Arene-metal π-complexation as a traceless reactivity enhancer for C-H arylation

Article abstract of DOI:10.1021/ja405936s

Current approaches to facilitate C-H arylation of arenes involve the use of either strongly electron-withdrawing substituents or directing groups. Both approaches require structural modification of the arene, limiting their generality. We present a new approach where C-H arylation is made possible without altering the connectivity of the arene via π-complexation of a Cr(CO)₃ unit, greatly enhancing the reactivity of the aromatic C-H bonds. We apply this approach to monofluorobenzenes, highly unreactive arenes, which upon complexation become nearly as reactive as pentafluorobenzene itself in their couplings with iodoarenes. DFT calculations indicate that C-H activation via a concerted metalation-deprotonation transition state is facilitated by the predisposition of C-H bonds in (Ar-H)Cr(CO)₃ to bend out of the aromatic plane.

Full text of DOI:10.1021/ja405936s

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Communication
Arene-Metal #-Complexation as a Traceless
Reactivity Enhancer for C–H Arylation
Paolo Ricci, Katrina Kramer, Xacobe Couso Cambeiro, and Igor Larrosa
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja405936s • Publication Date (Web): 20 Aug 2013
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Arene-Metal π-Complexation as a Traceless Reactivity Enhancer
for C–H Arylation
Paolo Ricci‡, Katrina Krämer‡, Xacobe C. Cambeiro and Igor Larrosa*
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School of Biological and Chemical Sciences, Queen Mary University of London, Joseph Priestley Building, Mile End
Road, E1 4NS, London, U.K.
Supporting Information Placeholder
Upon complexation to Cr(CO)3, the pKa of benzene is lowered
by 7 units, a similar effect as that of an ortho NO2 group.9 This
effect also lowers pKa at benzylic positions, which has recent-
ly been exploited by Walsh and coworkers in Pd-catalyzed
processes.10 Interestingly, the effect on arene C-H bonds has
never been explored in the context of C-H arylation. Thus, we
hypothesized that the Cr(CO)3 complexes of simple arenes
would display greatly enhanced reactivity under CMD type
arylation conditions, compared to the parent arenes. This
would lead to a new approach (Scheme 1b) for enhancing the
reactivity of simple arenes towards C-H arylation simply by
coordinating them to a Cr(CO)3 fragment without the need for
altering their connectivity.
ABSTRACT: Current approaches to facilitate C-H arylation of
arenes involve either the use of strongly electron-
withdrawing substituents or of directing groups. Both of these
approaches require the structural modification of the arene,
limiting their generality. We present a new approach where C-
H arylation is made possible without altering the connectivity
of the arene via π-complexation of a Cr(CO)3 unit, which great-
ly enhances the reactivity of the aromatic C-H bonds. We apply
this approach to monofluorobenzenes, highly unreactive
arenes, which upon complexation become nearly as reactive
as pentafluorobenzene itself in their couplings with io-
doarenes. DFT calculations indicate that C-H activation via a
concerted metallation-deprotonation (CMD) transition state is
facilitated by the predisposition of C-H bonds in (CO)3Cr-Ar-H
to bend out of the aromatic plane.
Scheme 1. Strategies for enhancing reactivity of a C-H
bond towards direct arylation
C-H arylation is a new and promising tool for the construc-
tion of biaryl containing molecules,1 which has already found
important applications in the synthesis of organic materials,
pharmaceuticals and natural products.2 Despite tremendous
advances and continuous effort in this field, C-H arylation of
arenes is to date almost exclusively limited to three types of
substrates (Scheme 1a): (1) arenes bearing a directing group
(DG), a functional group capable of coordinating the transition
metal catalyst and facilitating C-H activation;3,4 (2) highly elec-
tron-rich arenes;5 and (3) highly electron-poor arenes, gener-
ally requiring two electron-withdrawing groups ortho to the
C-H bond to be activated.6 These three approaches are only
suitable for arenes bearing an appropriate covalently bonded
'reactivity enhancing' substituent. Substrates lacking this fea-
ture are either unreactive, or must be used in large excesses
(often as solvents).7 Typically, fluorobenzene, with only one
electron-withdrawing group, is highly unreactive and 50 equiv
are required to facilitate its C-H arylation which leads to mix-
In order to test our hypothesis we chose monofluoroben-
zenes as benchmark substrates. The direct arylation of 2-
fluorotoluene has never been reported. Its complex, 1a, was
prepared and the reactivity of 1a towards C-H arylation was
examined (Table 1).11 Initially, we tested Fagnou's well-known
catalytic system,7b followed by in situ oxidative demetallation
(Table 1, entry 1).12 Complex 1a was incompatible with DMA
and solvent screening revealed PhCH3 as the ideal solvent
(entry 2).13 Carboxylic acid screening showed that 1-AdCO2H
7
b,f
t
tures of ortho, meta and para biaryls.
provided similar yields and cleaner reactions than BuCO2H
(entry 3). Ligandless conditions, initially suggested by Hart-
wig, were tested unsuccessfully (entry 4).14 Further Pd cata-
lyst screening revealed that Pd(PPh3)4 was optimal for this
transformation (entries 5-7). Lowering the temperature from
120 to 60 °C provided the best conditions (entry 8), due to
increased stability of Cr-complex 1a. The ortho regioisomer
3aa is observed exclusively. The presence of a carboxylic acid
is key for achieving high yields, consistent with previous re-
ports on CMD-type C-H activation methodologies (entry 9).6,7
It has been shown that the high reactivity of electron-poor
arenes can be explained by a concerted metallation-
deprotonation process (CMD).6a In many cases there seems to
be a paralleling trend between reactivity of the arene and the
Brønsted acidity of the C-H bond. It is well known that low
valent metal carbonyls such as Cr(CO)3 are able to form stable
ɳ6-complexes with arenes resulting in a decrease of electron-
density in the arene similar to that of a strong electron-
withdrawing group, and consequently an increase in acidity.8
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Table 1. Optimization of the Direct Arylation of (2-
fluorotoluene)Cr(CO)3 (1a) with 4-Iodoanisole (2a)
Figure 1. Relative reactivity between Cr-complex 1a
and polyfluorobenzenes towards C-H arylationa
a
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entry
1c
2
Pd cat
R-COOH
tBuCO2H
tBuCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
–
T (°C)
120
120
120
120
120
120
120
60
3aa (%)b
a
1a and a polyfluoroarene were reacted with 2a in the same flask.
Reactions were stopped at low conversions (10-20%) and ratios de-
termined by 1H NMR using an internal standard.
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Pd(OAc)2+DavePhos
Pd(OAc)2+DavePhos
Pd(OAc)2+DavePhos
Pd(OAc)2
0
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3
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Scheme 3. Scope of the Pd-catalysed Direct Arylation of
(fluoroarene)Cr(CO)3 1a-j with iodoarenes 2a-p. a,b
4
0
5
Pd(OAc)2+PPh3
Pd(OAc)2+PPh3
Pd(PPh3)4
24
6d
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7
68
8
Pd(PPh3)4
90 (89)e
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9
Pd(PPh3)4
60
10
Pd(PPh3)4
1-AdCO2H
60
0f
a Reactions carried out on 0.1 mmol scale with respect to 1a. 10% of
phosphine ligand was used in entries 1-3 and 5. The yield was de-
termined by 1H NMR using an internal standard. The reaction was
carried out in DMA instead of PhCH3. d 20% of PPh3 was used. e Isolat-
ed yield on 0.5 mmol scale. The reaction was carried out for 40 h in-
stead of 24 h. f 4-Chloroanisole and 4-bromoanisole were used instead
of 4-iodoanisole.
b
c
Control experiments with 1-10 equiv of 2-fluorotoluene
showed no C-H arylation reaction (Scheme 2), highlighting the
outstanding reactivity enhancing effect imparted by Cr(CO)3
coordination. In order to determine the extent of this en-
hancement, we performed a series of competition experi-
ments between Cr(CO)3 complex 1a and a number of
polyfluorobenzenes at short reaction times (Figure 1). Re-
markably, the reactivity of complex 1a towards C-H arylation
is close to that of pentafluorobenzene. A KIE of 2.1 was meas-
ured for the arylation of 1a indicating that the C-H activation
occurs in the turnover-limiting step.
Scheme 2. Reaction of uncomplexed 2-fluorotoluene
Having validated our hypothesis we set out to explore the
generality of the methodology with respect to the iodoarene
coupling partner (Scheme 3, a). The optimized conditions
were applicable to a wide range of iodoarenes with electron-
donating and electron-withdrawing substituents in para, meta
and ortho, affording the corresponding biaryl products 3 in
excellent yields. The reaction is compatible with Cl and Br
substituents (3ac-d), which would allow for further Pd-
mediated transformations, esters (3af and 3al), ketones
(3ag). Oxidisable functionalities, like aldehydes (3ak) and
SMe (3al) are compatible, but alcohols need to be protected
(3am). Pyridine and indole based iodoarene compounds can
also be used (3ar-s), albeit higher temperatures are required
in the case of 2r for the reaction to proceed satisfactorily.
c
a Reactions were performed on 0.5 mmol scale. b Isolated yields. Re-
action time was 48 h. d Performed at 70 °C with 3 equiv of 2o and 1.5
f
equiv of Ag2CO3. e Performed with 3.0 equiv of 2a or 2n. 14% of the
other ortho regioisomer was also obtained. g Performed with 4.0 equiv
of 2a.
excellent yields of the arylated products. Even in the presence
of
a strongly electron-donating group (MeO) on the
fluoroarene the arylation proceeded in good yield (3ea).
When the substituents were placed in the meta position, a
second arylation product could be observed in some cases,
with the major arylation product being at the least hindered
position (3ga). This could be avoided by employing an ortho-
substituted iodoarene (3hn-kn). Finally, with a substituent in
para-position (1n-m) or in the absence of a substituent (1l),
We then turned our attention to the substitution at the
fluoroarene core (Scheme 3, b).11 Functionalities in ortho such
as CH2OTBS (3ba), SiMe3 (3ca), CO2Me (3da) and long alkyl
chains (3fa) were all compatible with the reaction, affording
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mixtures of mono and double arylation were obtained. The calculated for C6H5F, which is consistent with the experimen-
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use of 3 equiv of iodoarene, allowed for the synthesis of the
bisarylated adducts 4la-ma in good yields. The reactivity of
other electron-poor arenes (Ph-CF3 and Ph-CO2Me) towards
C-H arylation is also enhanced via Cr(CO)3 complexation,
however, poor regioselectivities were observed leading to
complex mixtures of regioisomers and polyarylation.15
tally observed reactivity.
To gain better understanding of the different factors in-
volved in the energy difference between both TS, distortion-
interaction analysis was performed.19 This analysis separates
and quantifies the energy cost for distorting each of the rea-
gents from their minimum energy geometry to the geometry
adopted in the TS (ΔGdist), and the energy released in their
interaction (ΔGint). This revealed that while the interaction is
less favorable for complex 1k than for C6H5F (by 14.4
kcal/mol), this factor is overcome by the much lower distor-
tion energy cost of 1k compared to C6H5F (by –20.0 kcal/mol).
The Cr(CO)3 complexed biaryls can also be isolated before
decomplexation which allows easy functionalization of the C-F
bond via a variety of nucleophilic aromatic substitution reac-
tions.16 For example, arylated complex 3aa-Cr(CO)3 (Scheme
4) was isolated in 72% yield. The C-F bond could then be sub-
stituted with N-, C-, S-, and O-nucleophiles leading to a variety
of functionalities in excellent yields: pyrrolidine (5), indole
(6), NH2 (7), CN (8), SEt (9) and OPMB (10).
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The ground state and TS geometry of the arenes are essen-
tially identical except for the C-H bond undergoing activation:
in the TS of 1k this C-H bond is significantly elongated (1.419
Å versus 1.081 Å in the ground state) and the H is significantly
deviated from the arene plane (33.7° versus 2.1° in the ground
state). A study of the contribution of these two factors to ΔGdis
for C6H5F and 1k showed that while the elongation energy is
roughly the same in both cases (ΔGel(C6H5F)–ΔGel(1k) = 1.0
kcal/mol), the bending energy showed a very significant
change in favor of complex 1k (ΔGbend(C6H5F)– ΔGbend(1k) =
19.1 kcal/mol). Therefore, the role of the Cr(CO)3 fragment is
to facilitate the bending of the H in the TS leading to concerted
metallation-deprotonation. This is in stark contrast to previ-
ous results for a variety of arenes, where ΔGbend was found to
be generally constant, and ΔGel, which is directly related to the
acidity of the H, to be responsible for the differences in reac-
tivity.19h Interestingly, a survey of reported crystal structures
of (ArH)-Cr(CO)3 complexes shows that the arene C-H bonds
are generally bent out of the plane towards the Cr.20
Scheme 4. Nucleophilic aromatic substitution reac-
tions on arylation product 3aa-Cr(CO)3.
To test the applicability of our approach for enhancing the
reactivity of less electron-poor arenes, we examined the effect
of complexation on unsubstituted benzene, which has been
reported to be 11-fold less reactive than fluorobenzene under
CMD conditions.7b Gratifyingly, complex 1p reacted with 2a
under our standard conditions at 100 °C to form the corre-
sponding biaryl product in 42% yield. This demonstrates that
our approach is effective even in the absence of an electron-
withdrawing group in the arene (Scheme 5).
a) Pyrrolidine, K2CO3, DMSO; DMSO, 80 °C. b) NaH, CF3CONH2, DMF; NaOH, EtOH.
c) NaH, Indole, 15-crown-5-ether, PhCH3; MnO2, AcOH. d) KCN, DMSO; DMSO, 80 °C.
e) NaH, EtSH, THF; hν. f) NaH, PMB-OH, THF; MnO2, AcOH.
Figure 2. CMD pathway and distortion-interaction
analysis for C-H bond activation of complex 1k.a
Scheme 5. Complexation-enabled direct arylation of
benzene.
In conclusion, we have demonstrated a novel approach for
dramatically enhancing the reactivity of simple arenes to-
wards C-H arylation via π-complexation to Cr(CO)3. This is the
first general methodology for the direct arylation of mono-
fluorobenzenes affording excellent yields of ortho-substituted
biaryls with high selectivity. The arylated complexes can be
further derivatised, before decomplexation, by reaction with a
variety of nucleophiles. Our studies indicate that the observed
effect results from a decrease of the energy cost required for
distorting the C-H bond of the complexed arene in the CMD
transition state. Current studies are directed towards expand-
ing the substrate and reaction scope of this new strategy.
a Structures and energies calculated by DFT (B3LYP / DZVP / TZVP).
Gibbs free energies (G) in kcal·mol–1. ΔGdist: distortion energy; ΔGint
:
interaction energy.
In order to probe the origin of the enhanced reactivity of
Cr(CO)3 complexes 1 towards C-H arylation, DFT calculations
were carried out with C6H5F or C6H5F-Cr(CO)3 complex (1k)
and [Pd(PMe3)(Ph)OAc] (11) as the active species effecting
the C–H activation (Figure 2),17 which has already been shown
to accurately mimic the experimental results of CMD process-
es for simple arenes.18,19 The calculated transition state (TS)
for 1k is significantly lower (by 5.7 kcal/mol) than the one
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AUTHOR INFORMATION
K. Org. Lett. 2010, 12, 2116; (e) Chen, F.; Min, Q.-Q.; Zhang, X. J. Org.
Chem. 2012, 77, 2992; (f) Wang, Y.-N.; Guo, X.-Q.; Zhu, X.-H.; Zhong, R.;
Cai, L.-H.; Hou, X.-F. Chem. Commun. 2012, 48, 10437.
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Corresponding Author
* i.larrosa@qmul.ac.uk
7 For a recent review on “undirected” C-H activation, see: (a) Kuhl, N.;
Hopkinson, N.; Wencel-Delord, J.; Glorius, F. Angew. Chem. Int. Ed.
2012, 51, 10236. For selected examples, see: (b) Lafrance, M.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 16496; (c) Stuart, D. R.; Fagnou, K. Sci-
ence 2007, 316, 1172; (d) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V.
M. Chem. Sci. 2010, 1, 331; (e) Liu, W.; Cao, H.; Lei, A. Angew. Chem. Int.
Ed. 2010, 49, 2004; (f) Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc.
2011, 133, 13864.
Author Contributions
‡These authors contributed equally.
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ACKNOWLEDGMENT
We are grateful to the European Research Council for a Start-
ing Research Grant (I.L.), Marie Curie Foundation for an Intra-
European Fellowship (X.C.C.), QMUL for a studentship (K.K.)
and EPSRC National Mass Spectrometry Service (Swansea).
8
For recent publications on (arene)chromium tricarbonyl complexes
in organic synthesis, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed.
2002, 41, 4176; (b) Kündig, P. E., Ed. Topics in Organometallic
Chemistry: Transition Metal Arene π-Complexes in Organic Synthesis
and Catalysis, 1st ed.; Springer: Berlin Heidelberg, 2004; (c) Prim, D.;
Andrioletti, B.; Rose-Munch, F.; Rose, E.; Couty, F. Tetrahedron 2004,
60, 3325; (d) Rosillo, M.; Domínguez, G.; Pérez-Castells, J. Chem. Soc.
Rev. 2007, 36, 1589; (e) Murai, M.; Uenishi, J.; Uemura, M. Org. Lett.
2010, 12, 4788.
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15
The yields of mono-arylation products obtained after chromato-
graphic purification were: for Ph-CF3, 25% (o:m:p 4.5:7:1), and for
Ph-CO2Me, 24% (o:m:p 4:7:1).
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1995 , 251; (c) Semmelhack, S. F.; Schmalz, H. G. Tetrahedron Lett.
1996, 37, 3089; (d) Baldoli, C.; Del Buttero, P.; Maiorana, S. Tetrahe-
dron Lett. 1992, 33, 4049; (e) Semmelhack M. F.; Hilt, G.; Colley, J. H.
Tetrahedron Lett. 1998, 39, 7683; (f) Dickens, M. J.; Gilday, J. P.;
Mowlem, T. J.; Widdowson; D. A. Tetrahedron 1991, 47, 8621.
17 B3LYP functional and TZVP basis set were used for main group atoms
(C, H, F, O, P) and DZPV for transition metals (Pd, Cr).
4
For examples of meta arylation, see: (a) Phipps, R. J.; Gaunt, M. J.
18
For reviews, see: (a) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39,
Science 2009, 323, 1593; (b) Duong, H. A.; Gilligan, R. E.; Cooke, M. L.;
Phipps, R. J.; Gaunt, M. J. Angew. Chem. Int. Ed. 2011, 50, 463.
1118. (b) Ackermann, L. Chem. Rev. 2011, 111, 1315. (c) Gorelsky, S. I.
Coord. Chem. Rev. 2013, 257, 153.
5
For recent reviews on the direct arylation of heteroarenes, see:
19 (a) Garcia-Cuadrado, D.; De Mendoza, P.; Braga, A. A. C.; Maseras, F.
A. Echavarren, A. M. J. Am. Chem. Soc., 2007, 129, 6680; (b) Caron, L.;
Campeau, L.-C.; Fagnou, K. Org. Lett., 2008, 10, 4533; (c) Gorelsky, S.-
I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc., 2008, 130, 10848;
(d) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron, 2008, 64, 6015;
(e) Pascual, S.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren,
A. M. Tetrahedron, 2008, 64, 6021; (f) Liegault, B.; Lapointe, D.; Caron,
L; Vlassova, A.; Fagnou, K. J. Org. Chem., 2009, 74, 1826; (g) Liegault,
B.; Petrov, I; Gorelsky, S. I., Fagnou, K. J. Org. Chem., 2010, 75, 1047;
(h) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658.
20 (a) Rees, B.; Coppens, P. Acta Crystallogr., Sect B: Struct. Crystallogr.
Cryst. Chem. 1973, 29, 2515; (b) Muetterties, E. L.; Bleeke, J. R.; Wu-
cherer, E. J. 1982, 82, 499.
(a) Roger, J.; Gottumukkala, A. L.; Doucet, H. Chem Cat Chem 2010, 2,
20; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, 215; (c) Lebras-
seur, N.; Larrosa, I. in Advances in Heterocyclic Chemistry, Vol. 105;
Katritzky, A. R., Ed. 2012. For selected examples, see: (d) Turner, G. L.;
Morris, J. A.; Greaney, M. F. Angew. Chem. Int. Ed. 2007, 46, 7996; (e)
Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926; (f) Ciana,
C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.; Gaunt, M. J. Angew. Chem.
Int. Ed. 2011, 50, 458; (g) Nadres, E. T.; Lazareva, A.; Daugulis, O. J.
Org. Chem. 2011, 76, 471; (h) Kuhl, N.; Hopkinson, M. N.; Glorius, F.
Angew. Chem. Int. Ed. 2012, 51, 8230;
6 For selected examples, see: (a) Lafrance, M; Rowley, N. C.; Woo, T.K.,
Fagnou, K., J. Am. Chem. Soc. 2006, 128, 8754; (b) Wei, Y.; Kan. J.; Su,
N.; Hong, M., Org. Lett. 2009, 11, 3345; (c) Sun, Z.-M.; Zhang, S.; Manan,
R.-S.; Zhao, P. J. Am. Chem. Soc. 2010, 132, 6935; (d) Rene, O.; Fagnou,
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