Direct stereospecific amination of alkyl and aryl pinacol boronates

Article abstract of DOI:10.1021/ja305448w

The direct amination of alkyl and aryl pinacol boronates is accomplished with lithiated methoxyamine. This reaction directly provides aliphatic and aromatic amines, stereospecifically, and without preactivation of the boronate substrate.

Full text of DOI:10.1021/ja305448w

Communication
pubs.acs.org/JACS
Direct Stereospecific Amination of Alkyl and Aryl Pinacol Boronates
Scott N. Mlynarski, Alexander S. Karns, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
described above, we considered that more nucleophilic
ABSTRACT: The direct amination of alkyl and aryl
pinacol boronates is accomplished with lithiated methoxy-
amine. This reaction directly provides aliphatic and
aromatic amines, stereospecifically, and without preactiva-
tion of the boronate substrate.
amination reagents might overcome the decreased Lewis
acidity of the pinacol ester, favoring ate complex formation,
and perhaps allow direct amination of pinacol boronates.
A study by Beak suggested that lithiated alkoxy amines,
intermediates in the amination of alkyllithiums, might possess
features appropriate to direct amination of alkyl boroantes.9
These reagents bear a labile alkoxide leaving group while still
possessing an electron-rich nitrogen center. In a preliminary
experiment (entry 1, Table 1), octylB(pin) was added to a
he tremendous range of transformations available to
T
organoboron reagents renders these compounds strategi-
cally useful in organic synthesis.1 Among classes of boron
compounds, boronic acid pinacol esters have received a great
deal of attention from the catalysis community. While the
stability of pinacol boronates facilitates their handling and
allows them to be used under a broad range of reaction
conditions, this stability comes at a price: many of the
transformations that apply to electrophilic boranes are
inaccessible with pinacol boronates. This feature especially
pertains to the direct stereospecific amination of alkyl pinacol
boronate esters.2 Whereas alkyl azides, chloroamines, and
hydroxylamine derivatives are effective for the amination of
dichloroboranes,3 difluoroboranes,4 dialkylborinates,5 or tri-
alkylboranes,6 these reagents are unreactive with common
boronic esters.7 In this report, we describe a solution to this
problem and present a simple method for the direct
stereospecific amination of alkyl pinacol boronates. To the
best of our knowledge, this advance represents the only method
for direct conversion of common pinacol boronates to
alkylamine products.
a
Table 1. Amination of OctylB(pin)
entry
CH3ONH2 (equiv)
base (equiv)
yield (%)
1
2
3
4
5
6
7
8
1.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
n-BuLi (1.0)
n-BuLi (2.0)
n-BuLi (3.0)
MeLi (3.0)
41
72
84
48
<5
<5
16
<5
NaH (3.0)
KH (3.0)
K(OtBu) (3.0)
Li(OtBu) (3.0)
a
Reactions were conducted as described in the text. The percent value
given refers to the isolated yield of purified material and is an average
of two experiments.
As depicted in Scheme 1, stereoretentive amination of
organoboron compounds is generally achieved by conversion of
precooled (−78 °C) mixture of methoxyamine (1.0 equiv) and
n-BuLi (1.0 equiv) in THF. After allowing the mixture to warm
to ambient temperature, it was heated to 60 °C for 12 h and
then treated with Boc2O.10 Under these reaction conditions,
Boc-protected octylamine was generated in 41% yield; however,
it was contaminated with a 36% yield of Boc-protected
butylamine, presumably generated by amination of butyl-
lithium. With the assumption that amination of butyllithium
occurred competively during the deprotonation of methoxy-
amine and was unavoidable, the use of increased amounts of
the amination mixture was examined. As shown in entries 2 and
3, this strategy resulted in a significant improvement in product
yields such that, with 3 equiv of MeONH2 and n-BuLi, the
amination of octylB(pin) occurred in 84% isolated yield. As
shown by the remaining entries in Table 1, other bases are also
able to affect amination; however, none surpass the efficacy of
n-BuLi for this transformation. Also of note is that the
Scheme 1
the trivalent boron reagent to a tetravalent boron “ate” complex
derived from the amination reagent; subsequent 1,2-metalate
rearrangement results in C−N bond formation and delivers the
alkylamine product.8 We considered that the lack of reactivity
between common amination reagents (i.e., alkyl azides) and
pinacol boronates may be traced to ineffective association of the
two reagents. Indeed, as alluded to above, one solution to the
amination of boronate esters involves conversion of the
boronate to a dichloroborane, difluoroborane, or trialkylborane
intermediate; the enhanced Lewis acidity of the resulting boron
center enables association with the weak Lewis base and
facilitates reaction. As an alternative to the preactivation
Received: June 5, 2012
Published: September 24, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
amination conditions employ an elevated temperature (60 °C)
for 12 h; at lower temperatures or for shorter reaction times,
inferior yields resulted (<5% yield for entry 3 at 22 °C).
Once optimized conditions were established for the boronate
amination, the scope of this transformation was investigated. As
shown in Table 2, the amination proved to be effective over a
Table 3. Substrate Scope of Aryl Pinacol Boronate
Amination
a
Table 2. Substrate Scope of Alkyl Pinacol Boronate
a
Amination
a
Reactions were conducted as described in the text. The percent value
given refers to the isolated yield of purified material and is an average
of two experiments.
borylfuran, 3-borylfuran, and 3-borylthiophene) failed to give
the amination product (data not shown).
In line with the mechanism proposed in Scheme 1, it may be
anticipated that B→N bond migration would be stereospecific
and preserve the configuration at the migrating carbon atom.
To test this hypothesis, boronate (R)-23a, prepared in 83% ee
by copper-Me-DuPhos catalyzed hydroboration of styrene,12
was subjected to the amination reaction (eq 1). This
a
Reactions were conducted as described in the text. The percent value
given refers to the isolated yield of purified material and is an average
b
c
of two experiments. This experiment was conducted on 1 g scale. An
additional 15% yield of the bis(Boc)-protected amine could be isolated
from this experiment.
range of substrates. Notably, octylB(pin) was aminated on a
scale relevant to preparative organic synthesis (1 g) and
proceeded equally well compared to smaller scale experiments.
Also of note, benzyl ethers, silyl ethers, and acetals appear to be
tolerated in the reaction (compounds 2−4). While nitrile
functional groups are tolerated (compound 6), the yield is
diminished with these substrates even though the starting
material is completely consumed. It is also clear that the
reaction is not perturbed by the presence of pendant alkenes,
including those that are distal and those that are adjacent to the
boronate. Importantly, both cis- and trans- allylic boronates
react cleanly without any observed isomerization of the olefin
geometry (compounds 9 and 10). In terms of utility in
stereoselective synthesis, it is also important that the amination
operates on secondary boronates (compound 11); however,
when tertiary substrates were employed (compound 12), the
product was not detected.
The amination of pinacol boronates using methoxyamine is
not limited to aliphatic substrates. Although prolonged reaction
times are required, aryl boronates are also suitable substrates
producing aniline derivatives. This reaction represents a metal-
free alternative to Chan−Lam−Evans couplings between
boronates and ammonia.11 As depicted in Table 3, while steric
encumbrance does not appear to have a significant effect on the
efficiency of the amination (cf. 13, 15, and 22), the reaction
appears to be much more sensitive to the electronic properties
of the aryl ring. The observation that electron-rich substrates
undergo amination more efficiently than electron-poor
arylboronates (cf. 19 and 21) suggests that 1,2-metalate
rearrangement is likely the slow step in the reaction sequence.
Lastly, B(pin)-substituted heterocycles (4-borylpyridine, 2-
transformation provided Boc-protected α-methyl benzylamine
23b in 83% enantiomeric excess and in the (R) configuration.
Thus, the amination is stereospecific and occurs with retention
of configuration at carbon. In related experiments, amination of
exo-norbornyl boronate 24a (eq 2) provided exo-norbornyl
amine 24b, and amination of chiral aliphatic boronate 25a
provided 25b with retention of configuration.
In conclusion, we report a stereospecific method for the
direct conversion of alkyl and aryl pinacol boronates to amines.
This transformation exhibits a broad substrate scope and can be
run on gram scale without additional complications.
ASSOCIATED CONTENT
* Supporting Information
Procedures, characterization, and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
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Journal of the American Chemical Society
Communication
(10) While the nonprotected amine can be isolated, Boc protection
allows separation of octylamine from butyl amine by silica gel
chromatography.
(11) (a) Monaco, K. L; Wang, R. P.; Winters, M. P.; Chan, D. M. T.
Tetrahedron Lett. 1998, 39, 2933. (b) Katz, J. L.; West, T. R.; Evans, D.
A. Tetrahedron Lett. 1998, 39, 2937. (c) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941.
AUTHOR INFORMATION
■
Corresponding Author
morken@bc.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(12) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed. 2009, 48,
6062.
■
The NIH (GM-59471) is acknowledged for financial support;
AllyChem (B2(pin)2) and BASF (pinacolborane) are acknowl-
edged for donations of reagents. S.N.M. is grateful for a
LaMattina Fellowship.
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