Rhodium-catalysed ortho-alkynylation of nitroarenes

The ortho-alkynylation of nitro-(hetero)arenes takes place in the presence of a Rh(iii) catalyst to deliver a wide variety of alkynylated nitroarenes regioselectively. These interesting products could be further derivatized by selective reduction of the nitro group or palladium-catalysed couplings. Experimental and computational mechanistic studies demonstrate that the reaction proceeds via a turnover-limiting electrophilic C–H metalation ortho to the strongly electron-withdrawing nitro group.


Introduction
Nitrobenzenes are among the most important bulk chemicals, used in a range of applications such as dyes, organic materials, solvents and perfumes. 1 With a price comparable to benzene, nitrobenzene serves as precursor to most of the functionalized aromatic building blocks. Therefore, the development of methods for the functionalization of nitrobenzenes is of high interest.
Nitrobenzenes can be functionalized at the ipso-position by reduction to an aniline and formation of the diazonium salt, allowing access to versatile aryl halides (Sandmeyer reaction). 2 More recently, the functionalization of nitrobenzenes gained momentum with the discovery that rhodium, 3 copper, 4 and palladium 5 complexes can undergo oxidative addition to nitrobenzenes, opening the door to their use as coupling partners in transition-metal catalysis. Nitrobenzenes are usually functionalized at the meta-position via electrophilic aromatic substitution, although functionalization at the ortho-and para-positions is also possible via the so-called vicarious nucleophilic substitution (Scheme 1a), 1,6 where an a-halo-carbanion generated from an active methylene compound adds to the ortho-and/or para-position. However, this method is mainly limited to alkylation-type functionalization and oen requires electronically activated nitrobenzenes to achieve synthetically useful yields and good selectivity. Therefore, the selective ortho-functionalization of unbiased nitrobenzene derivatives is an important and yet underdeveloped transformation in organic chemistry.
The development of metal-catalysed directed C-H functionalization reactions has become an efficient method for the synthesis of functionalized arenes. Even though the ability of the ubiquitous nitro group to coordinate to metals is known, 7 its use as directing group in catalysis is rare and limited to direct arylation. 8 Our group observed the intramolecular Pd-catalysed ortho C-H arylation of nitrobenzene derivatives, although in that reaction the nitro group was not acting as a regiodirecting substituent. 9a The rst genuine intermolecular Pd-catalysed direct arylation of nitrobenzenes was achieved using aryl halides 8a and tosylates, 8b although an excess of nitrobenzene was required (Scheme 1b). The ortho C-H arylation of nitrosubstituted nitrogen heteroarenes has been developed to a greater extent, but, in these examples, the site-selectivity is a consequence of the heteroarene electronics and not of the regiodirecting effect of the nitro group. 10 Scheme 1 Intermolecular ortho-functionalization of nitrobenzenes and present studies. VNSH ¼ vicarious nucleophilic substitution of hydrogen.
Here we report the Rh-catalysed nitro-directed C-H alkynylation of nitrobenzenes, which tolerates a broad range of functional groups (Scheme 1c). 11 Our experimental and computational mechanistic investigations are consistent with a turnover limiting electrophilic C-H activation step, followed by alkyne insertion and bromide elimination. We also disclose preliminary results on a related C-H iodination reaction, which may pave the way for other types of ortho-functionalization via sequential Rh/Pd catalysis.

Results and discussion
As part of our research program on the selective C-H alkynylation of functionalized molecules, we recently found that the combination of a Cp*Rh(III) catalyst and bromo-alkyne 2a is a highly active system for the alkynylation of a broad-range of C-H bonds. 12 Our initial attempts to extend this reactivity to 2methylnitrobenzene (1a) at 50 C proved unsuccessful (Table 1, entry 1). Interestingly, formation of the corresponding alkynylated product 3a could be observed at 80 C as the only product ( The scope of the Rh-catalysed alkynylation of nitrobenzenes was explored using the optimized conditions for the synthesis of 3a (Scheme 2). Although the reactions were typically performed overnight for convenience, reaction times can be oen reduced to just a few hours. Alkynylation of nitrobenzene was performed under the optimised reaction conditions to obtain a 4 : 1 mixture of mono-and dialkynylated product in 75% yield. This ratio can be reversed by increasing the amount of bromoalkyne 2a, which results in the obtention of dialkynylated 3b 0 in excellent yield. Functionalities such as alkyl (3a, 3c), aryl (3d, 3j), ether (3e), aldehyde (3f) and halides (3g-i), groups at the ortho position were well tolerated, leading to 3a-j in 40-95% yield and complete ortho-selectivity. In the case of metasubstituted nitrobenzenes, the alkynylation occurred exclusively at the least hindered site leading to methyl, dimethyl amine or vinyl substituted compounds (3k-m) groups, whereas uoro and methoxy substituents led to a 2 : 1 mixture of monoand dialkynylated products, favoring the formation of 1,2,3trisubstituted nitrobenzenes (3n,o). Regarding para-substituted derivatives, mixtures of mono-and dialkynylated products (3p,q) with complete ortho-selectivity were also obtained. Polysubstituted substrates could also be efficiently alkynylated leading to (3r-ag) in 32-95% yield with perfect regioselectivity. In this context, substituents such as alkyl, aryl, ether, halide, and even triuoromethyl were employed in different substitution patterns. We followed our investigations with polyaromatic nitrobenzenes, which gave the corresponding products (3ah, 3ai, 3an) in moderate to excellent yields. The formation of dialkynylated compound 3an might arise from a subsequent electrophilic alkynylation directed by the electron-donating MeO group. Importantly, alkynylated 1-nitropyrene 3ai was obtained in 90% yield at 1 mmol scale in only 4 hours. Next, we applied our reaction conditions to the alkynylation of nitro- Table 1 Rh-catalysed ortho-alkynylation of 1a
Terminal alkyne 4 was easily accessed by treatment of 3b with a solution of TBAF in THF (Scheme 3). Selective reduction of the nitro group with Fe under acidic conditions delivered aniline 5 in excellent yield, with the triple bond untouched. We derivatized this compound further towards the synthesis of 2-(triisopropyl)silylindole (6) via Au(I)-catalysed cyclisation. This new protocol of alkynylation/reduction/cyclisation allows for the efficient synthesis of important indoles from nitroarene feedstocks. More complex anilines, such as chiral 7, can also be prepared by denitrative Pd-catalysed C-N coupling, following the procedure reported by Wu and coworkers. 5g This protocol can also be applied to the synthesis of more complex structures such as chiral aminoalkynylated indole 8, prepared in just two steps from simple nitroindole 1al.
Our alkynylation protocol can also be of high interest in the synthesis and modication of p-extended systems, which are attracting attention from the synthetic community due to their interesting properties. 14 In this context, we performed the alkynylation of 1-nitropyrene, easily accessed by electrophilic nitration, in a 1 mmol scale with an excellent result (Scheme 2). The corresponding alkynylated nitropyrene 3ai was then subjected to the C-N coupling conditions to form chiral secondary aniline 9, again in good yield (Scheme 3). Deprotection followed by Au(I)-catalysed cyclisation delivered chiral p-extended heteroarene 10 in excellent overall yield. Alternatively, denitrative Suzuki-Miyaura-type coupling was possible by slightly Scheme 2 Rh-catalyzed ortho-alkynylation of nitrobenzenes. Yields of isolated products in parentheses. In cases in which dialkynylated products were also formed, mono-vs. dialkynylation selectivity is shown in parentheses. a With 2 equiv. of bromo-alkyne. b At 100 C. c With 2 equiv. of nitro-heteroarene. d 4 h reaction time.
modifying the reported reaction conditions. 5a Different aromatic boronic acids were successfully coupled with 3ai to obtain the desired biaryl systems 11 and 12. The corresponding terminal alkynes are also accessible by TBAF deprotection. Thus, as an example of functionalized polycyclic aromatic hydrocarbon, 2-ethynyl-1-(naphthalen-2-yl)pyrene (13) can be easily obtained in just four steps regioselectively from pyrene by nitration, o-alkynylation, cross-coupling, and deprotection.
Interestingly, under our optimised reaction conditions, the alkynylation of nitrendipine, a commercialized antihypertensive agent, leads to alkynylated product 14 in 40% yield with concomitant oxidation of the 1,4-dihydropyridine ring (Scheme 4).
The site selective Rh-catalysed ortho-functionalization could also be extended to the iodination of nitrobenzenes using Niodosuccinimide (Scheme 5a). 15 Interestingly, an overall regioselective ortho-arylation of nitrobenzene could be performed by a sequential Rh-catalysed ortho-iodination/Pd-catalysed Suzuki-Miyaura coupling leading to biaryl 16 in 50% yield (Scheme 5b).
To understand the mechanism of this unprecedented nitrodirected Rh-catalysed ortho-alkynylation, we performed a series of studies encompassing experimental and computational approaches. The computational calculations were carried out using DFT at uB97XD/6-31G(d)(H, C, O, N, F, Cl) + LANL2DZ(Rh, Ag, Br)//6-311G++(d,p)(H, C, O, N, F, Cl) + LANL2DZ(Br) + LANL2TZ(Rh, Ag) level of theory, taking into account the solvent effect (SMD ¼ 1,2-dichloroethane). 16 First, we studied computationally the complete mechanism of the Rh-catalysed alkynylation of nitrobenzene 1a. 17 According to our studies, aer several dissociative ligand events, intermediate II undergoes a turnover limiting C-H bond cleavage (DG ‡ ¼ 25.1 kcal mol À1 , energy span) which proceeds through a concerted six-membered cyclic transition state with intramolecular acetate-assistance (TS II-III ) (Fig. 1, violet section). 18 Dissociative substitution of acetic acid by bromoalkyne 2a gives (h 2 -alkyne)Rh intermediate IV, which undergoes alkyne insertion through a low energy transition state (TS IV-V , DG ‡ ¼ 16.1 kcal mol À1 ) (Fig. 1, pink section). The nal step consists in an almost barrierless AgOAc-assisted b-debromination (DG ‡ ¼ 5.8 kcal mol À1 ) to form o-alkynylated nitrobenzene 3a in an overall exergonic reaction (DG ¼ À40.4 kcal mol À1 ) (Fig. 1, grey  sections). The C-H cleavage transition state (TS II-III ) features a slightly elongated C1-H1 (1.277Å) bond, whereas C1-Rh (2.248Å) and H1-O1 (1.359Å) bond distances are considerably contracted compared to the previous intermediate II (Table in Fig. 1). The NBO analysis of TS II-III reveals two main electronic interactions not present in intermediate II related to the C-H bond cleavage event. 13 First, a lone pair on O1 delocalized over H1 (h O1 , 86.3% O1 and 7.2% H1), which highlights the role of the acetate in the abstraction of H1 during TS II-III (Fig. S6 †). Second, a NLMO associated to s-C1-H1 bond which is delocalized over Rh (U C1-H1 , 65.4% C, 20.6% H and 8.6% Rh) indicating the formation of the C1-Rh bond during TS II-III (Fig. S7 †). All in all, the indicated bond distances and the NBO analysis suggest that TS II-III is considerably asynchronous with a greater extent of C1-Rh and O1-H1 bonds forming than C1-H1 bond cleavage.
Experimentally, we found a signicant kinetic isotope effect (KIE ¼ 4.0) (Scheme 6a), which supports the computational nding that the C-H bond cleavage corresponds to the turnover determining step of the catalytic cycle. Moreover, the computed KIE at 110 C using Cp*Rh was 4.2 and accurately reproduces the experimental results (Scheme 6b). 19 Interestingly, the computed KIE using a model system bearing Cp ligand was signicantly smaller (KIE ¼ 2.7).
Next, to understand whether or not a positive charge could build-up ortho to the nitro group, we performed initial rates measurements of meta-substituted 2-methylnitrobenzenes 1a,ty (Fig. 2a). A Hammett correlation was found (R 2 ¼ 0.95 using s p ) with a negative r value (r ¼ À3.6), suggesting a decrease of electron density at the aryl ring in the C-H activation step (Fig. 2c, dark blue data, triangles). A computational Hammett correlation was also found for a series of meta-substituted nitrobenzenes and the s p parameter (r ¼ À2.7, R 2 ¼ 0.81) (Fig. 2c, clear blue data, circles). 20,21 The computed negative r value is in agreement with the experimental results. To understand the charge distribution in the transition state of the turnover-limiting step, we assessed the charge accumulation (Dd + ) over the meta-substituted nitrobenzene fragment in the concerted transition states by NBO analysis (Fig. 2b and c, pink data). There is a slight positive charge built up on the Fig. 1 Simplification of the computed free energy profile for the Rh-catalysed alkynylation of 2-methylnitrobenzene (1a) and relevant structural information of stationary points II, TS II-III and III. Free energies in kcal mol À1 at 25 C.
Scheme 6 (a) Experimental and (b) computational KIE for the Rhcatalysed ortho-alkynylation of nitrobenzenes 1b and 1b-d 5 . Free energies in kcal mol À1 at 110 C. substituted nitrobenzenes (Dd + ¼ 0.06-0.14), which agrees with the trends observed by Hammett analysis. In fact, a straight regression line was obtained by plotting Dd + vs. s p parameters (R 2 ¼ 0.89) (Fig. S13 †). Both the Hammett and NBO analysis suggest that the Rh-catalysed C-H activation corresponds to an electrophilic concerted metalation deprotonation process, 12 in which both an electrophilic metal and a basic ligand cooperate in the cleavage of the C-H bond and subsequent rhodacycle formation.
Despite our previous observation of this mechanism for the alkynylation of esters, ethers and ketones, 12a the engagement of nitrobenzenes in acetate-assisted internal electrophilic substitution is rather remarkable, considering the strong electronwithdrawing character and reduced coordination ability of the nitro group. An inspection of the structural features in intermediate II (Table 2) shows an elongated O-Rh bond for the nitro (2.253Å) when compared to the other directing groups (2.178-2.209Å), showcasing the limited coordination offered by the -NO 2 group (Table 2). Moreover, TS II-III exhibits a shorter C1-H1 bond and longer C1-Rh and O-Rh distances for nitrobenzene.
We also examined theoretically the formation of dialkynylated nitrobenzene 3b 0 (Scheme 7). Structurally similar transition states were found both for the C-H cleavage of 1b and the subsequent C-H activation step of mono-alkynylated nitrobenzene 3b. 13 The small differences between the activation barriers calculated for the rst (DG ‡ CH-1 ¼ 26.2 kcal mol À1 ) and the second (DG ‡ CH-2 ¼ 26.4 kcal mol À1 ) ortho-C-H cleavages of nitrobenzene 1j explains the moderate mono/di-alkynylation selectivity observed experimentally under the optimal conditions ð3b : 3b 0 exp ; 4 : 1Þ: Regarding nitro-heteroarenes, we found that the activation energy for the C-H metalation step is energetically more demanding for thiophene (1aj) and 3-nitropyridine (1ao) than for nitroarenes which make the overall ortho-alkynylation more challenging. 13 Surprisingly, our calculations show that the alkyne insertion/ Ag-assisted-b-debromination sequence is energetically feasible for the experimentally unsuccessful alkyne counterparts 2c, 2d, and 2f, 13 which suggests that alkyne 2a has the correct steric and electronic balance to prevent scenarios in which the alkyne is unproductively consumed leading to secondary products prior to its insertion into the C-Rh bond. Particularly intrigued by the low activation barrier for the b-debromination for non-Si containing bromo phenylacetylene (2f) (DG ‡ ¼ 4.3 kcal mol À1 ), we examined the hyperconjugative interactions on the previous intermediates to the bromo elimination V and V 0 for alkynes 2a and 2f, respectively (Fig. 3). 22 For V, the NBO analysis revealed a strong interaction between s(Rh-C a ) and s*(Br-C b ) orbitals (E ij (2) ¼ 22.7 kcal mol À1 ) (Fig. 3, le), while no interaction was found between the s(Si-C a ) and s*(Br-C b ) orbitals. The same  scenario was encountered for V 0 , in which the s(Rh-C a ) and s*(Br-C b ) orbitals also interact signicantly (E ij ¼ 17.4 kcal mol À1 ) (Fig. 3, right). These results indicate that the Ag-assisted debromination is facilitated by the s-s-conjugation arising from the so-called "b-Rh effect", 17a,b rather than by b-Si effect. 23

Conclusions
We have developed the rst general o-alkynylation of abundant nitroarenes, which proceeds in a rather straightforward manner under catalytic conditions. Despite the strongly electronwithdrawing nature of the nitro group, our experimental and computational results demonstrate that the rhodium-catalysed o-alkynylation of nitroarenes takes place by an electrophilic concerted metalation/deprotonation pathway. The resulting oalkynyl nitroarenes are precursors of indoles by reduction to the corresponding anilines and cyclization 24 and have also been used as synthons for the preparation of other valuable products. 25 In this context, the nitro group can be viewed as a "super pseudo-halogen", that participates in a manifold of crosscoupling reactions, [3][4][5] while allowing also the introduction of highly versatile alkynyl groups at the ortho position under catalytic conditions.

Data availability
All experimental and computational data associated with the article are incorporated into the ESI. †

Conflicts of interest
There are no conicts to declare.