Modular C-H Functionalization Cascade of Aryl Iodides

Article abstract of DOI:10.1021/jacs.5b01082

We report the first example of ipso-borylation for the modular 1,2-bisfunctionalization of aryl iodides via C-H functionalization. The carbon-boron bond is used as a lynchpin to access ipso carbon-carbon, carbon-nitrogen, carbon-oxygen, and carbon-halogen (Cl, Br, I) bonds. The utility of our methodology is illustrated through quick, modular syntheses of the pharmaceuticals Abilify and Flunixin.

Full text of DOI:10.1021/jacs.5b01082

Communication
pubs.acs.org/JACS
Modular C−H Functionalization Cascade of Aryl Iodides
Hang Shi, David J. Babinski, and Tobias Ritter*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
S
* Supporting Information
Chart 1. Selected Pharmaceuticals Containing the 2,3-
Disubstituted Aniline Structure
ABSTRACT: We report the first example of ipso-
borylation for the modular 1,2-bisfunctionalization of aryl
iodides via C−H functionalization. The carbon−boron
bond is used as a lynchpin to access ipso carbon−carbon,
carbon−nitrogen, carbon−oxygen, and carbon−halogen
(Cl, Br, I) bonds. The utility of our methodology is
illustrated through quick, modular syntheses of the
pharmaceuticals Abilify and Flunixin.
ransition-metal-catalyzed cross-coupling reactions of aryl
Thalides are among the most reliable transformations for
arene functionalization.1 Directed transition-metal-catalyzed
ortho2 and meta3 C−H activations can functionalize arene C−
H bonds directly, but directing groups are often challenging to
remove or modify. Combining C−H activation with cross-
coupling could (1) form two new bonds in one step and (2)
avoid restriction to a particular directing group. However,
methods for bisfunctionalization of aryl halides that utilize C−
H activation/cross-coupling strategies have limited substrate
scope.4 Most notably, methods for the incorporation of
heteroatoms at the ipso position by this strategy are absent.
Here we report the first ortho-amination/ipso-functionalization
reaction of aryl iodides, which provides direct access to C−B,
C−C, C−N, C−O, C−Cl, C−Br, and C−I bonds at the ipso
position without the remnant of a coordinating directing group
(Scheme 1). We demonstrate how our methodology provides
quick access to a myriad of 2,3-disubstituted anilines, which can
be found in a variety of biologically active molecules (Chart 1).
The Catellani reaction is a bisfunctionalization of aryl halides
through a palladium-catalyzed/norbornene-mediated reaction
that proceeds via an initial ortho-C−H functionalization.4
Seminal reports by Catellani5 and Lautens6 have demonstrated
the utility of this reaction in the formation of C−C bonds.7
Developments of the norbornene-mediated bisfunctionalization
of aryl halides with two distinct coupling partners have been
limited to the formation of C−C bonds at the ortho position
and C−C or C−H bonds at the ipso position.8 While Dong and
co-workers have developed a method for the ortho-C−H
amination/ipso-hydrogenation of aryl halides,9 no method
currently exists for the intermolecular incorporation of C−
C(sp3) or C−heteroatom bonds at the ipso position in the Pd-
catalyzed bisfunctionalization of aryl halides.
Scheme 1. Synthesis of 1,2-Heterosubstituted Arenes
through C−H Activation
Our strategy to achieve a broadly useful, modular 1,2-
bisfunctionalization to access 1,2-disubstituted anilines involves
Received: January 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b01082
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Journal of the American Chemical Society
Communication
Table 1. ortho-Amination/ipso-Borylation and Derivatization
a
Aryl iodide (0.3 mmol), Pd(OAc)2 (5 mol % Pd), (4-MeOC6H4)3P (10.5 mol %), norbornene (1 equiv), BzO-amine (1.05 equiv), B2Pin2 (1
b
equiv), Cs2CO3 (2.5 equiv), toluene (0.05 M), 100 °C. Pd2dba3 (5 mol % Pd), DavePhos (10 mol %), electrophile (1 equiv), K2CO3 (3.75 equiv),
toluene/ethanol/water (8/8/1 v/v/v), 100 °C. Pd(OAc)2 (5 mol % Pd), DavePhos (10 mol %), electrophile (1 or 2 equiv), K3PO4 (2 equiv), n-
c
d
e
BuOH/water (5/2 v/v). NaN3 (1.5 equiv), Cu(OAc)2 (10 mol %), air, methanol, 50 °C. H2O2 (2.5 or 5 equiv), NaOH (2.5 or 5 equiv), THF.
f
g
h
CuCl2 (3 equiv), methanol/water (1/1 v/v), 80 °C. CuBr2 (3 equiv), methanol/water (1/1 v/v), 80 °C. Chloramine T (1.5 equiv), NaI (1.6
equiv), THF/water (1/1 v/v), 50 °C.
(1) oxidative addition into aryl iodides, (2) norbornene-
directed C−H functionalization, and (3) novel conversion to
ortho-substituted aryl pinacol boronates, which can be used as
lynchpins to access a wide variety of 1,2-bisfunctionalized
arenes. Treatment of ortho-substituted aryl iodides10 with N-
benzoyloxyamines (BzO-amines) and bis(pinacolato)diboron
in the presence of Pd(OAc)2, (4-MeOC6H4)3P, norbornene,11
and Cs2CO3 in toluene at 100 °C gave the ortho-aminated
phenyl pinacol boronate esters 2a and 2b (Table 1). The
results provide the first example of ipso-C−B bond formation in
ortho-C−H activation reactions. Subsequent functionalizations
allowed for the direct conversion of the C−B bond to C−C
(3c−f), C−N (3g−j), C−O (3k−n), C−Cl (3o, 3p), C−Br
(3q, 3r), and C−I (3s, 3t) bonds. Conventional C−C bond
formation at the ipso position in the norbornene-mediated
bisfunctionaliation of aryl halides is typically achieved via Heck,
Sonogashira, or Suzuki cross-coupling.6,12 Our approach allows
access to additional carbon substituents that cannot be obtained
readily with conventional reactions, such as benzyl and
isopropenyl groups (3c, 3e), and thereby further provides
access to functionality beyond the previous substrate scope.
A variety of BzO-amines derived from six-membered rings
were successfully employed in our methodology. BzO-amines
derived from complex amines such as paroxetine (3k) were
B
DOI: 10.1021/jacs.5b01082
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Journal of the American Chemical Society
Communication
a
Scheme 2. Application to the Synthesis of Abilify and the Formal Synthesis of Flunixin
a
Conditions: (a) Pd(OAc)2 (5 mol %), (4-MeOC6H4)3P (10.5 mol %), 2-chloroiodobenzene (1 equiv), 1-benzoyloxy-4-BOC-piperazine (1.05
equiv), B2Pin2 (1 equiv), norbornene (1 equiv), Cs2CO3 (2.5 equiv), toluene (0.05 M), 100 °C. (b) CuCl2 (3 equiv), methanol/water (1/1 v/v), 80
°C. (c) 4 (1.05 equiv), K2CO3 (1.55 equiv), NaI (1.43 equiv), DMF, rt. (d) Pd(OAc)2 (5 mol %), (4-MeOC6H4)3P (10.5 mol %), 2-
trifluoromethyliodobenzene (1 equiv), 1-benzoyloxy-4-piperidone ethylene ketal (1.05 equiv), B2Pin2 (1 equiv), norbornene (1 equiv), Cs2CO3 (2.5
equiv), toluene (0.05 M), 100 °C. (e) Pd(OAc)2 (5 mol %), DavePhos (10 mol %), K3PO4 (2 equiv), MeI (5 equiv), n-BuOH/water (5/2 v/v), 80
°C. (f) p-TSA (10 mol %), acetone/water (10/1 v/v), 65 °C. (g) JandaJel-NH2 (1.5 equiv), NH4Cl (1 equiv), ethanol, 95 °C.
conclude that ortho-C−H activation is reversible.15a All of the
Scheme 3. Simplified Catalytic Cycle
obtained data are consistent with the mechanism shown in
Scheme 3.
well-tolerated. BzO-amines derived from five-membered rings
as well as linear amines, however, are not currently suitable.
This limitation can be overcome by accessing 4-piperidone
analogues (e.g., 3q), which can be converted to the
corresponding primary anilines (3v → 5 in Scheme 2).13
The 1,2-bisfunctionalization method presented here could be
employed to quickly access the antipsychotic Abilify and the
anti-inflammatory Flunixin in only a few steps (Scheme 2).
Both examples reveal the potential and modularity of our
methodology in diversity-oriented synthesis to quickly generate
a wide variety of substituted anilines.
Our strategy was devised on the basis of previous hypotheses
of mechanistically related Pd-catalyzed, norbornene-mediated
transformations.15 Under the standard reaction conditions, the
ipso-H aniline (see, e.g., compound 6 in eq 1) is the major side
product. Resubjection of the aminoboronates 2 to the reaction
conditions in the presence of benzoic acid did not generate the
corresponding ipso-hydrogenation product.16 Therefore, for-
mation of the reduced proteo side product through proto-
deborylation is unlikely. When HBPin was added to the
reaction conditions, ipso-H aniline 6 became the major product
(eq 1), which suggests that the formation of 6 is due to the
reduction of intermediate C by HBPin.17 HBPin may be
generated under the standard reaction conditions in the ortho-
C−H activation step (intermediate A′ to B). In the absence of
BzO-amine, boronate 7 was the major product with 8 as the
minor product (eq 2). Because compound 7 was observed in
only trace amount under the standard reaction conditions, we
In conclusion, we have reported the first general method for
the formation of ipso-C−heteroatom bonds in the Pd-catalyzed,
norbornene-mediated ortho-C−H amination of aryl iodides. By
trapping Pd(II) intermediates with B2Pin2, we have developed a
simple, two-step procedure that harnesses the synthetic utility
of the C−B bond to access a variety of ortho-functionalized
anilines and provides the first example of intermolecular C−
heteroatom bond formation in Pd-catalyzed, norbornene-
mediated C−H functionalization. We believe that the strategy
outlined above can be utilized to overcome the functional
group limitations at the ipso position in current palladium-
catalyzed, norbornene-mediated 1,2-bisfunctionalization meth-
odologies and provide a modular strategy for the synthesis of
substituted anilines.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data for all new
compounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*ritter@chemistry.harvard.edu
C
DOI: 10.1021/jacs.5b01082
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Journal of the American Chemical Society
Communication
(13) Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett.
2006, 8, 2437.
Notes
The authors declare no competing financial interest.
(14) Jaouhari, R.; Quinn, P. Heterocycles 1994, 38, 2243.
(15) (a) Chai, D. I.; Thansandote, P.; Lautens, M. Chem.Eur. J.
2011, 17, 8175. For other mechanism studies, see: (b) Bocelli, G.;
Catellani, M.; Ghelli, S. J. Organomet. Chem. 1993, 458, C12.
(c) Amatore, C.; Catellani, M.; Deledda, S.; Jutand, A.; Motti, E.
Organometallics 2008, 27, 4549. (d) Cardenas, D. J.; Martín-Matute,
́
B.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 5033. (e)
Reference 7a.
(16) Aminoboronate 2t was resubjected to the reaction conditions in
the presence of benzoic acid. 1H NMR analysis of the reaction mixture
revealed no generation of the corresponding ipso-hydrogenation
product.
ACKNOWLEDGMENTS
■
We thank David Jaramillo for initial reaction development,
Heejun Lee for X-ray analysis, and the NSF (CHE-0952753)
for financial support.
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desired product was obtained in 34% yield. See the Supporting
Information.
(11) The best results were obtained when 1 equiv of norbornene was
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obtained in lower yields. See the Supporting Information.
(12) Additionally, cyanation (ref 6a) and N-tosylhydrazone insertion
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DOI: 10.1021/jacs.5b01082
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX