Nickel-Catalyzed Reductive Carboxylation of Cyclopropyl Motifs with Carbon Dioxide

Article abstract of DOI:10.1055/s-0035-1560439

A nickel-catalyzed reductive carboxylation technique for the synthesis of cyclopropanecarboxylic acids has been developed. This user-friendly and mild transformation operates at atmospheric pressure of carbon dioxide and utilizes either organic halides or alkene precursors, thus representing the first example of catalytic reductive carboxylation of secondary counterparts lacking adjacent π-components.

Full text of DOI:10.1055/s-0035-1560439

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
T. Moragas, R. Martin
Paper
Synthesis
Nickel-Catalyzed Reductive Carboxylation of Cyclopropyl Motifs
with Carbon Dioxide
Toni Moragasa
Ruben Martin*a,b
N
N
R1 R2
R1 R2
R1 R2
Ni catalyst, Cy3P
hydride source
n-Hex
n-Hex
Ni catalyst
a Institute of Chemical Research of Catalonia (ICIQ), The
Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona, Catalonia, Spain
b Catalan Institution for Research and Advanced Studies
(ICREA), Passeig Lluïs Companys 23, 08010 Barcelona,
Catalonia, Spain
R3
Br
R3
CO2H
CO2 (1 atm)
CO2 (1 atm)
14 examples
up to 79% yield
6 examples
up to 50% yield
rmartinromo@iciq.es
Received: 09.03.2016
Accepted: 13.03.2016
Published online: 11.04.2016
DOI: 10.1055/s-0035-1560439; Art ID: ss-2016-z0171-op
ers,4 we5 and others6 have recently developed a series of
metal-catalyzed reductive carboxylation techniques using
organic (pseudo)halides as precursors. While it might be ar-
gued that this field has already reached its full potential, a
close look at the developed protocols indicates otherwise.
Specifically, while the carboxylation of primary organic
(pseudo)halides poses no problems,5d the extension to sec-
ondary or tertiary motifs is rather problematic, and a solu-
tion to this challenge still remains elusive. At present, the
catalytic carboxylation of secondary or tertiary organic
(pseudo)halides remains limited to substrates containing
adjacent π-components such as alkenes,5c alkynes6d or aro-
matic motifs.5e,g,6a,b,e,f Challenged by such a perception, we
wondered whether the ring strain and orbital rehybridiza-
tion of cyclopropyl rings7 might facilitate the targeted car-
boxylation event of secondary cyclopropyl scaffolds, repre-
senting a new access to cyclopropanecarboxylic acids, a
scaffold that is particularly prevalent in natural products
and medicinally important compounds (Scheme 1).8 Here-
in, we describe the successful realization of this concept.
This transformation is distinguished by its mild reaction
conditions and by operating at atmospheric pressure of car-
bon dioxide, thus constituting a powerful alternative to ex-
isting methodologies for preparing cyclopropane-derived
carboxylic acids. Interestingly, a different stereoselectivity
profile was found when either organic halides or cyclopro-
penes were employed.
Abstract A nickel-catalyzed reductive carboxylation technique for the
synthesis of cyclopropanecarboxylic acids has been developed. This
user-friendly and mild transformation operates at atmospheric pressure
of carbon dioxide and utilizes either organic halides or alkene precur-
sors, thus representing the first example of catalytic reductive carboxyl-
ation of secondary counterparts lacking adjacent π-components.
Key words nickel, carboxylation, cross-coupling, carbon dioxide, ca-
talysis
Over the past few years, metal-catalyzed cross-electro-
phile coupling reactions of organic halides have become
powerful alternatives to the well-established cross-cou-
pling reactions based on nucleophilic/electrophilic re-
gimes.1 Although remarkable levels of sophistication have
been reached, the vast majority of these transformations
rely on the utilization of homogeneous precursors such as
carbonyl compounds or organic halides, among others.1 In-
deed, the employment of heterogeneous coupling partners
in these endeavors remains rather unexplored, constituting
an opportunity to increase the applicability of these pro-
cesses. In this context, the design of cross-electrophile cou-
pling reactions based on the utilization of abundant and
nontoxic carbon dioxide, probably the greenest C1 source in
nature,2 represents a unique strategy to explore the ability
to convert simple precursors into carboxylic acids, mole-
cules of utmost relevance in a wide variety of molecules
that display significant biological activities.3 Unfortunately,
the thermodynamic stability and kinetic inertness of car-
bon dioxide constitute serious drawbacks to be overcome
when designing catalytic processes.2 Driven by the seminal
stoichiometric studies reported by Osakada and co-work-
O
CO2H
Me Me
HN
HO2C
O
HO2C
CO2H
CO2H
Et
NH2
Me
Me
Me
insecticide
phytotoxin
antidepressant
Scheme 1 Representative cyclopropanecarboxylic acids of interest
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
T. Moragas, R. Martin
Paper
Synthesis
We started our investigations with bromide 1a as model
substrate (Table 1). After systematic evaluation of all
reaction parameters, we found that a combination of
NiBr2·glyme (10 mol%), ligand L3 (26 mol%), manganese as
reducing agent and lithium chloride as additive in DMA at
30 °C delivered 2a in 77% isolated yield. Interestingly, a sig-
nificant erosion in the yield was observed when the target-
ed reaction was conducted at higher temperatures (Table 1,
entry 2), with ring-opened product 3a obtained preferen-
tially.9 Precatalysts other than NiBr2·glyme resulted in a
lower efficiency (Table 1, entries 3 and 4). In contrast with
other catalytic carboxylation techniques,5b,d,e the presence
of COD did not significantly inhibit the formation of 2a (Ta-
ble 1, entry 3). Although DMF provided nearly identical re-
sults as DMA (Table 1, entry 6), further studies demonstrat-
ed the superior activity of DMF for less activated substrates.
In line with our expectations, the utilization of MeCN,
DMSO or the inclusion of zinc as reducing agent resulted in
negligible amounts of 2a (Table 1, entries 5 and 7). Al-
though it might be argued that similar yields were found in
the presence or absence of LiCl (Table 1, entries 1 and 8), its
presence was crucial for avoiding the formation of 3a. At
present we do not have an explanation for such an observa-
tion. In line with other reductive carboxylation tech-
niques,5,6 the nature of the ligand backbone exerted a pro-
found influence on the reaction outcome. Specifically, we
found that while phosphine ligands or bipyridines resulted
in lower yields of 2a (Table 1, entries 14 and 15), phenanth-
roline backbones were perfectly suited for our purposes
(entries 10–13). Furthermore, a subtle balance of electronic
and steric effects was critical for success, with ligands pos-
sessing ortho alkyl motifs and lacking substituents at the
para positions providing the best results (Table 1, entries 1
and 11 vs 10, 12 and 13). Control experiments revealed that
all of the critical reaction parameters [Ni(II) precatalyst, L3
and Mn] were essential for the reaction.
With our optimized conditions in hand, we next turned
our attention to exploring the generality of our nickel-cata-
lyzed reductive carboxylation of cyclopropyl bromides, pre-
cursors that are readily available in multigram quantities
from known literature procedures. As shown for 1c–h, cy-
clopropyl backbones containing alkyl substituents provided
similar reactivities to 1a, resulting in moderate to good
yields of the targeted carboxylic acids 2c–h (Scheme 2). It is
worth noting, however, that the presence of an aromatic
substituent is required for the reaction to occur, as cyclo-
propyl backbones exclusively containing alkyl residues,
such as 1n, failed to react. Likewise, we found that other-
wise related cyclobutyl rings did not deliver the expected
carboxylic acid 2o; while tentative, we believe that the sp2-
like character associated with cyclopropyl rings might be
critical,7 thus allowing for a greater interaction with the
Table 1 Screening of the Reaction Conditionsa
NiBr2·glyme (10 mol%)
Ph Ph
Ph Ph
Ph
Ph
L3 (26 mol%)
LiCl, Mn
Br
CO2H
CO2 (1 atm)
CO2H
1a
2a
3a
DMA, 30 °C
not observed
Entry
1
Deviation from standard conditions
2a (%)b
89,77c
16
None
2
At 60 °C
3
Ni(cod)2 (10 mol%) as catalyst
Ni(OTf)2 (10 mol%) as catalyst
MeCN (DMSO) as solvent
DMF as solvent
75
N
N
4
R1
R2
R1
R1
59
L1 (R1 = H)
L2 (R1 = Me)
L3 (R1 = n-Hex)
5
2(17)
89
6
7
Zn as reductant
11
R2
8
No LiCl was added
Using 10% of L3
80
9
81
10
11
12
13
14
15
16
Using L1 as ligand
Using L2 as ligand
Using L4 as ligand
Using L5 as ligand
Using L6 as ligand
Using Cy3P as ligand
No NiBr2·glyme or Mn
N
N
13
R1
84
L4 (R1 = Me; R2 = Ph)
L5 (R1 = n-Bu; R2 = Me)
58
47
26
1
N
N
0
Me
Me
L6
a Reaction conditions: 1a (0.20 mmol), NiBr2·glyme (10 mol%), L3 (26
mol%), LiCl (0.80 mmol), Mn (0.52 mmol), CO2 (1 atm), DMA (0.40 M),
30 °C, 40 h.
b HPLC yields using anisole as internal standard.
c Isolated yield.
nickel precatalyst and enhancing the corresponding carbox-
ylation event. Interestingly, the reaction could be extended
to monosubstituted cyclopropyl bromides 1i–m; in all cas-
es, the desired products were obtained in good yields. Nota-
bly, these reaction conditions tolerated backbones contain-
ing a fluoride (2f), chloride (2g), methyl ether (2b, 2j and
2k) or acetal (2m) group, residues that are known to partic-
ipate in nickel-catalyzed cross-coupling reactions.10 Grati-
fyingly, the reaction could also be extended to trisubstitut-
ed cyclopropyl bromides, as the reaction with 1p yielded
the desired product 2p in 70% isolated yield. It is worth
mentioning that all unsymmetrically substituted cyclopro-
panecarboxylic acids illustrated in Scheme 2 were obtained
as cis/trans mixtures. In all cases analyzed, the major iso-
mer possessed the aromatic ring and the carboxylic acid in
a trans configuration, an observation that is in line with
other carbometalations of cyclopropyl analogues.11 Impor-
tantly, the cis/trans ratios observed do not correlate well to
the ratios of the starting cyclopropyl bromides, suggesting
that radical intermediates might come into play. Such an as-
sumption was further corroborated by the reactions of dia-
stereomerically pure trans-1c and cis-1c; invariably, 2c was
obtained with an identical cis/trans ratio, albeit in different
yields (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
T. Moragas, R. Martin
Paper
Synthesis
sulted in an 85% yield of 2a, no reaction occurred in the ab-
sence of manganese (Scheme 4). Whether this result indi-
cates the intermediacy of nickel(I) intermediates13 or other
mechanistic scenarios is a matter of ongoing studies in our
laboratories.14
R1 R2
R1 R2
R1
R2
NiBr2·glyme (10 mol%)
L3 (26 mol%)
R3
R3
Br
R3
CO2H
LiCl, Mn
CO2 (1 atm)
CO2H
1a–p
2a–p
3a–p
DMA, 30 °C
not observed
Ph Ph
p-MeOC6H4 Ph
Ph Me
CO2H
CO2H
CO2H
CO2H
79% (2a)
Me
54% (2b)c
75% (2c)d
73% (2d)d
F
Cl
Me
Me
Me
Me
63% (2h)e
H
Scheme 4 Stoichiometric experiments with 4
CO2H
CO2H
CO2H
CO2H
While the successful preparation of cyclopropanecar-
boxylic acids (Scheme 2) represented the first catalytic re-
ductive carboxylation of secondary organic halides lacking
adjacent π-components, the poor stereoselectivity found
reinforced a change in strategy. To such end, we wondered
whether the use of otherwise related cyclopropenes could
promote an analogous hydrocarboxylation event with a
higher stereoselectivity profile.15 After considerable experi-
mentation, we found that a Ni(cod)2/Cy3P regime based on
the employment of Et3Al or Me2PhSiH as hydride sources
provided the best results (Scheme 5). While moderate
yields were generally observed, it is worth noting that the
corresponding products 2c,d were obtained as single dia-
stereoisomers. Although careful NMR spectroscopy re-
vealed that the compounds possess a trans configuration,
the structure of 2d was unequivocally established by X-ray
crystallographic analysis. While the intermediacy of well-
defined nickel hydride intermediates might be invoked with
a protocol based on Me2PhSiH,16 the successful utilization of
Et3Al in these hydrocarboxylation events might suggest the
intermediacy of nickelalactones followed by a subsequent
transmetalation/β-hydride elimination event.17,18
In conclusion, a new nickel-catalyzed reductive carbox-
ylation protocol for the synthesis of cyclopropanecarboxylic
acids has been developed using carbon dioxide as C1 syn-
thon. This user-friendly methodology is characterized by its
mild conditions at atmospheric pressure of carbon dioxide.
This work represents the first time that a catalytic reductive
carboxylation of secondary organic halides can be conduct-
ed in the absence of adjacent π-components. While poor
stereoselectivities were found when utilizing organic halide
counterparts, the employment of otherwise related cyclo-
propenes resulted in single diastereoisomers. Current in-
vestigations are focused on extending the scope of these re-
actions and unraveling the origin of the stereoselectivity
found with the cyclopropene analogues.
59% (2e)d
71% (2f)c
50% (2g)c
MeO
H
H
H
MeO
CO2H
CO2H
60% (2j)g
CO2H
CO2H
47% (2k)g
70% (2i)f
68% (2l)h
O
Ph
O
CO2H
H
H
Ph
Me
Ph
CO2H
CO2H
0% (2n)
CO2H
54% (2m)i
70% (2p)j
0% (2o)
Scheme 2 Carboxylation of cyclopropyl bromides.a,b a Reagents and
conditions: 1a–p (0.20 mmol), NiBr2·glyme (10 mol%), L3 (26 mol%),
LiCl (0.80 mmol), Mn (0.52 mmol), CO2 (1 atm), DMA (0.40 M), 30 °C,
48 h; b Isolated yields, average of at least two independent runs;
c dr = 1.4:1; d dr = 1.7:1; e dr = 1.5:1; f dr = 5:1; g dr = 3.3:1; h dr = 4.3:1;
i dr = 3.6:1; j dr = 1.1:1.
Ph Me
Ph Me
Ph Me
as Scheme 2
75% yield
as Scheme 2
55% yield
Br
trans-1c
CO2H
2c (dr = 1.7:1)
Br
cis-1c
Scheme 3 Catalytic carboxylation of trans-1c and cis-1c
Next, we focused our attention on studying the reactivi-
ty of the putative Ni(0)L2 intermediates. While the isolation
of complexes based on L3 proved particularly cumbersome,
we turned our efforts to the synthesis of Ni(0)(L2)2 (4)5c,12
as L2 provided an otherwise analogous reactivity to that
observed for L3 (Table 1, entry 11). In line with our expec-
tations, 4 was found to be competent as precatalyst, deliver-
ing 2a in 66% yield. Stoichiometric experiments revealed
that while the presence of 2 equivalents of manganese re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
T. Moragas, R. Martin
Paper
Synthesis
CH2Cl2. The combined organic layers were dried over MgSO4 and con-
centrated under reduced pressure. The products were purified by
flash chromatography (hexanes–EtOAc).
2,2-Diphenylcyclopropanecarboxylic Acid (2a)
Following the general procedure using 1a (54.6 mg) gave 2a as a pale
yellow solid; yield: 36.7 mg (77%); mp 167–169 °C.
IR (CDCl3): 3027, 1702, 1446, 1221, 903 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.34 (m, 2 H), 7.32–7.14 (m, 8 H),
2.53 (dd, J = 8.0, 5.9 Hz, 1 H), 2.14 (dd, J = 5.9, 4.8 Hz, 1 H), 1.69 (dd,
J = 8.1, 4.8 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 176.6, 144.7, 139.9, 129.9, 129.7,
128.7, 128.6, 128.5, 127.7, 127.2, 126.8, 41.2, 28.7, 20.9.
The spectroscopic data for 2a match those previously reported in the
Scheme 5 Hydrocarboxylation of cyclopropenes 5. Reagents and condi-
tions: A) 5a,c,d (0.20 mmol), Ni(cod)2 (10 mol%), Cy3P (20 mol%), Et3Al
(0.30 mmol), CO2 (1 atm), DMA (0.40 M), 30 °C, 40 h; B) 5a,c,d (0.20
mmol), Ni(cod)2 (10 mol%), Cy3P (20 mol%), MgF2 (0.40 mmol),
Me2PhSiH (0.30 mmol), CO2 (1 atm), DMA (0.40 M), 30 °C, 40 h.
literature.19
2-(4-Methoxyphenyl)-2-phenylcyclopropanecarboxylic Acid (2b)
Following the general procedure using 1b (60.6 mg) gave 2b as a pale
yellow solid; yield: 28.3 mg (53%); trans/cis = 1.4:1.
IR (CDCl3): 2954, 2929, 1698, 1511, 1245, 1176 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.32 (m, 2 H), 7.31–7.17 (m,
10.11 H), 6.86–6.77 (m, 3.46 H), 3.81 (s, 2.21 H), 3.78 (s, 3 H), 2.49
(ddd, J = 14.0, 8.0, 5.9 Hz, 1.73 H), 2.11 (dd, J = 5.9, 4.8 Hz, 1.73 H),
1.79–1.57 (m, 1.73 H).
13C NMR (101 MHz, CDCl3): δ = 176.4, 158.6, 158.4, 145.1, 140.3,
137.0, 132.0, 130.7, 129.5, 128.9, 128.6, 128.5, 127.6, 127.1, 126.7,
114.0, 114.0, 55.4, 55.3, 40.7, 40.4, 28.8, 28.6, 21.1, 20.8.
Commercially available materials were used without further purifica-
tion. Nickel(II) bromide–ethylene glycol dimethyl ether complex
(NiBr2·glyme) and manganese powder (99.99% trace metal basis)
were purchased from Aldrich. Anhydrous N,N-dimethylacetamide
(DMA, 99.8% purity) was purchased from Acros Organics. Bis(1,5-cy-
clooctadiene)nickel(0) [Ni(cod)2, 98%+ purity] and tricyclohexylphos-
phine (Cy3P) were obtained from Strem. 1H and 13C NMR spectra were
recorded on Bruker 400 MHz and 500 MHz instruments at 20 °C. All
1H NMR data are reported in parts per million (ppm) downfield of
TMS and were measured relative to the signals for CHCl3 (7.26 ppm)
or TMS (0.00 ppm). All 13C NMR spectra are reported in ppm relative
to residual CHCl3 (77.16 ppm), and were obtained with 1H decoupling.
Coupling constants, J, are reported in Hertz. Melting points were mea-
sured using open glass capillaries in a Büchi B540 apparatus. Infrared
spectra were recorded on a Bruker Tensor 27 spectrometer. Mass
spectra were recorded on a Waters LCT Premier spectrometer. High-
pressure liquid chromatography (HPLC) was performed on an Agilent
Technologies Model 1260 Infinity HPLC instrument equipped with an
Agilent Eclipse Plus C18 column (3.5 μm, 4.6 × 100 mm) and UV/vis
detector. Flash chromatography was performed with EM Science sili-
ca gel 60 (230–400 mesh) and using Hanessian’s stain or potassium
permanganate as TLC stain. The yields reported in Schemes 2 and 5
refer to isolated yields and represent an average of at least two inde-
pendent runs.
MS (ESI–): m/z = 267 [M – H].
HRMS: m/z calcd for C17H15O3: 267.1027; found: 267.1030.
2-Methyl-2-phenylcyclopropanecarboxylic Acid (2c)
Following the general procedure using 1c (42.2 mg) gave 2c as a pale
yellow oil; yield: 26.8 mg (76%); trans/cis = 1.7:1.
IR (CDCl3): 2958, 2928, 1695, 1443, 1427, 1224 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.49–7.11 (m, 7.95 H), 2.00 (dd, J = 8.1,
6.1 Hz, 1 H), 1.95 (dd, J = 7.7, 5.4 Hz, 0.59 H), 1.80 (t, J = 5.1 Hz, 0.59
H), 1.59 (s, 3 H), 1.55–1.45 (m, 3.59 H), 1.27 (dd, J = 7.7, 4.6 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 178.8, 177.7, 145.6, 141.3, 128.7,
128.5, 128.3, 128.3, 127.4, 126.8, 126.7, 125.8, 33.5, 32.1, 28.7, 28.1,
27.5, 21.5, 20.6, 20.1.
MS (ESI–): m/z = 175 [M – H].
HRMS: m/z calcd for C11H11O2: 175.0765; found: 175.0768.
3′,4′-Dihydro-2′H-spiro[cyclopropane-1,1′-naphthalene]-2-car-
boxylic Acid (2d)
Nickel-Catalyzed Carboxylation of Cyclopropyl Bromides 1
(Scheme 2); General Procedure
Following the general procedure using 1d (47.4 mg) gave 2d as a pale
yellow solid; yield: 30.8 mg (76%); trans/cis = 1.7:1.
An oven-dried Schlenk tube containing a stirring bar was charged
with NiBr2·glyme (0.02 mmol, 10 mol%), L3 (0.05 mmol, 26 mol%), Mn
(0.52 mmol, 2.60 equiv) and LiCl (0.80 mmol, 4 equiv). The Schlenk
tube was evacuated and backfilled under CO2 flow (this procedure
was repeated three times). Anhydrous DMA (0.50 mL) and the corre-
sponding cyclopropyl bromide 1 (0.20 mmol, 1 equiv) were then add-
ed under CO2 flow. The Schlenk tube was next closed at atmospheric
pressure of CO2 (1 atm) and the mixture was stirred for 48 h. The mix-
ture was then carefully quenched with 2 M HCl to hydrolyze the re-
sulting carboxylate, and extracted several times with EtOAc and
IR (CDCl3): 2929, 2861, 1690, 1430, 1224 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–6.99 (m, 5 H), 6.76–6.62 (m, 1 H),
2.94–2.90 (m, 0.59 H), 2.89 (t, J = 6.3 Hz, 2 H), 2.16–2.09 (m, 6.24 H),
2.08–1.73 (m, 6.24 H), 1.67 (dd, J = 8.3, 5.4 Hz, 1 H), 1.57 (dd, J = 6.5,
5.2 Hz, 1 H), 1.32 (dd, J = 7.9, 5.5 Hz, 0.59 H), 1.30–1.19 (m, 0.59 H).
13C NMR (101 MHz, CDCl3): δ = 177.5, 176.2, 139.2, 139.1, 138.1,
134.1, 129.3, 128.5, 126.7, 126.4, 126.1, 124.8, 121.9, 35.9, 33.5, 32.2,
32.0, 30.6, 30.4, 29.5, 27.8, 23.3, 22.3, 22.0, 18.6.
MS (ESI–): m/z = 201 [M – H].
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T. Moragas, R. Martin
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Synthesis
HRMS: m/z calcd for C13H13O2: 201.0921; found: 201.0923.
2-Methyl-2-(p-tolyl)cyclopropanecarboxylic Acid (2e)
13C NMR (126 MHz, CDCl3): δ = 178.4, 177.2, 143.1, 139.0, 133.6,
133.5, 132.6, 132.4, 128.4, 128.1, 127.9, 127.8, 127.7, 127.5, 127.0,
126.4, 126.1, 126.0, 125.9, 125.7, 33.7, 32.4, 28.9, 28.3, 27.5, 21.6,
20.9, 20.3.
Following the general procedure using 1e (45.0 mg) gave 2e as a pale
yellow oil; yield: 21.7 mg (57%); trans/cis = 1.7:1.
MS (ESI–): m/z = 225 [M – H].
IR (CDCl3): 2958, 2926, 1695, 1445, 1429, 1223 cm–1
.
HRMS: m/z calcd for C15H13O2: 225.0921; found: 225.0924.
1H NMR (400 MHz, CDCl3): δ = 7.21–7.16 (m, 3.25 H), 7.14–7.02 (m,
3.28 H), 2.33 (s, 3 H), 2.32 (s, 1.88 H), 1.97–1.86 (m, 1.63 H), 1.75 (t,
J = 5.0 Hz, 0.63 H), 1.55 (s, 3 H), 1.52–1.40 (m, 3.82 H), 1.22 (dd, J = 7.7,
4.6 Hz, 0.63 H).
2-Phenylcyclopropanecarboxylic Acid (2i)
Following the general procedure using 1i (39.4 mg) gave 2i as a pale
yellow oil; yield: 22.8 mg (70%); trans/cis = 5.0:1.
13C NMR (101 MHz, CDCl3): δ = 178.5, 177.2, 142.8, 138.5, 136.4,
129.3, 129.2, 128.6, 127.4, 33.3, 31.9, 29.0, 28.2, 27.6, 21.6, 21.3, 21.1,
20.7, 20.3.
IR (CDCl3): 3029, 2927, 1689, 1445, 1231 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.27 (m, 2.98 H), 7.27–7.20 (m,
1.25 H), 7.17–7.10 (m, 1.94 H), 2.70 (td, J = 9.0, 7.8 Hz, 0.20 H), 2.62
(ddd, J = 9.3, 6.7, 4.1 Hz, 1 H), 2.13 (ddd, J = 9.2, 7.7, 5.6 Hz, 0.20 H),
1.93 (ddd, J = 8.4, 5.2, 4.1 Hz, 1 H), 1.76 (dt, J = 7.8, 5.3 Hz, 0.20 H),
1.68 (dt, J = 9.5, 4.9 Hz, 1 H), 1.45–1.40 (m, 1.20 H).
MS (ESI–): m/z = 189 [M – H].
HRMS: m/z calcd for C12H13O2: 189.0921; found: 189.0924.
13C NMR (101 MHz, CDCl3): δ = 179.6, 139.7, 136.0, 129.4, 128.7,
128.1, 127.0, 126.8, 126.4, 27.2, 26.8, 24.1, 21.6, 17.6, 12.3.
2-(4-Fluorophenyl)-2-methylcyclopropanecarboxylic Acid (2f)
Following the general procedure using 1f (45.8 mg) gave 2f as a pale
yellow oil; yield: 30.3 mg (78%); trans/cis = 1.4:1.
The spectroscopic data for 2i match those previously reported in the
literature.20
IR (CDCl3): 2958, 2928, 1697, 1512, 1429, 1220 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (m, 3.56 H), 7.09–6.94 (m,
3.28 H), 1.97–1.87 (m, 1.7 H), 1.76 (t, J = 5.1 Hz, 0.70 H), 1.56 (s, 3 H),
1.51–1.44 (m, 4.10 H), 1.26 (dd, J = 7.7, 4.7 Hz, 0.70 H).
13C NMR (101 MHz, CDCl3): δ = 178.4, 177.4, 161.8 (d, J = 244.8 Hz),
161.7 (d, J = 245.2 Hz), 141.5 (d, J = 3.2 Hz), 137.2 (d, J = 3.2 Hz), 130.3
(d, J = 8.0 Hz), 129.2 (d, J = 8.0 Hz), 115.4 (d, J = 21.5 Hz), 115.3 (d,
J = 21.3 Hz), 32.8, 31.6, 28.8, 28.3, 27.6, 21.5, 20.8, 20.5.
2-(4-Methoxyphenyl)cyclopropanecarboxylic Acid (2j)
Following the general procedure using 1j (45.4 mg) gave 2j as a pale
yellow solid; yield: 22.9 mg (60%); trans/cis = 3.3:1.
IR (CDCl3): 2955, 2931, 1694, 1516, 1456, 1249 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 8.2 Hz, 0.62 H), 7.06 (d,
J = 8.6 Hz, 2 H), 6.88–6.75 (m, 2.62 H), 3.81 (s, 3.93 H), 2.69–2.61 (m,
0.31 H), 2.57 (ddd, J = 9.2, 6.8, 4.2 Hz, 1 H), 2.08 (ddd, J = 9.2, 7.9, 5.6
Hz, 0.31 H), 1.83 (ddd, J = 8.3, 5.1, 4.0 Hz, 1 H), 1.69 (dt, J = 7.7, 5.3 Hz,
0.31 H), 1.63 (ddd, J = 9.5, 5.2, 4.5 Hz, 1 H), 1.45–1.40 (m, 0.31 H),
1.39–1.33 (m, 1 H).
19F NMR (376 MHz, CDCl3): δ = –116.1.
MS (ESI–): m/z = 193 [M – H].
HRMS: m/z calcd for C11H10FO2: 193.0670; found: 193.0672.
13C NMR (101 MHz, CDCl3): δ = 179.0, 158.5, 158.4, 131.5, 130.3,
127.9, 127.5, 114.0, 113.5, 55.3, 55.2, 26.6, 26.0, 23.5, 21.3, 17.2, 12.2.
2-(4-Chlorophenyl)-2-methylcyclopropanecarboxylic Acid (2g)
Following the general procedure using 1g (49.1 mg) gave 2g as a yel-
low oil; yield: 21.0 mg (50%); trans/cis = 1.4:1.
The spectroscopic data for 2j match those previously reported in the
literature.21
IR (CDCl3): 2960, 2927, 1695, 1495, 1448, 1429 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.17 (m, 6.84 H), 2.05–1.91 (m,
1.71 H), 1.76 (t, J = 5.1 Hz, 0.71 H), 1.56 (s, 3 H), 1.51–1.42 (m, 4.13 H),
1.28–1.25 (m, 0.71 H).
2-(2-Methoxyphenyl)cyclopropanecarboxylic Acid (2k)
Following the general procedure using 1k (45.4 mg) gave 2k as a
white solid; yield: 18.0 mg (47%); trans/cis = 3.3:1.
13C NMR (126 MHz, CDCl3): δ = 178.2, 177.2, 144.2, 140.0, 132.6,
132.6, 130.3, 130.2, 129.0, 128.8, 128.6, 126.4, 32.9, 31.6, 28.6, 28.2,
27.6, 21.5, 20.7, 20.2.
IR (CDCl3): 2928, 1693, 1498, 1459, 1248 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.12 (m, 1.60 H), 6.96–6.72 (m,
3.60 H), 3.85 (s, 3 H), 3.79 (s, 0.90 H), 2.80 (ddd, J = 9.2, 7.0, 4.3 Hz, 1
H), 2.58 (q, J = 8.5 Hz, 0.30 H), 2.18–2.07 (m, 0.30 H), 1.82 (dt, J = 7.8,
4.8 Hz, 1 H), 1.67–1.54 (m, 1.30 H), 1.49–1.33 (m, 1.30 H).
MS (ESI–): m/z = 209 [M – H].
HRMS: m/z calcd for C11H10ClO2: 209.0375; found: 209.0375.
13C NMR (101 MHz, CDCl3): δ = 180.4, 178.1, 158.9, 158.5, 130.5,
128.1, 127.9, 127.9, 126.2, 124.9, 120.5, 120.2, 110.5, 110.0, 55.6, 55.4,
22.7, 22.5, 22.3, 20.7, 16.3, 12.6.
2-Methyl-2-(naphthalen-2-yl)cyclopropanecarboxylic Acid (2h)
Following the general procedure using 1h (52.2 mg) gave 2h as a pale
yellow oil; yield: 28.3 mg (63%); trans/cis = 1.5:1.
The spectroscopic data for 2k match those previously reported in the
literature.21
IR (CDCl3): 2958, 2925, 1690, 1445, 1427, 1218 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.85–7.77 (m, 4.19 H), 7.77–7.68 (m,
2.21 H), 7.52–7.34 (m, 5.13 H), 2.05 (dd, J = 8.1, 6.0 Hz, 1 H), 1.99 (dd,
J = 7.6, 5.4 Hz, 0.65 H), 1.90 (t, J = 5.0 Hz, 0.65 H), 1.63 (s, 3 H), 1.60
(dd, J = 8.3, 4.8 Hz, 1 H), 1.56–1.50 (m, 2.95 H), 1.32 (dd, J = 7.7, 4.6 Hz,
0.65 H).
2-(Naphthalen-2-yl)cyclopropanecarboxylic Acid (2l)
Following the general procedure using 1l (45.4 mg) gave 2l as a yellow
solid; yield: 28.0 mg (66%); trans/cis = 4.3:1.
IR (CDCl3): 3052, 2927, 1690, 1453, 1435, 1231 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
T. Moragas, R. Martin
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.88–7.72 (m, 3.92 H), 7.64–7.57 (m, 1
H), 7.55–7.37 (m, 2.56 H), 7.34–7.14 (m, 1.23 H), 2.90–2.74 (m, 1.23
H), 2.27–2.18 (m, 0.23 H), 2.03 (dt, J = 8.7, 4.7 Hz, 1 H), 1.90 (dt, J = 7.9,
5.4 Hz, 0.23 H), 1.76 (dt, J = 9.5, 4.9 Hz, 1 H), 1.61–1.47 (m, 1.23 H).
13C NMR (101 MHz, CDCl3): δ = 179.5, 137.1, 133.5, 133.4, 132.7,
132.5, 128.4, 128.2, 127.9, 127.8, 127.7, 127.6, 126.5, 126.0, 125.8,
125.7, 125.1, 124.7, 29.9, 27.5, 27.0, 24.0, 17.6, 12.5.
backfilled under CO2 flow (this procedure was repeated three times).
Anhydrous DMA (0.50 mL), the corresponding cyclopropene 5 (0.20
mmol, 1 equiv) and Me2PhSiH (0.30 mmol, 1.5 equiv) were then add-
ed under CO2 flow. The Schlenk tube was next closed at atmospheric
pressure of CO2 (1 atm) and the mixture was stirred for 40 h. The mix-
ture was then carefully quenched with 2 M HCl to hydrolyze the re-
sulting carboxylate, and extracted several times with EtOAc and
CH2Cl2. The combined organic layers were dried over MgSO4 and con-
centrated under reduced pressure. The products were purified by
flash chromatography (hexanes–EtOAc).
MS (ESI–): m/z = 211 [M – H].
HRMS: m/z calcd for C14H11O2: 211.0765; found: 211.0769.
2-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic Acid (2m)
trans-2-Methyl-2-phenylcyclopropanecarboxylic Acid (trans-2c)
Following the general procedure using 1m (48.2 mg) gave 2m as a yel-
low solid; yield: 22.6 mg (55%); trans/cis = 3.6:1.
Following general procedure A using 5c (26.0 mg) gave 2c as a color-
less oil and single stereoisomer; yield: 15.9 mg (45%).
IR (CDCl3): 2924, 1689, 1504, 1442, 1233, 1038 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 4 H), 7.25–7.18 (m, 1 H),
1.99 (dd, J = 8.1, 6.1 Hz, 1 H), 1.58 (s, 3 H), 1.55–1.46 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 178.0, 145.7, 128.7, 127.6, 126.8, 32.2,
1H NMR (400 MHz, CDCl3): δ = 6.85–6.68 (m, 1.77 H), 6.68–6.52 (m,
2.06 H), 5.95 (s, 2.56 H), 2.67–2.49 (m, 1.28 H), 2.16–1.99 (m, 0.28 H),
1.89–1.78 (m, 1 H), 1.74–1.52 (m, 1.28 H), 1.44–1.30 (m, 1.28 H).
27.5, 21.6, 20.3.
13C NMR (126 MHz, CDCl3): δ = 179.4, 176.9, 148.0, 147.4, 146.6,
133.5, 129.9, 122.7, 120.0, 109.9, 108.4, 108.0, 106.9, 101.2, 101.1,
27.2, 26.6, 23.8, 21.5, 17.4, 12.6.
trans-3′,4′-Dihydro-2′H-spiro[cyclopropane-1,1′-naphthalene]-2-
carboxylic Acid (trans-2d)
Following general procedure A using 5d (31.2 mg) gave 2d as a white
MS (ESI–): m/z = 205 [M – H].
solid and single stereoisomer; yield: 14.1 mg (35%); mp 162–164 °C.
HRMS: m/z calcd for C11H9O4: 205.0506; found: 205.0506.
1H NMR (500 MHz, CDCl3): δ = 7.15–7.06 (m, 3 H), 6.81–6.67 (m, 1 H),
2.89 (dd, J = 7.1, 5.6 Hz, 2 H), 2.09–1.95 (m, 3 H), 1.89 (dddd, J = 12.8,
6.5, 5.6, 3.0 Hz, 1 H), 1.81 (dtd, J = 13.2, 7.0, 3.1 Hz, 1 H), 1.68 (dd,
J = 8.1, 5.2 Hz, 1 H), 1.57 (dd, J = 6.5, 5.2 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 176.7, 139.2, 138.2, 129.3, 126.4,
126.1, 121.9, 31.8, 30.6, 30.4, 27.8, 23.3, 22.3.
1-Phenylbicyclo[4.1.0]heptane-7-carboxylic Acid (2p)
Following the general procedure using 1p (50.2 mg) gave 2p as a yel-
low solid; yield: 30.3 mg (70%); trans/cis = 1.1:1.
IR (CDCl3): 2930, 1692, 1446, 1243 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.26 (m, 4.51 H), 7.25–7.18 (m,
3.45 H), 2.32–2.12 (m, 3.62 H), 2.05 (ddd, J = 13.4, 8.4, 6.4 Hz, 0.75 H),
1.96–1.71 (m, 5.57 H), 1.66–1.15 (m, 7.74 H).
13C NMR (101 MHz, CDCl3): δ = 177.9, 177.6, 148.9, 144.0, 128.5,
128.3, 128.2, 127.7, 126.4, 126.3, 38.2, 33.4, 32.8, 31.6, 29.2, 27.5,
26.0, 24.2, 22.7, 21.2, 21.13, 21.1, 21.0, 18.5.
Acknowledgment
We thank ICIQ, the European Research Council (ERC-277883), MINE-
CO (CTQ2012-34054 & Severo Ochoa Excellence Accreditation 2014–
2018, SEV-2013-0319) and the Cellex Foundation for support. John-
son Matthey, Umicore and Nippon Chemical Industrial are acknowl-
edged for a gift of metal and ligand sources. We sincerely thank M.
Martínez for the X-ray crystallographic data.
The spectroscopic data for 2p match those previously reported in the
literature.22
Nickel-Catalyzed Hydrocarboxylation of Cyclopropenes 5 (Scheme
5); General Procedure A
An oven-dried Schlenk tube containing a stirring bar was charged
with Ni(cod)2 (0.02 mmol, 10 mol%) and Cy3P (0.04 mmol, 20 mol%).
The Schlenk tube was evacuated and backfilled under CO2 flow (this
procedure was repeated three times). Anhydrous DMA (0.50 mL), the
corresponding cyclopropene 5 (0.20 mmol, 1 equiv) and a 1 M solu-
tion of Et3Al in hexanes (0.30 mmol, 1.5 equiv) were then added un-
der CO2 flow. The Schlenk tube was next closed at atmospheric pres-
sure of CO2 (1 atm) and the mixture was stirred for 40 h. The mixture
was then carefully quenched with 2 M HCl to hydrolyze the resulting
carboxylate, and extracted several times with EtOAc and CH2Cl2. The
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The products were purified by flash chroma-
tography (hexanes–EtOAc).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560439.
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Primary Data
Primary data for this article are available online at http://www.thieme-
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be cited using the following DOI: 10.4125/pd0076th.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G