Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation

Article abstract of DOI:10.1021/jacs.0c05887

Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.

Full text of DOI:10.1021/jacs.0c05887

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Article
Direct Synthesis of Cyclopropanes from gem-
Dialkyl Groups through Double C–H Activation
Antonin Clemenceau, Pierre Thesmar, Maxime Gicquel, Alexandre Le Flohic, and Olivier Baudoin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c05887 • Publication Date (Web): 12 Aug 2020
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Journal of the American Chemical Society
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Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through
Double C–H Activation
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Antonin Clemenceau,† Pierre Thesmar,† Maxime Gicquel,‡ Alexandre Le Flohic,‡ and Olivier Baudoin†*
†University of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel, Switzerland.
‡Oril Industrie, 13 rue Auguste Desgenétais, CS60125, 76210 Bolbec, France.
Supporting Information Placeholder
two-step sequence involving palladium(II)-catalyzed,
oxazoline-directed C(sp3)–H diiodination of gem-
dimethyl groups followed by radical cyclization.
(Scheme 1b).5 Besides, cyclopropanes have been
generated through domino reactions including olefin
carbopalladation and C(sp3)–H activation, leading to
putative 4-membered palladacyclic intermediates
(Scheme 1c).6,7
ABSTRACT: Cyclopropanes are important structural
motifs found in numerous bioactive molecules, and a
number of methods are available for their synthesis.
However, one of the simplest cyclopropanation reactions
involving the intramolecular coupling of two C–H bonds
on gem-dialkyl groups has remained an elusive
transformation. We demonstrate herein that this reaction
is accessible using aryl bromide or triflate precursors
and the 1,4-Pd shift mechanism. The use of pivalate as
the base was found to be crucial to divert the
mechanistic pathway toward the cyclopropane instead of
the previously obtained benzocyclobutene product.
Stoichiometric mechanistic studies allowed the
identification of aryl- and alkylpalladium pivalates,
which are in equilibrium via
palladacycle. With pivalate,
a
five-membered
a
second C(sp3)–H
activation leading to the four-membered palladacycle
intermediate and the cyclopropane product is favored. A
catalytic reaction was developed and showed a broad
scope for the generation of diverse arylcyclopropanes,
including valuable bicyclo[3.1.0] systems. This method
was applied to a concise synthesis of lemborexant, a
recently approved anti-insomnia drug.
Figure 1. Examples of drugs or drug candidates containing
an arylcyclopropane motif relevant to this study.
The current work reports the first single-step synthesis
of cyclopropanes via coupling between two geminal
methyl groups or one methyl and one activated
methylene group (Scheme 1d). This reaction is based on
the propension of the arylpalladium halide, generated in
the initial oxidative addition step, to undergo 1,4-Pd
shift to generate a -alkylpalladium intermediate.8 Since
seminal observations by Dyker,9 such alkylpalladium
intermediates have been exploited in various
transformations: -H elimination to generate olefins,10
trapping with boronic acids11 and anilines,12 or
INTRODUCTION
Cyclopropanes are widespread structural motifs in
natural products and bioactive molecules (see Figure 1
for examples).1 Indeed, the cyclopropane ring can
improve the pharmacological properties of active
substances by reducing their lipophilicity, increasing
their metabolic stability, or modifying their acido-
basicity.2 Although a great number of methods have
been developed to synthesize cyclopropanes,3 the
cycloaddition of alkenes and carbenes or carbenoids
largely prevails for applications to complex molecules.4
In this context, one of the simplest ways to construct
cyclopropanes, through C–C bond formation from two
geminal alkyl groups (Scheme 1a), has remained an
elusive transformation to this date. In 2006, Yu and co-
workers reported the synthesis of cyclopropanes via a
intramolecular
dearomatizing
carbopalladation,
furnishing spiroannulation products.13 Recently, we
showed that such organopalladium species are also able
to perform the cleavage of an activated C(sp3)–H bond
(i. e., benzylic and adjacent to a carbonyl group) to
generate oxygen and nitrogen heterocycles.14 The
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extension of this mechanism to the formation of under the shown conditions provided BCB 2a as the sole
1
2
3
4
5
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8
cyclopropanes is reported herein.
observable C–H activation product (entry 1), together
with the proto-dehalogenated byproduct (not shown).
Replacing carbonate with pivalate led to a complete
change of selectivity, with cyclopropane 3a becoming
the sole C–H activation product (entry 2). The ligand
also had a noticeable effect on the selectivity, with the
bulky P(t-Bu)3 favoring the BCB product, as previously
reported (entry 3).15
RESULTS AND DISCUSSION
Initial Work and Mechanistic Study. The origin of
this work stems from our initial studies on the
generation of benzocyclobutenes (BCBs) by Pd0-
catalyzed
C(sp3)–H
activation.15
Recent
re-
investigations pointed to a spectacular influence of the
base on the reaction outcome (Scheme 2).
9
Scheme 2. Influence of the Base on the Formation of
Benzocyclobutene vs. Cyclopropane
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Scheme 1. Synthesis of Cyclopropanes by Pd-
Catalyzed C(sp3)–H Activation
a 1H NMR yield using CH2Br2 as internal reference. b Using
Pd2dba3 (5 mol%)/P(t-Bu)3 (20 mol%) instead of
Pd(PPh3)4.
Following these initial observations, and inspired from
a study by Martin and co-workers,16 we decided to
reinvestigate the reaction mechanism by following each
step through stoichiometric experiments (see the
Supporting Information for details).
A
tentative
mechanism, represented in qualitative energy profile
format, is displayed in Figure 2. The oxidative addition
of prototypical aryl bromide 1b to Pd(PPh3)4 gives rise
to complex A, which undergoes bromide substitution
with pivalate, producing complex B1.
As initially reported, using potassium carbonate as the
base in the intramolecular C–H arylation of substrate 1a
Figure 2. Qualitative energy profile of the reaction of substrate 1b based on experimental observations. The relative
stabilities of B2 and D1, C1 and E1, and 2b and 3b were calculated by DFT (see the Supporting Information for details). L =
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PPh3. TS = transition state; OA = oxidative addition; Sub = substitution; CH = C–H activation; PROT = protonation; RE =
reductive elimination.
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The latter is in equilibrium with complex B2,
containing one phosphine ligand and pivalate
coordinated in the 2 mode,17c which undergoes base-
mediated C(sp3)–H activation via the concerted
metalation–deprotonation mechanism15,17 to give five-
membered palladacycle C1. Reductive elimination from
C1 provides the BCB product 2b. Alternatively,
mixing complex A with KOPiv (Scheme 3b). This step
was relatively easy, with -arylpalladium pivalate B1
being slowly formed at room temperature (25% after 16
h, not shown) and in 82% yield at 60 °C. Raising the
temperature to 80 and 100 °C led to the formation of
cyclopropane 3b at the expense of complex B1. This
result shows that the formation of the cyclopropane
product is faster than the oxidative addition, and
therefore that the latter is the slowest step of the
reaction. The reaction of the known -alkylpalladium
9
protonation of C1 with pivalic acid15,17e furnishes
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1
alkylpalladium complex D1. The sequence B1
C
→
→
D1 results in an overall 1,4-Pd shift.8,14 A second base-
induced C(sp3)–H activation from D1 leads to the rare
four-membered palladacycle E1,6,7,18 already suggested
by Martin,16 which reductively eliminates to generate
cyclopropane 3b.
complex (PhCMe2CH2)Pd(COD)Cl D2 (COD
=
cyclooctadiene)19 in the presence of KOPiv and PPh3 in
toluene at room temperature led to alkylpalladium
pivalate D1 in 88% yield (Scheme S1, see Figure 2 or
Scheme 3 for the structure of D1). In contrast, at 60 °C
arylpalladium pivalate B1 was formed from D2, thus
showing that B1 is more stable than D1. The thermal
decomposition of B1 was next analyzed at various
temperatures (Scheme 3c). At 80 °C, both D1 and
cyclopropane 3b were formed, and the proportion of
cyclopropane markedly increased at 100 °C. The
reactivity of alkylpalladium pivalate D1 was also
analyzed (Scheme 3d). At 80 °C, a new complex, which
was assigned to arylpalladium species B2 containing one
PPh3 ligand and the 2-coordinated pivalate, was formed
together with degradation products.
The oxidative addition of the bulky aryl bromide 1b
1
was followed by H and 31P NMR and was found to be
slow using PPh3 as the ligand, with only 26% of
complex A formed at 80 °C after 16 h, and 72% at 120
°C together with 20% remaining starting material
(Scheme 3a). Complex A was independently synthesized
in 88% yield from 1b and Pd(PPh3)4 (toluene, 120 °C),
and its three-dimensional structure was confirmed by
Xray diffraction analysis (Scheme 3). Consistent with
results displayed in Scheme 2, heating A to 100 °C in
the presence of K2CO3 furnished BCB 2b in 65% yield
(Scheme 3b). The substitution step was then analyzed by
Scheme 3. Stepwise Study of the Reaction Mechanism through Stoichiometric Experimentsa
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a)
b)
K2CO3
(2 equiv)
KOPiv
(2 equiv)
1
Pd(PPh3)4
2
3
4
5
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8
100 °C
PdBr(PPh3)2
Pd(PPh3)2OPiv
B1
82%
76%
13%
Br
PdBr(PPh3)2
1b
A
0%
26%
55%
72%
2b
65%
A
3b
0%
14%
80%
60 °C 100%
80 °C 74%
100 °C 45%
120 °C 20%
60 °C 10%
80 °C 0%
100 °C 0%
c)
Pd(PPh3)OPiv
9
Pd(PPh3)2OPiv
B1
80 °C 27%
100 °C 2%
D1
15%
10%
3b
22%
68%
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d)
Pd(PPh3)OPiv
Xray structure complex Ab
Pd(PPh3)OPiv
B2
29%
22%
52%
0%
Pd(PPh3)2OPiv
D1
B1
0%
22%
0%
0%
3b
80 °C
0%
0%
0%
0%
12%
21%
30%
71%
80 °C/PPh3
100 °C/PPh3
100 °C/PPh3/PivOK
e)
PPh3 (2 equiv)
80 °C
KOPiv (1 equiv)
PivOH (1 equiv)
Pd(PPh3)OPiv
PPh3 (2 equiv)
Pd
COD
Pd(PPh3)2OPiv
C2
3b
2b
78%
D1
B1
12%
56%
0%
20 °C 85%
80 °C 20%
100 °C 0%
0%
11%
61%
a 1H NMR yields using CH2Br2 as internal reference. All reactions were performed in C6D6 for 16 h. b Thermal ellipsoids at
50% probability, H atoms omitted for clarity. COD = 1,5-cyclooctadiene.
Adding PPh3 (1 equiv) led to a cleaner transformation,
with both mono- and bis-ligated complexes B1-B2 and
cyclopropane 3b being formed in comparable amounts.
Heating this mixture to 100 °C furnished a higher
proportion of B2 and cyclopropane 3b, and upon
addition of 1 equiv of KOPiv the cyclopropane was
formed exclusively. These results show that aryl- and
alkylpivalate complexes B1, B2 and D1 are in
equilibrium from 80 °C and are all competent
intermediates en route to cyclopropane 3b. Finally, since
we did not observe the formation of five-membered
palladacycles such as C1 (Figure 2) during the above
studies, likely because they are higher-energy
intermediates, we decided to prepare the known20 five-
membered COD-stabilized palladacycle C2 and study its
reactivity (Scheme 3e). In the presence of KOPiv,
PivOH and PPh3 at room temperature, complex D1 was
formed as major product, together with minor amounts
of B1, thereby showing that the protonation with PivOH
is kinetically favored on the aromatic vs. the alkyl
ligand. Heating to 80 °C inversed the ratio between D1
and B1, thus confirming the higher thermodynamic
stability of B1, and produced a minor amount of
cyclopropane 3b. At 100 °C, only the latter was formed
(61% yield). In contrast, heating palladacycle C2 to 80
°C in the presence of PPh3 only provided BCB 2b in
good yield.16
organopalladium complexes: B1 > B2 > D1 > C1. In
addition, DFT calculations indicated that the four-
membered palladacycle E1 is less stable than the five-
membered isomer C1 by ca. 7 kcal mol–1, hence
establishing the stability order B1 > B2 > D1 > C1 > E1.
Furthermore, cyclopropane 3b was found to be more
stable than BCB 2b by 1.7 kcal mol–1. Figure 2 provides
a
qualitative overview of the reaction profile
summarizing all experimental results and calculations.
The oxidative addition is the highest kinetic barrier,
which arises from the fact that the relatively
electronically neutral PPh3 was employed as ligand. In
the presence of carbonate and the absence of pivalate,
reductive elimination from five-membered palladacycle
C1 occurs preferentially to give BCB product 2b. In
contrast, pivalate promotes the formation of
cyclopropane 3b via C(sp3)–H activation of a second
methyl
group
producing
the
four-membered
palladacycle intermediate E1. Both bicarbonate21 and
pivalic acid are able to open up palladacycle C1 to give
alkylpalladium intermediates, and therefore the unique
ability of pivalate to promote the second C(sp3)–H
activation event leading to cyclopropanation remains
unclear, and will be the object of later studies.
Reaction Optimization and Scope. Taking advantage
of the above mechanistic study, a catalytic version of
this transformation was successfully developped (see the
Supporting Information for details). Unsubstituted
cycloproprane 3b was obtained from both aryl bromide
Taken together, these experimental observations allow
to deduce the following relative stabilities for
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and triflate precursors in good yield using 10 mol% have a significant influence on the reaction outcome. In
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2
3
4
5
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7
8
Pd(PPh3)4 and 2 equiv potassium pivalate in toluene at
120 °C (Scheme 4a). However, this volatile product was
best isolated from the triflate precursor in 72% yield. For
functionalized cyclopropanes, a temperature of 140 °C
was essential to ensure complete conversion. Besides,
the addition of DMSO (5% vol.) was found to diminish
the formation of the proto-dehalogenated side-product,
presumably by increasing the solubility of pivalate.
addition, the pyridinylcyclopropane 3q was generated in
70% yield, hence indicating the compatibility of
heteroarenes. Moreover, substrates functionalized in
ortho position to the quaternary carbon (1r) or to the
bromine atom (1s, 1t) provided the corresponding
cyclopropane products 3r-t in good yields (69-78%).
Remarkably, a twofold cyclopropanation reaction was
successfully carried out, allowing formation of bis-
cyclopropane 3u in 92% yield via two consecutive
cyclopropanations including four C(sp3)–H activation
steps.
9
With these standard conditions in hand, the versatility
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of
this
double
C(sp3)–H
activation-based
cyclopropanation was inspected. Substrates bearing an
ester (3a, 3c), amide (3d), protected amine (3e) or
protected alcohol (3i, 3m) on the quaternary benzylic
carbon worked well under the optimized conditions (72-
85% yields). Of note, the reaction producing
cyclopropane 3a was successfully scaled up to 1 mmol
using o-xylene as the solvent for practical reasons. In
addition, substrate 1f bearing a substituted linear alkyl
chain provided a mixture of the desired cyclopropane 3f
(50% yield) and olefin 4f arising from methylene C–H
activation and -H elimination, consistent with previous
work.10a,17e Reactants containing various electron-
donating groups on the aromatic ring such as dimethoxy
(3g-i), methylenedioxy (3j) or TIPS-protected phenol
(3k) gave the desired cyclopropanes in good yields (65-
81%). Likewise, electron-withdrawing groups such as
fluoro (3l, 3m, 3o), nitro (3n) and trifluoromethyl (3p)
were found to be compatible. The position of the
substituent on the aromatic ring (meta or para) did not
As expected, substrates bearing benzyl instead of methyl
groups did not undergo C(sp3)–H activation and
cyclopropanation, but rather direct C(sp2)–H arylation,
as illustrated with the 6-membered ring product 5
(Scheme 4b). In contrast, in the case of substrates
bearing a quaternary carbon with one methyl and one
methylene adjacent to an ester or nitrile group, the
construction of trisubstituted cyclopropanes was
possible. First, cyclopropanes 3aa and 3ab containing
two esters were synthesized in average yields and good
diastereoselectivity,
probably
arising
from
thermodynamic control. The positional isomers 3ac and
3ad containing nitrile groups were also produced, albeit
with
a
reduced diastereoselectivity. Finally, the
trisubstituted cyclopropane 3ae was generated in 86%
combined yield and with a weak, but opposite
diastereoselectivity compared to 3ab.
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Scheme 4. Reaction Scopea
1
2
H H
R2
R3
R2
Pd(PPh3)4 (10 mol%)
KOPiv (2 equiv)
3
4
5
6
R3
R1
R1
toluene/DMSO (95:5), 140 °C
X
1
3
X = Br or OTf
7
8
9
a) disubstituted cyclopropanes (R2 = H)
Me
NMe2
O
NMeTs
CO2R
CO2Et
CO2Et
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3b, (98%)b,c
R = Me: 3a, 76%d
R = t-Bu: 3c, 75%
3d, 76%
3e, 80%
3f, 50%
4f, 20%
from X = OTf:b (84%)c 72%
MeO
MeO
MeO
NMeTs
TIPSO
F
MeO
MeO
OTIPS
O
O
Me
CO2Me
CO2Me
CO2Me
MeO
O2N
3g, 81%
3h, 75%
3i, 72%
3o, 73%
3j, 71%
3p, 71%
3k, 65%
3l, 69%
Me
NMeTs
F
OPiv
NMeTs
CO2Me
3n, 64%
Me
Me
CO2Et
N
F
CF3
3m, 85%
3q, 70%
from X = OTf: 3r, 74%
t-Bu
t-Bu
Me
Me
Me
t-Bu
3t, 78%
Me
3s, 69%
from X = OTf: 3u, 92%
b) trisubstituted cyclopropanes (R2 ≠ H)
Bn
MeO2C
CO2Me
CO2Me
CO2Me
CN
CO2Me
CO2Me
Me
MeO
MeO
MeO
MeO
CO2Me
CO2Me
CN
5, 88%
C(sp2)-H arylation
3aa, 56%
d.r. 8:1
3ab, 60%
d.r. 9:1
3ac, 70%
d.r. 5:2
3ad, 45%
d.r. 2:1
3ae, 86%
d.r. 2:1
a Reactions were performed on a 0.2 mmol scale. The aryl bromide precursor was employed unless otherwise noted. Yields
refer to the isolated product or mixture of diastereoisomers. Diastereomeric ratios (d.r.) were determined by 1H NMR of the
crude mixture. Relative configurations were determined by NOESY NMR. Performed at 120 °C without DMSO. c 1H
b
NMR yield using CH2Br2 as internal reference. d Performed on a 1 mmol scale using o-xylene as the solvent.
Molecules containing an aryl-substituted [3.1.0]
bicyclic system show interesting biological activities,2
but only a few methods have been developped for their
synthesis22-26 The access to these attractive scaffolds was
investigated by applying our newly developped Pd-
catalyzed double C(sp3)–H activation reaction (Scheme
5). Starting from lactone 6a, the cyclopropane-fused
product 7a was formed in low yield and the major
product was the butenolide 8a resulting from -
hydrogen elimination (Scheme 5a). A similar result was
obtained from lactam 6b. To supress the olefin
formation, the reaction was conducted with -lactones
and lactams 9 bearing the quaternary carbon in 
position to the carbonyl group (Scheme 5b).
Gratifyingly, this modification led to the cyclopropane-
fused lactones 10a-b and lactam 10c in 65-79% yields.
To further increase the complexity, a more substituted
substrate bearing a CH2CO2Me instead of the CH3 group
was employed. A separable 3:1 diastereomeric mixture
of fused -lactams was obtained in 79% combined yield,
with the major diastereoisomer 10c having the aryl and
ester groups in cis relationship. This example shows that
our methodology can also be employed to couple two
activated methylene groups for the synthesis of
tetrasubstituted cyclopropanes.
Lemborexant 11 (Dayvigo®, Figure 1) is a dual
antagonist of the orexin OX1 and OX2 receptors, which
was recently approved for the treatment of insomnia.27
The application of the current method to a short
synthesis of this bioactive target is depicted in Scheme
6. Esterification of commercially available aryl bromide
12 and sequential alkylation and allylation led to methyl
ester 13. The latter was subjected to ester reduction and
oxidative cleavage of the alkene, which directly
provided
-butyrolactone
9e.28
The
key
cyclopropanation of 9e was performed under the
optimized conditions, to furnish the fused lactone 10e in
good yield (79%). Direct amidation of the latter with
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aminopyridine 14 and LiHMDS according to Szostak
and co-workers,29 followed by Mitsunobu reaction with
pyrimidinol 16 furnished racemic lemborexant 11 in
Scheme 6. Application to the Synthesis of
1
2
3
4
Lemborexanta
28% overall yield over 8 steps.
5
6
7
8
Scheme 5. Synthesis of Cyclopropane-Fused
Lactones and Lactams
a) with an -quaternary carbon
O
X
X
O
Me
O
9
H
H
X
Pd(PPh3)4 cat.
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
+
KOPiv
Br
6a
6b
7a, 21%b
7b, 34%b
8a, 48%b
8b, 40%b
X = O
X = NMe
b) with a -quaternary carbon
R2
H
H
R2
O
O
Pd(PPh3)4 cat.
R1
X
R1
X
KOPiv
Br
10
9
H
H
H
H
MeO2C
O
O
O
MeO
MeO
MeO
O
NMe
NBn
R1
R
MeO
1 = H: 10a, 72%c
1 = OMe: 10b, 65%c
10c, 79%c
10d, 59%c (20%)d
d.r. 3:1e
R
a
Conditions: Pd(PPh3)4 (10 mol%), KOPiv (2 equiv),
toluene/DMSO (95:5), 140 °C, 16 h. b NMR yield. Yield
c
d
a Conditions: 1. MeOH, H2SO4 (0.1 equiv), 50 °C; 2. LDA
(1.2 equiv), MeI (1.05 equiv), –78 to 25 °C; 3. LiHMDS (3
equiv), allyl bromide (5 equiv), THF, 0 to 25 °C (72% for 3
steps); 4. DIBAL-H (2.1 equiv), Et2O, –78 to 25 °C (82%);
5. RuCl3 (5 mol%), NaIO4 (6 equiv), MeCN/H2O 10:1, 25
°C; 6. Pd(PPh3)4 (10 mol%), KOPiv (2 equiv), o-
xylene/DMSO 95:5, 140 °C; 7. LiHMDS (3 equiv), 14 (3
equiv), toluene, 25 °C (89%); 8. 16 (1.5 equiv), PPh3 (1.5
equiv), DIAD (1.5 equiv), THF, 25 °C (68%).
of the isolated product.
Yield of the isolated minor
e
1
diastereoisomer. Ratio determined by H NMR of the
crude mixture, relative configuration determined by
NOESY NMR.
CONCLUSIONS
The elusive intramolecular cyclopropanation reaction
cleaving two C–H bonds and forging a C–C bond has
been developed by taking advantage of the 1,4-Pd shift
mechanism. Stoichiometric studies indicated that
oxidative addition is the rate-limiting step with the
employed substrates and catalyst. The characterization
of intermediate Pd complexes allowed the delineation of
a mechanistic pathway including -aryl- and -
alkylpalladium pivalates, which are in equilibrium via
the five-membered diorganopalladacycle. With pivalate
as the base and PPh3 as the ligand, the reductive
elimination from this palladacycle is disfavored and the
activation of a second C(sp3)–H bond is favored, leading
to a high-energy four-membered palladacycle which
reductively eliminates to give the cyclopropane product.
A catalytic version was developed, which enabled the
generation of an array of arylcyclopropanes in good
yields, including fused ring systems, from simple aryl
bromide or triflate precursors. The generation of fused
cyclopropanes was applied to a straightforward synthesis
of the anti-insomnia drug lemborexant.
This work further illustrates that tuning the catalyst
and base in Pd-catalyzed C–H activation reactions may
allow to divert mechanistic pathways toward the
formation of high value-added products.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website at DOI: Full optimization
tables, crystallographic, procedural and spectral data.
AUTHOR INFORMATION
Corresponding Author
*olivier.baudoin@unibas.ch
ORCID
Olivier Baudoin: 0000-0002-0847-8493
Antonin Clemenceau: 0000-0002-2024-2061
Notes
The authors declare no competing financial interest.
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Rahim, A.; Feng, J.; Gu, Z. 1,4-Migration of Transition
Metals in Organic Synthesis. Chin. J. Chem. 2019, 37, 929–
945.
(9) (a) Dyker, G. Palladium-Catalyzed C-H Activation of
Methoxy Groups: A Facile Synthesis of Substituted 6H-
Dibenzo[b,d]pyrans. Angew. Chem. Int. Ed. 1992, 31, 1023–
1025. (b) Dyker, G. Palladium-Catalyzed C–H Activation of
1
2
3
4
5
6
7
8
ACKNOWLEDGMENT
This work was financially supported by Oril Industrie,
affiliated to Les Laboratoires Servier, and the University of
Basel. We thank Dr. Lucile Vaysse-Ludot, Dr. R. Tamion
and J. Fournier, ORIL Industrie, for fruitful discussions and
constant support, Dr. D. Häussinger, University of Basel,
for NMR experiments, and Dr. M. Pfeffer, University of
Basel, for MS analyses.
tert-Butyl Groups:
A
Simple Synthesis of 1,2-
Dihydrocyclobutabenzene Derivatives. Angew. Chem. Int. Ed.
1994, 33, 103–105. (c) Dyker, G. Palladium-Catalyzed C–H
Activation at Methoxy Groups: Regiochemistry of the
Domino Coupling Process. Chem. Ber. 1994, 127, 739–742.
(10) (a) Baudoin, O.; Herrbach, A.; Guéritte, F. The
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
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Palladium‐Catalyzed
C–H
Activation
of
Benzylic
REFERENCES
gem‐Dialkyl Groups. Angew. Chem. Int. Ed. 2003, 42, 5736-
5740. (b) Hitce, J.; Retailleau, P.; Baudoin, O. Palladium-
Catalyzed Intramolecular C(sp3)–H Functionalization:
Catalyst Development and Synthetic Applications. Chem.
Eur. J. 2007, 13, 792–799. (c) Motti, E.; Catellani, M.
Catalytic Dehydrogenation of o-Alkylated or o-Alkoxylated
Iodoarenes with Concomitant Hydrogenolysis. Adv. Synth.
Catal. 2008, 350, 565–569. (d) Bheeter, C. B.; Jin, R. ; Bera,
J. K.; Dixneuf, P. H. ; Doucet, H. Palladium-Catalysed
Dehydrogenative sp3 C–H Bonds Functionalisation into
Alkenes: A Direct Access to N-Alkenylbenzenesulfonamides.
Adv. Synth. Catal. 2014, 356, 119–124.
(1) Faust, R. Fascinating Natural and Artificial Cyclopropane
Architectures. Angew. Chem. Int. Ed. 2001, 40, 2251–2253.
(2) (a) Talele, T. T. The "Cyclopropyl Fragment" is a Versatile
Player that Frequently Appears in Preclinical/Clinical Drug
Molecules. J. Med. Chem. 2016, 59, 8712–8756. (b) Časar, Z.
Synthetic Approaches to Contemporary Drugs that Contain
the Cyclopropyl Moiety. Synthesis 2020, 52, 1315–1345.
(3) (a) Roy, M.-N.; Lindsay, V. N. G.; Charette, A. B.
Cyclopropanation Reactions. In Science of Synthesis, De
Vries, J. G.; Molander, G. A.; Evans, P. A., Eds.; Thieme:
Stuttgart, 2011; Vol. 1, pp 731–817. (b) Kulinkovich, O. G.
Cyclopropanes in Organic Synthesis, John Wiley & Sons,
Inc.: Hoboken, 2015.
(4) (a) Chen, D. Y.-K.; Pouwerb, R. H.; Richard, J.-A. Recent
Advances in the Total Synthesis of Cyclopropane-Containing
Natural Products. Chem. Soc. Rev. 2012, 41, 4631–4642. (b)
Ebner, C.; Carreira, E. M. Cyclopropanation Strategies in
Recent Total Syntheses. Chem. Rev. 2017, 117,
11651−11679.
(11) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S.
L. Catalysts for Suzuki–Miyaura Coupling Processes: Scope
and Studies of the Effect of Ligand Structure. J. Am. Chem.
Soc. 2005, 127, 4685–4696.
(12) Pan, J.; Su, M.; Buchwald, S. L. Palladium(0)-Catalyzed
Intermolecular Amination of Unactivated Csp3–H Bonds.
Angew. Chem. Int. Ed. 2011, 50, 8647–8651.
(13) Tan, B.; Bai, L.; Ding, P.; Liu, J.; Wang, Y.; Luan, X.
Palladium-Catalyzed Intermolecular [4+1] Spiroannulation by
C(sp3)–H Activation and Naphthol Dearomatization. Angew.
Chem. Int. Ed. 2019, 58, 1474–1478.
(14) Rocaboy, R.; Anastasiou, I.; Baudoin, O. Redox-Neutral
Coupling between Two C(sp3)–H Bonds Enabled by 1,4-
Palladium Shift for the Synthesis of Fused Heterocycles.
Angew. Chem. Int. Ed. 2019, 58, 14625–14628.
(5) Giri, R.; Wasa, M.; Breazzano, S. P.; Yu, J.-Q. Converting
gem-Dimethyl Groups into Cyclopropanes via Pd-Catalyzed
Sequential C−H Activation and Radical Cyclization. Org.
Lett. 2006, 8, 5685–5688.
(6) (a) Liron, F.; Knochel, P. Reactivity of Stable Neopentyl-Pd
Intermediates in the Absence of Nucleophile. Tetrahedron
Lett. 2007, 48, 4943–4946. (b) Kim, H. S.; Gowrisankar, S.;
Kim, S. H.; Kim, J. N. Synthesis of 6-
Oxacyclopropa[a]indene Derivatives Starting from Baylis-
Hillman Adducts via Pd-Mediated C(sp3)–H Activation.
Tetrahedron Lett. 2008, 49, 3858–3861. (c) Huang, Q.;
Larock, R. C. Synthesis of Cyclopropanes by Pd-Catalyzed
Activation of Alkyl C–H Bonds. Tetrahedron Lett. 2009, 50,
7235–7238. (d) Mao, J.; Zhang, S.-Q.; Shi, B.-F.; Bao, W.
(15) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.; Peglion,
J.-L.; Clot, E.; Baudoin, O. Synthesis of Benzocyclobutenes
by Palladium-Catalyzed C–H Activation of Methyl Groups:
Method and Mechanistic Study. J. Am. Chem. Soc. 2008, 130,
15157–15166.
(16) Gutiérrez-Bonet, Á.; Juliá-Hernández, F.; de Luis, B.; Martin,
R. Pd-Catalyzed C(sp3)–H Functionalization/Carbenoid
Insertion: All Carbon Quaternary Centers via Multiple C–C
Bond Formation. J. Am. Chem. Soc. 2016, 138, 6384–6387.
(17) (a) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. High-Yielding
Palladium-Catalyzed Intramolecular Alkane Arylation:ꢀ
Reaction Development and Mechanistic Studies. J. Am.
Chem. Soc. 2007, 129, 14570–14571. (b) Kefalidis, C. E.;
Baudoin, O.; Clot, E. DFT Study of the Mechanism of
Benzocyclobutene Formation by Palladium-Catalysed C(sp3)–
H Activation: Role of the Nature of the Base and the
Phosphine. Dalton Trans. 2010, 39, 10528–10535. (c)
Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K.
Investigation of the Mechanism of C(sp3)–H Bond Cleavage
in Pd(0)-Catalyzed Intramolecular Alkane Arylation Adjacent
to Amides and Sulfonamides. J. Am. Chem. Soc. 2010, 132,
10692–10705. (d) Rousseaux, R.; Davi, M.; Sofack-Kreutzer,
J.; Pierre, C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin,
O. Intramolecular Palladium-Catalyzed Alkane C–H
Arylation from Aryl Chlorides. J. Am. Chem. Soc. 2010, 132,
10706–10716. (e) Kefalidis, C. E.; Davi, M.; Holstein, P. M.;
Clot, E.; Baudoin, O. Mechanistic Study on the Selectivity of
Olefin versus Cyclobutene Formation by Palladium(0)-
Palladium(0)-Catalyzed
Cyclopropanation
of
Benzyl
Bromides via C(sp3)–H Bond Activation. Chem. Commun.
2014, 50, 3692–3694. (e) Du, W.; Gu, Q.; Li, Z.; Yang, D.
Palladium(II)-Catalyzed
Intramolecular
Tandem
Aminoalkylation via Divergent C(sp3)–H Functionalization. J.
Am. Chem. Soc. 2015, 137, 1130–1135. (f) Chung, D. S.; Lee,
J. S.; Ryu, H.; Park, J.; Kim, H.; Lee, J. H.; Kim, U B.; Lee,
W. K.; Baik, M.-H.; Lee, S.-g. Palladium-Catalyzed
Divergent Cyclopropanation by Regioselective Solvent-
Driven C(sp3)–H Bond Activation. Angew. Chem. Int. Ed.
2018, 57, 15460–15464.
(7) For the construction of cyclopropanes via C–C activation and
C(sp3)–H activation: Cao, J.; Chen, L.; Sun, F.-N.; Sun, Y.-L.;
Jiang, K.-Z.; Yang, K.-F.; Xu, Z.; Xu, L.-W. Pd-Catalyzed
Enantioselective
Cylopropanation of Cyclobutanones. Angew. Chem. Int. Ed.
2019, 58, 897–901.
Ring
Opening/Cross-Coupling
and
(8) (a) Ma, S.; Gu, Z. 1,4‐Migration of Rhodium and Palladium
in Catalytic Organometallic Reactions. Angew. Chem. Int. Ed.
2005, 44, 7512–7517. (b) Shi, F.; Larock, R. C. Remote C–H
Activation via Through-Space Palladium and Rhodium
Migrations. Top. Curr. Chem. 2010, 292, 123–164. (c)
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Page 9 of 10
Journal of the American Chemical Society
Catalyzed Intramolecular C(sp3)–H Activation. J. Org. Chem.
2014, 79, 11903–11910.
(23) 1-Aryl cyclopropane-fused -lactones: (a) Shuto, S.; Ono, S.;
Hase, Y.; Kamiyama, N.; Matsuda, A. Synthesis of (+)- and
(−)-milnaciprans and their conformationally restricted
analogs. Tetrahedron Lett. 1996, 37, 641–644. (b) Doyle, M.
P.; Hu, W. A New Enantioselective Synthesis of Milnacipran
and an Analogue by Catalytic Asymmetric Cyclopropanation.
Adv. Synth. Catal. 2001, 343, 299–302.
(24) 1-Aryl cyclopropane-fused -lactams: Wang, K.-B.; Ran, R.-
Q.; Xiu, S.-D.; Li, C.-Y. Synthesis of 3-Aza-
bicyclo[3.1.0]hexan-2-one Derivatives via Gold-Catalyzed
Oxidative Cyclopropanation of N-Allylynamides. Org. Lett.
2013, 15, 2374–2377.
1
2
3
4
5
6
7
8
(18) (a) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M.
J. Palladium-Catalysed C–H Activation of Aliphatic Amines
to Give Strained Nitrogen Heterocycles. Nature 2014, 510,
129–133. (b) He, C.; Gaunt, M. J. Ligand-Enabled Catalytic
C–H Arylation of Aliphatic Amines by a Four-Membered-
Ring Cyclopalladation Pathway. Angew. Chem., Int. Ed.
2015, 54, 15840-15844. (c) Su, B.; Bunescu, A.; Qiu, Y.;
Zuend, S. J.; Ernst, M.; Hartwig, J. F. Palladium-Catalyzed
Oxidation of β‐C(sp3)−H Bonds of Primary Alkylamines
through a Rare Four-Membered Palladacycle Intermediate. J.
Am. Chem. Soc. 2020, 142, 7912–7919.
9
(25) Pedroni,
J.;
Cramer,
N.
Enantioselective
C−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
(19) Gutiérrez, E.; Nicasio, M. C.; Paneque,; M.; Ruiz, C.; Salazar,
V. Synthesis and Reactivity of New Palladium Alkyl
Complexes Containing PMe3 Ligands: Insertion Reactions
and Formation of Bis(pyrazolyl)borate Derivatives J.
Organomet. Chem. 1997, 549, 167–176.
(20) Cámpora, J.; López, J. A.; Palma, P.; del Rio, D.; Carmona,
E.; Valerga, P.; Graiff, C.; Tiripicchio, A. Synthesis and
Insertion Reactions of the Cyclometalated Palladium–Alkyl
Functionalization−Addition Sequence Delivers Densely
Substituted 3‑Azabicyclo[3.1.0]hexanes. J. Am. Chem. Soc.
2017, 139, 12398−12401.
(26) Zhang, Z.-Z.; Han, Y.-Q.; Zhan, B.-B.; Wang, S.; Shi, B.-F.
Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt-Catalyzed
Multiple C(sp3)–H Activation Strategy. Angew. Chem. Int.
Ed. 2017, 56, 13145–13149.
(27) Yoshida, Y.; Naoe, Y.; Terauchi, T. ; Ozaki, F. ; Doko, T. ;
Takemura, A.; Tanaka, T.; Sorimachi, K.; Beuckmann, C. T.;
Suzuki, M.; Ueno, T.; Ozaki, S.; Yonaga, M. Discovery of
(1R,2S)‐2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-
fluorophenyl)‐N‐(5-fluoropyridin-2-yl)cyclopropanecarboxam
ide (E2006): A Potent and Efficacious Oral Orexin Receptor
Antagonist. J. Med. Chem. 2015, 58, 4648–4664.
(28) Gao, R.; Fan, R.; Canney, D. J. Synthesis of β,β-Disubstituted
γ-Butyrolactones by Chemoselective Oxidation of 1,4-Diols
and γ-Hydroxy Olefins with RuCl3/NaIO4. Synlett 2015, 26,
661–665.
(29) Li, G.; Ji, C.-L.; Hong, X. ; Szostak, M. Highly
Chemoselective, Transition-Metal-Free Transamidation of
Unactivated Amides and Direct Amidation of Alkyl Esters by
N–C/O–C Cleavage. J. Am. Chem. Soc. 2019, 141, 11161–
11172.
Complexes Pd(CH2CMe2-o-C6H4)L2. Observation of
a
Pentacoordinated Intermediate in the Insertion of SO2. Inorg.
Chem. 2001, 40, 4116–4126.
(21) The opening of five-membered palladacycle C1 under
carbonate-mediated conditions was indirectly observed
through the formation BCB isomers and deuterium
incorporation on the aryl ring.15
(22) 2-Aryl cyclopropane-fused -lactones: (a) Milewska, M. J.;
Gdaniec, M.; Polonski, T. Synthesis, Stereochemistry, and
Chiroptical Spectra of Cyclopropyl Lactones and
Thionolactones. Tetrahedron Asymmetry 1996, 7, 3169–3180.
(b) Muraoka, O.; Tanabe, G.; Momose, T. Accentuation of the
Di-p-Methane Reactivity by Central Carbon Substitution in
the 4-(Phenylmethyl)-2(5H)-furanone. Heterocycles 1990,
31,1589–1592.
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R1 R2
R3
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H H
1
2
3
R1
R2
R3
Pd(PPh3)4 cat., KOPiv
4
5
6
toluene/DMSO, 120-140 °C
X
X = Br or OTf
31 examples
45-92%
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TOC graphic
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