Enantiospecific Synthesis of ortho-Substituted 1,1-Diarylalkanes by a 1,2-Metalate Rearrangement/anti-SN2′ Elimination/Rearomatizing Allylic Suzuki–Miyaura Reaction Sequence

Article abstract of DOI:10.1002/anie.201811343

The one-pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N-activator, the boronate complex formed from an ortho-lithiated benzylamine and a boronic ester undergoes stereospecific 1,2-metalate rearrangement/anti-S_N2′ elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ-selective allylic Suzuki–Miyaura cross-coupling to generate 1,1-diarylalkanes. When enantioenriched α-substituted benzylamines are employed, the corresponding 1,1-diarylalkanes are formed with high stereospecificity.

Full text of DOI:10.1002/anie.201811343

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Enantiospecific Synthesis of ortho-Substituted 1,1-Diarylalkanes
by a 1,2-Metalate Rearrangement/anti-SN2' Elimination/
Rearomatizing Allylic Suzuki-Miyaura Reaction Sequence
Authors: Belén Rubial, Beatrice S. L. Collins, Raphael Bigler, Stefan
Aichhorn, Adam Noble, and Varinder Kumar Aggarwal
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811343
Angew. Chem. 10.1002/ange.201811343
Link to VoR: http://dx.doi.org/10.1002/anie.201811343
http://dx.doi.org/10.1002/ange.201811343

10.1002/anie.201811343
Angewandte Chemie International Edition
COMMUNICATION
Enantiospecific Synthesis of ortho-Substituted 1,1-Diarylalkanes
by
a
1,2-Metalate
Rearrangement/anti-SN2'
Elimination/
Rearomatizing Allylic Suzuki-Miyaura Reaction Sequence
Belén Rubial,† Beatrice S. L. Collins,† Raphael Bigler, Stefan Aichhorn, Adam Noble, Varinder K.
Aggarwal*
Abstract: The one-pot sequential coupling of benzylamines, boronic
esters and aryl iodides has been investigated. In the presence of an
N-activator, the boronate complex formed from an ortho-lithiated
benzylamine and a boronic ester undergoes stereospecific 1,2-
metalate rearrangement/anti-SN2' elimination to form a dearomatized
tertiary boronic ester. Treatment with an aryl iodide under palladium
catalysis leads to rearomatizing γ-selective allylic Suzuki-Miyaura
cross-coupling to generate 1,1-diarylalkanes. When enantioenriched
-substituted benzylamines are employed, the corresponding 1,1-
diarylalkanes are formed with high stereospecificity.
recognised that the stereospecific cross-coupling of these
enantioenriched benzylic boronic esters with an aryl electrophile
3, in line with reports from Crudden,[7] would provide access to the
valuable 1,1-diarylalkane motif.[10] A more direct route to such
motifs, however, would be through the interruption of the cascade
sequence at the dearomatized intermediate 4, engaging this
species in a rearomatizing γ-selective allylic Suzuki-Miyaura
cross-coupling (Scheme 1C).[11] We envisioned that such a
pathway, passing through a six-membered ring transition state,
TS-I, would allow transfer of the chiral information in 4 and provide
a route to enantioenriched 1,1-diarylalkanes with extensive
functionalization in the ortho position. Herein, we report the
realisation of this process, which proceeds through two
consecutive stereospecific 1,3-transpositions of stereogenicity,
including a 1,2-metalate rearrangement/anti-SN2' elimination and
a syn-SE2' γ-selective Suzuki-Miyaura reaction, to provide a one
pot procedure to transform enantioenriched α-branched
benzylamines into enantioenriched 1,1-diarylalkanes bearing
considerable steric congestion in the ortho position.
The 1,1-diarylalkane motif is found in many biologically relevant
molecules and, as a result, approaches to its stereocontrolled
synthesis have garnered considerable attention in recent years.[1]
A remarkably diverse array of reactivity platforms has been
developed for its synthesis, including the decarbonylation of β,β-
diarylpropionaldehydes,[2]
the
hydrogenation
of
1,1-
diarylalkenes,[3] and the difunctionalization of both alkyl- and aryl-
substituted alkenes.[4] A more convergent strategy is the Ni-
catalyzed cross-coupling of benzylic electrophiles, through both
enantiospecific[5]
and
enantioconvergent[6]
pathways.
Alternatively, benzylic nucleophiles, such as boron reagents, can
be used. For example, Crudden has described the stereospecific
Pd-catalyzed cross-coupling of chiral secondary boronic esters
with aryl iodides (Scheme 1A).[7] Accessing the required
secondary benzylic boronic esters through the asymmetric
rhodium-catalyzed hydroboration of styrene derivatives,[8] this
method proceeds with good levels of enantioretention to provide
the desired 1,1-diarylethane derivatives. While all these methods
together provide a broad reactivity platform from which to access
1,1-diarylalkanes, limitations remain with respect to substrate
scope, where many methods are restricted to naphthyl-based or
sterically unencumbered substrates.
We recently reported a method for the enantiospecific
synthesis of ortho-substituted secondary benzylic boronic
esters.[9] Enantioenriched α-methyl o-bromo benzylamines 1 were
transformed into dearomatized intermediate 4 through 1,2-
metalate rearrangement/anti-SN2' elimination reaction triggered
by N-activation of arylboronate complex 2' (formed from lithiation
of 1 and addition of boronic ester 2). Subsequent suprafacial 1,3-
borotropic shift provided the secondary α-methyl benzylic boronic
esters with excellent levels of enantiopurity (Scheme 1B). We
Scheme 1. Access to 1,1-diarylalkanes.
We began our studies with dearomatized tertiary boronic ester
4aa, which was chosen because it is stable to isolation by column
chromatography (see SI for details) and can be accessed via our
previously reported 1,2-metalate rearrangement/anti-SN2'
elimination reaction. After optimization (see SI for details), cross-
coupled product 6aaa could be formed in 98% 1H NMR yield
(Scheme 2A). We then undertook optimization of the one-pot
procedure. Dearomatized tertiary boronic ester 4aa was
[*]
Dr. Belén Rubial, Dr. Beatrice S. L. Collins, Dr. Raphael Bigler, Dr.
Stefan Aichhorn, Dr. Adam Noble, Prof. Dr. Varinder K. Aggarwal*
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
†
Authors contributed equally.
Supporting information for this article is given via a link at the end of the
document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201811343
Angewandte Chemie International Edition
COMMUNICATION
generated
by
successive
treatment
of
ortho-bromo
While cyclohexyl product 6aaa showed rotameric behaviour by 1H
NMR, cyclopentyl (6aba), cyclobutyl (6aca) and cyclopropyl
naphthylamine 1a with nBuLi, to form ortho-lithiated
naphthylamine; cyclohexylboronic acid pinacol ester (CyBpin, 2a), (6ada) coupled products were observed as single species. An
giving the arylboronate complex; and the N-activator, Me2Troc−Cl, acyclic secondary boronic ester also coupled smoothly, providing
to promote 1,2-metalate rearrangement/anti-SN2' elimination. The
6aea in 84% yield, where broadening of the methylene signal
reaction mixture was then treated with Ag2O, followed by Pd(dba)2, indicated restricted rotation on the 1H NMR timescale. For primary
RuPhos and iodobenzene (3a) and heated to 75 °C for 6 h. While
some of the desired product 6aaa was observed, the yield was
considerably lower (8%) than that obtained when using isolated
4aa. Pleasingly, changing the silver salt from Ag2O to Ag2CO3 and
optimizing the stoichiometry led to a significant improvement in
yield (90%). Furthermore, reducing the temperature from 75 °C to
50 °C had no detrimental effect on the yield, providing 6aaa in
92% yield as determined by 1H NMR (Scheme 2B). Interestingly,
the 1H NMR spectrum of the purified material contained two sets
of signals in a ratio of 87:13, which were shown to interconvert
through variable temperature 1H NMR experiments. We identified
a coalescence temperature of 55 ºC and determined a rate of
exchange from the major to the minor species of 30.9 Hz and a
rotational barrier of 17.0 kcal/mol.[12] The rate of exchange from
the minor to the major species was determined to be 207.1 Hz
and the rotational barrier 15.8 kcal/mol (See SI for details). In
combination with two-dimensional EXSY/NOESY NMR
experiments, these studies led us to assign the two sets of signals
as rotamers, 6aaa-RA and 6aaa-RB, where interconversion occurs
through rotation about the naphthyl–cyclohexyl bond (Scheme
2C).[13] Furthermore, NOESY correlations support the assignment
of the major rotamer as 6aaa-RA. Having identified the two sets of
signals as rotamers, we were then able to confirm that 6aaa was
isolated in 88% yield.[14]
alkylboronic esters, the reaction was performed at room
temperature for 18 h with improved yields, providing coupled
product 6afa in 66% yield. Interestingly, the homocoupling of the
dearomatized intermediate could also be isolated in 8% yield. We
attribute this product to an alternative mechanism, involving
double transmetalation at a palladium(II) center, followed by
reductive elimination and re-oxidation using Ag2CO3 as a terminal
oxidant. No coupling product was observed with sterically
demanding tertiary boronic ester 2g; use of benzylamine 1b,
however, led to coupled product 6bga in excellent yield (88%).
Phenylboronic ester 2h also underwent coupling to provide biaryl
6aha in 76% yield. In line with previous reports, the 1,2-boron-to-
carbon migration proceeded with excellent levels of retentive
enantiospecificity, providing chiral products in high e.r. (6aia, 95:5
and 6bja, 98:2) and d.r. (6aka, >95:5 and 6ala, >95:5). These
substrates also highlight the functional group tolerance of the
process, with tert-butyl carboxyesters, azides and TBDPS-
protected alcohols tolerated.
We then assessed the scope of the aryl iodide and
benzylamine coupling partners (Table 1, parts B and C). The
electronics of the aryl iodide appeared to have limited effect on
reactivity and both electron-donating (6aab) and electron-
withdrawing substituents (6aac) were well tolerated, as were
halides (6aad, 6aae, 6aaf) and ortho-substitution (6aag).
Nitrogen heterocycles could also be incorporated, giving coupled
product 6aah, albeit in reduced yield. Simple ortho-bromo
benzylamine 1b underwent smooth coupling to provide 6baa in
67% yield. Electron-rich and electron-poor benzylamines were
viable substrates, providing 6caa and products 6dai–6gai. Ortho-
substitution was tolerated, as illustrated by bis-ortho-substituted
product 6dai, and heteroaryl benzylamines could also by used, as
highlighted by benzothiophenyl amine 1h, which provided product
6hai in moderate yield.[15]
We then turned our attention towards the synthesis of
enantioenriched
1,1-diarylethane
derivatives.
α-Methyl
benzylamine (R)-1i (99:1 e.r.) was subjected to the standard
reaction conditions using cyclohexylboronic ester 2a (Scheme
3A). Coupled product 6iaa was formed in 50% 1H NMR yield and
91:9 e.r., corresponding to an enantiospecificity of 84% from (R)-
1i. Since 4ia is formed in 96:4 e.r.,[9] this result indicates that the
γ-selective allylic Suzuki-Miyaura cross-coupling (4ia to 6iaa)
proceeds in 87% es. For comparison, we prepared and tested α-
methyl benzylic boronic ester 5ia (94:6 e.r.) under Crudden’s
cross-coupling conditions, which provided 24% of 6iaa in 88:12
e.r. (86% es), along with 30% β-hydride elimination product 7,
30% of returned starting boronic ester 5ia and 4%
protodeboronation product 8 (Scheme 3B). The lower yield and
formation of side-products is a consequence of the considerable
steric hindrance of boronic ester substrate 5ia, highlighting a
positive feature of the new process which does not suffer from the
same issues.
Scheme 2. Optimization of γ-selective allylic Suzuki-Miyaura cross-coupling.
Me2Troc−Cl = 2,2,2-trichloro-1,1-dimethylethyl chloroformate.
With the optimized conditions in hand, we went on to
investigate the scope of the three-component coupling reaction
(Table 1, part A). Symmetrical cyclic secondary boronic esters
gave coupled products 6aaa – 6ada in excellent isolated yields.
This article is protected by copyright. All rights reserved.

10.1002/anie.201811343
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Substrate scope.[a]
[a] Reactions were performed using 0.3 mmol of 3, 1.5 equiv of 1, 2, nBuLi (1.6 M in hexanes) and ClCO2CMe2CCl3, 3 equiv of Ag2CO3, 5 mol% of Pd(dba)2 and 10 mol% of
RuPhos. See SI for exact experimental procedures. Yields refer to isolated products unless otherwise indicated. Diastereomeric ratios were determined by 1H NMR analysis of
the purified compounds. [b] Final cross-coupling step at RT for 18 h. [c] Yield determined by 1H NMR analysis of the crude reaction mixture using dibromomethane as internal
standard. [d] Cross-coupling step at 75 ºC for 5 h.
Scheme 3. 1,1-Diarylethanes from α-methyl benzylamines.
This article is protected by copyright. All rights reserved.

10.1002/anie.201811343
Angewandte Chemie International Edition
COMMUNICATION
Scheme 4. Mechanistic proposal for chirality transfer.
To further highlight the utility of this methodology, doubly
stereospecific transformations were carried out using both
enantiomers of α-methyl benzylamine 1i and (–)-menthol-derived
boronic ester 2m (Scheme 3C). Couplng with (R)-1i provided
product 6ima in 40% isolated yield and >95:5 d.r. and the
enantiomeric α-methyl benzylamine (S)-1i gave the
diastereomeric product 6ima' in 44%, again in excellent d.r.
(>95:5).[16] In addition, reaction of enantioenriched boronic ester
2n with (R)-1i and (S)-1i afforded diastereomeric products 6ina
and 6ina', respectively, both with >95:5 d.r. (Scheme 3C). These
examples indicate that no matched/mismatched effects occur
between the benzylamine and boronic ester components.
are transformed into valuable optically active 1,1-diarylethanes
with good stereospecificity. In terms of reactivity, the key syn γ-
selective allylic Suzuki-Miyaura cross-coupling process appears
to overcome structural limitations encountered in the traditional
direct cross-coupling of certain sterically hindered secondary
benzylic boronic esters. The highly convergent nature of this
coupling process affords sterically encumbered 1,1-diarylethanes
with three readily addressable points of diversification.
Acknowledgements
We thank the EPSRC (EP/I038071/1), and H2020 ERC (670668)
for financial support. B.R. thanks the Principality of Asturias and
the EU for a Clarin-COFUND postdoctoral grant (ACA17-23). S.A.
thanks the Austrian Science Fund (FWF) for an Erwin
Schrꢀdinger fellowship (J3919-N28). R.B. thanks the Swiss
While secondary boronic ester 5ia does undergo direct cross-
coupling to provide cross-coupled product 6iaa when subjected to
Crudden’s conditions (Scheme 3B), we believe that a 1,3-
borotropic shift/direct cross-coupling pathway for α-methyl
benzylamine (R)-1i is unlikely. To rule out such a pathway, we
subjected boronic ester 5ia to our reaction conditions, and
observed no evidence of cross-coupled product 6iaa (Scheme
4A).[17] Furthermore, naphthylamine 1a, which has been used
extensively as a substrate in these studies, is stable with respect
to the 1,3-borotropic shift: heating 4aa in the presence of NaBPh4,
in line with our previously reported conditions,[9] provided no
evidence of the borotropic shift product (Scheme 4B). Moreover,
heating 4aa in the presence of Ag2CO3, in analogy to our
optimized allylic cross-coupling conditions, also showed no
reactivity towards 1,3-borotropic shift. We thus propose that the
transformation of α-methyl benzylamines into 1,1-diarylethane
derivatives proceeds via a series of four highly stereospecific
processes: (i) a stereospecific 1,2-metalate rearrangement that
occurs concurrently with (ii) a stereospecific anti-SN2' elimination
of the N-acylated leaving group to give the dearomatized
intermediate, 4, followed by (iii) a stereospecific syn γ-selective
allylic transmetalation via a six-membered transition state to give
intermediate 5 and (iv) a stereospecific retentive reductive
elimination (Scheme 4C). In this way, the chirality in the staring α-
methyl benzylamine is transferred through four sequential
processes into the final coupled product with high
stereospecificity.
National
Science
Foundation
fellowship
program
(P2EZP2_165268). We thank Dr. H. Sparkes for X-ray
crystallography of 6ima', and Prof. C. Butts and Prof. J. Clayden
for helpful discussions.
Conflict of interest
The authors declare no conflict of interest.
Keywords: 1,1-diarylalkane • stereospecific • cross-coupling •
one-pot • boronic ester
[1]
For examples of 1,1-diarylakanes with biological activity, see: a) K.-L. Yu,
P. Spinazze, J. Ostrowski, S. J. Currier, E. J. Pack, L. Hammer, T.
Roalsvig, J. A. Honeyman, D. R. Tortolani, P. R. Reczek, et al., J. Med.
Chem. 1996, 39, 2411; b) C. J. Hills, S. A. Winter, J. A. Balfour, Drugs
1998, 55, 813; c) M. J. Perry, J. O’Connell, C. Walker, T. Crabbe, D.
Baldock, A. Russell, S. Lumb, Z. Huang, D. Howat, R. Allen, et al., Cell
Biochem. Biophys. 1998, 29, 113; d) A. L. McRae, K. T. Brady, Expert
Opin. Pharmacother. 2001, 2, 883; e) M. Gordaliza, P. A. Garcıa, J. M.
́
Miguel del Corral, M. A. Castro, M. A. Gómez-Zurita, Toxicon 2004, 44,
441; f) A. Zhang, J. L. Neumeyer, R. J. Baldessarini, Chem. Rev. 2007,
107, 274; g) J. E. Sheppeck, J. L. Gilmore, T. G. M. Dhar, H.-Y. Xiao, J.
Wang, B. V. Yang, L. M. Doweyko, WO2008057857 (A1), 2008; h) A.
Kodimuthali, S. S. L. Jabaris, M. Pal, J. Med. Chem. 2008, 51, 5471; i) J.
In conclusion, we report a new method for the synthesis of
enantioenriched 1,1-diarylethane derivatives. Through a series of
four stereospecific steps, enantioenriched α-methyl benzylamines
This article is protected by copyright. All rights reserved.

10.1002/anie.201811343
Angewandte Chemie International Edition
COMMUNICATION
Zhang, B. Xiong, X. Zhen, A. Zhang, Med. Res. Rev. 2009, 29, 272; j) A.
Abad, J. L. López-Pérez, E. del Olmo, L. F. García-Fernández, A.
Francesch, C. Trigili, I. Barasoain, J. M. Andreu, J. F. Díaz, A. San
Feliciano, J. Med. Chem. 2012, 55, 6724.
j) G. A. Molander, S. R. Wisniewski, J. Am. Chem. Soc. 2012, 134,
16856; k) L. Li, S. Zhao, A. Joshi-Pangu, M. Diane, M. R. Biscoe, J. Am.
Chem. Soc. 2014, 136, 14027; l) G. L. Hoang, Z.-D. Yang, S. M. Smith,
R. Pal, J. L. Miska, D. E. Pérez, L. S. W. Pelter, X. C. Zeng, J. M. Takacs,
Org. Lett. 2015, 17, 940; m) G. L. Hoang, J. M. Takacs, Chem. Sci. 2017,
8, 4511; n) S. Zhao, T. Gensch, B. Murray, Z. L. Niemeyer, M. S. Sigman,
M. R. Biscoe, Science 2018, 362, 670.
[2]
[3]
T. C. Fessard, S. P. Andrews, H. Motoyoshi, E. M. Carreira, Angew.
Chem. Int. Ed. 2007, 46, 9331; Angew. Chem. 2007, 119, 9492.
a) J. Mazuela, J. J. Verendel, M. Coll, B. Schäffner, A. Börner, P. G.
Andersson, O. Pàmies, M. Diéguez, J. Am. Chem. Soc. 2009, 131,
12344; b) X. Wang, A. Guram, S. Caille, J. Hu, J. P. Preston, M. Ronk,
S. Walker, Org. Lett. 2011, 13, 1881; c) S. Song, S.-F. Zhu, Y.-B. Yu, G.-
L. Zhou, Angew. Chem. Int. Ed. 2013, 52, 1556; Angew. Chem. 2013,
125, 1596; d) E. N. Bess, M. S. Sigman, Org. Lett. 2013, 15, 646.
[11] a) B. W. Glasspoole, K. Ghozati, J. W. Moir, C. M. Crudden, Chem.
Commun. 2012, 48, 1230; b) B. M. Partridge, L. Chausset‐Boissarie, M.
Burns, A. P. Pulis, V. K. Aggarwal, Angew. Chem. Int. Ed. 2012, 51,
11795; Angew. Chem. 2012, 124, 11965; c) L. Chausset‐Boissarie, K.
Ghozati, E. LaBine, J. L.-Y. Chen, V. K. Aggarwal, C. M. Crudden, Chem.
Eur. J. 2013, 19, 17698; d) B. Potter, E. K. Edelstein, J. P. Morken, Org.
Lett. 2016, 18, 3286.
[4]
a) K. M. Gligorich, S. A. Cummings, M. S. Sigman, J. Am. Chem. Soc.
2007, 129, 14193; b) V. Saini, L. Liao, Q. Wang, R. Jana, M. S. Sigman,
Org. Lett. 2013, 15, 5008; c) E. Yamamoto, M. J. Hilton, M. Orlandi, V.
Saini, F. D. Toste, M. S. Sigman, J. Am. Chem. Soc. 2016, 138, 15877;
d) S. D. Friis, M. T. Pirnot, S. L. Buchwald, J. Am. Chem. Soc. 2016, 138,
8372; e) K. M. Logan, M. K. Brown, Angew. Chem. Int. Ed. 2017, 56,
851; Angew. Chem. 2017, 129, 869.
[12] a) H. Shanan-Atidi, K. H. Bar-Eli, J. Phys. Chem. 1970, 74, 961; b) J.
Sandstrꢀm, Dynamic NMR Spectroscopy, Academic Press, New York,
1982.
[13] For examples of restricted rotaion around C(sp2)−C(sp3) bonds, see: a)
G. P. Newsoroff, S. Sternhell, Tetrahedron Lett. 1967, 8, 2539; b) S. E.
Boiadjiev, D. A. Lightner, Monatsh. Chem. 2002, 133, 1469; c) H. Berber,
P. Lameiras, C. Denhez, C. Antheaume, J. Clayden, J. Org. Chem. 2014,
79, 6015; d) M. Flos, P. Lameiras, C. Denhez, C. Mirand, H. Berber, J.
Org. Chem. 2016, 81, 2372.
[5]
a) B. L. H. Taylor, E. C. Swift, J. D. Waetzig, E. R. Jarvo, J. Am. Chem.
Soc. 2011, 133, 389; b) M. A. Greene, I. M. Yonova, F. J. Williams, E. R.
Jarvo, Org. Lett. 2012, 14, 4293; c) P. Maity, D. M. Shacklady-McAtee,
G. P. A. Yap, E. R. Sirianni, M. P. Watson, J. Am. Chem. Soc. 2013, 135,
280; d) Q. Zhou, H. D. Srinivas, S. Dasgupta, M. P. Watson, J. Am.
Chem. Soc. 2013, 135, 3307; e) H. M. Wisniewska, E. C. Swift, E. R.
Jarvo, J. Am. Chem. Soc. 2013, 135, 9083; f) I. M. Yonova, A. G.
Johnson, C. A. Osborne, C. E. Moore, N. S. Morrissette, E. R. Jarvo,
Angew. Chem. Int. Ed. 2014, 53, 2422; Angew. Chem. 2014, 126, 2454.
[14] The 1H NMR yields reported in Scheme 2 were extrapolated by
integrating the major rotamer in the crude reaction mixture and applying
a correction factor based on the 87:13 ratio of rotamers observed for the
pure compound (see SI for details).
[15] 1-Iodo-3-methoxybenzene (3i) was used in place of iodobenzene (3a) in
some examples as it facilitated purification, particularly from
homocoupling product.
[6]
[7]
a) H.-Q. Do, E. R. R. Chandrashekar, G. C. Fu, J. Am. Chem. Soc. 2013,
135, 16288; b) K. E. Poremba, N. T. Kadunce, N. Suzuki, A. H. Cherney,
S. E. Reisman, J. Am. Chem. Soc. 2017, 139, 5684; c) L. K. G.
Ackerman, L. L. Anka-Lufford, M. Naodovic, D. J. Weix, Chem. Sci. 2015,
6, 1115.
[16] The stereochemistry of 6ima' was confirmed by X-ray crystallography.
[17] Subjecting primary benzylic boronic ester 5ba to these conditions does,
however, provide coupled product 6baa in 21% NMR yield, along with
21% recovered 5ba (see SI for details). Thus, for benzylamines without
α-substitution (e.g., 1b), we cannot rule out a minor pathway that
proceeds via 1,3-borotropic shift followed by direct Suzuki-Miyaura
cross-coupling.
a) D. Imao, B. W. Glasspoole, V. S. Laberge, C. M. Crudden, J. Am.
Chem. Soc. 2009, 131, 5024; b) S. C. Matthew, B. W. Glasspoole, P.
Eisenberger, C. M. Crudden, J. Am. Chem. Soc. 2014, 136, 5828; c) J.
P. G. Rygus, C. M. Crudden, J. Am. Chem. Soc. 2017, 139, 18124. d) C.
M. Crudden, C. Ziebenhaus, J. P. G. Rygus, K. Ghozati, P. J. Unsworth,
M. Nambo, S. Voth, M. Hutchinson, V. S. Laberge, Y. Maekawa, D. Imao,
Nat. Commun. 2016, 7, 11065.
[8]
a) T. Hayashi, Y. Matsumoto, Y. Ito, J. Am. Chem. Soc. 1989, 111, 3426;
b) T. Hayashi, Y. Matsumoto, Y. lto, Tetrahedron: Asymmetry 1991, 2,
601; c) J. Zhang, B. Lou, G. Guo, L. Dai, J. Org. Chem. 1991, 56, 1670;
d) K. Burgess, W. A. Van der Donk, S. A. Westcott, T. B. Marder, R. T.
Baker, J. C. Calabrese, J. Am. Chem. Soc. 1992, 114, 9350.
[9]
S. Aichhorn, R. Bigler, E. L. Myers, V. K. Aggarwal, J. Am. Chem. Soc.
2017, 139, 9519.
[10] For stereospecific Suzuki-Miyaura cross-couplings of benzylic
organoboron compounds, see: a) T. Ohmura, T. Awano, M. Suginome,
J. Am. Chem. Soc. 2010, 132, 13191; b) T. Awano, T. Ohmura, M.
Suginome, J. Am. Chem. Soc. 2011, 133, 20738; c) D. Leonori, V. K.
Aggarwal, Angew. Chem. Int. Ed. 2015, 54, 1082; Angew. Chem. 2015,
127, 1096; d) Y. Lou, P. Cao, T. Jia, Y. Zhang, M. Wang, J. Liao, Angew.
Chem. Int. Ed. 2015, 54, 12134; Angew. Chem. 2015, 127, 12302. For
stereospecific Suzuki-Miyaura cross-couplings of non-benzylic
organoboron compounds, see: e) S.-M. Zhou, M.-Z. Deng, L.-J. Xia, M.-
H. Tang, Angew. Chem. Int. Ed. 1998, 37, 2845; Angew. Chem. 1998,
110, 3061; f) G.-H. Fang, Z.-J. Yan, M.-Z. Deng, Org. Lett. 2004, 6, 357;
g) S. D. Dreher, P. G. Dormer, D. L. Sandrock, G. A. Molander, J. Am.
Chem. Soc. 2008, 130, 9257; h) D. L. Sandrock, L. Jean-Gérard, C.
Chen, S. D. Dreher, G. A. Molander, J. Am. Chem. Soc. 2010, 132,
17108; i) J. C. H. Lee, R. McDonald, D. G. Hall, Nat. Chem. 2011, 3, 894;
This article is protected by copyright. All rights reserved.

10.1002/anie.201811343
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
Belén Rubial, Beatrice S. L. Collins,
Raphael Bigler, Stefan Aichhorn, Adam
Noble, Varinder K. Aggarwal*
Page No. – Page No.
Enantiospecific Synthesis of ortho-
Substituted 1,1-Diarylalkanes by a 1,2-
The coupling of benzylamines, boronic esters and aryl iodides gives1,1-diarylalkanes
with high stereospecificity through a sequential 1,2-metalate rearrangement/anti-SN2'
elimination/rearomatizing allylic Suzuki-Miyaura cross-coupling reaction.
Metalate
Elimination/Rearomatizing
Suzuki-Miyaura Reaction Sequence
Rearrangement/anti-SN2'
Allylic
This article is protected by copyright. All rights reserved.