Diverse ortho-C(sp2)-H functionalization of benzaldehydes using transient directing groups

Article abstract of DOI:10.1021/jacs.6b11188

Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho-C(sp²)-H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C-H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed in situ via imine linkage can override other coordinating functional groups capable of directing C-H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C-H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue.

Full text of DOI:10.1021/jacs.6b11188

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Article
Diverse ortho-C(sp2)-H Functionalization of
Benzaldehydes using Transient Directing Groups
Xi-Hai Liu, Hojoon Park, Jun-Hao Hu, Yan Hu, Qun-Liang Zhang, Bao-
Long Wang, Bing Sun, Kap-Sun Yeung, Fang-Lin Zhang, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Dec 2016
Downloaded from http://pubs.acs.org on December 22, 2016
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Diverse ortho-C(sp2)−H Functionalization of
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Benzaldehydes using Transient Directing Groups
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Xi-Hai Liu†,┴, Hojoon Park‡,┴, Jun-Hao Hu†,┴, Yan Hu†,┴, Qun-Liang Zhang†, Bao-Long Wang†,
†
‡
Bing Sun†, Kap-Sun Yeung§, Fang-Lin Zhang*, , Jin-Quan Yu*,
†Department School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of
Technology, Wuhan 430070, People’s Republic of China
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‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla,
California 92037, United States
§Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research
Parkway, Wallingford, Connecticut 06492, United States
*yu200@scripps.edu
*fanglinzhang@whut.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. Pd-catalyzed CH functionalizations promoted by transient directing group remain largely
limited to C–H arylation only. Herein, we report a diverse set of ortho-C(sp2)−H functionalizations of
benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary
directing group, Pd(II)-catalyzed C−H arylation, chlorination, bromination, and Ir(III)-catalyzed
amidation could be achieved on benzaldehyde substrates. The transient directing groups formed in situ
via imine linkage can override other coordinating functional groups capable of directing C−H activation
or catalyst poisoning, significantly expanding the scope for metal-catalyzed C−H functionalization of
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benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-
stage diversification of a drug analogue.
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1. Introduction
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Benzaldehydes are highly desirable substrates for directed C(sp2)−H functionalization due to their
abundance and synthetic versatility. Currently, however, only a handful of reports describe aldehyde-
directed C−H functionalization with transition metal catalysts.1 The development of such methodology is
impeded by the aldehyde’s weak coordinating ability, susceptibility towards oxidation, and undesired
metal insertion into acyl C−H bond (Scheme 1a). The weak coordinating ability of an aldehyde group is
easily outcompeted by that of a wide range of functional groups, including amide, ester, and even ketone,1e
which significantly restricts the substrate scope. Also, the scope of transformation is limited due to the
difficulty of preferentially activating an inert aryl C−H bond over an aldehydic C−H bond, which can
undergo either metal-free oxidation or metal-insertion.2,3 In order to address this issue, several groups
have reported C−H functionalization methods using pre-installed imine or oxime directing groups.4
However, the practicality of this strategy is compromised by additional steps required for
installation/removal of the directing group.
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As an alternative approach to overcome the present limitations, we focused on using the reversible
imine formation between aldehyde and amines to direct metal catalysts. A pioneering study of Jun and
coworkers demonstrated that 2-iminopyridyl moiety formed from reversible condensation of aldehyde
and 2-aminopyridine can direct Rh insertion into acyl C(sp2)−H bonds.5 Also, Seayad and coworkers
reported the Rh-catalyzed oxidative coupling of benzaldehydes using 4-trifluoromethylaniline to
reversibly form an imine directing group.6 More recently, our group disclosed the first Pd-catalyzed
C(sp3)−H functionalization of aldehydes and ketones using transient directing group (DG) strategy.7 In
this case, only a catalytic amount of amino acid is necessary to reversibly form an imino acid directing
group for C(sp3)−H activation. Subsequently, Hu8 and Ge9 also reported the C(sp3)−H arylation of
aldehyde substrates using acetohydrazide and -Ala-OH as transient DGs respectively. Based on these
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results, we further envisioned that this bidentate, transient DG strategy can be applied as a practical, and
broadly useful approach for C(sp2)−H functionalization of simple benzaldehyde substrates (Scheme 1b).
First, the use of stoichiometric amount of reagents and additional steps for installation/removal of the
directing group are avoided. Second, the bidentate binding mode can override other coordinating
functional groups that can either direct C−H activation at other positions or poison the catalyst, which can
significantly improve site-selectivity and broaden the substrate scope.
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Herein, we report the development of a series of weakly coordinating transient DGs for diverse
ortho-C(sp2)−H functionalization reactions of benzaldehydes. Pd(II)-catalyzed arylation, chlorination,
and bromination using bidentate amino acid-type transient DG, and Ir(III)-catalyzed amidation using
monodentate aniline as a transient DG have been developed (Scheme 2a). To the best of our knowledge,
C(sp2)−H heteroarylation, chlorination, and bromination have not been achieved on benzaldehyde
substrates to date. The aldehyde oxidation issue was circumvented by the careful choice of reaction
conditions and oxidants that preferentially participate in the Pd(II)→Pd(IV) process. Also, unlike the
previously reported aldehyde-directed C(sp2)−H functionalization method,1e this new approach can
override and tolerate the directing effects of a wide range of functional groups present within the aldehyde
substrates, such as amides, carbamates, and heterocycles with complete site-selectivity (Scheme 2b).
Thus, sequential CH functionalizations in the absence and in the presence of transient DG allows
multiple diversifications via CH activation, which can lead to diverse tetra-substituted arene cores that
are widespread in pharmaceuticals (Scheme 3).
Scheme 1. C(sp2)H Functionalization of Benzaldehydes
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Scheme 2. Diverse ortho-C(sp2)H Functionalizations using Transient Directing Group Strategy
Scheme 3. Application towards Multi-substituted Arene Synthesis
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2. Results and Discussion
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(1) Arylation
Our efforts to develop transient DGs to promote Pd-catalyzed CH activation reactions have met
with tremendous difficulties in the past decade. Our failure can be largely attributed to the use of strongly
coordinating transient DGs which can result in formation of various unreactive Pd(II) complexes when
they are covalently associated or dissociated with the substrates. In addition, the CH insertion Pd(II)
intermediates arisen from bischelation with these strongly coordinating directing group, even if
generated, are often too stable for functionalization or dissociation of the transient DG. Progress was
recently made by attaching a weakly coordinating carboxyl group to aldehydes and ketones via an imine
linkage.7 Based on this previous work on C(sp3)H arylation of aldehyde and ketone using -amino acid
as the transient DG, we began to develop diverse ortho-C(sp2)H activation reactions of simple
benzaldehydes. Ortho-C(sp2)H arylation was selected as the first target as this can lead to wide range of
biaryl compounds with synthetically useful formyl group. We first tested the effect of transient DG
structure on the ortho-arylation of m-chlorobenzaldehyde (1a) with methyl 4-iodobenzoate (2a) (Table
1). While -amino acids gave similar results (T1~T4), quaternary amino acid T5 proved to be the best
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transient DG yielding 56% of the arylated product 3. It is interesting to note that T1 gave the best result
for benzylic C(sp3)H activation in our previous study, which forms a 6-membered palladacycle unlike
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ortho-C(sp2)H activation (5-membered palladacycle). This implies that the 5-membered palladacycle
formation is promoted by the smaller bite angle generated from the quaternary carbon center of T5.
Indeed, cyclopropyl quaternary amino acid T6, which generates a larger bite angle due to the ring system,
was far less effective. Transient DGs that form 6-membered chelation (T7, T8) also afforded low yields.
The result was further optimized to 89% NMR yield when the acid additive was replaced with TFA and
the silver loading was lowered to 1 equivalent (Table 1). A control experiment without using the transient
DG gave no product formation.
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Table 1. Optimization of ortho-C(sp2)H Arylation of Benzaldehydea,b
aReaction conditions: substrate 1a (0.1 mmol, 1.0 equiv.), 2a (2.0 equiv.), Pd(OAc)2 (10 mol%), Transient DG (40 mol%),
Ag(TFA) (1.5 equiv.), CH2ClCO2H (10 equiv.), HFIP (0.5 mL), 100 °C, 24 h. bThe yield was determined by 1H NMR
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analysis of the crude product using CH2Br2 as the internal standard. HFIP:TFA = 9:1 was used instead of
HFIP/CH2ClCO2H, 1 equiv. of Ag(TFA) was used.
With the optimized reaction conditions in hand, the ortho-CH arylation was applied to different
benzaldehyde substrates and aryl iodide coupling partners (Table 2). First, the scope of substrates was
tested with 2a as the coupling partner. Substrates with different halogen substitutions underwent arylation
to provide the products in good to moderate yields (3a~3f). Both electron-withdrawing (3g~3i) and
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electron-donating substituents (3j~3k) were well tolerated to give the arylated products in excellent to
moderate yields. To our delight, heterocyclic substrate 3-formylindole also underwent arylation at the 4-
position to yield 3l in 82% yield. Next, the scope of aryl iodides was tested. To prevent the decomposition
of some aryl iodides, the acid was changed from TFA to AcOH or CH2ClCO2H. Under this modified
condition, arylation was carried out smoothly regardless of the electronic property of the aryl iodide (3k,
3m~3p). Also, both meta- and ortho-substituted aryl iodides were tolerated (3q, 3r). Lastly, arylation
with heteroaryl iodides was tested. We envisioned that the transiently formed bidentate directing group
can sufficiently outcompete the coordinating ability of heterocyclic moieties and allow CH
heteroarylation. While simple iodopyridines and iodothiophenes did not yield any product, we were able
to achieve heteroarylation when the 2-position of the heterocycles were substituted. The model substrate
reacted with 2-acetyl-6-iodothiophene to give the product 3s in 55% yield. With higher catalyst loading,
iodopyridines also yielded heteroarylation products 3t~3v in synthetically useful yields. Albeit low yield,
heteroarylation also proceeded with both iodoquinoline and iodoquinoxaline to afford 3w and 3x
respectively.
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Table 2. Scope of ortho-C(sp2)H Arylation of Benzaldehydesa,b
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aReaction conditions: substrate 1 (0.1 or 0.2 mmol, 1.0 equiv.), 2 (2.0 equiv.), Pd(OAc)2 (10 mol%), T5 (40 mol%),
Ag(TFA) (1.0 equiv.), HFIP:TFA = 9:1 (0.2 M), 100 °C, 24 h. bIsolated yields.
csubstrate 1 (0.1 or 0.2 mmol, 1.0 equiv.), 2 (3.0 equiv.), Pd(OAc)2 (10 mol%), T5 (40 mol%), Ag(TFA) (2.0 equiv.),
HFIP (0.2 M), CH2ClCO2H or AcOH (10 equiv.), 100 °C, 24 h. d110 oC
esubstrate 1 (0.1 mmol, 1.0 equiv.), 2 (2.0 equiv.), Pd(OAc)2 (10 mol%), T5 (20 mol%), Ag(TFA) (3.0 equiv.),
HFIP:AcOH = 1:1 (0.2 M), 110 oC, 24 h. f Pd(OAc)2 (15 mol%), T5 (30 mol%) were used.
(2) Chlorination/Bromination
Aryl halides are extremely useful compounds due to their distinct role as precursors for
organometallic reagents10 and versatile application via transition metal-catalyzed cross-coupling
reactions.11 Based on a number of reports on transition metal-catalyzed CH halogenation,12 we sought
to apply our transient DG strategy towards ortho-halogenation of benzaldehydes using N-halosuccinimide
(NXS) as the oxidant. We first investigated the ortho-chlorination of 1b with NCS as the chlorinating
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reagent. To our delight, we found that using T5 as the transient DG with catalytic amount of AgTFA can
yield the chlorinated product 4a in 52% NMR yield (Table 3). Next, the transient DG scaffold was
screened to further improve the result. It was interesting to find that unlike arylation, anthranilic acid T7
proved to be the optimal transient DG for ortho-chlorination. While having electron-withdrawing groups
on the anthranilic acid gave similar or lower yields (T9~T12), having electron-donating group completely
inhibited the reaction (T13). Also, T8 showed lower reactivity as transient DG for chlorination. Under
optimized conditions, the NMR yield drops to 52% when catalytic Ag(TFA) is not added. The substantial
enhancing effect of the catalytic Ag(TFA) is intriguing, and we believe that Ag(I) activates the NCS
oxidant towards Pd(II)→Pd(IV) process by interacting with the halogen atom but without forming
stoichiometric AgCl.
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Next, we screened the reaction conditions for ortho-bromination using NBS as the brominating
reagent. Gratifyingly, the ortho-brominated product 5a was obtained in 37% NMR yield using similar
reaction conditions with chlorination at higher temperature (Table 4, T7). Further screening of anthranilic
acid derivatives led us to identify the electron-deficient 4-nitroanthranilic acid T10 as the best transient
DG, and 1 equivalent of p-TsOH as a beneficial additive providing 85% NMR yield of 5a. It was crucial
to optimize the concentration of acid and transient DG, as these factors directly affect the equilibrium of
the imine formation and catalytic turnover of the transient DG. The detrimental effect of a –OMe group
in both chlorination and bromination implies the importance of weak-coordination in achieving CH
functionalization reactivity.13 Control experiments for both chlorination and bromination without using
the transient DGs gave trace amount of product formation.
Table 3. Optimization of ortho-C(sp2)H Chlorination of Benzaldehydea,b
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aReaction conditions: substrate 1b (0.3 mmol, 1.0 equiv.), NCS (1.5 equiv.), Pd(OAc)2 (10 mol%), Transient DG (50
mol%), Ag(TFA) (10 mol%), TFA (10 equiv.), DCE (3 mL), 60 °C, 24 h. bThe yield was determined by 1H NMR analysis
of the crude product using CH2Br2 as the internal standard. c30 mol% of Transient DG was used.
Table 4. Optimization of ortho-C(sp2)H Bromination of Benzaldehydea,b
aReaction conditions: substrate 1b (0.3 mmol, 1.0 equiv.), NBS (1.2 equiv.), Pd(OAc)2 (10 mol%), Transient DG (50
mol%), Ag(TFA) (10 mol%), DCE:TFA = 1:1 (3.0 mL), 90 °C, 24 h. bThe yield was determined by 1H NMR analysis
of the crude product using CH2Br2 as the internal standard. c1.0 equiv. of p-TsOH was used as additive.
We first examined the scope of benzaldehydes for the ortho-C(sp2)H chlorination reaction (Table
5). Benzaldehydes bearing different halogen substitutions (4a~4g), electron-donating groups (4h~4m),
and electron-withdrawing groups (4n~4q) all underwent smooth chlorination to provide the
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corresponding products in moderate to excellent yields. Using transient DG, we were able to obtain
exquisite site-selectivity ortho to the aldehyde group for substrates containing functional groups that are
known to direct transition metal catalysts for ortho-C-H activation, including ester (4n, 4o), sulfone (4p),
amide (4k, 4l), carbamate (4m), and nitrile (4q). The high site-selectivity and efficiency were also
pertained in biaryl substrates, where the aldehyde can override carbamate (4r), amide (4s), and ester (4t)
that are placed on the different aryl ring. Next, we discovered that we can further push the reaction towards
dichlorination when excess NCS was used under slightly more acidic condition (4u~4y). Both electron-
donating and electron-withdrawing groups at the para position or the second aryl ring can be tolerated to
give the dichlorinated product in moderate to good yields with complete site-selectivity. Also, the
scalability of this transformation was demonstrated by gram-scale preparation of 4t and 4y.
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Table 5. Scope of ortho-C(sp2)H Chlorination of Benzaldehydesa,b
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aReaction conditions: substrate 1 (0.3 mmol, 1.0 equiv.), NCS (1.5 equiv.), Pd(OAc)2 (10 mol%), T7 (30 mol%), Ag(TFA)
(10 mol%), TFA (10 equiv.), DCE (3.0 mL), 60 °C, 24 h. bIsolated yields. c2.5 equiv. of NCS was used. d4.0 mmol scale
e2.5 equiv. of NCS, DCE:TFA = 4:1 (3.0 mL) were used. f5.0 mmol scale.
Next, we evaluated the scope of the ortho-C(sp2)H bromination reaction (Table 6). Substrates
with halogen substitutions at different position underwent bromination to give the corresponding products
(5a~5f) in excellent to moderate yields. Both electron-donating groups (5g~5i) and electron-withdrawing
groups (5j~5m) were tolerated as well, providing moderate yields of the products. Interestingly, we could
carry out bromination on a thiophene ring (5n), showing the compatibility with heterocyclic substrates.
Bromination was also achieved with biaryl substrates that contain coordinating functionalities on the other
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aryl ring (5o~5q). Indeed, in all of the above cases the transient imino acid directing group can completely
override other directing functional groups such as ester, carbmate, amide, nitrile, and sulfone. Also,
dibromination can be achieved when excess NBS was used (5r).
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Table 6. Scope of ortho-C(sp2)H Bromination of Benzaldehydesa,b
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aReaction conditions: substrate 1 (0.3 mmol, 1.0 equiv.), NBS (1.2 equiv.), Pd(OAc)2 (10 mol%), T10 (50 mol%),
Ag(TFA) (10 mol%), p-TsOH (1 equiv.), DCE:TFA = 1:1 (3.0 mL), 90 °C, 24 h. bIsolated yields. csubstrate 1 (0.3 mmol,
1.0 equiv.), NBS (1.5 equiv.), Pd(OAc)2 (10 mol%), T10 (50 mol%), Ag(TFA) (10 mol%), TfOH (0.5 equiv.), DCE (3.0
mL), 90 °C, 24 h. d2.0 equiv. of NBS was used .
(3) Amidation
Aromatic amines are widespread in pharmaceuticals and natural products.14 Accordingly, a
number of catalytic C(sp2)H amination/amidation reactions were reported in the past decade using
different transition-metal species.15 Among those methods, Ir(III)-catalyzed amidation using organic
azides as nitrogen source has a number of advantages, including mild reaction condition (as low as room
temperature), no byproduct except N2, and no requirement for external oxidants.16 Therefore, we decided
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to investigate whether our transient DG strategy could also be applied to CH amidation reaction using
Ir(III) catalysis.17 After extensive screening, we found that anilines can serve as effective transient DGs
for Ir-catalyzed amidation reaction with tosyl azide (Table 7). It is important to note that unlike the
previous Pd-catalyzed reactions where bidentate amino acid-type transient DGs were used, a monodentate
transient DG is utilized in this reaction. Next, the effect of substitution on the aniline transient DG was
evaluated. With simple aniline T14, we observed 23% formation of the product 6. When p-methoxy group
is present (T15), the reaction only gave 6% of product, implying a similar trend with the previous
halogenation reactions. Indeed, the yield was improved when electron-withdrawing CF3 group was
introduced at either para- (T16), meta- (T17), or ortho- (T18) position. On the other hand, perfluorinated
aniline (T19) was not effective, presumably due to the weak nucleophilicity of the aniline. These results
led us to fine tune the electronics of the aniline, and the optimal results were obtained with 3,5-
bis(trifluoromethyl)aniline (T20) and 2-fluoro-5-(trifluoromethyl) aniline (T21), affording 83% and 86%
of the amidation product respectively. Under optimized conditions, the NMR yield drops to 16% when
TFA is omitted, indicating the crucial effect of the acid. Most likely, the acid promotes the catalytic
turnover of the transient DG. While the role of Ag(TFA) is currently unclear, it was not as crucial for the
reaction to proceed (45% NMR yield without Ag(TFA)). Finally, a control experiment without using the
transient DG gave no product formation.
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Table 7. Optimization of ortho-C(sp2)H Amidation of Benzaldehydea,b
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aReaction conditions: substrate 1 (0.1 mmol, 1.0 equiv.), TsN3 (1.5 equiv.), [Ir(Cp*)Cl2]2 (4 mol%), Transient DG (10
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mol%), Ag(NTf2) (16 mol%), Ag(TFA) (30 mol%), TFA (5 equiv.), DCE (1.0 mL), 50 °C, 24 h. The yield was
determined by 1H NMR analysis of the crude product using CH2Br2 as the internal standard.
Based on this optimized condition, we examined the scope of the amidation reaction (Table 8).
Benzaldehydes with electron-donating carbamates (6a~6b), amides (6c), and sulfonamide (6h) smoothly
reacted with tosyl azide to provide the amidated products in moderate to good yields with complete site-
selectivity. Electron-withdrawing esters (6d~6e) and nitriles (6f~6g) were also well-tolerated to give
moderate yields of the products. It is noteworthy that functional groups such as amide16b and ester16c
groups are known to direct Ir-catalyzed amidation reaction, which clearly demonstrates the effectiveness
of the transient DG strategy in overriding selectivity. As shown before, we also applied this system
towards biaryl substrates with multiple coordinating groups. The transient DG can override the ortho-
directing effect of carbamate (6i~6k), amide (6l~6n), and ester (6o~6p) groups on the different aryl ring.
Table 8. Scope of ortho-C(sp2)H Amidation of Benzaldehydesa,b
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aReaction conditions: substrate 1 (0.2 mmol, 1.0 equiv.), TsN3 (1.5 equiv.), [Ir(Cp*)Cl2]2 (4 mol%), T21 (10 mol%),
Ag(NTf2) (16 mol%), Ag(TFA) (30 mol%), TFA (5 equiv.), DCE (1.0 mL), 50 °C, 24 h. bIsolated yields. cT20 was used
instead of T21.
(4) Application
One of the key features we have shown in the above transformations is that we can selectively
functionalize the CH bond ortho to the aldehyde in the presence of a functional group that is also known
to direct CH functionalization. Accordingly, we can selectively synthesize multi-substituted aryl/biaryl
compounds with our new CH functionalization methods using transient DG in conjunction with
previously known methods. In Scheme 4, we synthesized a tetra-substituted arene and penta-substituted
biaryl compound via sequential CH functionalization. In the first functionalization step without using
any transient DG, Pd is directed towards the ortho-position of the anilide18 and carbamate19 group with
complete site-selectivity. In the second functionalization step with transient DG, Pd is directed towards
the ortho-position of the aldehyde group. Thus, an aldehyde group can be utilized as a latent directing
group that is functional only in the presence of a transient DG.
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Scheme 4. Multi-substituted Arene Synthesis via Sequential CH Functionalizations
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Next, we sought to apply our methods to the late-stage diversification of drug molecules. Our group has
reported a diverse set of CH functionalizations on a celecoxib analogue, directed by an acidic
sulfonamide group.20 Here, we performed CH chlorination, bromination, and amidation on a celecoxib
analogue 11 using our newly developed transient DGs (Scheme 5). Remarkably, the transient DG can
override the directing ability of both sulfonamide and pyrrazole with complete site-selectivity, allowing
CH functionalization on the other aryl ring. The versatility of aryl halides and anilines imply an
additional element for diversification of this drug scaffold. Also, this example clearly demonstrates how
transient DG-mediated CH functionalization methods could potentially be utilized in pharmaceuticals
containing multiple coordinating sites including heterocycles.
Scheme 5. Diversification of Celecoxib Analogue using Transient DG Strategy
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Lastly, in an attempt to demonstrate the synthetic utility of our new CH functionalization methods, the
ortho-functionalized benzaldehyde products were subjected to various annulation reactions to form
valuable heterocyclic scaffolds. First, ortho-chlorobenzaldehydes were reacted with thioglycollic acid
ethyl ester to form diverse benzothiophenes (Table 10).21 Both electron-donating and electron-
withdrawing substituents were well-tolerated, giving the desired benzothiophenes in moderate to good
yields. Interestingly, the celecoxib analogue 11-Cl also underwent smooth annulation, generating an
additional heterocycle on its structure. Next, ortho-aminobenzaldehydes were reacted with nitroalkene 13,
to form N-Ts-1,2-dihydroquinolines with different substitutions in excellent to moderate yields (Table
11).22 Again, the annulation was performed on the amidated celcoxib analogue 11-NHTs which provided
the corresponding product in excellent yield.
Table 9. Benzothiophene Synthesis from o-Chlorobenzaldehydesa,b
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aReaction conditions: 4 (0.2 mmol, 1.0 equiv.), ethyl thioglycolate (1.0 equiv.), K2CO3 (1.1 equiv.), DMF (2.0 mL), 60
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oC, 2 h. b Isolated yields.
Table 10. N-Tosyl-1,2-Dihydroquinoline Synthesis from o-Aminobenzaldehydesa,b
aReaction conditions: substrate 6 (0.1 mmol, 1.0 equiv.), Nitroalkene 13 (2.0 equiv.), NEt3 (2.0 equiv.), DCM (2.0 mL),
room temperature. bIsolated yields.
3. Conclusion
In summary, a set of ortho-C(sp2)H functionalization methods of benzaldehydes using transient
DG strategy has been disclosed. We developed Pd(II)-catalyzed arylation, chlorination, bromination, and
Ir(III)-catalyzed amidation, indicating that a ubiquitous and versatile aldehyde group can also function as
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a competent directing group for various transformations. The transiently-formed imino acid or imine
directing group can override other directing functionalities such as amide, ester, carbamate, sulfonamide,
and heterocycle, allowing a broad range of benzaldehyde substrates to undergo site-selective C-H
functionalization. The selective syntheses of multi-substituted aryl/biaryl compounds via sequential C-H
functionalization have been demonstrated. Also, our reaction conditions were directly applicable to a
celecoxib analogue, allowing a late-stage diversification on a drug molecule. Finally, we demonstrated
that our ortho-functionalization products can be readily transformed into valuable heterocycles, such as
benzothiophenes and 1,2-dihydroquinolines.
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4. Experimental Section
General procedure for ortho-C–H arylation of benzaldehydes using bidentate transient DG.
A sealed tube with magnetic stir bar was charged with substrate 1 (0.10 mmol), Pd(OAc)2 (0.01 mmol,
2.2 mg), T5 (0.04 mmol, 4.1 mg), AgTFA (0.10 mmol, 22.1 mg), and 2a (0.20 mmol, 52.4 mg) in air.
Then, a premixed solution of HFIP:TFA = 9:1 (0.5 mL) was added. The reaction mixture was stirred at
room temperature for 10 minutes, then at 100 oC for 24 hours. Upon completion, the reaction mixture was
cooled to room temperature, diluted with EtOAc, filtered through a silica gel plug, and concentrated in
vacuo. The crude reaction mixture was purified by preparative TLC on silica gel using hexanes/EtOAc as
the eluent to afford the desired products.
Full experimental details and characterization of new compounds can be found in the Supplementary
Information.
Corresponding author. *yu200@scripps.edu, *fanglinzhang@whut.edu.cn
Author Contributions. ┴X.H.L., H.P., J.H.H, & Y.H. contributed equally to this work.
Notes. The authors declare no competing financial interest.
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Acknowledgements. We gratefully acknowledge The Scripps Research Institute, Wuhan University of
Technology, and the National Science Foundation (CHE-1465292) for financial support. We also thank
Bristol-Meyers Squibb for financial support and providing chemicals. H.P. thanks the Korea Foundation
for Advanced Studies for a predoctoral fellowship.
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Supporting Information Available. Detailed experimental procedures, characterization of new
compounds. This material is available free of charge via the internet at http://pubs.acs.org.
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