Cu(II) Porphyrin-catalyzed Coupling of Alkyl Tosylates and Grignard Reagents

Article abstract of DOI:10.1246/cl.200064

Copper(II) porphyrin-catalyzed coupling of alkyl tosylates and alkyl Grignard reagents afforded substituted alkanes. The role of the copper(II) porphyrin complex was examined using EPR and in-situ synchrotron-based X-ray absorption fine structure measurements. These studies suggested that neither Cu redox nor substitution via in-situ generated cuprate was involved in catalysis. The results supported a reaction mechanism involving single electron transfer from copper(II) porphyrin to tosylate to facilitate the nucleophilic addition of Grignard reagents.

Full text of DOI:10.1246/cl.200064

CL-200064
Received: January 28, 2020 | Accepted: February 18, 2020 | Web Released: April 14, 2020
Cu(II) Porphyrin-catalyzed Coupling of Alkyl Tosylates and Grignard Reagents
Iori Matsuoka, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
E-mail: kurahashi.takuya.2c@kyoto-u.ac.jp (T. Kurahashi), matsubara.seijiro.2e@kyoto-u.ac.jp (S. Matsubara)
Table 1. Metalloporphyrin-catalyzed coupling reactionsa
Copper(II) porphyrin-catalyzed coupling of alkyl tosylates
and alkyl Grignard reagents afforded substituted alkanes. The
catalyst (1 mol %)
+
OTs
BrMg
role of the copper(II) porphyrin complex was examined using
EPR and in-situ synchrotron-based X-ray absorption fine struc-
ture measurements. These studies suggested that neither Cu redox
nor substitution via in-situ generated cuprate was involved in
catalysis. The results supported a reaction mechanism involving
single electron transfer from copper(II) porphyrin to tosylate to
facilitate the nucleophilic addition of Grignard reagents.
Et2O, 25 °C, 2 h
1
2
3
entry
catalyst
yield (%)
1
2
3
4
5
6
7
8
CuTPP
CuTPP
CoTPP
NiTPP
MnTPP
ZnTPP
H2TPP
®
64
56b
<1
<1
<1
<1
<1
<1
60
Keywords: Cross-coupling reaction
| Electron-transfer |
In-situ XAFS
Coupling reactions are one of the most important and
versatile carbon-carbon bond-forming transformations in organ-
ic synthesis.1 Continuous efforts have been made to develop
transition metal-catalyzed sp3-sp3 coupling reactions, and there
are currently a wide range of alkyl halides and pseudohalides
available for use with a variety of organometallic reagents for
this purpose.2 Burns et al. and Cahiez et al. have shown that
cuprate acts as a key intermediate for nucleophilic substitution
with halide leaving groups in copper-catalyzed coupling
reactions between alkyl halides and Grignard reagents.3 Kambe
and co-workers have developed copper-catalyzed cross-coupling
reactions between alkyl halides and Grignard reagents, in which
carbon-carbon bond formation occurred via reductive elimina-
tion at the copper metal center.4,5 Furthermore, copper catalyzed
reaction of higher alkyl halides including tertiary halides with
allylic Grignard reagents were reported by Yorimitsu and
Oshima.6 In this communication, we describe the coupling of
alkyl tosylates with Grignard reagents promoted by a copper
porphyrin complex via an alternative reaction mechanism.
We initially found that secondary alkyl tosylate 1 reacted
with secondary alkyl Grignard reagent 2 in the presence of the
copper(II) porphyrin complex, CuTPP (Table 1, Entry 1). The
reaction proceeded at 25 °C for 2 h to provide the sp3-sp3
coupling product in 64% yield. The product yield slightly
decreased when the reaction was performed at ¹10 °C (Entry 2).
Among the metalloporphyrin complexes examined, only cop-
per(II) porphyrin promoted the reaction, with the cobalt(II),
nickel(II), manganese(II), and zinc(II) complexes yielding only
trace amounts of product (Entries 3-6). Mesityl-substituted
copper(II) porphyrin, CuTMP, was also found to catalyze the
reaction, although with a slight decrease in yield (60%).
Copper(II) porphyrin-catalyzed coupling could also be applied
to primary alkyl tosylates and tertiary Grignard reagents
(Scheme 1). Primary alkyl tosylate 4 reacted with tertiary
Grignard 5 in the presence of the copper(II) porphyrin complex
to provide the sp3-sp3 coupling product 6 in 88% yield. Notably,
product 6 failed to form in the absence of the copper(II)
porphyrin complex, indicating that the catalyst is essential for
the sp3-sp3 coupling of both the secondary alkyl tosylate with
9
10
CuTMP
CuTMP
23b
aReaction conditions: catalyst (1 mol %), alkyl tosylate 1
(0.2 mmol), and CyMgBr 2 (0.4 mmol) in Et2O (1 mL) at
25 °C for 2 h. TPP = meso-tetraphenylporphyrinato, TMP =
b
meso-tetramesitylporphyrinato. Reaction at ¹10 °C.
CuTPP (1 mol %)
+
TsHN
OTs
TsHN
BrMg
Et2O, 25 °C, 24 h
4
5
6 88% yield
(w/o CuTPP <1% yield)
Scheme 1. Copper(II) porphyrin-catalyzed coupling reactions.
the secondary alkyl Grignard reagent and the primary alkyl
tosylate with the tertiary alkyl Grignard reagent.
To obtain mechanistic information for this coupling reac-
tion, we performed Cu K-edge X-ray absorption spectroscopy
(XAS) (Figure 1).7 Cu K-edge X-ray absorption near edge struc-
ture (XANES) spectra of the copper(II) porphyrin complex was
obtained using Cu(0) foil, Cu(I) chloride, and Cu(II) dichloride
as references. In contrast to Cu(0) foil (orange line) and Cu(I)
chloride (black line), the main edge of copper(II) porphyrin
(navy line) shifted to a higher energy with an increased
oxidation state. Notably, the absorption edge energies (E0) of
Cu(II) dichloride and copper(II) porphyrin were almost identical
(Table 2, Entries 3 and 7, respectively), indicating that the
oxidation state of copper with the porphyrin ligand resembled
that of Cu(II) dichloride. To compare the reaction mechanism of
the previously reported Cu(II) dichloride/butadiene-catalyzed
reaction with that of the copper(II) porphyrin-catalyzed reaction,
we investigated the active species of the Cu(II) dichloride/
butadiene catalyst. The solution-phase Cu K-edge XAS of
Cu(II) dichloride and Cu(II) dichloride with either butadiene,
CyMgBr, or both butadiene and CyMgBr in THF was measured
(Figure 2). The addition of CyMgBr (navy line) led to
remarkable changes in the pre-edge and main edge regions of
442 | Chem. Lett. 2020, 49, 442–445 | doi:10.1246/cl.200064
© 2020 The Chemical Society of Japan

Figure 1. Solid-phase Cu K-edge XANES spectra (pellet):
Cu(0) foil (orange line), CuCl (black line), CuCl2 (red line), and
CuTPP (navy line).
Figure 2. Solution-phase Cu K-edge XANES spectra: CuCl2
(black line), CuCl2 with butadiene (red line), CuCl2 with
CyMgBr (navy line), and CuCl2 with butadiene and CyMgBr
(orange line).
Table 2. Cu K-edge absorption energy (E0)
a
entry
copper
E0
1
2
3
4
5
6
7
8
Cu foil
CuCl
CuCl2
8978.4
8984.0
8988.5
8988.5
8986.9
8987.4
8988.3
8988.3
CuCl2/butadiene
CuCl2/CyMgBr
CuCl2/butadiene/CyMgBr
CuTPP
CuTPP/CyMgBr
aSecond peak of the first derivative of ¯(E).
the XANES spectra as compared to Cu(II) dichloride (black
line), confirming the reduction of Cu(II) to low-valent copper
species. The addition of CyMgBr decreased the E0 value of
Cu(II) dichloride, further suggesting a decreased oxidation state
(Table 2, Entries 3 and 5, respectively). It is noteworthy that the
XANES spectra for the solution of Cu(II) dichloride with both
butadiene and CyMgBr (orange line) is not identical to that
of Cu(II) dichloride with CyMgBr (navy line), indicating that
butadiene indeed coordinated to lower-valence copper species,
as previously reported by Kambe and co-workers.4d,8
Figure 3. Solution-phase Cu K-edge XANES spectra: CuTPP
(black line) and CuTPP with CyMgBr (red line).
We next investigated the copper(II) porphyrin-catalyzed
reaction using K-edge XAS, as it is ideal for identifying
active copper species. The solution-phase Cu K-edge XAS of
copper(II) porphyrin and copper(II) porphyrin with CyMgBr in
THF were measured (Figure 3). There were no observable
changes in the pre-edge or main edge regions of the copper(II)
porphyrin XANES spectra (black line) upon addition of
CyMgBr (red line), indicating that copper(II) was not reduced
to a lower valence species when complexed to porphyrin. This
was further confirmed by the identical E0 values of the copper(II)
porphyrin complex with and without added CyMgBr (Table 2,
Entries 7 and 8, respectively).
X-ray absorption fine structure (EXAFS) analysis of the
copper(II) porphyrin complex was performed with and without
CyMgBr (Figure 4). The spectral features arising from the
coordination sphere of the copper atoms, i.e., the radial distance,
Figure 4. Solution-phase Cu K-edge EXAFS analysis (Fourier
transform of k3-weighted spectrum): CuTPP (black line) and
CuTPP with CyMgBr (red line).
Chem. Lett. 2020, 49, 442–445 | doi:10.1246/cl.200064
© 2020 The Chemical Society of Japan | 443

CuTPP (1 mol %)
Et2O, 25 °C, 2 h
OTs
+
BrMg
N
N
Ts
Ts
7 (99% ee)
2
8 25% yield (99% ee)
(w/o CuTPP <1% yield)
CuTPP (1 mol %)
Et2O, 25 °C, 2 h
+
OTs
BrMg
9
5
10 10% yield
(w/o CuTPP <1% yield)
Scheme 2. Nucleophilic substitution type substitution cou-
pling reactions.
firming that this reaction also proceeded via a nucleophilic
substitution type mechanism with respect to both the elimination
of the leaving group and formation of the carbon-carbon bond.
In addition, coupling between secondary alkyl tosylate 9 and
tertiary alkyl Grignard 5 provided 10 in lower yield compared to
that of secondary alkyl tosylate 1 with secondary alkyl Grignard
2 or primary alkyl tosylate 4 with tertiary alkyl Grignard 5. This
influence of steric hindrance on the reaction productivity further
supports a nucleophilic substitution type mechanism.
Figure 5. X-Band EPR spectrum of CuTPP in frozen THF
at 77 K (black line) and simulated spectrum (red line). EPR
experimental parameters: microwave frequency = 9.104859
GHz, power = 0.998 mW, modulation amplitude = 0.1 mT.
Based on this work, we propose a catalytic reaction
mechanism involving initial single electron transfer (SET) from
copper(II) porphyrin to alkyl tosylate, which is coordinated
to the Lewis acidic magnesium of the Grignard reagent.
Subsequent nucleophilic substitution type addition of the
activated Grignard carbanion via SET, which enhances the
Lewis basicity of the oxygen atom coordinated to magnesium,
forms the carbon-carbon bond. The tosylate moiety and
copper(II) porphyrin catalyst are then regenerated through a
second SET between the tosyl radical and copper(II) porphyrin
to form tosyl magnesium bromide.10
In summary, we developed a copper(II) porphyrin-catalyzed
coupling reaction between nonactivated alkyl tosylates and alkyl
Grignard reagents. The reaction proceeded via formal nucleo-
philic substitution type addition with inversion of stereochem-
istry upon leaving group elimination and carbon-carbon bond
formation. A mechanistic investigation revealed that the reaction
did not proceed via a cuprate intermediate or low-valent copper
species, as had been reported for previous Cu-catalyzed coupling
reactions. This coupling reaction may provide new insight into
transition and non-transition metal-catalyzed coupling reactions.
Further experimental and theoretical investigations into the
reaction mechanism are underway and will be reported in due
course.11
Figure 6. Spin density plot of CuTPP calculated with DFT
[CPCM(THF)-B3LYP/def2-TZVP// CPCM(THF)-B3LYP-D3/
Lanl2dz(f)(Cu), 6-31G(d)(else)].
were similar for the copper(II) porphyrin solutions with and
without CyMgBr. These results clearly suggest that copper(II)
porphyrin does not react with CyMgBr to afford either low-
valent copper species or cuprate reagents.
To further investigate the catalytically active species
involved in the coupling reaction, X-band electron paramagnetic
resonance (EPR) spectroscopy was measured for the copper(II)
porphyrin catalyst at 77 K.9 A frozen solution of the copper(II)
porphyrin catalyst displayed a signal characteristic for radical
species (Figure 5). This finding was in agreement with the
simulated EPR spectrum obtained using the DFT-calculated EPR
parameters for the corresponding copper(II) porphyrin model
(Figures 6).
This work was supported by Grant-in-Aid for Scientific
Research (Nos. 18H04253 and 17KT0006) from the Ministry
of Education, Culture, Sports, Science and Technology (Japan).
We thank Dr. Tetsuo Honma and Dr. Hironori Ofuchi (JASRI:
Japan Synchrotron Radiation Research Institute), and Mr.
Kyohei Fujiwara (Ajinomoto Co., Inc.) for their valuable help
with X-ray absorption fine structure analysis. A portion of
this study was performed at the BL14B2 beamline of the
SPring-8 synchrotron radiation facility with the approval of the
Japan Synchrotron Radiation Research Institute (Proposal Nos.
2015B1770, 2016A1549, 2016A1680, 2016B1766, 2017A1700,
2017B1748, 2018A1690, 2018B1594, 2019A1712, and
2019B1842).
To examine the stereochemistry of the copper(II) porphyrin-
catalyzed coupling reaction during formation of the carbon-
carbon bond and thereby elucidate the reaction mechanism,
chiral tosylate
7 was reacted with Grignard reagent 2
(Scheme 2). The copper-catalyzed coupling of alkyl halides
and tosylates with Grignard reagents has previously been shown
to proceed via nucleophilic substitution type stereochemistry.
Coupling product 8 was obtained in 99% ee with inversion of
configuration at the newly formed carbon-carbon bond, con-
444 | Chem. Lett. 2020, 49, 442–445 | doi:10.1246/cl.200064
© 2020 The Chemical Society of Japan

Supporting Information is available on https://doi.org/
10.1246/cl.200064.
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briefly summarized in the Supporting Information.
Chem. Lett. 2020, 49, 442–445 | doi:10.1246/cl.200064
© 2020 The Chemical Society of Japan | 445