Exploiting the Bis-Nucleophilicity of α-Aminoboronates: Copper-Catalyzed, Intramolecular Aminoalkylations of Bromobenzoyl Chlorides

Article abstract of DOI:10.1021/acs.orglett.6b00586

α-Aminoboronate salts are interesting examples of heteroatomic species containing adjacent nucleophilic centers. We have developed an acylation/arylation reaction using 2-bromobenzoyl chlorides as bis-electrophiles that harnesses the nucleophilicity of both positions, leading to isoindolinones. The reactions proceed under mild conditions via an intramolecular, Cu-catalyzed sp³-sp² coupling, giving products in up to 95% yield. These conditions enable arylation of α,α-disubstituted aminoboronates, which are difficult to accomplish using methods based on less abundant and more expensive transition metals.

Full text of DOI:10.1021/acs.orglett.6b00586

Letter
pubs.acs.org/OrgLett
Exploiting the Bis-Nucleophilicity of α‑Aminoboronates: Copper-
Catalyzed, Intramolecular Aminoalkylations of Bromobenzoyl
Chlorides
Aaron M. Dumas,* Adrian J. Sieradzki, and Liam J. Donnelly
Department of Process Chemistry, Merck Sharp and Dohme Ltd., Hertford Road, Hoddesdon EN11 9BU, United Kingdom
S
* Supporting Information
ABSTRACT: α-Aminoboronate salts are interesting examples
of heteroatomic species containing adjacent nucleophilic
centers. We have developed an acylation/arylation reaction
using 2-bromobenzoyl chlorides as bis-electrophiles that
harnesses the nucleophilicity of both positions, leading to
isoindolinones. The reactions proceed under mild conditions via an intramolecular, Cu-catalyzed sp3−sp2 coupling, giving
products in up to 95% yield. These conditions enable arylation of α,α-disubstituted aminoboronates, which are difficult to
accomplish using methods based on less abundant and more expensive transition metals.
Scheme 1. Use of Doubly Nucleophilic Aminoboronates in
Cu-Catalyzed Cyclizations
α-Aminoboronates are stable heteroatomic bis-nucleophiles that
are finding wider use as methods to access them broaden.1 The
nitrogen’s reactivity is essentially unchanged compared to
standard amines, and coupling of aminoboronates to carboxylic
acids is used routinely, for example, in the synthesis of boronic
acid-based protease inhibitors such as bortezomib.2 However,
reactions of the nucleophilic C−B bond in, for example, Suzuki
coupling, are made more difficult by the adjacent nitrogen atom.
This is likely due to a combination of factors including a higher
barrier to transmetalation at sp3-centers, increased steric
hindrance around the reactive carbon atom, and facile
competitive protodeboronation via 1,2-boryl migration. Never-
theless, advances in transition metal-catalyzed C−C bond
forming reactions of aminoboronates have been achieved.
Molander has performed extensive studies on aromatic amino-
methylations using a variety of substituted R2NCH2BF3K salts by
Pd- or photoredox/Ni-catalysis.3 Pd-catalyzed aminobenzyla-
tions of branched aminoboronates were pioneered by the group
of Suginome.4 Additionally, Rh(I)-catalyzed additions to
carbonyls were reported by Ellman,5 and transition metal-free
arylations of cyclic aminoboronates were recently disclosed by
Aggarwal.6
Inspired by this precedent, we reasoned that reactions that
exploit the geminal nucleophility of both the nitrogen atom and
the C−B bond in aminoboronates could be useful, so long as a
suitable bis-electrophilic partner was identified. Herein, we
describe the one-pot amidation/arylation of aminoboronates
with 2-halobenzoyl chlorides as a means of preparing
isoindolinones (Scheme 1).7 Key to this transformation was
the discovery of a mild Cu-catalyzed coupling reaction that
enabled intramolecular sp3−sp2 arylation without relying on
more expensive and less abundant transition metals.
sources, ligands, bases, and solvent systems failed to provide any
of the expected product, isoindolinone 2a (entry 1). However, a
screen of additives revealed that Cu(I) salts were effective in
promoting the desired coupling (entry 2). Surprisingly though, a
control experiment revealed that the coupling occurred in the
absence of a Pd source and that 2a was obtained in essentially
identical yield with only the Cu additive (entry 3). Further
investigation showed that Cu(II) salts were more effective
promoters (entry 4), and subsequent optimization was carried
out using this metal oxidation state. Performing the reaction at
lower temperature slowed down competitive protodeboronation
and led to cleaner reaction profiles, but decreased the solubility of
the catalyst and amide 1a. Addition of a chelating ligand, 2,2′-
bipyridine (bpy), improved Cu(II) availability (entry 5), while
the use of DCE or THF as a cosolvent increased the solubility of
amide 1a (entries 6 and 7). As a probe of reactivity and functional
group compatibility, couplings were attempted within the
halogen series (entries 8−10). While iodide 1b coupled with
With the expectation that amidation would precede benzylic
arylation in the proposed domino process, initial optimization
focused on identifying conditions for the Suzuki coupling step
using bromobenzamide 1a (Table 1). Extensive screening of Pd
Received: March 1, 2016
© XXXX American Chemical Society
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Analysis of the crude reaction mixtures showed that this was due
to reduced levels of undesired side-products, which were
identified as benzaldehyde (5) and 2-bromobenzamide (6).
The origin of these side-products was traced to hydrolysis of
imine 7, which was identified by LCMS analysis as a minor
intermediate in the coupling of benzamide 1a (Scheme 2). A
Table 1. Optimization of Reaction Conditions for Conversion
of Amidoboronate 1a into Isoindolinone 2a
Scheme 2. Competitive Hydrolysis via Imine Intermediates
Suppressed by Catalytic Coupling Conditions
ligand
yield
a
entry
X
metal (equiv)
(equiv)
solvent
PhCH3
2a
b
1
Br
Pd(OAc)2 (0.05)
X-Phos
(0.1)
0
b
2
Br
Pd(OAc)2 (0.05)
CuCl (1.0)
X-Phos
(0.1)
PhCH3
45
b
3
Br
Br
Br
Br
Br
I
CuCl (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
PhCH3
44
65
29
85
53
51
0
b
4
PhCH3
5
bpy
bpy
bpy
bpy
bpy
bpy
PhCH3
6
PhCH3/DCE
PhCH3/THF
PhCH3/THF
PhCH3/THF
PhCH3/THF
7
8
9
Cl
F
10
CuCl2 (1.0)
0
plausible explanation for imine formation is C−B bond
chlorination by CuCl2,8 followed by elimination of HCl from
the resulting α-chloroamide 8. By performing the coupling with a
catalytic amount of CuCl2, formation of side-products 5 and 6
was minimized, and the desired pathway predominated to favor
coupling to 2a.
With a high yielding and catalytic method to couple
aminoboronate 3a in hand, the scope of the reaction was
examined with substituted acid chlorides 4b−i (Scheme 3). Since
a
1
Yield determined by H NMR relative to an internal standard of
b
1,3,5-trimethoxybenzene. Reaction performed at 70 °C.
essentially the same efficiency as bromide 1a (entry 8), the
corresponding chloride 1c and fluoride 1d gave no isoindolinone
2a (entries 9 and 10). Considering the wider availability of aryl
bromides relative to iodides, further investigation was carried out
using bromo derivatives.
Having successfully identified conditions for the challenging
C−C bond forming step, further improvements in the method
were sought. This had two main aims, the first being to avoid the
low yielding isolation of amide 1a by forming it in situ during the
coupling reaction from aminoboronate salt 3a and benzoyl
choride 4a. Further experiments proved this to be facile since the
basic conditions required for the coupling also promoted N-
acylation; the overall yield of 3a improved to 85% via the one-pot
procedure versus an overall yield of 42% when amide 1a was
isolated before coupling (entry 1). With a simple procedure in
hand, reactions using catalytic amounts of CuCl2 were examined
next. We were pleased to find that the catalyst loading could be
reduced easily, with reactions at 50 mol % (entry 2) and 10 mol %
(entry 3) being equally effective. To the best of our knowledge,
these results are the first examples of base metal-catalyzed C−C
bond forming reactions of aminoboronates.
Scheme 3. Catalytic Cyclization of Aminoboronate 3a and
Diverse Benzoyl Chlorides 4b−i
Somewhat surprisingly, the catalytic conditions were also
higher yielding than couplings using stoichiometric CuCl2.
Table 2. Catalytic, One-Pot Amidation/Arylation of
Aminoboronate 3a
a
Reaction performed with CuCl2 (1.0 equiv) and bpy (2.0 equiv); see
Supporting Information for details.
aryl chlorides did not themselves react under the coupling
conditions, this useful functional handle could be introduced at
any position of the ring, including ortho to the reactive bromide
group (2b−e). Electron-donating groups were compatible, with
conjugation into both the bromide (2f) or carboxyl (2g) groups.
As expected based on the results of Table 1, entry 10, a
fluoroaromatic was equally tolerated (2h). Of particular note was
the formation of brominated product 2i, where cyclization
occurred exclusively at the 2-Br group, and no products resulting
a
entry
equiv of CuCl2
equiv of bpy
yield 2a (%)
b
1
2
3
1.0
0.5
0.1
2.0
1.0
0.2
85 (42)
85
93
a
b
Isolated yield. Yield in brackets is for reaction over two steps from
3a using isolated amide 1a
B
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from intermolecular coupling at the 5-Br substituent were
detected.
Based on the literature precedent for Cu(I)-catalyzed Suzuki-
coupling of arylboronates and the seminal recent studies of
Giri,15 we propose the mechanism shown in Scheme 5. To access
the catalytically active Cu(I) oxidation state, the Cu(II)-
precatalyst A is reduced by a sacrificial amount of boronate 1a.
Following that, C−B transmetalation would generate benzylic
Cu(I) intermediate C, which should racemize readily especially
after the loss of chelation from the carbonyl oxygen that would be
necessary to bring the bromide group proximate to the metal
center.16 Following oxidative addition to form Cu(III)
intermediate D, reductive elimination would give the product
2a and regenerate the Cu(I) catalyst B.
The reaction performed equally well starting from amino-
boronates other than 3a (Scheme 4).9 As was the case with the
benzoyl chloride substituents, halogen substitution including
bromide was compatible with the reactions conditions (2j and
2k), as were electron-donating groups (2l).10 More importantly,
the Cu-catalyzed arylation enabled the formation of 3,3-
disubstituted isoindolinones 2m and 2n by coupling of
quaternary aminoboronates.11 To the best of our knowledge,
these are the first examples of arylation of fully substituted
aminoboronates or Cu-catalyzed couplings of quaternary
boronates. The importance of an adjacent aromatic ring in the
aminoboronate partner was highlighted by the formation of
alkyl-substituted 2o, which coupled in low yield with a large
amount of protodeboronated side-products.
Scheme 5. Proposed Mechanism for Cu-Catalyzed Arylation
Scheme 4. Catalytic Cyclization of Aminoboronates 3b−g
with Benzoyl Chloride 4a
To conclude, we have described the use of stable and readily
available aminoboronate salts as bisnucleophiles in the
preparation of isoindolinones. This was made possible by the
discovery of a novel sp3−sp2 cross-coupling reaction catalyzed by
a cheap and abundant copper complex. This work provided the
first examples of intramolecular coupling of aminoboronates as
well as the first arylation of quaternary derivatives. We have also
demonstrated the use of aminoboronates in domino processes
that involve both of the geminal reactive groups, which we hope
will prove useful in other transformations.
Cu-promoted cross-couplings are emerging as a viable
alternative to precious metal-catalyzed processes.12 While Cu-
catalyzed couplings of aminoboronates have not previously been
described, observations made during the course of this work
point toward a likely mechanism for the arylation reaction. First,
complete racemization of enantioenriched aminoboronate 3a
occurred in formation of product 2a, suggesting that a
configurationally unstable intermediate formed during the
reaction (eq 1). Second, the coupling likely proceeded via
initiation at the C−B bond rather than the aryl halide since other
C−Br groups in both partners were well-tolerated (2i and 2k).
Third, the C−C bond formed via a cross-coupling mechanism
involving oxidative addition into the weaker C−Br bond rather
than a SNAr or ipso radical substitution;13 otherwise, aryl
fluorides and chlorides would be competent electrophiles (Table
1, entries 9 and 10).14
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00586.
Experimental details and characterization data for
preparation of isoindolinones and precursor amino-
boronate salts(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: aaron.michael.dumas@merck.com or aaron.michael.
dumas@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
A.J.S. and L.J.D. were undergraduate placement students from
the Universities of Bristol and Nottingham, respectively. We are
■
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Organic Letters
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(16) For examples of the stereolability of 2° α-amido cuprates, see:
Dieter, R. K.; Topping, C. M.; Chandupatla, K. R.; Lu, K. J. Am. Chem.
Soc. 2001, 123, 5132.
grateful to MSD for support of this program. We thank Andy
Gibb, Alexandra Ridge, and David Murray (Hoddesdon
Analytical Chemistry) for chiral SFC, HRMS, and LCMS
support, respectively, and Ed Cleator and Jeremy Scott
(Hoddesdon Process Chemistry) for critical reading of this
manuscript.
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DOI: 10.1021/acs.orglett.6b00586
Org. Lett. XXXX, XXX, XXX−XXX