New arylaziridinyldifluoroborates: Useful Suzuki-Miyaura reagents

Article abstract of DOI:10.1002/chem.200902056

Blossoming promises fruit! A new class of shelf stable organoboron reagents has been obtained from ortho- and laterally lithiated aziridines and benzylamines. Their usefulness as Suzuki-Miyaura reagents has been investigated, proving that they could be fruitful reagents for the preparation of arylated aziridines and benzylamines, even in enantioenriched form, and promising new bifunctional Lewis pairs for catalysis or small-molecule binding. (Chemical Equation Presented)

Full text of DOI:10.1002/chem.200902056

COMMUNICATION
DOI: 10.1002/chem.200902056
New Arylaziridinyldifluoroborates: Useful Suzuki–Miyaura Reagents
Renzo Luisi,* Arianna Giovine, and Saverio Florio*[a]
The directed ortho-metalation/cross-coupling strategy is
an important synthetic tool for the preparation of biaryls,
heterobiaryls and useful functionalized aromatic and hetero-
aromatic molecules.[1] Related synthetic applications are nor-
mally based on a one-pot procedure involving the genera-
tion of the suitable metalated intermediate followed by the
coupling reaction.[2] Most of the organometallic partners
needed for the cross-coupling reaction are usually prepared
from organolithium or Grignard reagents by transmetalation
with tin, zinc, indium or boron derivatives.[3,4] Within this
methodology, although the one-pot protocol is undoubtedly
advantageous in planning a synthetic process, in order to
find the best reaction conditions (e.g., effective catalyst,
ligand, solvent, co-catalyst or additive), it is often much
better to be able to handle the organometallic or organome-
talloid partner separately. In this context, we envisaged that
ortho-lithiated arylaziridines, recently investigated in our
laboratory,[5] could be used for the preparation of new stable
organometallic derivatives, useful, on the other hand, for the
direct introduction of the aziridine moiety by the cross-cou-
pling strategy. Among the organometallic coupling partners,
several possibilities could be envisaged as depicted in
Scheme 1.
Scheme 1. Directed ortho-metalation/cross-coupling strategy using aryl
aziridines. Suzuki–Miyaura reactions: M BR2, shelf stability, water
compatible. Negishi reactions: M = ZnX, in situ preparation, moisture
sensitive. Corriu–Kumada: M = MgX, air and water sensitive, not suit-
=
AHCTUNTGRENaGUNN ble for storage. Stille reactions: M = SnR3, toxic reagents, byproducts.
al, a white powder was obtained containing not the expected
trifluoroborate salt 1, according to a reported protocol,[7]
but the cyclic derivative 3 in nearly quantitative yield. It was
nice to find that 3 could be easily obtained in multigram
quantity and purified by chromatography on silica gel (85%
isolated yield).[8]
Scheme 2. Synthesis of cyclic difluoroborate 3.
The organotrifluoroborates are by far the most versatile
because of their low toxicity, high-shelf stability, ease of
preparation and the precise stoichiometry.[6] In particular,
aziridine-functionalized organotrifluoroborates have not
been described thus far. We are pleased to report that a new
aziridinylaryldifluoroborate (3) has been prepared by ortho-
lithiation of N-methyl-2-phenylaziridine (2), subsequent re-
1
The structure of 3 was established on the basis of H, 13C,
11B and 19F NMR analysis (Figure 1). The 11B NMR spectra
showed a triplet at 8.0 ppm typical of a tetracoordinated
boron atom (1JBÀF of 55 Hz) and the 19F NMR showed two
identical signals belonging to two diastereotopic fluorine
atoms as proved by 19F COSY experiment. The ipso carbon
(Ci) and the N-methyl group at d = 141.3 and 38.5 ppm, re-
spectively, were split for a 3J coupling with the fluorine
groups on the boron atom. It is worth noting that the
13C–19F coupling observed for the N-methyl group is an ad-
ditional proof of the N–B interaction.[9] 19F–11B HMQC
hetero-correlated experiment and 1D-NOESY further con-
firmed the structure of the difluoroborate and its cyclic
nature (Figure 1).[10]
action with BACHTUNGTRENNUNG(OiPr)3 and treatment with aqueous KHF2
(Scheme 2). After washing with acetone and solvent remov-
[a] Prof. R. Luisi, Dr. A. Giovine, Prof. S. Florio
Dipartimento Farmaco-Chimico
Interuniversity Consortium C.I.N.M.P.I.S.
University of Bari, Via E. Orabona 4, 70125 Bari (Italy)
Fax : (+39)0805442539
E-mail: luisi@farmchim.uniba.it
florio@farmchim.uniba.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902056.
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the substituent on the aromatic
bromide and also smoothly
benzylated giving access to in-
teresting ortho-functionalized
aziridines 4a–d that are not
easily obtainable by other
routes.[12]
The double functionalization
was also investigated with the
aim to obtain p-conjugated
units with two aziridine moiet-
ies potentially useful as a fluo-
rescent probe or ligands.[13] As
can be seen in Table 2, the cou-
pling reaction of 3 with aryl di-
bromides gave
a mixture of
mono- and bis-functionalized
products, which, however, were
easily separated by flash chro-
matography and fully character-
ized.[14]
This strategy represents
new approach to this kind of
bis-functionalized aziridines
a
Figure 1. Multinuclear magnetic resonance analysis of difluoroborate 3 (selected NOE interactions shown).
and proves the usefulness of di-
The difluoroborate 3 was found to be very stable under
air and moisture and could be stored for months on the
shelf. Preliminary stability tests showed that this derivative
is stable under neutral and acidic conditions while it is sensi-
tive to basic conditions suggesting that it could be consid-
ered as a masked form of a boronic acid.[11] In order to con-
firm this hypothesis, the reactivity of 3 was verified in
Suzuki–Miyaura coupling reactions obtaining the results
summarized in Table 1.
It was found that 3 gave cross-coupling reactions with aryl
or benzyl bromides by using 5% [PdCl2ACHTUNRGTNEUNG(dppf)]·CH2Cl2 as
the catalyst, K2CO3 as the base and a mixture of THF/H2O
as reaction solvent. Difluoroborate 3 could be ortho-arylat-
ed with good yields regardless of the electronic nature of
fluoroborate 3 as a new Suzuki–Miyaura reagent.
Concerning the stereochemistry of the bis-functionalized
products 6a–e, it is worth pointing out that the use of race-
mic difluoroborate 3 produces a mixture of two inseparable
diastereoisomers which were undistinguishable by 1H and
13C NMR analysis. Only chiral HPLC analysis revealed the
presence of two enantiomers and a meso form (see Support-
ing Information) in a 1:1 ratio. In order to set up an enantio-
selective synthesis of bis-functionalized derivatives of 6, the
enantioenriched difluoroborate (S)-3 was prepared from the
readily available chiral aziridine (S)-2[15] and cross-coupled
with 4,4’-dibromobiphenyl, 2,7-dibromo-9H-fluorene obtain-
ing the p-conjugated bis-aziridine (S,S)-6a,b highly enan-
tioenriched. Coupling of (S)-3 with ethyl p-bromobenzoate
gave ortho-arylated aziridine (S)-4a also as single enantio-
mer (Scheme 3).
The preparation of optically active aziridinylaryldifluoro-
borates was successively pursued. Chiral difluoroborate
(S,S)-8 was prepared following the lithiation/boronation se-
quence on chiral aziridine (S,S)-7 (Scheme 3).[16] (S,S)-8[17]
was isolated by flash chromatography, fully characterized by
NMR (see Supporting Information), in order to demonstrate
the presence of the intramolecular N–B interaction, and
used in a test cross-coupling reaction with ethyl p-bromo-
benzoate, to give the derivative (S,S)-9 in good yields and
highly enantioenriched.
The results described above, jointly to other literature ex-
amples,[18] seem to highlight that the benzylic nitrogen atom
is prone to undergo intramolecular N–B interactions with
the boron atom on the ortho position of the aromatic ring.
In order to further verify this hypothesis and expand on the
number of ortho-functionalized organodifluoroborates,
Table 1. Suzuki–Miyaura reactions of 3 with aryl bromides.
Product 4
Yield
Product 4
Yield
[%][a,b]
[%][a,b]
64 (4a)
57 (4b)
65 (4c)
70 (4d)
[a] Isolated yields. [b] Yields not optimized.
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Arylaziridinyldifluoroborates
COMMUNICATION
Table 2. Suzuki–Miyaura reactions of 3 with aryl dibromides.
and KHF2 gave the difluorobo-
rate 11 exclusively in 90% yield
as a shelf-stable colorless oil
that could be purified by flash
chromatography.
The intramolecular B–N in-
teraction of difluoroborate 11
was established by multinuclear
Product 5[b]
Yield [%][a]
Product 6[b,c]
Yield [%][a]
1
(19F,11B, 13C, H) magnetic reso-
nance analysis and 1D-NOESY
experiments (see Supporting In-
14 (5a)
52 (6a)
formation). The difluoroborate
11 was then tested in a cross-
coupling reaction with ethyl p-
bromobenzoate obtaining the
18 (5b)
22 (5c)
7 (5d)
40 (6b)
28 (6c)
23 (6d)
functionalized derivative 12
(20% isolated yield). For sake
of comparison, the reactivity of
ortho-lithiated
benzylamines
13a,b was investigated. The
lithiated derivatives were gener-
ated as reported[20] and were
subjected to boronation reac-
tion obtaining a mixture of di-
fluoroborates 14a,b and tri-
fluoroborate 15a,b (Scheme 5)
in
a ratio 14a/15a of 1:0.6
(93% overall yield) and 14b/
15b of 1:0.16 (70% overall
yield) as confirmed by NMR
analysis of the crude reaction
mixture.[21] Flash chromatogra-
phy (petroleum ether/AcOEt
1:1) of this mixture, furnished
nearly pure difluoroborates
–
–
45 (6e)
[a] Isolated yields. [b] Yields not optimized. [c] Inseparable mixture of two diastereoisomers was obtained (see
main text).
which can serve as masked boronic acid derivatives, the lith-
iation/boronation sequence was executed on o-tolylaziridine
10 (Scheme 4). Lithiation occurred regioselectively at the
14a,b (ca. 30% isolated yield) which were fully character-
ized by NMR analysis (see Supporting Information). It is
likely that the higher degree of freedom of these benzylic
derivatives and steric effects[22] favor the presence of the
acyclic trifluoroborate which was never observed with more
constrained aziridines. The reason of this different behavior
is currently under investigation. However, difluoroborates
14a,b were prone to undergo palladium-catalyzed cross-cou-
pling reactions giving the ortho-functionalized benzyl
amines 16a,b (Scheme 5).
lateral position[19] and subsequent reaction with B
ACTHNUTRGNEN(UG OiPr)3
Scheme 3. Synthesis of enantioenriched p-conjugated bis-aziridines 6a,b.
Scheme 4. Synthesis and reaction of difluoroborate 11.
Chem. Eur. J. 2010, 16, 2683 – 2687
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S. Florio, R. Luisi and A. Giovine
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In summary, this work describes the preparation of new
shelf-stable aziridinyldifluoroborates even in enantioen-
riched form that can serve either as Suzuki–Miyaura re-
agents and as new bifunctional Lewis pairs potentially
useful as catalysts or tweezers for small-molecule binding.[23]
Such thus far undescribed aziridinedifluoroborates, which
can be used for the ortho-functionalization of aromatic aziri-
dines, are, to the best of our knowledge, the first examples
of aziridine-functionalized cross-coupling reagents. The
methodology could be expanded to other benzylamine de-
rivatives and aryl-substituted N-heterocycles in order to
obtain new shelf-stable organoboron reagents. More work is
underway in our laboratory in order to expand the synthetic
utility of these new reagents.
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Experimental Section
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General procedure for Suzuki–Miyaura cross-coupling reactions: To a de-
gassed solution of aziridinedifluoroborate 3 (127 mg, 0.7 mmol) in THF/
H2O 10:1 (10 mL) were added K2CO3 (290 mg, 2.1 mmol), aryl halide
(0,7 mmol) and [PdCl2ACHTUNGTRENNUNG(dppf)]·CH2Cl2 (28 mg, 0.035 mmol). The reaction
mixture was stirred at 708C, until aryl halide had been completely con-
sumed as determined by TLC or GC-MS. The reaction mixture was al-
lowed to cool to RT and diluted with water followed by extraction with
Et2O. The solvent was removed in vacuo, and the crude product was puri-
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[14] Attempts to improve yields and selectivity reported in Table 1 and 2
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Acknowledgements
This work was carried out under the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni” and
supported by the University of Bari. We are grateful to Professor Piero
Mastrorilli and Dr. Vito Gallo of the Department of Water Engeneering
and of Chemistry of the Polytechnic of Bari for 19F–11B HMQC experi-
ments.
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À
Keywords: aziridines · C C coupling · directed lithiation ·
NMR spectroscopy · organoboron reagents
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trum and two multiplets, ascribable to two diastereotopic fluorine
atoms of the cyclic structure, in the 19F NMR spectrum. The spatial
relationship between groups was established by 1D NOESY experi-
ments.
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Arylaziridinyldifluoroborates
COMMUNICATION
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Received: July 23, 2009
Revised: November 11, 2009
Published online: January 29, 2010
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