Chiral Aniline Synthesis via Stereospecific C(sp3)-C(sp2) Coupling of Boronic Esters with Aryl Hydrazines

Article abstract of DOI:10.1021/acs.orglett.8b02615

An enantiospecific coupling between alkylboronic esters and lithiated aryl hydrazines is described. The reaction proceeds under transition-metal-free conditions and is promoted by acylation of a hydrazinyl arylboronate complex, which triggers a N-N bond cleavage with concomitant 1,2-metalate rearrangement. Judicious choice of the acylating agent enabled the synthesis of ortho- and para-substituted anilines with essentially complete enantiospecificity from a wide range of boronic ester substrates.

Full text of DOI:10.1021/acs.orglett.8b02615

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chiral Aniline Synthesis via Stereospecific C(sp3)−C(sp2) Coupling of
Boronic Esters with Aryl Hydrazines
Venkataraman Ganesh, Adam Noble, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
S
* Supporting Information
ABSTRACT: An enantiospecific coupling between alkylbor-
onic esters and lithiated aryl hydrazines is described. The
reaction proceeds under transition-metal-free conditions and is
promoted by acylation of a hydrazinyl arylboronate complex,
which triggers a N−N bond cleavage with concomitant 1,2-
metalate rearrangement. Judicious choice of the acylating agent
enabled the synthesis of ortho- and para-substituted anilines
with essentially complete enantiospecificity from a wide range of
boronic ester substrates.
itrogen-containing compounds are of immense impor-
tance in medicine, constituting 84% of all small-molecule
sequent elimination of the boron and halide moieties from the
dearomatized intermediate providing the coupled product. A
limitation of this method is the requirement for meta-electron-
donating groups, which promote the SEAr pathway, whereas
those bearing ortho- or para-substituents react through an
undesired SE2 pathway.8
N
drugs.1 Within this class of molecules, chiral anilines possessing
benzylic stereocenters make up a significant subset (Figure 1).2
In related work, we showed that activation of heteroatoms of
nitrogen- or oxygen-containing arylboronate complexes could
also induce a 1,2-metalate rearrangement to provide coupled
products.9−11 For example, we demonstrated that boronate
complexes formed from ortho-lithiated benzylamines undergo
acylation and 1,2-metalate rearrangement (Figure 2B).
Subsequent 1,3-borotropic shift of the dearomatized inter-
mediate provides enantioenriched benzylic boronic esters. We
recognized that this C−N bond cleavage-triggered coupling
reaction could be extended to a related N−N bond cleavage if
hydrazine derivatives were implemented in the place of
benzylic amines (Figure 2C). Such a protocol would provide
a convenient method for the synthesis of chiral ortho- and
para-substituted anilines, products that are currently inacces-
sible using our previously developed coupling reactions.7
Herein, we describe the successful development of such a
method in which unactivated secondary and tertiary
alkylboronic esters undergo stereospecific, transition-metal-
free coupling with ortho- and para-lithiated aryl hydrazines.
The resulting aniline products are generated in high yield and
with complete enantiospecificity for a range of structurally
diverse boronic esters.
Figure 1. Chiral aniline drugs.
The development of new methods to access such structures in
a stereocontrolled fashion is, therefore, highly desirable. One
potential approach would involve introducing the aniline motif
through a stereoselective cross-coupling of a halogenated
aniline with an enantioenriched alkylmetal species, such as an
organoboron reagent.3 This would be particularly attractive
given the numerous available methods for synthesizing chiral
secondary and tertiary alkylboronic esters in high enantiomeric
purity.4 However, such transformations are not trivial, with
challenges associated with slow transmetalation and competing
β-hydride elimination generally necessitating the use of
activated organoboron reagents.3a,5,6
We recently initiated a research program focused on
developing alternative, transition-metal-free coupling strategies
that proceed through 1,2-metalate rearrangements of in situ
generated arylboronate complexes (Figure 2A).7 The rear-
rangements are triggered by electrophilic attack (SEAr) of a
nucleophilic π-system by a halogenating agent, with sub-
Key to the success of the proposed coupling was the
identification of an acylating agent that would selectively react
at the dimethylamino group of boronate complex 1, in
preference to the oxygen of the pinacolate,12 generating acyl
ammonium 2 and triggering the 1,2-metalate rearrangement to
Received: August 15, 2018
© XXXX American Chemical Society
A
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a
Scheme 2. Scope of para-Bromoaryl Hydrazines
a
Reactions carried out with 4 (1.1 equiv), n-BuLi (1.1 equiv), 5 (0.18
mmol, 1.0 equiv), and TFAA (2.1 equiv). Yields are of isolated
b
products after purification by flash column chromatography. Number
in parentheses is the isolated yield on a 1.2 mmol scale.
acylating reagents were tested to determine the feasibility of
the proposed 1,2-metalate rearrangement.13 Ultimately,
trifluoroacetic anhydride (TFAA) was identified as an effective
promoter of the reaction, as treatment of a solution of
boronate complex 6 with 2.1 equiv of TFAA resulted in the
formation of trifluoroacetyl-protected aniline 7a in 82% yield.
The use of this stoichiometry of TFAA was necessary to
achieve a high yield in this reaction as the unprotected aniline
product was never observed (Figure 2C, path A). This suggests
that the second equivalent of TFAA reacts with the 1,4-
cyclohexadienyl imine intermediate 3 prior to rearomatization
by elimination of boron (Figure 2C, path B). Several other
para-bromoaryl hydrazines (4b−c) also underwent efficient
coupling with 5 to generate the corresponding para-alkylated
anilines in high yields. These included naphthalene derivative
7b, dihydroindazole-derived bisamide 7c, and indoline 7d.
Furthermore, the reaction could be scaled without loss in
efficiency, with product 7a isolated in 79% yield on a 1.2 mmol
scale.
Figure 2. Electrophile-induced coupling reactions of arylboronate
complexes.
The successful formation of para-substituted aniline
products 7a−d is of note considering the failure of the related
reactions of para-lithiated benzylic amines (compare Figure 2B
with ref 14).10 In our previous study, it was found that the
dearomatized intermediates, formed upon acylation and 1,2-
metalate rearrangement of para-benzylic amine boronate
complexes, underwent a radical-mediated von Auwers-type
rearrangement rather than the desired double 1,3-borotropic
shift sequence, resulting in a nonstereoselective benzylation
reaction instead of the expected arylation.14,15 However, in the
reactions with para-lithiated phenyl hydrazines, the 1,4-
cyclohexadienyl imine intermediates 3 presumably undergo
rapid acylation followed by nucleophile-promoted elimination
of the boronic ester group (Figure 2C, path B). Therefore, the
desired rearomatization does not require a borotropic shift,
which eliminates any potential competing reaction pathways
and enables the generation of para-substituted aniline products
in excellent yield.
form dearomatized intermediate 3 (Figure 2C). We selected
N,N,N′-trimethyl phenyl hydrazines as substrates for our
proposed reaction because they can be easily prepared in two
steps from readily available anilines (Scheme 1).
Scheme 1. Synthesis of Permethylated Bromophenyl
Hydrazines
We commenced our investigations by studying the coupling
of 1-(4-bromophenyl)-1,2,2-trimethylhydrazine (4a, R = H)
with cyclohexylboronic acid pinacol ester (5) (Scheme 2).
Lithium−halogen exchange between 4a and n-butyllithium
followed by reaction of the resulting lithiated phenyl hydrazine
with 5 formed arylboronate complex 6. A range of different
Pleasingly, ortho-bromoaryl hydrazines 8 also underwent
efficient coupling with boronic ester 5 (Scheme 3).
Interestingly, reaction of boronate complex 9 with trifluoro-
B
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a
With conditions developed for the efficient synthesis of
ortho- and para-substituted anilines, we proceeded to test the
scope of the methods with respect to the alkylboronic ester
substrate (Scheme 4). Primary alkylboronic esters (11) were
successfully coupled with para-bromophenyl hydrazine 4a. In
addition to cyclohexylboronic ester 5, other cyclic secondary
boronic esters, including cyclododecanyl (12) and N-Boc-
piperidinyl (13), underwent efficient coupling to generate the
aniline products in high yield. Given the well-documented
stereospecificity of 1,2-metalate rearrangements of boronate
complexes formed from enantioenriched alkylboronic es-
ters,7,9−11 we next investigated the application of this reaction
to the coupling of enantioenriched chiral boronic esters.
Gratifyingly, para-bromophenyl hydrazine 4a reacted with an
enantioenriched secondary boronic ester to give the aniline
product 14 in excellent yield and enantiospecificity (es).16 This
was also observed with substrates bearing azide (15) and
terminal olefin (16) moieties. Furthermore, para-substituted
aniline products 17 and 18 could be prepared in high yield and
with complete stereospecificity from a secondary benzylic
boronic ester and a tertiary nonbenzylic boronic ester. In
addition to enantiospecific couplings, several diastereospecific
examples were also performed, enabling the generation of
silylated tetralin 19 and natural product derivatives 20, from
the terpene menthol, and 21, from the steroid cholesterol, all
with complete diastereospecificity (ds).
Scheme 3. Scope of ortho-Bromoaryl Hydrazines
a
Reactions carried out with 8 (1.1 equiv), n-BuLi (1.1 equiv), 5 (0.18
mmol, 1.0 equiv), and Me2Troc−Cl (2.1 equiv). Yields are of isolated
products after purification by flash column chromatography.
b
Reaction carried out using the corresponding aryl iodide.
Finally, the reaction of ortho-bromophenyl hydrazine 8a with
various alkylboronic esters was investigated (Scheme 4). A
range of primary and secondary alkylboronic esters yielded
ortho-substituted anilines possessing synthetically useful func-
tional groups, such as acetals (22), terminal olefins (23), azides
(24), and carbamates (25). Arylboronic esters were also viable
substrates, allowing the formation of hindered ortho-
substituted biaryls (26). Pleasingly, 8a also reacted with an
enantioenriched secondary boronic ester to give the chiral
acetic anhydride led to a complex mixture of products, whereas
2,2,2-trichloro-1,1-dimethylethyl chloroformate (Me2Troc-Cl)
gave the desired acylated aniline product 10a in excellent
yield.13 Using Me2Troc-Cl as the activator, a range of other
substituted ortho-bromoaryl hydrazines were coupled with
boronic ester 5, including those possessing electron-with-
drawing (10b), electron-donating (10c), and halide sub-
stituents (10d−f).
Scheme 4. Boronic Ester Scope
a
b
c
Prepared from para-bromophenyl hydrazine 4a and TFAA (see Scheme 2 for conditions). See Supporting Information for details. Prepared
from ortho-bromophenyl hydrazine 8a and Me2Troc-Cl (see Scheme 3 for conditions). TFA = trifluoroacetyl. DMT = 2,2,2-trichloro-1,1-
dimethylethoxycarbonyl.
C
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aniline 27 in high yield and with excellent enantiospecificity.
Unfortunately, the coupling of hindered secondary and tertiary
boronic esters with ortho-substituted hydrazine 8a was not
successful, presumably due to the high steric hindrance
preventing N-acylation of the intermediate boronate com-
plex.17
In conclusion, we have developed a stereospecific coupling
reaction between alkylboronic esters and ortho- and para-
lithiated aryl hydrazines. The reactions proceed via hydrazine
acylation and N−N bond cleavage-induced 1,2-metalate
rearrangement of arylboronate complexes, providing efficient
access to enantioenriched aniline products from readily
available substrates. By utilizing this N-activation strategy,
both ortho- and para-substituted chiral anilines could be
accessed, which overcomes a limitation of previously
developed coupling protocols.
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Gerard, L.; Chen, C.; Dreher, S. D.; Molander, G. A. J. Am. Chem. Soc.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02615.
́
L.; Yang, Z.-D.; Smith, S. M.; Pal, R.; Miska, J. L.; Perez, D. E.; Pelter,
L. S. W.; Zeng, X. C.; Takacs, J. M. Org. Lett. 2015, 17, 940−943.
(i) Hoang, G. L.; Takacs, J. M. Chem. Sci. 2017, 8, 4511−4516.
(7) (a) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal,
V. K. Nat. Chem. 2014, 6, 584−589. (b) Odachowski, M.; Bonet, A.;
Essafi, S.; Conti-Ramsden, P.; Harvey, J. N.; Leonori, D.; Aggarwal, V.
K. J. Am. Chem. Soc. 2016, 138, 9521−9532. For related
transformations, see: (c) Ganesh, V.; Odachowski, M.; Aggarwal, V.
K. Angew. Chem., Int. Ed. 2017, 56, 9752−9756. (d) Bigler, R.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2018, 57, 1082−1086.
(8) Larouche-Gauthier, R.; Elford, T. G.; Aggarwal, V. K. J. Am.
Chem. Soc. 2011, 133, 16794−16797.
General procedures, characterization data, and copies of
NMR spectra for all novel compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: v.aggarwal@bristol.ac.uk.
ORCID
(9) For coupling of lithiated pyridines, see: (a) Llaveria, J.; Leonori,
D.; Aggarwal, V. K. J. Am. Chem. Soc. 2015, 137, 10958−10961. For a
related process, see: (b) Panda, S.; Coffin, A.; Nguyen, Q. N.;
Tantillo, D. J.; Ready, J. M. Angew. Chem., Int. Ed. 2016, 55, 2205−
2209.
Adam Noble: 0000-0001-9203-7828
Varinder K. Aggarwal: 0000-0003-0344-6430
Notes
The authors declare no competing financial interest.
(10) Aichhorn, S.; Bigler, R.; Myers, E. L.; Aggarwal, V. K. J. Am.
Chem. Soc. 2017, 139, 9519−9522.
ACKNOWLEDGMENTS
■
(11) Wilson, C. M.; Ganesh, V.; Noble, A.; Aggarwal, V. K. Angew.
Chem., Int. Ed. 2017, 56, 16318−16322.
We thank the EPSRC (EP/I038071/1) and the H2020 ERC
(670668) for financial support. V.G. thanks the Royal Society
for a Newton International Fellowship. We thank Dr.
Meganathan Nandakumar for performing the scale-up reaction.
(12) (a) Chen, J. L. Y.; Scott, H. K.; Hesse, M. J.; Willis, C. L.;
Aggarwal, V. K. J. Am. Chem. Soc. 2013, 135, 5316−5319. (b) Chen, J.
L. Y.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2014, 53, 10992−10996.
(13) See Supporting Information for details.
(14) Reactions of para-benzylic amine boronate complexes were
found to proceed via a von Auwers-type rearrangement (see reference
10):
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(16) The enantiospecificity (es) was calculated as follows:
% ee of product
es =
× 100.
% ee of starting material
(17) For example, the secondary benzylic and tertiary nonbenzylic
boronic esters used to prepare para-substituted aniline products 17
and 18 (see Scheme 4) failed to yield the desired ortho-substituted
anilines upon reaction with 8a.
D
DOI: 10.1021/acs.orglett.8b02615
Org. Lett. XXXX, XXX, XXX−XXX