A Protocol for Direct Stereospecific Amination of Primary, Secondary, and Tertiary Alkylboronic Esters

Article abstract of DOI:10.1055/s-0037-1610172

The direct, stereospecific amination of alkylboronic and borinic esters can be conducted by treatment of the organoboron compound with methoxyamine and potassium tert -butoxide. In addition to being stereospecific, this process also enables the direct amination of tertiary boronic esters in an efficient fashion.

Full text of DOI:10.1055/s-0037-1610172

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
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E. K. Edelstein et al.
Letter
Synlett
A Protocol for Direct Stereospecific Amination of Primary,
Secondary, and Tertiary Alkylboronic Esters
Emma K. Edelstein
Andrea C. Grote◊
Maximilian D. Palkowitz◊
O
O
H2N Me
n-butyl
MeONH2
t-BuOK
B(OR)2
R3
NH2
82%
R1
73%, >98% es
toluene/THF
80 °C
R2
James P. Morken*
NH2
Ph
n-butyl
47%, >98% es
• 1°, 2°, and 3° amines
• stereospecific
• non-pyrophoric base
Department of Chemistry, Boston College, Chestnut
Hill, MA 02467, USA
morken@bc.edu
◊These authors contributed equally this work
Received: 03.04.2018
Accepted after revision: 11.05.2018
Published online: 20.06.2018
there are currently no methods available that directly con-
vert tertiary boronic esters into the corresponding amine in
a stereospecific fashion and thus this process fills an im-
portant gap in synthetic methods.8
DOI: 10.1055/s-0037-1610172; Art ID: st-2018-r0200-l
Abstract The direct, stereospecific amination of alkylboronic and
borinic esters can be conducted by treatment of the organoboron com-
pound with methoxyamine and potassium tert-butoxide. In addition to
being stereospecific, this process also enables the direct amination of
tertiary boronic esters in an efficient fashion.
Previous amination (Ref. 7):
n-BuLi (3 equiv)
MeONH2 (3 equiv)
Li
Key words organoboron, asymmetric synthesis, amination, chiral
amines, stereochemistry
MeO
N
NH2
R2
(RO)2B
R1
H
H
1°, 2° only
(1)
(2)
R2
R1
THF
–78 to 60 °C
Although a number of synthetic methods have been de-
veloped that target construction of stereodefined alkyl-
amines, efficient access to stereodefined tertiary carbin-
amines remains a most challenging task. Recently, access to
enantioenriched alkylamines has been made possible
through metal-free amination of boron reagents.1 Although
early examples of this transformation include the amina-
tion of trialkylboranes,2 several recent examples detail the
amination of boronic acids,3 borinic esters,2d,4 boroxines,5
and dichloroboranes.6 Despite this progress, direct amina-
tion of common alkylboronic esters remains a challenge,
with the only effective process being one developed by our
laboratory that employs lithiated methoxyamine as a reac-
tive reagent (Scheme 1, eq. 1).7 While this method is effi-
cient and stereospecific, it is cumbersome to implement,
limited to reactions of primary and secondary boronic es-
ters, and it requires the use of a large excess of n-BuLi and
methoxyamine to generate the amination reagent. Indeed,
when we attempted to employ this reaction for the reaction
in Scheme 1, eq. 2, <5% amination was observed. Herein, we
report a modified amination process (Scheme 1, eq. 3) that
is not only experimentally simple and avoids the use of py-
rophoric reagents, but also extends to the stereospecific
amination of tertiary alkyl boronic esters. Importantly,
MeONH2 (3 equiv)
n-BuLi (3 equiv)
B(pin)
NH2
Me
Me
Me
THF
–78 to 60 °C
Me
OTBDPS
OTBDPS
<5% yield
This work:
R3
R2
R3
R2
(RO)2B
R1
H2N
R1
MeONH2
t-BuOK
(3)
1°, 2°, 3°
toluene/THF, 80 °C
Scheme 1 Amination of alkylboronic esters
In connection to borylation methods under study in our
laboratory, we recently attempted the conversion of tertia-
ry alkylboronic esters into α-tertiary amines. Preliminary
experiments focused on stereospecific amination using
lithiated methoxyamine as an amination reagent. Using
previously described reaction conditions (Scheme 1, eq. 2;
deprotonation of methoxyamine at –78 °C, followed by ad-
dition of the alkylboronic ester and warming to 60 °C), this
process failed to deliver useful quantities of the amine-de-
rived reaction products. Considering the proposed mecha-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
E. K. Edelstein et al.
Letter
Synlett
nism of this process (Scheme 2, A), it was considered that
with a congested tertiary boronic ester, the lithiated me-
thoxyamine (A) may be unable to coordinate efficiently to
the electrophilic tert-alkylboronic ester and that, upon
heating, the uncoordinated amination reagent may decom-
pose to nitrene prior to formation of the ‘ate’ complex (B).
To avoid decomposition of the lithium nitrenoid species at
elevated temperatures, we considered amination condi-
tions that do not require the use of a preformed anionic ni-
trogen reagent. Instead, it was considered that use of neu-
tral methoxyamine, in conjunction with an alkoxide base,
might enable an alternate mechanistic manifold wherein
the weak base is only able to deprotonate the amination re-
agent once the nitrogen atom is acidified by coordination to
the boron center (D, Scheme 2, B). By avoiding the interme-
diacy of free lithium nitrenoid species, it was considered
that the amination reagent might survive at higher tem-
peratures required for more challenging aminations.
amination reaction. Functional groups such as an arene,
pyridine, silane, and benzyl- and silyl-protected alcohols
were also tolerated in the process and were converted into
the Boc-protected amine derivatives in good yield. Similar
to the process employing preformed lithiated methoxy-
amine, the process employing soft deprotonation in
Scheme 3 is stereospecific and proceeds without detectable
loss of enantiomeric purity when non-racemic organobo-
ron compounds were employed as substrates (10–16). The
observation that the reaction is stereoretentive provides
further compelling evidence that the reaction proceeds via
a 1,2-metallate shift, consistent with the proposed mecha-
nism in Scheme 2 (eq. B). Unlike the process employing
lithiated methoxyamine, it was noted that a benzylic boron-
ic ester suffers greatly diminished yield with the conditions
of Scheme 3: with substrate 14, significant amounts of pro-
todeboration products were formed, in addition to the ami-
nation product. Lastly, it should be noted that attempts to
directly prepare substituted amines by use of N-methylme-
thoxyamine in place of methoxyamine have, so far, been
unsuccessful.
A:
(pin)B
MeO
Li+
HN
R
R
(pin)BNH
Li
H
B(pin)
R
n-BuLi
–78 °C
Having determined that efficient amination of primary
and secondary organoboron compounds can be accom-
plished with methoxyamine and potassium tert-butoxide,
we sought to determine whether the reaction would be ef-
MeO
N
MeO NH2
R
R
R
–78 °C
60 °C
R
R
R
A
B
C
B:
OMe
OMe
HN
M+
(pin)BNH
B(pin)
R
H2N
R
MOR
-ROH
B(pin)
B(pin)
+
R
MeO NH2
MeONH2 (1.5 equiv)
t-BuOK (1.5 equiv)
R
R
R
Boc2O
R
R
R
R
R
R
B(OR)2
R
R
NHBoc
toluene/THF
80 °C, 16 h
22 °C, 1 h
D
E
Scheme 2 Prospective mechanisms for boronic ester amination
Ph
B(pin)
B(pin)
n-Oct B(pin) n-Hex B(neo)
1, 85% 2, 61%
n-Hex B(dmp)
3, 61%
4, 92%
Previous studies in our laboratory suggested that potas-
sium tert-butoxide can serve as a competent base to effect
amination of alkyl pinacol boronates with methoxyamine
as the aminating reagent.7 Although low conversion and
low isolated yields (16%) in the amination of n-octylB(pin)
were observed, the observation that the product was
formed at all suggested that the soft deprotonation strategy
depicted in Scheme 2 (B) can operate. Further experiments
aimed at optimizing amination of n-octylB(pin) with t-
BuOK and methoxyamine revealed that increasing the reac-
tion temperature (80 °C) and using toluene/THF as the reac-
tion solvent, resulted in complete conversion and good
yield; after Boc protection to ease product purification, the
protected amine derivative could be isolated in good yield
(85%).9 With effective conditions in hand we explored the
scope of the reaction with primary and secondary boronic
esters (Scheme 3).
[ ]6
B(pin)
[ ]3
B(pin)
BnO
Me2PhSi
6, 89%
N
5, 84%
7, 91%
B(pin)
B(neo)
Ph
Ph
B(pin)
Cy B(pin)
[ ]3
8, 79%
n-Bu
n-Bu
TBDPSO
10, 78%
>98% es
11, 75%
>98% es
9, 83%
OMe
B(pin)
B(pin)
B(pin)
Me
Ph
Ph
n-Bu
Ph
12, 68%
>98% es
13, 47%
>98% es
14, 12%
>98% es
Me
Me
O
O
O
O
B(pin)
Me
Me
B
R
B
R
B
Ph
SiMe2Ph
Ph
O
Me
Me
n-Oct
R-B(neo)
R-B(dmp)
15a, 60%
As depicted in Scheme 3, while alkyl pinacol boronic
esters were smoothly converted into the corresponding
amine, it was also found that other boronic esters such as
neopentylglycol (2) and 1,3-dimethylpentane-1,3-diol (3)
derivatives, as well as a borinic ester 15 also engaged in the
16, 72%
>98% es
>98% es
Scheme 3 Substrate scope in the amination of primary and secondary
alkylboronic esters. a Experiment conducted with 5 equiv MeONH2 and
7 equiv t-BuOK.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
E. K. Edelstein et al.
Letter
Synlett
fective with more challenging tertiary boronic esters. Using
the same conditions that were employed for primary and
secondary organoboron reagents, it was found that amina-
tion of tertiary boronates could indeed occur; however, the
process occurred with only moderate conversion (70%) of
starting material. Increasing the amount of methoxyamine
and t-BuOK to 3.0 and 5.0 equivalents, respectively, resulted
in complete conversion of starting material, and the desired
α-tertiary amines or Boc-protected derivatives could be iso-
lated in good yield. Gratifyingly, the aminations of tertiary
boronic esters were also stereospecific and gave the desired
amines without erosion of enantioselectivity (21 and 23,
Scheme 4). Sterically encumbered tertiary centers such as
those with an isopropyl substituent and substrates contain-
ing protected aryl and alkyl ether groups were also success-
fully converted into the amine. A highly congested tertiary
center, however, such as that with an adjacent tert-butyl
substituent (24), did not undergo amination, and the start-
ing material was fully recovered. Similar to the case with
secondary substrates, tertiary benzylic boronic esters (i.e.,
25) did not give any desired amination product, with the
starting material undergoing non-stereospecific conversion
into the protodeboration product 26.
tert-butoxide-derived ‘ate’ complex is formed reversibly
and reaction occurs either with a small equilibrium con-
centration of the deprotonated amine, or through depro-
tonation of a low equilibrium concentration of the adduct
formed between methoxyamine and the boronic ester (via
E, Scheme 2, B). Similar to computational experiments on
hydroxylamine sulfonic acid amination,10 we do not expect
amination to occur by rearrangement directly on com-
pound D (Scheme 2, B).
To probe the utility of the amination process for prepar-
ative scale chemistry and to study conditions that might be
employed routinely by practicing synthetic chemists, we
conducted the experiments described in Scheme 5. In the
first experiment (Scheme 5, eq. 1), we conducted a gram-
scale amination of TBDPS-protected substrate 8. As shown,
this reaction proceeded as efficiently as the smaller scale
experiment presented in Scheme 3. In a second experiment
(Scheme 5, eq. 2), we conducted a gram-scale amination of
cyclohexylB(pin) in the open atmosphere. In addition, rath-
er than employing solid t-BuOK dispensed in a glovebox, a
syringe-transferred 1 M THF solution of t-BuOK was em-
ployed. In this experiment, only a modest diminution in
yield was obtained relative to the experiment in Scheme 3.
OTBDPS
OTBDPS
MeONH2 (1.5 equiv)
t-BuOK (1.5 equiv)
workup A:
NH2
B(pin)
NHBoc
H2O
(1)
toluene/THF
80 °C, 16 h
R
R
MeONH2 (3 equiv)
t-BuOK (5 equiv)
8
27, 79%
1.03 g
B(pin)
R
R
then Boc2O
22 °C, 1 h
R
Boc2O, NaHCO3
80 °C, 5 h
toluene/THF
80 °C, 16 h
NHBoc
R
R
B(pin)
NHBoc
R
workup B:
MeONH2 (1.5 equiv)
R
t-BuOK (1.5 equiv, 1 M solution)
(2)
B(pin)
Me
toluene/THF
80 °C, 16 h
B(pin)
B(pin)
Me
B(pin)
Me
9
28, 78%
934 mg
then Boc2O
22 °C, 1 h
Me
OBn Me TBDPSO
17b, 83%
18a, 82%
(pin)B
19a, 89%
20a, 83%
reaction conducted in air
O
Scheme 5 Preparative amination reactions
(pin)B
n-Bu
(pin)B
n-Bu
Me
Me
Me
Ph
Ph
O
i-Pr
22a, 88%
21b, 87%
>98% es
23b, 73%
>98% es
In summary, we have described a simple protocol for
the direct amination of a range of alkylboronic esters in an
efficient and stereospecific fashion. Collectively, these ex-
periments suggest that the amination of alkylboronic esters
using MeONH2/t-BuOK can be a broadly useful reaction for
the construction of amine derivatives.
(pin)B
t-Bu
B(pin)
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
25
26, 84%
(57:43 er)
24, <5%
90:10 er
Scheme 4 Amination of tertiary boronic esters. a Using workup proce-
dure A, the primary amine was isolated. b Using workup procedure B,
the product was isolated as the Boc-protected amine.
Funding Information
This work was supported by the NIH (NIGMS 59417).
N
oaitn
a
l
n
Itsu
i
te
of
G
e
n
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l
M
e
dcai
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Secinces
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9
4
1
7)
In terms of reaction mechanism, the 11B NMR spectrum
of the boronic ester is unchanged upon addition of me-
thoxyamine alone, whereas addition of t-BuOK and me-
thoxyamine gives a resonance consistent with tert-butoxide
binding to the boronic ester. Thus, it is plausible that the
Acknowledgment
We thank Mr. Keats Ewing for experimental assistance.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
E. K. Edelstein et al.
Letter
Synlett
Supporting Information
(7) Mlynarski, S. N.; Karns, A. S.; Morken, J. P. J. Am. Chem. Soc. 2012,
134, 16449.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610172.
(8) Aggarwal has accomplished the stereospecific amination of ter-
tiary boronic esters employing multistep route that involves
conversion of the boronic ester into a trifluoroborate, chlorina-
tion to provide the dichloroborane, and then reaction with ben-
zylazide.6b
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(9) General Procedure
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Greck, C. Tetrahedron Lett. 1992, 33, 2677. For a recent copper-
catalyzed amination of primary 9-BBN boranes, see: (e) Rucker,
R. P.; Whittaker, A. M.; Dang, H.; Lalic, G. J. Am. Chem. Soc. 2012,
134, 6571.
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In a glove box, a 2-dram vial equipped with magnetic stir bar
was charged with t-BuOK (5.0 equiv). The vial was sealed with a
septum cap and was removed from the glove box. Toluene and
methoxyamine (1.96 M in THF, 3.0 equiv) were added via
syringe. Subsequently, the alkyl boronic ester (1.0 equiv) was
added as a solution in toluene to achieve a final substrate con-
centration of 0.2 M. The vial was sealed with tape and left to stir
for 16 h at 80 °C behind a blast shield. The reaction mixture was
then cooled to room temperature before Boc2O (5.0 equiv) and
saturated NaHCO3 were added. After stirring under N2 at 80 °C
for 5 h, the mixture was cooled to room temperature, water was
added, and the mixture and extracted three times with ethyl
acetate. Drying (Na2SO4), filtration, and purification on silica gel
delivered the final product.
Product from 10
1H NMR (600 MHz, CDCl3): δ = 7.32–7.26 (m, 2 H), 7.24–7.14 (m,
3 H), 4.29 (br s, 1 H), 3.82 (br s, 1 H), 2.76 (br m, 2 H), 1.52–1.91
(m, 15 H), 0.87 (t, J = 6.7 Hz, 3 H). 13C NMR (150 MHz, CDCl3): δ =
155.6, 138.5, 129.7, 128.4, 126.3, 79.1, 51.7, 41.5, 34.0, 28.5,
28.3, 22.7, 14.2. IR (neat): νmax = 3339.4 (m), 2958.1 (m), 2928.4
(m), 2857.0 (w), 1699.6 (m), 1683.0 (s), 1524.6 (s), 1454.7 (w),
1363.5 (m), 1251.4 (s), 1169.2 (s), 1045.4 (m), 1014.2 (m), 743.3
(w), 699.0 (m) cm–1. HRMS (DART+) for C17H28NO2 [M + H]+
20
calcd: 278.2120; found: 278.2107. [α]D –15.953 (c = 0.890,
CHCl3, l = 50 mm).
Product from 19
1H NMR (600 MHz, CDCl3): δ = 7.36–7.30 (m, 4 H), 7.30–7.26 (m,
1 H), 4.50 (s, 2 H), 3.48 (t, J = 6.5 Hz, 2 H), 1.62 (p, J = 6.5 Hz, 2 H),
1.47 (br s, 2 H), 1.43–1.33 (m, 4 H), 1.08 (s, 6 H). 13C NMR (150
MHz, CDCl3): δ = 138.7, 128.5, 127.8, 127.6, 73.0, 70.4, 49.7,
44.9, 30.5, 30.3, 21.3. IR (neat): νmax = 2935.3 (br), 2860.1 (w),
1453.9 (w), 1362.9 (m), 1100.0 (s), 841.9 (br), 733.0 (s), 696.4
(s) cm–1. HRMS (DART+) for C14H23NO [M + H]+ calcd: 222.1858;
found: 222.1852.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D