Readily Available Primary Aminoboranes as Powerful Reagents for Aldimine Synthesis

Article abstract of DOI:10.1002/anie.201814081

Primary aminoboranes (RNHBR₂), which are readily available by spontaneous dehydrocoupling of amines and boranes cleanly react at room temperature with aldehydes to give aldimines. The overall transformation from amines to aldimines can be conveniently performed by a sequential one-pot reaction. This synthetic strategy is especially useful for electron poor and bulky amines which are reluctant to react with aldehydes under dehydration conditions. Using a Glorius robustness screen, we show that this methodology is chemoselective, and functional group tolerant. Computational and experimental data support the irreversible formation of the aldimine product in marked contrast with traditional methods.

Full text of DOI:10.1002/anie.201814081

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Accepted Article
Title: Readily Available Primary Aminoboranes as Powerful Reagents
for Aldimine Synthesis
Authors: Glen Junor, Erik Romero, Xi Chen, Rodolphe Jazzar, and Guy
Bertrand
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814081
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http://dx.doi.org/10.1002/ange.201814081

10.1002/anie.201814081
Angewandte Chemie International Edition
COMMUNICATION
Readily Available Primary Aminoboranes as Powerful Reagents
for Aldimine Synthesis
Glen P. Junor, Erik A. Romero, Xi Chen, Rodolphe Jazzar* and Guy Bertrand*
Dedication ((optional))
Abstract: Primary aminoboranes (RNHBR2), which are readily
available by spontaneous dehydrocoupling of amines and boranes
cleanly react at room temperature with aldehydes to give aldimines.
The overall transformation from amines to aldimines can be
conveniently performed by a sequential one-pot reaction. This
synthetic strategy is especially useful for electron poor and bulky
amines which are reluctant to react with aldehydes under
dehydration conditions. Using a Glorius robustness screen, we show
that this methodology is chemoselective, and functional group
tolerant. Computational and experimental data support the
irreversible formation of the aldimine product in marked contrast with
traditional methods.
To test this hypothesis, we considered the reaction of p-tolyl-
anilino-pinacolborane with pivaldehyde (Figure 1). In a benzene-
d6 solution full conversion to the desired aldimine with
concomitant elimination of PinBOH occurred at room
temperature within a few minutes.
BPin
O
O
- PinBOH
N
tBu
tBu
N
O
+
B
H
C6D6 (0.5 M)
10 min, 25 o
C
BPin
T = 0 mins
T = 0 mins
In 2016, we reported that the catalyst-free dehydrocoupling of
primary and secondary amines with hydridoboranes
(pinacolborane
and
9-borabicyclononane)
affords
the
corresponding aminoboranes in quantitative yields (A, Scheme
1).[1] Prior to this report, primary aminoboranes (RNHBR2) were
not readily available, and thus not investigated for applications in
organic chemistry.[2] Additionally, only seven reports described
reactions involving their secondary counterparts (R2NBR2).[2-6]
Herein we report that primary aminoboranes are powerful tools
for the mild and chemoselective preparation of aldimines,[7-9]
especially those hard to access with previous methods.[10]
We hypothesized that primary aminoboranes should be
sufficiently Lewis acidic to react with aldehydes to afford
unstable hemi-aminals B; the latter would eliminate boronic acid
giving access to aldimines C (Scheme 1).
N
tBu
PinBOH
T = 10 mins
Figure 1. 1H NMR monitoring of the reaction
In an effort to optimize the conditions (Table 1), we found that
the reaction of p-tolyl-anilino-pinacolborane with pivaldehyde
proceeds well in various solvents. However, when using more
bulky amines, we observed that the reaction was faster at higher
concentrations and in less polar solvents.
Table 1. Optimization of the reaction conditions
R1
R1 BPin
O
O
R2
- PinBOH
solvent
N
R2
N
H
O
+
B
R1
R1
BPin
time, 25 o
C
R1
R2
Solvent
Time
Conc. (M)
Yield[a]
H
H
H
tBu
tBu
tBu
C6D6
10 min
10 min
10 min
0.5
0.5
0.5
99
99
99
CDCl3
CD3CN
Scheme 1. Catalyst-free dehydrocoupling of primary and secondary amines
with hydridoboranes, and proposed synthesis of aldimines.
Me
Me
Me
Me
Me
CH(Et)2
CH(Et)2
CH(Et)2
CH(Et)2
CH(Et)2
C6D6
4 h
4 h
4 h
4 h
1 h
0.5
0.5
0.5
0.1
1.1
93
91
89
82
99
CDCl3
CD3CN
C6D6
C6D6
UCSD-CNRS Joint Research Laboratory (UMI 3555), Department of
Chemistry and Biochemistry, University of California, San Diego, La Jolla,
CA 92093-0358, USA.
[a] Yield determined by 1H NMR
E-mail: rjazzar@ucsd.edu; guybertrand@ucsd.edu
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201814081
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COMMUNICATION
Using our optimized conditions [1:1 ratio of aminoborane to
aldehyde in C6D6 (1.1 M) at 25 °C], we examined the substrate
scope (Scheme 2). With respect to the substituents on nitrogen
this methodology is readily applicable to a variety of amines
featuring different steric and electronic properties (1-13), and
even to hydrazines (14). Although aminoboranes derived from
very electron poor anilines (7,8) exhibit lower conversions this is
circumvented by using 2 equivalents of the corresponding
aminoborane. With respect to aldehydes, the reaction is widely
applicable to both alkyl- and aryl-aldehydes (15-26). The
reaction is applicable to two aliphatic partners (27-28) and also
two bulky substrates (29-30) with longer reaction times.
We also probed the reactivity of the more electrophilic borane
partner, 9-borabicyclononane (9-BBN). As shown by the kinetic
plot of the reaction, the 9-BBN aminoborane derived from the
electron-poor pentafluoroaniline performs faster than its pinacol
counterpart (Figure 2). Here we noticed again that increasing the
concentration leads to a faster reaction.
Et
BY2
Et
- BY2OH
+ O
N
N
H
C6F5
Et
C6D6, 25 o
C
C6F5
Et
BY2 = 9-BBN [2 M]
BY2 = 9-BBN [1.1 M]
BY2 = Bpin [1.1 M]
Figure 2 Influence of the borane partner and of the concentration on the rate
of the reaction.
We next compared the efficiency of this aminoborane
methodology with the most effective methods reported in the
literature (Table 2): 4 Å molecular sieves (Method 1)[10] and 4 Å
molecular sieves plus a pyrrolidine organocatalyst (Method 2).[11]
We found that our method performs equally well with electron
rich substrates, but more importantly, it is much more efficient
with troublesome bulky and electron-poor substrates.
Table 2. Method comparison
X
- XOH
R2
R2
+
O
N
N
R1
NMR yields
R1
H
solvent
25 o
C
X = H (Method 1 and 2)
X = BPin or 9-BBN (this work)
Time
(h)
Conc.
(M)
Method
1
Method
R1
Cy
R2
tBu
This work
2
1
1.1[a]
1.1[a]
1.1[a]
2[a]
2[a]
2[b]
99
13
46
4
99
72
30
18
8
99 (Bpin)
Ph
1
99 (Bpin)
Mes
CH(Et)2
Ph
1
99 (Bpin)
Mes
C6F2H3
C6F2H3
C6F5
1
99 (9-BBN)
99 (9-BBN)
96 (9-BBN)
93 (9-BBN)
CH(Et)2
Ph
1
5
12
3
1
69
24
Scheme 2. Substrate scope. Isolated yields and NMR yields in parentheses.
[a] Reaction performed using 2 equivalents of aminoborane. [b] Reaction time
24 h. [c] Reaction time 48 h.
C6F5
CH(Et)2
2[b]
2
[a] in C6H6; [b] in cyclohexane
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10.1002/anie.201814081
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COMMUNICATION
To demonstrate further the broad utility of this synthetic route,
we examined the functional group tolerance using a modified
Glorius robustness screen[12] (Scheme 3). We found that the
reaction is unaffected by various common functional groups
such as ketones, esters, ethers, alkenes, alkynes, amides,
thiols, silanes, pyridines, alkyl halides and triflates.
Unsurprisingly, alcohols and acyl halides, which react with
aminoboranes, are not compatible with this reaction. Note
that pinacolborane and 9-BBN adducts performed equally
well in this screening.
aminoborane across the carbonyl bond, leading to the
hemi-aminal
I
, is exergonic with an energy barrier of 28-29
, we considered two possible
kcal.mol-1
(
TS1). From
I
pathways leading to the aldimine. Path 1 involves a
concerted 1,3-proton shift from nitrogen to oxygen with
concomitant elimination of PinBOH. We were able to locate
a transition state TS2 showing a barrier of 44 kcal.mol-1,
which makes this process highly unlikely at room
temperature. Path 2 involves the dimerization of
I followed
by a double intermolecular proton transfer/elimination,
giving two molecules of both PinBOH and aldimine, through
a barrier of 26-32 kcal.mol-1. It is worth noting that these
data clearly show why the reaction is not reversible. Indeed,
reverse addition of PinBOH to the aldimine should occur
through the Reverse Path 1, which proceeds through an
inaccessible ~40-45 kcal.mol-1 reaction barrier.
To further support this mechanism, we were able to
characterize the pyrimidine-stabilized hemi-aminal IPy from
the reaction of 2-aminopyrimidine-9-BBN and benzaldehyde
(Scheme 4).[18] As anticipated, the locked configuration of
IPy prevented the formation of a dimeric structure of type II
and thus the efficient formation of the corresponding
aldimine even at elevated temperatures (100 oC).
H
N
H
N
N
N
Ph
O
Ph
B
N
N
O
DCM
B
10 min, 25 o
C
Scheme 3. Modified Glorius robustness screen for aldimine formation in the
presence of common functional groups.
IPy
X-ray of IPy
y
Scheme 4. Isolation of hemi-aminal IP
.
To gain insight into the reaction mechanism, we performed
calculations at the M062X[13] 6-31G**[14] level of theory to
compare the reaction of anilino-pinacolborane (methyl
groups on pinacol were replaced by hydrogens) with
isobutyraldehyde and benzaldehyde in benzene (Figure
3).[15-17] We found that the concerted addition of the
Beg
TS2Ph : 41
O
H
R
TS2iPr : 36
N
R
R
Ph
Beg
Ph
Ph
TS1Ph : 29
TS1iPr : 28
R
32
O
H
N
TS2
Beg
O
TS3Ph : 24
TS3iPr : 23
R
H
O
H
N
e
R
v
N
Ph
e
Beg
r
s
R
e
TS1
P
a
R
t
h
TS3
1
16
0
h
1
t
H
N
a
2
P
h
t
Ph
O
Beg
a
P
+
R
IIPh : -2
IIiPr : -9
Beg
Ph
Ph
N
R
O
N
H
Ph
IPh : -3
IiPr : -8
0
+
H
N
H
- 4
N
OBeg
O
HOBeg
Ph
Beg
R
R
I
II
R = Ph or iPr
-16
Reaction coordinate
Figure 3. Proposed reaction mechanism at the M062X 6-31G** level of theory;[16] Beg = B(OCH2CH2O)
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10.1002/anie.201814081
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COMMUNICATION
Synth. Catal. 2017, 359, 2375; i) S. Wubbolt, M. S. Maji, E. Irran, M.
Oestreich, Chem. Eur. J. 2017, 23, 6213.
In summary, we have shown that primary aminoboranes, which
are readily available by spontaneous dehydrocoupling of amines
and boranes,[1] are powerful tools for the preparation of
aldimines. The overall transformation from amines to aldimines
can be conveniently performed by a sequential one-pot reaction.
The method is shown to be chemoselective, functional group
tolerant, and widely applicable to various amines, aldehydes and
boranes. Computational and experimental data support the
irreversible formation of the aldimine, which is mechanistically
orthogonal to traditional methods. We are currently investigating
other potential applications for this class of ambiphilic primary
aminoborane reagents.
[8] Main group reduction: a) Y. Hoshimoto, T. Kinoshita, S. Hazra, M. Ohashi,
S. Ogoshi, J. Am. Chem. Soc. 2018, 140, 7292; b) E. Dorkó, M. Szabó, B.
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Allcock, M. J. Fuchter, C. J. Tighe, A. E. Ashley, Adv. Synth. Catal. 2018,
360, 1066.
[9] Biological relevance of compounds with fluorinated-aniline moieties a) P.
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127, 1013.
[10] a) M. E. Belowich, J. F. Stoddart, Chem. Soc. Rev. 2012, 41, 2003; b)
C. D. Meyer, C. S. Joiner, J. F. Stoddart, Chem. Soc. Rev. 2007, 36,
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[12] a) K. D. Collins, F. Glorius, Nat. Chem. 2013, 5, 597; b) K. D. Collins, A.
Rühling, F. Glorius, Nat. Protoc. 2014, 9, 1348.
Acknowledgements
[13] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215.
[14] G. A. Petersson, M. A. Al-Laham, J. Chem. Phys. 1991, 94, 6081.
[15] Relevant considerations for computational methods: H. Ryu, J. Park, H. K.
Kim, J. Y. Park, S.-T. Kim, M.-H. Baik, Organometallics 2018, 37, 3228.
[16] Output files from DFT calculations can be viewed and downloaded from
This work was supported by the U.S. Department of Energy,
Office of Science, Basic Energy Sciences, Catalysis Science
Program, under Award No. DE-SC0009376. Thanks are due to
the U.S. Department of Education for a GAANN fellowship
(E.A.R.), and to the Alfred P. Sloan Foundation’s University
Centre for Exemplary Mentoring (G.P.J.). This material is based
upon work supported by the National Science Foundation
Graduate Research Fellowship Program under Grant No. (DGE-
1650112; G.P.J.). Any opinions, findings, and conclusions or
recommendations expressed in this material are those of the
author(s) and do not necessarily reflect the views of the National
Science Foundation. We also acknowledge the Keck Foundation
as well as the Extreme Science and Engineering Discovery
Environment (XSEDE),[19] which is supported by National
Science Foundation grant number ACI-1548562 for provided
computational resources.
the
https://doi.org/10.6075/J00Z71HW
[17] Additional calculations with range of amines and aldehydes are
available in the supporting information section.
[18] CCDC 1883939 (14), 1883941
Py) and 1883940 (19) contain the
UC
San
Diego
Library
Digital
Collections
at:
a
(I
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre.
[19] J. Towns, T. Cockerill, M.l Dahan, I. Foster, K. Gaither, A. Grimshaw,
V.Hazlewood, S. Lathrop, D. Lifka, G. D. Peterson, R. Roskies, J. R. Scott,
N. Wilkins-Diehr, Comput. Sci. Eng. 2014, 16, 62.
Keywords: Aminoboranes • Aldimines • Density Functional
Calculations • Kinetics
References and Notes
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10.1002/anie.201814081
Angewandte Chemie International Edition
COMMUNICATION
31 examples
R2
Glen P. Junor, Erik A. Romero, Xi Chen,
Rodolphe Jazzar* and Guy Bertrand*
R2
C
H
N
O
H2
Chemoselective
Functional group tolerant
Widely applicable
R1
H
H
Y
H
N
R1
N
Y
H
R1
+
B
Y
H
25 o
C
25 o
Page No. – Page No.
quantitative
B
Y
CH3CN
quantitative
C6H6
Readily Available Primary
Readily available primary aminoboranes (RNHBR2) are powerful tools for the
chemoselective, functional group tolerant, and widely applicable synthesis of
aldimines. According to Density Functional and experimental methods, this reaction
proceeds in a non-reversible way that is orthogonal to, and outperforms,
conventional dehydration methods.
Aminoboranes as Powerful Reagents
for Aldimine Synthesis
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