Atom economical coupling of benzophenone and N-heterocyclic aromatics with SmI2

Article abstract of DOI:10.1039/d0cc05164k

The use of stoechiometric SmI₂in combination with benzophenone and N-heterocyclic aromatics such as bipyridine, phenanthroline and pyridine allows the directortho-coupling of both partners in an atom economical reaction free of any other coupli

Full text of DOI:10.1039/d0cc05164k

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Atom economical coupling of benzophenone and N-heterocyclic
aromatics with SmI2
Received 00th January 20xx,
Accepted 00th January 20xx
Arnaud Jaoul, a Yan Yang,b Nicolas Casaretto,a Carine Clavaguéra,c* Laurent Maronb* and Grégory
Nocton a*
DOI: 10.1039/x0xx00000x
The use of stoechiometric SmI2 in combination with from pyridine and various ketones (Scheme 1),16 which
benzophenone and N-heterocyclic aromatics such as bipyridine, originally employed either aluminium or magnesium in
phenanthroline and neat pyridine allows the direct ortho-coupling combination with mercuric chloride and iodine or a mixture of
of both partners in an atom economical reaction free of any other Hg/HgCl.17 Greener alternatives for carbinol syntheses are
coupling additives. The transformation was investigated by 1H reported from aldehydes using strong Lewis acids but prevent
NMR, X-ray studies and theoretical calculations providing reaction the synthesis of tertiary alcohols.16
intermediates and the reaction mechanism.
The substitution of pyridine-based heteroarenes is an
important area of research considering the numerous
applications of such compounds in pharmaceutical,
Scheme 1. General strategy for the synthesis of -substituted pyridinemethanols
agrochemical, materials and organometallic chemistry, in
which they are common ligand motifs.1-3 Originally, the general
synthetic scheme for the substitution of aromatics lied in the
Friedel-Crafts alkylation or acylation (electrophilic aromatic
substitution) using strong Lewis acids, which is more difficult
for neat pyridine.4-6 The acylation is particularly well adapted
for the preparation of aryl ketones, which can be further
reduced in alcohol or alkanes via adapted methods, but suffers
from the use of high energy electrophiles.7
With heteroaromatics, traditional electrophilic aromatic
substitutions are also well documented and usually involve a
first step of C-H or C-X activation with strong bases or reducing
metals (Li, Zn, Mg),8-10 followed by the addition of an
(carbinols).
Additionally, the seminal work by Helquist and co-workers
focalized on the coupling of various ketones and several N-
aromatic heterocycles, notably phenanthroline and bipyridine,
19
using a simple divalent halide, SmI2.18,
In this article, we
propose insights in the mechanism of such a reaction that we
were able to extend to neat pyridine with benzophenone,
yielding the corresponding bisphenylpyridyl alcohol (Scheme
2).
electrophile, or the use of regioselective coupling catalysts
11
such as palladium,2,
rhodium,12 or iridium metal
complexes.13 Alternatively, radical reactions are used such as
the Minisci-type reactions.14 However, these radical reactions
have limitations, especially in the regioselectivity of the
products and the moderate yields.15
Scheme 2. Direct coupling of benzophenone and pyridine, bipyridine and
phenanthroline with SmI2.
One important aspect of this peculiar chemistry lies in the
preparation of -substituted pyridinemethanols (carbinols)
Divalent samarium halides are well-known single electron
transfer reagents in organic chemistry.20-25 In particular, Kagan
reported the reaction of ketones for the preparation of
alcohols or pinacols, depending upon the reaction
conditions.26 After some of us demonstrated that this typical
radical coupling induced by divalent lanthanides was reversible
in multiple cases,27-30 we were interested in investigating the
Kagan reaction with benzophenone and SmI2 in THF.
a. LCM, CNRS, Ecole polytechnique, Institut polytechnique Paris, Route de Saclay,
91128 Palaiseau, France.
b. LPCNO, UMR 5215, Université de Toulouse-CNRS, INSA, UPS, Toulouse, France
c. Institut de Chimie Physique, CNRS-Université Paris-Sud, Université Paris-Saclay, 15
avenue Jean Perrin, 91405 Orsay Cedex, France
Electronic Supplementary Information (ESI) available: Information on syntheses, 1H
NMR, UV-Vis and X-ray studies and theoretical computations details. See
DOI: 10.1039/x0xx00000x
The reaction with 1 eq. of SmI2 and benzophenone in
anhydrous THF led to the fast formation of a white precipitate,
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poorly soluble in THF, which can be crystallized from hot THF At lower temperatures, the purple colour turnsViteow Abrtliuclee Oanlninde
DOI: 10.1039/D0CC05164K
and analyzed by X-ray diffraction, confirming the pinacol form then to yellow at -40 °C. The band at 575 nm disappears and
of the product (1).31 In 1, each samarium ion is coordinated by the visible spectrum becomes similar to that of I at room
two iodide ions and three THF molecules (See SI) in a distorted temperature (Figure S14).
square pyramidal fashion. The Sm-I average distance is 3.10(1) As shown in the crystal structure of 1 (Figure 1), the solvent
Å while the Sm-O(THF) and the Sm-O(alcoholate) are 2.44(5) also acts as a ligand, completing the coordination sphere of
and 2.075(12) Å, respectively. The carbon-carbon distance the samarium ion. The THF is -donating allowing the
between the two Ph2CO motifs is 1.56(3) Å and is indicative of samarium to be more easily oxidized. Thus, the redox potential
a single bond. It is informative to compare this solid-state of the SmI2(THF)3(benzophenone) fragment is lower than that
structure to the bridged structure that was proposed by Hoz in of the SmI2(pyr)3(benzophenone) fragment. Subsequently, the
THF solution by stopped-flow kinetics.32 However, the solid- I  II equilibrium is strongly displaced toward the monomeric
state structure does not necessary reflect the solution form (II) in pyridine at room temperature and lower
speciation.
temperatures (-40 °C) are needed to favour I. These
observations are in good agreement with previous work on the
reversibility of these radical coupling reactions.27, 28
When a solution of II was heated up to 100 °C, new features
appeared in the visible spectrum, in particular around 475 and
700 nm. Both of these features are characteristic of SmI2 in
neat pyridine (Figure S13). According to the literature, SmI2 is
capable of reducing pyridine (III),34 which probably allows the
displacement of another equilibrium at higher temperature
(Scheme 4).
Figure 1. ORTEP of 1. Thermal ellipsoids are at 50% level. 1a and 1b are two
different views. In 1b, the thf are shown in light grey wireframes.
Along the communication, Arabic numbers are for solid-state
compounds, capital Latin numbers for solution structures and
capital alphabetical letters for computed gas phase
compounds. When a suspension of 1 is prepared in THF-d8 (I)
and heated, the colour of the solution turns purple in good
agreement with the formation of a ketyl radical. Visible
spectroscopy was performed at various temperatures and
showed an evolution upon heating of the band at 575 nm,
which is attributed to the *  * transition of the charge-
separated ketyl radical (II) (Scheme 3, Figure S15).33 The colour
Scheme 4. Electron transfer from the benzophenone to the pyridine in
SmI2(pyr)3(benzophenone).
change is reversible upon lowering the temperature. The low With this information in hand, we could now evaluate the
solubility of the dimeric form at room temperature prevented equilibrium of the ketyl radical over other -accepting N-
us to follow quantitatively the equilibrium by 1H NMR studies.
heteroaromatics such as bipyridine (bipy) or phenanthroline
(phen) with higher reduction potentials than pyridine. The
addition of one equivalent of bipy or phen to a room
temperature purple solution of II in pyridine led to a slight
colour change to dark brown. These solutions faded to lighter
brown, orange and yellow in a period of time of 16 h,
indicating
crystallization at cold of both solutions (-40 °C) produced pale
yellow X-ray suitable crystals of (bipyridine) and
a degradation of the ketyl radical (II). The
2
3
(phenanthroline, Figure 2, Table 1), in which the
benzophenone has been reduced to an alcoholate and is linked
to the bipyridine and phenanthroline in the -position to the
nitrogen (Scheme 2, Figure 2), similar to what Helquist
reported.18, 19 In 2, one residual neutral bipyridine coordinates
while in 3 three solvent molecules are coordinated to the
samarium ion, which is then octa-coordinated by two iodide
atoms and the novel tridentate ligand. The Sm-I distances are
3.288(1) and 3.23(5) Å in 2 and 3, respectively, in good
agreement with the presence of a trivalent samarium.35 The
C(Ph2)-O distances of 1.38(1) and 1.395(7) Å in 2 and 3 agree
with an alcoholate form. The OCCN torsion angle is small two
very different sets of Sm-N distances are noted.
Scheme 3. Reversible coupling of benzophenone with SmI2(L)3 fragments (L=
pyridine or THF).
The white crystals of 1 can be dissolved in pyridine to yield an
immediate colour change, the solution turning to deep purple,
in agreement with the ketyl radical form of the benzophenone
(II). The visible spectrum highlights a transition at 575 nm,
1
similar to that of I at higher temperature (Figure S13). The H
NMR spectrum contains several broad signals, in agreement
with the presence of paramagnetic species but remains
difficult to assign. The ketyl radical (II) was found to be stable
over several weeks in pyridine solutions at room temperature.
2 | J. Name., 2012, 00, 1-3
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the DFT level (B3PW91) were performed. The formation of a
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ketyl radical was already investigated byDZOhIa: 1o0.e1t03a9l/.3D60,CKCe0f5a1li6d4iKs
et al.37 or Werner et al.38 and therefore its formation was not
investigated computationally in this report. The nature of the
equilibrium depicted in scheme
4
was investigated
computationally for pyridine and phenanthroline. In
compound B, the ketyl radical appears to be favoured by 7.8
kcal/mol over the phenanthroline radical, whereas the
preference for the kethyl radical is 12.7 kcal/mol in
comparison with the pyridine radical (see SI). This in
agreement with a higher π* energy for pyridine compared to
phenanthroline. A plausible mechanism for the formation of D
(2 in the solid-state) from the coupling between the ketyl
radical and phenanthroline/pyridine was determined
computationally (Figure 4). The formation of the ketyl radical is
favoured by 7.6 kcal/mol but the coordination of the
phenanthroline does not imply any electron transfer from the
ketyl radical to the phenanthroline moiety, in agreement with
the computed 7.8 kcal/mol needed to achieve this transfer.
The unpaired electron is mainly located on the oxygen and the
carbon atoms of the ketyl (see figure 4 and ESI). The system
reaches an accessible C-C coupling transition state (barrier of
18.5 kcal/mol). The C-C bond is developing between the ketyl
carbon atom that bears unpaired spin density and the carbon
in alpha to the nitrogen of phenanthroline. The latter position
is imposed by the cis-coordination of the phenanthroline to
the samarium centre through the two nitrogen lone pairs. This
TS is described as a radical coupling reaction because the
unpaired electron of the ketyl radical couples with the π
electron of alpha carbon of the phenanthroline ligand,
explaining the height of the barrier. Following the intrinsic
reaction coordinate, it yields the alcoholate intermediate (C)
whose formation is endothermic by 8.8 kcal/mol from the
ketyl radical form. This is due to the formation of an sp3 carbon
on bipyridine inducing a loss in aromaticity.
Figure 2. ORTEPs of 2-4 (from left to right). Thermal ellipsoids are at 50% level.
The reactivity clearly resembles the preparation of carbinols
from pyridine and ketones but without the use of mercuric
chloride17 or any coupling additives other than SmI2, a much
cleaner and atom economical pathway, as reported by
Helquist.18, 19 However, the useful reaction was not reported
with neat pyridine and although this reactivity does not
happen at room temperature with neat pyridine, a solution of
II was heated at 110 °C for 16 h and turned yellow. The yellow
solution was crystallized and X-ray suitable colourless crystals
of
4 were obtained (Figure 2, Table 1). The overall
arrangement is similar to that in 2 and 3 with a newly-formed
bidentate NO ligand, two iodides and three pyridine molecules
coordinated to the Sm atom. Noticeably shorter Sm-I and Sm-
N(pyr) distances are observed due to the smaller coordination
number.
Table 1. Main distances and angles in 2-4.
35
SmI2(py)5
3.288(1)
2.70(1)
-
2 (bipy)
3.208(6)
3.70(1)
2.556(9)
2.654(10)
2.145(8)
1.38(1)
1.52(2)
7.3
3 (phen)
3.23(5)
2.67(4)
2.56(2)
2.70(2)
2.15(2)
1.395(7)
1.54(1)
5.6(8)
4 (pyridine)
3.12(2)
2.62(6)
Sm-I
Sm-N(pyr)
Sm-N(L)
2.568(4)
Sm-O
O-C(Ph2)
C-C(Ph2)
OCCN
-
-
-
-
2.128(3)
1.395(6)
1.545(7)
3.6
The syntheses of the compounds 5 and 6 are performed in
pyridine in one pot with one equivalent of SmI2,
benzophenone and bipyridine or phenanthroline, respectively.
The synthesis of 7 is also performed in pyridine. After acidic
treatment and purification by re-crystallization, 6 and 7 are
obtained as white powders in 70-75% yield, while 5 is obtained
as an oil.
Figure 4. Computed enthalpy profile at room temperature for the formation of 2
from the coupling between II and phenanthroline
Figure 3. ORTEPs of 6 and 7 (from left to right). Thermal ellipsoids are at 50%
level.
At this stage, the intermediate (C) can further evolve in order
to retrieve the aromaticity of the phenanthroline by
undergoing an intramolecular 1,3 proton shift in the alcoholate
ligand. The associated barrier is 29.6 kcal/mol from C
In order to get further insights in the reaction mechanism of
these important transformations, theoretical computations at
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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indicating kinetically possible reaction and the rate-
Journal Name
15.
16.
17.
18.
F. Minisci, E. Vismara and F. Fontana, Heterocycles, 1989,
a
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28, 489-519.
DOI: 10.1039/D0CC05164K
determining step of the process. The height of the barrier is
due to the lack of samarium involvement in the proton
transfer as well as the decrease of the Sm-O stabilizing
interaction. This yields to D, whose formation is favoured by
9.0 kcal/mol from the entrance. Similar calculations were
performed for the formation of the pyridine analogue (see
ESI). The mechanism appears to be similar but all
intermediates are shifted up in energy by up to 10.6 kcal/mol
for the rate determining step TS and the final product
formation. This is in line with the experimental observation
that higher temperature is required to drive the reaction. The
deprotonation of the alcohol is then assisted by the pyridine
base as the solvent as well as by the coordination of the
samarium ion.
In conclusion, this article reports the easy formation of
carbinols from benzophenone and N-heterocycles, such as
bipyridine, phenanthroline and even neat pyridine. The
equilibrium between the ketyl radical and its coupled form
(pinacolate) is the key step of this atom-economical method
that allows direct radical coupling with the N-heterocycle
followed by an intra-molecular hydrogen transfer without any
other coupling additives. The mechanism was confirmed by
theoretical computations and further work is being conducted
to enlarge the scope of the reaction with substrates more
difficult to reduce.
A. Harikrishnan, J. Sanjeevi and C. Ramaraj Ramanathan,
Org. Biomol. Chem., 2015, 13, 3633-3647.
C. H. Tilford, R. S. Shelton and M. G. v. Campen, J. Am.
Chem. Soc., 1948, 70, 4001-4009.
J. A. Weitgenant, J. D. Mortison, D. J. O'Neill, B. Mowery,
A. Puranen and P. Helquist, J. Org. Chem., 2004, 69, 2809-
2815.
J. A. Weitgenant, J. D. Mortison and P. Helquist, Org. Lett.,
2005, 7, 3609-3612.
G. A. Molander and C. R. Harris, Chem. Rev., 1996, 96,
307-338.
K. C. Nicolaou, S. P. Ellery and J. S. Chen, Angew. Chem.
Int. Ed., 2009, 48, 7140-7165.
M. Szostak, N. J. Fazakerley, D. Parmar and D. J. Procter,
Chem. Rev., 2014, 114, 5959-6039.
X. Just-Baringo and D. J. Procter, Acc. Chem. Res., 2015,
48, 1263-1275.
C. Beemelmanns and H.-U. Reissig, Chem. Soc. Rev., 2011,
40, 2199-2210.
S. Shi and M. Szostak, Molecules, 2017, 22, 2018.
H. B. Kagan, J. Alloys Compd., 2006, 408, 421-426.
G. Nocton, W. L. Lukens, C. H. Booth, S. S. Rozenel, S. A.
Melding, L. Maron and R. A. Andersen, J. Am. Chem. Soc.,
2014, 136, 8626-8641.
G. Nocton and L. Ricard, Chem. Commun., 2015, 51, 3578-
3581.
A. Jaoul, G. Nocton and C. Clavaguéra, Chem. Phys. Chem.,
2017, 18, 2688-2696.
T. Cheisson, L. Ricard, F. W. Heinemann, K. Meyer, A.
Auffrant and G. Nocton, Inorg. Chem., 2018, 57, 9230-
9240.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Conflicts of interest
There are no conflicts to declare.
31.
P. Girard, R. Couffignal and H. B. Kagan, Tet. Lett., 1981,
22, 3959-3960.
32.
33.
H. Farran and S. Hoz, J. Org. Chem., 2009, 74, 2075-2079.
T. Shida, Electronic absorption spectra of radical ions,
Elsevier Science Ldt., Amsterdam and New York, 1988.
Y. Kamochi and T. Kudo, Heterocycles, 1993, 36, 2383-
2396.
J. C. Berthet, P. Thuery and M. Ephritikhine, CCDC 959301:
Experimental Crystal Structure Determination, 2013, DOI:
10.5517/cc11676p.
X. Zhao, L. Perrin, D. J. Procter and L. Maron, Dalton
Trans., 2016, 45, 3706-3710.
C. E. Kefalidis, L. Perrin and L. Maron, Eur. J. Inorg. Chem.,
2013, 2013, 4042-4049.
Notes and references
1.
Y. Fujiwara, J. A. Dixon, F. O’Hara, E. D. Funder, D. D.
Dixon, R. A. Rodriguez, R. D. Baxter, B. Herlé, N. Sach, M.
R. Collins, Y. Ishihara and P. S. Baran, Nature, 2012, 492,
95-99.
34.
35.
2.
3.
P. Guo, J. M. Joo, S. Rakshit and D. Sames, J. Am. Chem.
Soc., 2011, 133, 16338-16341.
M. Schlosser and F. Mongin, Chem. Soc. Rev., 2007, 36,
1161-1172.
36.
37.
38.
4.
5.
6.
7.
C. M. Jephcott, J. Am. Chem. Soc., 1928, 50, 1189-1192.
N. O. Calloway, Chem. Rev., 1935, 17, 327-392.
P. H. Gore, Chem. Rev., 1955, 55, 229-281.
G. A. Olah, Friedel-Crafts Chemistry, Willey, New York,
1973.
D. Werner, X. Zhao, S. P. Best, L. Maron, P. C. Junk and G.
B. Deacon, Chem. Eur. J., 2017, 23, 2084-2102.
8.
T. Bresser, G. Monzon, M. Mosrin and P. Knochel, Organic
Process Research & Development, 2010, 14, 1299-1303.
V. Snieckus, Chem. Rev., 1990, 90, 879-933.
K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069-1084.
M. Ye, G.-L. Gao and J.-Q. Yu, J. Am. Chem. Soc., 2011,
133, 6964-6967.
9.
10.
11.
12.
13.
14.
J. C. Lewis, R. G. Bergman and J. A. Ellman, J. Am. Chem.
Soc., 2007, 129, 5332-5333.
I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy
and J. F. Hartwig, Chem. Rev/, 2010, 110, 890-931.
M. A. J. Duncton, Med. Chem. Comm, 2011, 2, 1135-1161.
4 | J. Name., 2012, 00, 1-3
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