and table S1). Chiral ligand screening
revealed the sterically hindered ferrocenyl ligand
L2, as well as phosphoramidite-type ligands L6
and L7, to be ineffective, while ferrocenyl ligand
L3 furnished product 2a in a modest yield and
The activation of electrophilic substrates toward
nucleophilic addition is commonly achieved using
Lewis acids (LAs) (21–23). We anticipated that
LA activation of alkenyl-heteroaromatic substrates
could be a viable strategy to overcome the re-
activity issues. During our previous studies, fo-
cused on the synthesis of silyl-substituted chiral
tertiary alcohols via addition of Grignard reagents
to acyl silanes, we used LA mixtures to promote
the addition over the reduction pathway (24). We
also learned that LAs are compatible with both
chiral copper catalysts and Grignard reagents, as
long as reactions are carried out at temperatures
below −50°C. Inspired by these findings, we set
out to evaluate the effect of LA in the aforemen-
tioned reaction (table S1). To our surprise, no
Here, we report an operationally simple, chemo-
selective, and highly enantioselective transfor-
mation of a wide range of b-substituted conjugated
alkenyl-heteroaromatics to their correspond-
ing chiral products via a copper-catalyzed ad-
dition of Grignard reagents, promoted by Lewis
acid. Initially, we examined the reactivity of 2-
styrylbenzoxazole (1a) toward EtMgBr (Et, ethyl)
to produce racemic product 2a (Fig. 1 and table
S1). In the presence of CuBr·SMe2 (Me, methyl),
full conversion was not achieved and a com-
plex mixture resulted after 24 hours at −25°C,
which confirms the markedly lower reactivity of
b-substituted alkenyl-heteroaromatic substrates
Fig. 1. Chiral ligands and heterocycle scope. (A) Structure of chiral
ligands tested during the optimization studies. (B) Heterocycle scope.
Reactions were conducted on a 0.2 mmol scale. Reported yields are for
isolated products. Full conversion was obtained in all cases after 18 hours
(isolated yields below 65% are due to the by-product derived from formal
trapping of the product enolate by the substrate). Absolute configu-
rations were assigned by analogy with the literature. *3 equiv of EtMgBr
and 2.2 equiv of BF3·OEt2 were used in this case. †Using tBuOMe or
toluene instead of diethyl ether provides the addition product 2m with
92% and 80% isolated yields, respectively, and 99% ee.
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enantioselectivity. Both binaphthyl diphosphine–
type ligand L4 (BINAP) and ligand L5 performed
better, furnishing the addition product with >90% ee.
We concluded that several chiral diphosphine
ligands, in combination with a Cu(I) salt, are ca-
pable of effectively addressing the reactivity of the
substrate and the enantioselectivity of the re-
action. However, the superior yield obtained with
ferrocenyl ligand L1 prompted us to select it as
the optimal ligand. Therefore, we studied the ef-
fect of different solvents (table S1) using the
catalytic system derived from CuBr·SMe2 and L1.
With the exception of tetrahydrofuran, all sol-
vents tested [Et2O, tBuOMe (Bu, butyl), toluene,
CH2Cl2] were effectively tolerated by the alkyla-
tion protocol, providing 2a with excellent ee. The
best results—excellent yield (94%) and enantiose-
lectivity (96%)—were obtained in Et2O. Thus, we
adopted the following optimized reaction con-
ditions for the remainder of our experiments:
CuBr·SMe2/(R,Sp)-L1 (5 mol %), Grignard reagent
(1.5 equiv), BF3·OEt2 (1.5 equiv), 18 hours of
reaction time at –78°C in Et2O solvent.
For the evaluation of the substrate scope, we
chose the reaction between alkenyl-heteroaromatic
substrates 1a to 1p and EtMgBr (Fig. 1B). To assess
the stereoelectronic effects of the b-substituent on
the reaction, we synthesized a range of substrates
1a to 1h, derived from benzoxazole, and subjected
them to our alkylation protocol.
The enantioselectivity of the reaction was found
to be consistently high for substrates bearing
both electron-rich and electron-poor substituents.
However, the reactivity of the substrate proved to
be strongly dependent on the nature of these
substituents, providing products 2a to 2g with a
broad range of isolated yields and no clear trend.
The addition of EtMgBr to benzoxazole 1h,
bearing an adjacent propenyl moiety, proceeded
smoothly, furnishing the corresponding product
2h in good yield and enantioselectivity. We also
explored other heteroaromatic substrates, such as
thiazoles (1i and 1j), oxazoles (1k and 1l), pyrim-
idines (1m and 1n), triazines (1o), and quinoline
(1p), and were pleased that our protocol was suc-
cessful for all tested examples, furnishing the cor-
responding alkylated products with high yields
and enantiopurities. This insensitivity to the pres-
ence of heteroatoms in the substrate, which might
be expected to interfere with the stability of the
chiral copper catalyst, makes the reaction remark-
ably general.
Next, we used two structurally different con-
jugated alkenyl-heteroaromatic compounds as
Fig. 2. Grignard scope. Reaction conditions were the same as specified in Fig. 1. *3 equiv of EtMgBr and 2 equiv of BF3·OEt2 were used in this case. †Solvent
mixture Et2O/CH2Cl2 (2:1) was used in this case.
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Fig. 3. Scale-up and mechanistic considerations. (A) Experiments (i) with 1 mol % of CuBr·SMe2/(R,Sp)-L1, (ii) on a preparative scale, and (iii) with the
recovered catalyst. (B) Catalytic asymmetric addition of EtMgBr to (E)-1i and (Z)-1i. (C) Studies on (E)/(Z) isomerization of 1i. (D) Hypothetical catalytic cycle.
substrates—1a and 1m, derived from benzoxa-
zole and pyrimidine, respectively—to evaluate the
scope of the nucleophile (Fig. 2). Nearly all Gri-
gnard reagents assessed provided excellent en-
antioselectivities. It was particularly gratifying
that, where previous reports on additions to con-
jugated alkenyl-heteroaromatics were restricted
to arylations, our catalytic system enabled the
addition of a wide variety of alkyl Grignard re-
agents. Different chain lengths (Et, n-Bu, and
n-hexyl) furnished the corresponding products (2a,
3a, 2m, and 3j) with excellent enantioselectivities
(96 to 99%). Sterically more demanding a-, b-, g-,
and d-branched Grignard reagents were also
well tolerated, providing the corresponding pro-
ducts (3b to 3e; 3k to 3m) with enantioselectiv-
ities ranging from 90 to 99%.
The presence of an olefinic or trimethylsilyl
moiety in the Grignard reagent was also toler-
ated, demonstrating that functionalized products
(3f to 3h; 3n to 3p) can be obtained in high
enantiopurity as well, albeit with moderate yields
in a few cases. Only for the least reactive Gri-
gnard reagent, MeMgBr, was no conversion of
either substrate obtained. Although the enantio-
selective arylation by organoboron reagents is a
well-established methodology for this type of sub-
strate (16), we were curious as to whether our
protocol could tolerate aryl nucleophiles as well.
To our satisfaction, we observed that the same
protocol supported the addition of a phenyl
group, and product 3i could be obtained with
92% enantioselectivity when PhMgBr was used
as nucleophile. The addition of various Grignard
reagents to the pyrimidine-derived substrate 1m
provided the corresponding products 2m and 3j
to 3p consistently with enantioselectivities above
97%. However, 1m is more sensitive than other
heteroaromatic substrates to steric hindrance. For
instance, no conversion of 1m was observed for
the addition of c-pentyl-MgBr.
To examine the potential for the scaling up of
these reactions, we performed a series of exper-
iments for the addition of EtMgBr to substrate
1m: (i) with 1 instead of 5 mol % of CuBr·SMe2/
(R,Sp)-L1, (ii) on a preparative scale (1 mmol),
and (iii) with recovered catalyst in the form of
the Cu complex of (R,Sp)-L1 (Fig. 3A). In all three
experiments, we were able to obtain the product
2m with excellent yield and enantioselectivity,
without any erosion from the original values.
All heteroaromatic substrates prepared in this
work were obtained with more than 99% (E)-
configurational purity. Because the geometry of
the double bond is expected to have substantial
influence on the stereoselectivity in asymmetric
reactions involving alkene transformations, we
studied the effect of the alkene geometry in the
addition of EtMgBr to (E)- and (Z)-stereoisomers
of 2-styrylbenzothiazole (1i). Upon ultraviolet light
irradiation of (E)-1i, its stereoisomer, (Z)-1i, was
obtained with 90% purity. The enantioselective
addition of EtMgBr to both (E)-1i and (Z)-1i, cat-
alyzed by the CuBr·SMe2/(R,Sp)-L1 catalyst, led
to the addition product 2i with opposite configu-
ration and distinctly different enantioselectivities
[40% ee for (Z)-1i and 86% ee for (E)-1i] (Fig. 3B).
The lower enantioselectivity obtained when (Z)-1i
was used as substrate can be explained by partial
isomerization of the substrate during the reaction,
caused by the active catalyst. Unfortunately, the
high reaction rate of the catalytic addition of
EtMgBr to (Z)-1i prevented the analysis of the
reaction mixture at different times. Using MeMgBr,
with which no conversion occurs, we found that
isomerization indeed took place, but only when
CuBr·SMe2, (R,Sp)-L1, BF3·OEt2, and MeMgBr
were all present in solution (Fig. 3C). This isom-
erization is similar to that observed in the Cu(I)-
catalyzed conjugate addition of Grignard reagents
to a,b-unsaturated esters (25). By analogy, this
isomerization supports the catalytic cycle (Fig. 3D)
involving transmetallation of the copper com-
plex formed from CuBr·SMe2 and L1, followed
by reversible formation of the p-Cu(I) complex,
the s-Cu(III) complex, and finally, irreversible
reductive elimination to form aza-enolate of 2i
(25, 26).
The precise mechanism of this reaction remains
under investigation, as the role of the LA additive
is not clear. It seemed plausible for the LA to
activate the heteroaromatic substrate toward
the addition reaction. However, preliminary nu-
clear magnetic resonance (NMR) spectroscopic
studies have revealed that new species are formed
upon addition of BF3·OEt2 to each of the com-
ponents of the reaction individually, indicating
that the LA can modulate the reactivity of Gri-
gnard reagents and can also be involved in the
structure of the catalytically active species.
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Ministry of Education, Culture and Science Gravity program
grant 024.001.035 (S.R.H.). We thank J. T. A. de Jong,
B. Maciá, and J. F. Collados for helpful comments on
the manuscript.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/352/6284/433/suppl/DC1
Materials and Methods
Table S1
NMR spectra
References (27–35)
ACKNOWLEDGMENTS
Supported by Netherlands Organization for Scientific
Research NWO-Vidi and ECHO grants (S.R.H.) and
6 January 2016; accepted 22 March 2016
10.1126/science.aaf1983
21. H. Yamamoto, Ed., Lewis Acids in Organic Synthesis,
Volume 1–2 (Wiley-VCH, 2000).
MAGNETISM
ner has turned out to be challenging. In this
work, we relied on the simplest (albeit demand-
ing) experimental approach to remove a single pz
orbital from the graphene network by means of
the adsorption of a single H atom. Atomic H
chemisorbs on graphene on top of carbon atoms,
changing the initial sp2 hybridization of carbon
to essentially sp3 (17, 18) and effectively removing
the corresponding pz orbital (4, 19, 20). In this
sense, chemisorbed H atoms are equivalent to
carbon vacancies (4, 12, 14) but with the advantage
that, unlike vacancies, they leave the graphene
atomic lattice with no unsaturated dangling bonds,
preserving the threefold symmetry. Our exper-
iments, supported by ab initio calculations, provide
a comprehensive picture of the origin, coupling,
and manipulation of the magnetism induced by
H atoms on graphene layers.
We deposited atomic H on graphene grown
on a SiC(000-1) substrate (21). In this system,
the rotational disorder of the graphene layers
electronically decouples the p bands, leading to
a stacking of essentially isolated graphene sheets
(22–24). Scanning tunneling microscopy (STM)
visualizes single H atoms as a bright protrusion
(apparent height, ~2.5 Å) surrounded by a com-
plex threefold √3×√3 pattern that is rotated 30°
degrees with respect to the graphene lattice. (25, 26)
[Fig. 1B and section 1 in (27)]. The resolution that
we achieved allowed us to identify the adsorbate as
a single H atom and to determine the atomic site
(and thus the corresponding atomic sublattice)
where each H atom was chemisorbed by means of
comparison with density functional theory (DFT)–
simulated STM images [Fig. 1D and section 1 in
(27)]. As depicted in Fig. 1A, graphene magnetic
moments induced by H adsorption should be
reflected in the appearance of a spin-polarized
state at EF, which, according to DFT calculations,
should be characterized by two narrow peaks in
the density of states (DOS) (Fig. 1E) (4).
Atomic-scale control of graphene
magnetism by using hydrogen atoms
Héctor González-Herrero,1,2 José M. Gómez-Rodríguez,1,2,3 Pierre Mallet,4,5
Mohamed Moaied,1,6 Juan José Palacios,1,2,3 Carlos Salgado,1 Miguel M. Ugeda,7,8
Jean-Yves Veuillen,4,5 Félix Yndurain,1,2,3 Iván Brihuega1,2,3
*
Isolated hydrogen atoms absorbed on graphene are predicted to induce magnetic
moments. Here we demonstrate that the adsorption of a single hydrogen atom on
graphene induces a magnetic moment characterized by a ~20–millielectron volt spin-split
state at the Fermi energy. Our scanning tunneling microscopy (STM) experiments,
complemented by first-principles calculations, show that such a spin-polarized state is
essentially localized on the carbon sublattice opposite to the one where the hydrogen atom
is chemisorbed. This atomically modulated spin texture, which extends several nanometers
away from the hydrogen atom, drives the direct coupling between the magnetic moments at
unusually long distances. By using the STM tip to manipulate hydrogen atoms with atomic
precision, it is possible to tailor the magnetism of selected graphene regions.
dding magnetism to the long list of graphene’s
capabilities has been pursued since this ma-
terial was first isolated (1). From a theoret-
ical point of view, magnetic moments in
graphene can be induced by removing a
on the spatial localization of the state, because
this defines the proximity of the electrons (Fig.
1A). In contrast to magnetic moments of a strong-
ly localized atomic character that are commonly
found in magnetic materials, these induced mo-
ments are predicted to extend over several na-
nometers, suggesting a strong direct coupling
between them at unusually long distances. The
coupling rules between the induced magnetic
moments are also expected to be simple. Because
of the bipartite atomic structure of graphene—
which consists of two equivalent triangular sub-
lattices, labeled A and B—and according to Lieb’s
theorem (7), the ground state of the system pos-
sesses a total spin given by S = 1/2 × |NA–NB|, where
NA and NB are the number of pz orbitals removed
from each sublattice (4, 8, 9). Thus, to generate a
net magnetic moment in a particular graphene
region, a different number of pz orbitals from
each sublattice needs to be locally removed.
Many theoretical proposals have been put for-
ward on this subject, involving zigzag edges,
graphene clusters, grain boundaries, and atomic
defects (2, 4, 5, 8–11). Experimentally, the remov-
al of pz orbitals from the p system has been
achieved by randomly creating atomic vacan-
cies or adsorbing adatoms (12–16). However,
removing those pz orbitals in a controlled man-
A
single pz orbital from the p-graphene system; this
removal creates a single p-state at the Fermi en-
ergy (EF) around the missing orbital. The double
occupation of this state by two electrons with
different spins is forbidden by the electrostatic
Coulomb repulsion; namely, once an electron oc-
cupies the state, a second one with opposite spin
needs to “pay” an extra energy U. This leaves a
single electron occupying the state and therefore
a net magnetic moment (2–6). The strength of U,
which determines the spin splitting, depends
1Departamento de Física de la Materia Condensada,
Universidad Autónoma de Madrid, E-28049 Madrid, Spain.
2Condensed Matter Physics Center (IFIMAC), Universidad
Autónoma de Madrid, E-28049 Madrid, Spain. 3Instituto
Nicolás Cabrera, Universidad Autónoma de Madrid, E-28049
Madrid, Spain. 4Université Grenoble Alpes, Institut NEEL, F-
38042 Grenoble, France. 5Centre National de la Recherche
Scientifique (CNRS), Institut NEEL, F-38042 Grenoble,
France. 6Department of Physics, Faculty of Science, Zagazig
University, 44519 Zagazig, Egypt. 7CIC nanoGUNE, 20018
Donostia-San Sebastian, Spain. 8Ikerbasque, Basque
Foundation for Science, 48013 Bilbao, Spain.
Differential conductance spectra (dI/dV; I, cur-
rent; V, sample voltage) probe the energy-resolved
local DOS under the STM tip position and
thus are ideal for investigating this question.
Figure 1C shows two dI/dV spectra, measured
at 5 K, that are representative of our findings.
The dI/dV spectra measured on clean graphene,
located far enough away from defects, have the
characteristic featureless V shape of graphene,
with a minimum at EF indicating the position of
*Corresponding author. Email: ivan.brihuega@uam.es
SCIENCE sciencemag.org
22 APRIL 2016 • VOL 352 ISSUE 6284 437

Catalytic asymmetric addition of Grignard reagents to
alkenyl-substituted aromatic N-heterocycles
Ravindra P. Jumde, Francesco Lanza, Marieke J. Veenstra and
Syuzanna R. Harutyunyan (April 21, 2016)
Science Translational Medicine 352 (6284), 433-437. [doi:
10.1126/science.aaf1983]
Editor's Summary
Copper adds alkyls asymmetrically
Nitrogen-bearing rings are very common features in the molecular structures of modern drugs.
Reactions that can modify these N heterocycles selectively are thus especially useful to optimize
pharmaceutical properties. Jumde et al. developed a method to append alkyl groups in a single
mirror-image orientation to substituted C=C double bonds dangling from N heterocycles. The
copper-catalyzed reaction, which relies on Grignard reagents to introduce the alkyl groups, manifests
high selectivity across a broad range of substrates, with no interference from the nitrogen.
Science, this issue p. 433
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