Transition-metal-free direct arylation: Synthesis of halogenated 2-amino-2′-hydroxy-1,1′-biaryls and mechanism by DFT calculations

Article abstract of DOI:10.1021/ja400897u

A transition-metal-free, regioselective direct aryl-aryl bond-forming process for the synthesis of halogenated 2-amino-2′-hydroxy-1,1′- biaryls that are currently either inaccessible or challenging to prepare using conventional methods is disclosed. The addition of ArMgX to an o-halonitrobenzene at low temperature generates a transient N,O- biarylhydroxylamine that rapidly undergoes either [3,3]- or [5,5]-sigmatropic rearrangement in one-pot to form a 2-amino-2′-hydroxy-1,1′-biaryl or 1-amino-1′-hydroxy-4,4′-biaryl, respectively. The periselectivity is controlled by the choice of solvent and temperature. This direct arylation process is also readily scalable (1-10 mmol). DFT calculations suggest that from the N,O-biarylhydroxylamine intermediate there is a low-energy stepwise pathway that involves initial Mg-mediated N-O bond cleavage followed by pathway branching toward either [3,3]- or [5,5]-rearrangement products via C-C bond formation and rearomatization.

Full text of DOI:10.1021/ja400897u

Communication
pubs.acs.org/JACS
Transition-Metal-Free Direct Arylation: Synthesis of Halogenated
2‑Amino-2′-hydroxy-1,1′-biaryls and Mechanism by DFT Calculations
Hongyin Gao,† Daniel H. Ess,‡ Muhammed Yousufuddin,§ and Laszlo Kurti*,†
́
́
̈
†Division of Chemistry, Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas
75390, United States
‡Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, United States
§Center for Nanostructured Materials, The University of Texas at Arlington, Arlington, Texas 76019, United States
S
* Supporting Information
used as ligands in a range of catalytic enantioselective processes,3
including several on an industrial scale.4,3b Ar−Ar axial chirality
ABSTRACT: A transition-metal-free, regioselective direct
aryl−aryl bond-forming process for the synthesis of
halogenated 2-amino-2′-hydroxy-1,1′-biaryls that are cur-
rently either inaccessible or challenging to prepare using
conventional methods is disclosed. The addition of ArMgX
to an o-halonitrobenzene at low temperature generates a
transient N,O-biarylhydroxylamine that rapidly undergoes
either [3,3]- or [5,5]-sigmatropic rearrangement in one-
pot to form a 2-amino-2′-hydroxy-1,1′-biaryl or 1-amino-
1′-hydroxy-4,4′-biaryl, respectively. The periselectivity is
controlled by the choice of solvent and temperature. This
direct arylation process is also readily scalable (1−10
mmol). DFT calculations suggest that from the N,O-
biarylhydroxylamine intermediate there is a low-energy
stepwise pathway that involves initial Mg-mediated N−O
bond cleavage followed by pathway branching toward
either [3,3]- or [5,5]-rearrangement products via C−C
bond formation and rearomatization.
has also been found in more than 1000 natural products, many of
which exhibit remarkable biological activities.2c In view of the
abundance and importance of the biaryl motif as a privileged
structure, a pharmacophore in natural products (e.g., TMC-95A,
biphenomycin B, gossypol, etc.; Figure 1) and prescription drugs
(e.g., diovan), and a key structural element in ligands for
asymmetric catalysis (e.g., NOBIN) and novel organic materials
(e.g., liquid crystals, light-emitting diodes, conducting polymers,
etc.), it is not surprising that numerous synthetic approaches for
its construction have been developed (Figure 2).5
he biaryl structural motif appears in a large number of
Tbiologically active natural products, pharmaceuticals,
agrochemicals, and functional organic materials (Figure 1).1
Stereoisomerism (i.e., axial chirality) due to hindered rotation
about the C−C bond may also arise in biaryl compounds. The
rotational barrier depends on the size and number of substituents
at the ortho positions flanking the Ar−Ar bond.2 Axially chiral
nonracemic biaryls (e.g., NOBIN, BINOL, BINAP) are widely
Figure 2. Methods for the intermolecular construction of Ar−Ar bonds,
including our novel transition-metal-free direct arylation process.
Some of the most widely used Ar−Ar bond-forming strategies
include: (1) transition metal (TM)-catalyzed Ar−Ar traditional
cross-coupling,6 which requires prefunctionalization of both
coupling partners (e.g., Negishi, Stille, Kumada, and Suzuki
reactions, Figure 2A); (2) oxidative direct arylation,5e,7 which
requires prefunctionalization of one coupling partner (Figure
2B); and (3) dehydrogenative cross-coupling,8 in which neither
coupling partner must be prefunctionalized (Figure 2C). Despite
the abundance of methods for Ar−Ar bond formation, several
biaryl linkages are very difficult to construct in an atom- and step-
economical fashion. In particular, 2,2′-diheteroatom-substituted
unsymmetrical 1,1′-biaryls (e.g., the highly functionalized 2-
amino-2′-hydroxy-1,1′-biaryl motif found in TMC-95A) are not
readily accessible and require multiple-step syntheses.9
Received: January 26, 2013
Figure 1. The biaryl structural motif in a range of organic compounds.
© XXXX American Chemical Society
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Communication
Our group is pursuing new methods for the synthesis of highly
functionalized symmetrical and unsymmetrical biaryls. Ideally,
these new routes should (a) be operationally simple; (b) utilize
readily available and inexpensive starting materials; (c) avoid the
use of TM catalysts, ligands, and strong oxidizing agents; (d)
achieve C−C bond formation with high regioselectivity; (e)
build molecular complexity rapidly (e.g., in one pot); (f) tolerate
functional groups that are generally incompatible with TMs (e.g.,
halogens, which allow further functionalization via cross-
coupling); and (g) complement existing cross-coupling methods
by allowing the preparation of currently inaccessible biaryls.
The above attributes present a tall order for reaction design.
We were inspired by the intriguing multistep mechanism10 of the
Bartoli indole synthesis11 (Scheme 1), in which intermediate 2,
Table 1. Optimization Studies
a
1 mmol scale (0.2 M solution) in the indicated solvent at the
Scheme 1. Proposed TM-Free Direct Arylation Inspired by
the Bartoli Indole Synthesis
b
indicated temperature and reaction time. Use of PhLi instead of 8a
led to complex mixtures. Isolated yields.
c
(entry 3), while at 0 °C only 9a was detected as the major
product (entry 5).
The above results are especially remarkable when compared
with the synthesis of N,N-diarylamines from nitroarenes with
functionalized arylmagnesium compounds as reported by
Sapountzis and Knochel,15 where addition of the aryl group at
the N atom (i.e., N-arylation) of the nitrosoarene intermediate
formed in situ by the reduction of the nitroarene always occurs.
In sharp contrast, here the o-halonitrosoarene intermediates
likely undergo O-arylation to give 4. Clearly, the o-halogen
substituent changes the regioselectivity of the aryl addition across
the NO bond, leading to 1,1′-linked biaryl products that were
not observed by Sapountzis and Knochel.16 Indeed, when
exposed to our optimized reaction conditions, o-alkyl- and o-
alkoxy-substituted nitroarenes did not afford even trace amounts
of the corresponding 2-amino-2′-hydroxy-1,1′-biaryls.17
To explore possible reaction mechanisms leading to the [3,3]-
and [5,5]-rearrangement products, we performed density
functional theory (DFT) calculations at the M06-2X/6-31G-
(d,p) level using Gaussian 09.18 The optimizations shown here
were carried out in THF using the SMD19 solvent model20 [data
for toluene and Et2O are given in the Supporting Information
(SI)]. Enthalpies are reported at 0 K.
presumably formed from the corresponding nitrosoarene
intermediate via O-vinylation, undergoes a facile [3,3]-
sigmatropic rearrangement to alkylate the aromatic ring at low
temperature. We surmised that a similar approach using ArMgX
would initially give N,O-biarylhydroxylamines 4,12 which would
furnish highly functionalized 2-amino-2′-hydroxy-1,1′-biaryl
products 6 via [3,3]-sigmatropic rearrangement and rear-
omatization. This reaction would thus result in TM-free direct
arylation of unactivated C−H bonds to form a new Ar−Ar bond.
Our choice of 2-bromonitrobenzene (7a) as the first substrate
proved to be highly successful. A solution of 7a in
tetrahydrofuran (THF) was treated with 3 equiv of PhMgBr
(8a) at −78 °C and then warmed to 0 °C over a period of 30 min.
Thin-layer chromatography showed the complete consumption
of 7a and the formation of a major polar product identified as 3-
bromo-2-amino-2′-hydroxy-1,1′-biphenyl (9a) (see the single-
crystal X-ray structure in Table 2). A thorough analysis of the
crude reaction mixture revealed the presence of four different
products (9a−12), three of which had the same molecular weight
based on LC/MS analysis. We presumed that carbazole 10 was
formed from a doubly dearomatized intermediate similar to 5.13
Formation of the 4,4′-linked biaryl product 11 may be explained
by invoking a [5,5]-sigmatropic rearrangement (i.e., similar to
the benzidine rearrangement14) or two sequential [3,3]-
rearrangements. N,N-Diarylhydroxylamine 12 could be formed
by the direct attack of 8a on the N atom of the in situ-formed
nitrosoarene derivative of 7a. The use of solvents other than
THF, such as Et2O, 1,4-dioxane, dimethoxyethane (DME), and
toluene led to lower yields of 9a and increased yields of 10 and 12
(Table 1, entries 6−9). A temperature screen in THF (entries 1−
5) revealed that the highest isolated yield of 9a was achieved at 0
°C (entry 5). Surprisingly, the ratio of the [3,3]- and [5,5]-
rearrangement products strongly depended on the temperature.
For example, a nearly 1:1 mixture of 9a and 11 formed at −25 °C
Scheme 2 outlines the lowest-energy pathways for N−O bond
cleavage and C−C bond formation for intermediate 4a. All begin
Scheme 2. Lowest-Energy Pathways for N−O Cleavage and
C−C Bond Formation (Energies in kcal/mol)
with MgBr-mediated N−O bond cleavage via transition state 4a-
TS (ΔH⧧ = 14.2 kcal/mol; Figure 3) to give closed-shell
intermediate 4a-int (ΔH = 8.2 kcal/mol). In 4a-TS, MgBr
develops chelation with O as the N−O bond stretches from 1.41
Å in 4a to 1.99 Å in 4a-TS. The chelation orients the arene
groups in a π-stacked geometry. All attempts to locate a TS for
B
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Table 2. Scope of Substrates and 1,1-Linked Biaryl Products
and Single-Crystal X-ray Structures of 9a and 9n
Figure 3. Transition states in the [3,3]- and [5,5]-rearrangements.
concerted [3,3]-rearrangement mediated by MgBr converged to
4a-TS. From 4a-int there are several pathways that branch to give
C−C bond formation. 5a-TS (ΔH⧧ = 14.9 kcal/mol) is the
lowest-energy TS that gives 5a, which upon deprotonation/
rearomatization affords 9a. The TS for C−C bond formation at
the Br-substituted arene C atom is 4 kcal/mol higher in energy
than 5a-TS. The [5,5]-rearrangement product can be accessed
through 11-TS, for which ΔH⧧ is 13.6 kcal/mol.
The 0 K enthalpic barriers of 5a-TS and 11-TS suggest that the
C−C bond formed via the [5,5]-rearrangement is kinetically
favored at low temperatures. The ΔG⧧298K values of these TSs are
both 15.4 kcal/mol, in qualitative accordance with the increase in
9a relative to 11 at higher temperatures (Table 1). Modeling of a
single explicit THF solvent molecule coordinated to the Mg
center did not change the [3,3] versus [5,5] selectivity at 0 K but
did show a 0.5 kcal/mol preference for the [3,3]-rearrangement
pathway on the free energy surface at 298 K (see the SI).
Intermediates 5a and 11-int are endothermic by 5.3 and 4.8
kcal/mol, respectively, raising the possibility that C−C bond
formation may be reversible if deprotonation is slow. The TS for
intermolecular deprotonation of 5a by PhMgBr has a barrier of
∼10 kcal/mol. Intramolecular 1,3- and 1,4-proton transfers have
much larger barriers. The 10 kcal/mol barrier for intermolecular
deprotonation is close to the barrier for conversion of 5a back to
4a, so no definitive conclusion about the reversibility of C−C
bond formation can be drawn; however, the correlation between
the computed and observed selectivities suggests irreversibility.
With these exciting first results in hand, we examined the scope
of nitroarene substrates for this direct arylation process (Table
2). Several o-chloro- and o-bromonitrobenzenes gave the
corresponding 2-amino-2′-hydroxy-1,1′-biaryls in moderate to
good isolated yields.21 The structure of the nitrobenzene
substrate can vary widely, and even multiple halogen substituents
are well-tolerated. Likewise, the aryl-Grignard coupling partner
can be either monocyclic or fused. In the case of 2-napththyl-
Grignard coupling partners (8c and 8d), the arylation is also
regiospecific since only the 1-position of the naphthalene ring
undergoes arylation (entries 12−25). In none of the reactions
could 3-arylnaphthalene products be isolated. There are three
general situations in which the yield of the biaryl product tends to
be moderate: (a) when the nitroarene contains electron-
donating groups (e.g., Me or OMe; entries 3, 7, 17, and 18);
(b) when both coupling partners contain electron-donating
groups (entry 10); and (c) when the biaryl product is sterically
congested and shows atropisomerism (entries 3 and 10).
However, steric factors do not seem to have a negative influence
on the efficient formation of 1-arylnaphthalene derivatives
(entries 19 and 20).
a
b
0.2 M solution. The use of a sacrificial equivalent of Grignard
reagent to affect the initial in situ Ar−NO2 to Ar−NO reduction led
to complex reaction mixtures because of the higher reactivity of
c
nitrosoarenes vs the nitroarene substrates. Rf values and eluents for
the products are given in the SI. Side products (e.g., carbazole,
hydroxylamine) were readily separated from the products.
Scheme 3. Direct Arylation on a Multigram Scale
By virtue of their 3-halogen substituents, the 2-amino-2′-
hydroxy-1,1′-biaryl products are useful intermediates en route to
various unusually substituted heterocycles22 such as indole 13,
benzothiazole 15, and dibenzofuran 16 (Scheme 4). In addition,
Suzuki cross-coupling of 9a with phenylboronic acid efficiently
formed aminohydroxyterphenyl 14.
In summary, we have developed a regioselective, TM-free,
scalable direct arylation method for the synthesis of halogen-
substituted 2-amino-2′-hydroxy-1,1′-biaryls. Four distinct pro-
cesses take place at low temperature in one pot: (i) reduction of
the NO2 group; (ii) O-arylation of the nitrosoarene
To demonstrate the synthetic utility of this direct arylation
process on a multigram scale, we chose two nitroarenes (7a and
7k; Scheme 3) and two aryl-Grignard reagents (8a and 8c) as
substrates. To our delight, we found that in just 15 min at 0 °C in
THF, biaryls 9a and 9w were readily formed in isolated yields of
59 and 63%, respectively.
C
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(3) (a) Ojima, I. Catalytic Asymmetric Synthesis, 3rd ed.; Wiley:
Hoboken, NJ, 2010. (b) Busacca, C. A.; Fandrick, D. R.; Song, J. J.;
Senanayake, C. H. Adv. Synth. Catal. 2011, 353, 1825. (c) Magano, J.;
Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
Scheme 4. Convenient Preparation of Unusually-Substituted
Heterocycles and Terphenyls
(4) (a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155.
(b) Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. Rev. 2003, 103, 3213.
(c) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric
Catalysis; Springer: New York, 2004. (d) Akiyama, T. Chem. Rev. 2007,
107, 5744. (e) Blaser, H.-U.; Federsel, H.-J. Asymmetric Catalysis on
Industrial Scale: Challenges, Approaches, and Solutions, 2nd ed.; Wiley-
VCH: Weinheim, Germany, 2010.
(5) (a) Anastasia, L.; Negishi, E.-I. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley: New York, 2002; Vol. 1, Chapter
3, p 311. (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359. (c) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174. (d) Ackermann, L. Modern Arylation
Methods; Wiley: New York, 2009. (e) McGlacken, G. P.; Bateman, L. M.
Chem. Soc. Rev. 2009, 38, 2447.
intermediate; (iii) [3,3]-rearrangement of the in situ-generated
transient N,O-biarylhydroxylamine; and (iv) rearomatization.
The efficiency of each step is 75−90%. DFT calculations showed
that from the N,O-biarylhydroxylamine intermediate there is a
low-energy stepwise pathway to form the new Ar−Ar bond. The
step efficiency and operational simplicity of this transformation
allow the rapid generation of molecular complexity and furnish
compounds with 1,1′-biaryl linkages that are either very difficult
to prepare using conventional methods or otherwise syntheti-
cally inaccessible. The resulting structurally diverse halogen-
substituted 2-amino-2′-hydroxy-1,1′-biaryl products and their
unique heterocyclic derivatives are expected to find broad utility
in asymmetric catalysis, drug discovery, and materials science.
(6) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062.
(7) (a) Lei, A.; Liu, W.; Liu, C.; Chen, M. Dalton Trans. 2010, 39,
10352. (b) Su, Y.-X.; Sun, L.-P. Mini-Rev. Org. Chem. 2012, 9, 87.
(8) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(9) (a) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 512.
(b) Albrecht, B. K.; Williams, R. M. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 11949. (c) Ashburn, B. O.; Rathbone, L. K.; Camp, E. H.; Carter, R.
G. Tetrahedron 2008, 64, 856. (d) Masters, K.-S.; Brase, S. Angew. Chem.,
Int. Ed. 2013, 52, 866.
(10) Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J.
Chem. Soc., Perkin Trans. 2 1991, 657.
(11) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett.
1989, 30, 2129.
(12) To our knowledge, N,O-diarylhydroxylamines have not been
isolated and characterized, but they have been invoked as highly unstable
intermediates. See: (a) Cox, J. R., Jr.; Dunn, M. F. Tetrahedron Lett.
1963, 4, 985. (b) Sheradsky, T.; Salemnick, G. Tetrahedron Lett. 1971,
12, 645. (c) Sheradsky, T.; Nov, E. J. Chem. Soc., Perkin Trans. 1 1977,
1296. (d) Sheradsky, T.; Nov, E.; Avramovici-Grisaru, S. J. Chem. Soc.,
Perkin Trans. 1 1979, 2902.
(13) 9a could not be converted to 10 under strongly basic conditions
(i.e., excess 8a). Thus, it is reasonable to assume that once 9a is formed,
it does not convert to 10 under the reaction conditions.
(14) (a) Banthorpe, D. V.; Bramley, R.; Thomas, J. A.; Ingold, C.;
Hughes, E. D. J. Chem. Soc. 1964, 2864. (b) Yamabe, S.; Nakata, H.;
Yamazaki, S. Org. Biomol. Chem. 2009, 7, 4631. (c) Ghigo, G.;
Maranzana, A.; Tonachini, G. Tetrahedron 2012, 68, 2161.
(15) Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124, 9390.
(16) o-Halonitroarene substrates were not used in ref 15.
(17) In these cases, complex reaction mixtures were obtained.
(18) (a) Frisch, M. J.; et al. Gaussian 09, revision B.01; Gaussian, Inc.:
Wallingford, CT, 2009. (b) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc.
2008, 120, 215. (c) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41,
157.
ASSOCIATED CONTENT
* Supporting Information
Experimental and computational details, characterization data,
crystallographic data (CIF), and complete ref 18a. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
laszlo.kurti@utsouthwestern.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.K. thanks the UT Southwestern Endowed Scholars in
Biomedical Research Program (W. W. Caruth, Jr., Endowed
Scholarship in Biomedical Research), the Robert A. Welch
Foundation (Grant I-1764), the ACS Petroleum Research Fund
(Doctoral New Investigator Grant 51707-DNI1), and the
American Cancer Society and Simmons Cancer Center Institu-
tional Research Grant (New Investigator Award in Cancer
Research, ACS-IRG 02-196) for generous financial support.
D.H.E. thanks BYU and Fulton Supercomputing Lab. We also
thank Prof. Kevin Schug, Dr. Maciej Kukula, and the Shimadzu
Center for Advanced Analytical Chemistry (UT Arlington) for
help with compound characterization.
(19) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378.
(20) All structures were confirmed as minima or saddle points through
vibrational normal-mode analysis.
(21) Under the optimized conditions, o-fluoro- and o-iodonitroarenes
either gave low yields of the corresponding 1,1′-linked biaryls or resulted
in very complex reaction mixtures.
(22) (a) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina,
V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129. (b) Shen, G.; Lv, X.; Bao,
W. Eur. J. Org. Chem. 2009, 5897. (c) Stokes, B. J.; Jovanovic, B.; Dong,
H.; Richert, K. J.; Riell, R. D.; Driver, T. G. J. Org. Chem. 2009, 74, 3225.
REFERENCES
■
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893.
(2) (a) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384. (b) Wolf,
C. In Dynamic Stereochemistry of Chiral Compounds: Principles and
Applications; RSC: Cambridge, U.K., 2007; Chapter 3, p 29. (c) Bring-
mann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011,
111, 563.
D
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