Protic additives or impurities promote imine reduction with pinacolborane

Article abstract of DOI:10.1039/c8ob02330a

We report here that addition of stoichiometric amounts of alcohols or water to mixtures of imines and pinacolborane promote reduction reactions. The reactions of several imines were examined, revealing that alkyl imines were reduced, while aniline derived imines were not effectively reduced. The use of binol as an additive resulted in modest enantioinduction, however other chiral additives that were screened gave negligible enantioinduction. While the reactions described herein are not competitive in conversion with established imine reduction technologies, this work reveals that the presence of protic impurities must be considered as a promoter of side reactions in catalyzed imine hydroborations. Amines also promote imine reduction in certain cases, raising the possibility of a slow autocatalytic reaction. The ability of water or other protic impurities to promote the reduction of imines with pinacolborane represents an important identification of a potential source of background reaction in catalyzed reductions of imines.

Full text of DOI:10.1039/c8ob02330a

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Protic additives or impurities promote imine
reduction with pinacolborane†
Cite this: DOI: 10.1039/c8ob02330a
Blake S. N. Huchenski and Alexander W. H. Speed
*
We report here that addition of stoichiometric amounts of alcohols or water to mixtures of imines and
pinacolborane promote reduction reactions. The reactions of several imines were examined, revealing
that alkyl imines were reduced, while aniline derived imines were not effectively reduced. The use of binol
as an additive resulted in modest enantioinduction, however other chiral additives that were screened
gave negligible enantioinduction. While the reactions described herein are not competitive in conversion
with established imine reduction technologies, this work reveals that the presence of protic impurities
must be considered as a promoter of side reactions in catalyzed imine hydroborations. Amines also
promote imine reduction in certain cases, raising the possibility of a slow autocatalytic reaction. The
ability of water or other protic impurities to promote the reduction of imines with pinacolborane rep-
resents an important identification of a potential source of background reaction in catalyzed reductions
of imines.
Received 20th September 2018,
Accepted 6th November 2018
DOI: 10.1039/c8ob02330a
rsc.li/obc
coinage metal complexes in imine hydroboration with cate-
cholborane, main-group element-based catalytic systems have
Introduction
The use of pinacolborane as a reductant for carbonyl and grown to occupy a pre-eminent position in imine hydrobora-
imine compounds has undergone extensive growth in recent tion reactions with pinacolborane, which is considered to be
years.1 A variety of protocols and catalysts have been disclosed less reactive than catecholborane.7 In 2012, Crudden and co-
for carbonyl reduction with pinacolborane. Frequently, Lewis- workers reported borenium catalysed imine hydroboration
base activation of the borane is an integral part of the
reduction mechanism.2 Alkoxides, and recently butyllithium
have been used as Lewis-bases in the reduction of carbonyls.3
Under neat conditions, it has been shown that the hydride
transfer can proceed from pinacolborane to aldehydes or
benzophenone imine in an uncatalyzed manner.4
Imine reduction by neutral boranes such as pinacolborane
has undergone many relatively recent developments (Fig. 1).
In contrast to Lewis-base mediated ketone and aldehyde
hydroborations with pinacolborane, Lewis or Brønsted acid
mechanisms appear to be more prevalent in imine hydrobora-
tion. Seminal reports on imine hydroboration with catechol-
borane showed that coinage metal complexes could catalyse
imine hydroboration.5 Catecholborane slowly reacts with
imines in the absence of catalysis, however Brønsted acid cata-
lysed imine reductions with catecholborane employing chiral
phosphoric acids did allow significant enantioinduction,
demonstrating the merit of exploring catalysed processes even
when a background reaction exists.6 Despite the initial use of
Department of Chemistry, Dalhousie University, 6274 Coburg Road, Halifax,
Nova Scotia, Canada, B3H 4R2. E-mail: aspeed@dal.ca
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Selected existing systems for imine reduction with
c8ob02330a
pinacolborane.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
with pinacolborane, which did not undergo a non-catalyzed
background reaction with imines.8 The proposed mechanism
for this reaction involves hydride delivery from a borane–imine
complex to an imine activated by complexation to a borenium
cation. After this report, a number of protocols for imine
hydroboration with pinacolborane have been reported, invol-
ving several different mechanistic proposals.9 Neutral boron-
based Lewis acids have been shown to catalyse imine hydro-
boration, with a proposed mechanism involving imine acti-
vation by the Lewis acid, rather than a borenium-catalyzed
reaction.10 Magnesium centres have also proven competent at
imine hydroboration, via the intermediacy of magnesium
hydrides which are regenerated through pinacolborane.11 Most
recently, the use of diazaphospholene-based phosphorus
hydride complexes for imine hydroboration has recently been
reported by our group and others.12 Diazaphospholene
hydrides effect reduction through delivery of a phosphorus
hydride to an imine, and represent one of the least Lewis-
acidic catalyst systems for imine reduction. Finally, several
transition metal based catalysts, including ruthenium,
rhenium, and cobalt-based catalysts have been employed in
imine hydroboration.13 These reductions are typically proposed
to occur through the intermediacy of metal-hydride bonds.
Scheme 1 Investigation of primary, secondary, and tertiary alcohols as
reduction promoters.
in the 11B NMR spectra during acquisition of the initial
During the course explorations of catalysed imine hydro- spectra in these experiments. Conversion was measured by
boration reactions, we explored the use of methanol to rapidly measuring ratios of starting material to product as determined
1
quench reactions. We observed that with the use of methanol by integration of the H NMR spectra of the reaction mixtures.
as a quenching agent, even control reactions without added The ratios are shown under the corresponding equation
catalyst showed high conversions to the amine product. Since arrows in Scheme 1. The reduction reactions were relatively
previous reports of imine hydroboration had not reported clean, generally only showing starting material and product as
background reactions between pinacolborane and imines, this the only nitrogen containing compounds, supporting the use
result suggested that methanol was promoting the observed of this measurement method. Use of ferrocene as an internal
reduction reaction. In addition, we conducted experiments standard in some cases to calculate NMR yield gave good
verifying no background reaction between pinacolborane and agreement with the ratios of starting material to product deter-
the imines under question in the absence of methanol, mined by NMR spectroscopy. Switching to isopropyl alcohol or
suggesting that other contaminants in our solvents or sub- tert-butyl alcohol resulted in higher conversions (eqn (3) and
strates were not promoting this observed background reaction. (4), Scheme 1). Use of isopropyl alcohol allowed determination
of the fate of the B(pin) moiety. The boron was transferred to
the isopropyl alcohol with concomitant loss of the proton, as
revealed by comparison of spectral data of the reaction
mixture with an authentic sample of iPrOB(pin) in chloro-
Results and discussion
It has been reported that reduction of carbonyl functionality form-d.
with pinacolborane occurs in some cases in the absence of
Despite the use of excess pinacolborane relative to imine,
solvent, while addition of solvent supresses the reduction reac- some imine starting material remained, despite complete con-
tion.4 Verifying the absence of a background reaction for sumption of the pinacolborane, indicating that dehydrocou-
imine reduction at room temperature under neat conditions, pling of the alcohol and pinacolborane is a competitive
mixing imine 1 with pinacolborane (2) for 3 hours, followed by process. Non-catalyzed dehydrocoupling of HB(pin) and alco-
dissolution in chloroform-d showed no reduction reaction. hols, amines, and thiols with concomitant loss of hydrogen
Upon addition of 10 equiv. of methanol as a 2 M solution in gas has been reported by Bertrand and co-workers.14
chloroform-d to a mixture of 1 and 2 we observed conversion
to the amine by NMR spectroscopy (eqn (1), Scheme 1).
In these dehydrocoupling reactions, simple mixing of the
pinacolborane, with the protic substrates in the presence or
Spectra were obtained within 10 minutes of mixing, with absence of solvent results in loss of hydrogen, and formation
the time limitation being transport of the sample to the of a boron–heteroatom bond. In our reactions, gas bubbles,
spectrometer, and subsequent pre-acquisition steps of sample presumed to be hydrogen, were observed during the mixing
insertion, locking, and shimming. No additional conversion process. In conjunction with the formation of iPrOB(pin),
was observed after further reaction time. Supporting this lack these results show a dehydrocoupling process is also active
of further reactivity, unreacted boron hydride was not observed under our reported reaction conditions. We attribute the
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
higher conversions for imine reduction with the bulkier alco-
hols isopropyl alcohol and tert-butyl alcohol to a slower rate of
dehydrocoupling relative to imine reduction.
Given the ability of alcohols to promote reduction of imines
by pinacolborane, we decided to explore the ability of water to
promote this reaction. While pinacolborane rapidly reacts with
water and is therefore intrinsically dry, water would be
expected to be the most common protic contaminant in sol-
vents or imines that have not been adequately dried. If water
can promote imine reduction in a fashion analogous to alco-
hols, this would represent an important source of non-cata-
lyzed reactivity of the reactions of imines with pinacolborane.
This could lead to unexpected outcomes, or erosion of stereo-
selectivity in reactions conducted with chiral catalysts. We pre-
Fig. 2 Substrates that were not efficiently reduced with pinacolborane/
alcohol mixtures.
Aniline derived imines have lower Lewis-basicity than alkyl
pared a 0.25 M solution of water in either THF or acetonitrile. imines. The above results suggest that a relatively basic alkyl
These water-miscible and hygroscopic solvents are commonly imine is important for high conversion, and that addition of
used in imine reduction chemistry.11 While addition of 1.25
alcohol or water is necessary for reduction to take place.
equivalents of water in either acetonitrile (eqn (1), Scheme 2) A mechanism involving a six membered transition state is
or tetrahydrofuran (eqn (2), Scheme 2) to neat mixtures of proposed for the reduction reaction (Scheme 3).
pinacolborane and imine 1 resulted in rapid gas release indi-
Association of the HB(pin) and alcohol would be expected
cating significant reaction of pinacolborane with water, con- to increase both the acidity of the alcohol, and hydricity of the
centration of the resulting mixture and analysis by NMR spec- boron hydride.13 In the absence of an imine, dehydrocoupling
troscopy in chloroform-d showed approximately 80% conver-
and release of hydrogen would occur. In the presence of a
sion to the amine, indicating water is also an effective promo- reducible imine, the hydride and hydrogen could be delivered
ter of this reduction reaction. The gas release was observed to the imine via the cyclic six-membered transition state. The
only for the first couple of seconds of mixing, implying that
current data do not rule out an open transition state or non
reaction of pinacolborane with water is rapid. For the observed concerted proton/hydride transfer for this reaction and this
levels of reduction of the imine to have occurred, the imine scenario is also shown in Scheme 3. The use of deuterated
reduction must also be rapid. These results indicate the impor-
tance of ensuring the dryness of solvent and substrate in the
exploration of catalytic hydroboration reactions, especially
asymmetric ones, since
a rapid and uncatalyzed water-
mediated background reaction would erode catalyst-mediated
selectivity.
We explored several other reducible substrates, including
electron rich and poor aniline derived imines 5 and 6, chal-
cone 7, ketone 8, pyridine 9, and cyclic imine 10, which is a
precursor to the pharmaceutical candidate SIB-1508Y
(Fig. 2).15 In the case of aniline derived imines 5, and 6, only
trace conversion to the product amines was observed, in con-
trast to the relatively high conversion observed with 1.
Chalcone 7, ketone 8, pyridine 9, and imine 10 did not
undergo reduction reactions, with dehydrocoupling of the
pinacolborane being the only observed reaction.
Scheme 2 Water as a reduction promoter.
Scheme 3 Proposed mechanism for imine reduction.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
pinacolborane as a reductant resulted in delivery of the deuter- in the 2 position of the pyridyl ring may attenuate the pyridine
ium to the imine carbon, which is consistent with the mechan- basicity by withdrawing electrons through conjugation, redu-
istic proposals presented in Scheme 3.16 The results of the cing its interference in proton transfer, as compared with
small substrate screen shown in Fig. 2 suggest that having a imine 10. It is also possible that even if the pyridine is proto-
relatively basic substrate is important. We postulate that the nated, the close proximity of the imine nitrogen would allow
reduced basicity of the aniline derived imines reduces the rapid proton transfer, and subsequent imine reduction.
extent of intermolecular interaction with the HB(pin)/alcohol Imines 15 and 16 were reduced uneventfully. Imine 16 is the
complex, either by hydrogen bonding, or a full deprotonation, precursor to fendiline, which is a pharmaceutical molecule. A
increasing the relative proportion of dehydrocoupling within reduction of imine 1 on 200 mg scale was also conducted
the complex. The other unreactive substrates shown in Fig. 2 using tert-butyl alcohol. The product was isolated and purified,
can be considered in this context: carbonyl-based substrates 7 affording amine 3 in 77% isolated yield. These reaction con-
and 8 are also less basic than alkyl imines, corroborating the ditions are convenient, however imine reductions employing
need for a relatively basic substrate. The failure of pyridine 9 alternative reagents such as sodium borohydride or catechol-
to undergo reduction may be a consequence of the added ener- borane can reach higher conversions, which means this
getic penalty of pyridine dearomatization making the rate of reported method does not have added preparative value.
reduction uncompetitive with dehydrocoupling. The failure of
Since alcohols promote the observed reduction, we decided
imine 10 to undergo reduction was slightly more unexpected, to investigate if the use of chiral non-racemic alcohols could
since it is an alkyl imine. In this case, the basicity of the pyri- result in chirality transfer. Solutions of the alcohols in chloro-
dine may interfere with imine reduction by changing the site form-d were added to mixtures of 1 and pinacolborane (2). The
of protonation on the molecule.
use of the alcohols cedrenol (17), (1S,2R,5S)-(+)-menthol (18), 1
We subsequently explored a small scope of alkyl imines. (S)-and endo-(−)-borneol (19) did provide varying levels of con-
The imines shown in Scheme 4 were reduced with varying con- version, however the amines obtained were essentially
versions. The yields reported under substrates 11–16 were racemic. Use of (R)-(+)-1,1′-bi-2-naphthol resulted in modest
obtained by integration of NMR spectra with addition of induction (63 : 37 R to S). The sense of induction was deter-
0.050 mmol of ferrocene as an internal standard. These mined by HPLC on a chiral stationary phase, and by compar-
numbers were in good agreement with observed ratios of start- ing the order of elution a previous report of analysis of amine
ing material to product, showing that the reactions were rela- 3 of known configuration under the same HPLC conditions.11
tively clean. Substitution of the 4-methoxybenzyl (PMB) group Finally, we investigated the use of Ellman’s (S)-(−)-tertbutyl-
for a benzyl group (11) did not perturb the reaction. The pre- sulfinimide (21), to examine if this protic functionality could
cursor to the antidepressant sertraline (12) was reduced, also promote hydroboration. Meng and Du have reported
however an essentially 1 : 1 mixture of diastereomers was catalytic reductions of imines employing an adduct of Piers’
obtained.17 An alkyne in the precursor to rasagiline (13) did borane and Ellman’s sulfinimide.18 While addition of 21 to a
not interfere with the reaction. A pyridyl imine (14) was mixture of imine 1 and pinacolborane (2) did promote
reduced, in contrast to imine 10. In this substrate, the imine reduction, but in our case, no asymmetric reduction was
observed (Scheme 5).
Scheme 4 Imines reduced with tert-butyl alcohol/pinacolborane (NMR
yields from integration with internal standard).
Scheme 5 Investigation of chiral additives.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
The observation that nitrogen containing compound 21 rather than measuring product formation, decrease of peak
promoted reduction raised the possibility that other nitrogen- area corresponding to imine starting material were used to
containing compounds may promote the reaction. Of special ascertain starting material consumption. The observation of
interest as promoters are alkyl amines, since these are the pro- continued conversion over several hours, in contrast to results
ducts of the reduction reaction of imines, raising the possi- with the water and alcohol mediated reactions suggests that
bility that imine reduction by pinacolborane could occur via autocatalysis is occurring, however the reaction is slow relative
an autocatalytic reaction. Since imines are typically made from to the reduction observed in the presence of alcohols or water.
the condensation of an amine and carbonyl compound, excess Dehydrocoupling of amine with pinacolborane and loss of
amine is a likely impurity in imines, representing another hydrogen would terminate the autocatalytic process by remov-
potentially confounding factor in amine reduction.
ing free amine without producing more amine to continue the
To test for autocatalysis, two substrates were examined. catalytic cycle. The structure (steric environment) of the imine
Imines 1 and 13 were separately mixed with pinacolborane in and amine is probably a factor in the extent of autocatalysis,
chloroform-d, in the presence of ferrocene as an internal stan- and some substrates may prove to be more susceptible to auto-
dard (Scheme 6). Amine 3 was added to each sample. NMR catalysis than others. Because of the lack of high conversion
spectra were obtained for each reaction after approximately for the substrates tested, and slow progression, amine autoca-
30 minutes, then again after 24 hours. In both cases, approxi- talysis is probably not
a significant factor in ketimine
mately 30% consumption of starting imine was observed in reductions with pinacolborane, but ensuring imine substrates
the 30-minute NMR spectra. Neither reaction went to com- are free of amines would ensure absence of this possible back-
pletion in the 24-hour timeframe but there was an increase in ground reaction in future catalytic investigations.
conversion to approximately 60% consumption of starting
material for each reaction in the 24-hour measurement. The
spectra were complicated compared to those obtained from
the use of stoichiometric protic additives because of the pres- Conclusion
ence of a mixture of borylated and non-borylated amines, so
We have demonstrated that a combination of pinacolborane
and alcohol or water results in the reduction of alkyl imines.
Imines that are electron deficient are not reduced under these
conditions. The use of chiral alcohols in chloroform-d did not
result in chirality transfer except for binol, which afforded
modest selectivity. This transformation is operationally simple
and rapid, however the preparative value is limited by incom-
plete conversion of imine to amine because of competitive
dehydrocoupling of the pinacolborane with the protic additive.
The most important consideration arising from this work is
that the promotion of imine reduction with pinacolborane by
protic contaminants represents an important potential back-
ground reaction that must be considered in future studies of
catalysed reductions of imines, since this reactivity could
erode intended selectivity of catalytic systems.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Mr. Toren Hynes is thanked for preparation of substrate 10.
Mr. Casper Macaulay is thanked for preparation of DB(pin).
Dr. Alex McLellan and NeuroQuest are thanked for the
donation of a rotary evaporator, scale and vacuum pump. The
Killam Foundation and the Nova Scotia Graduate Scholarship
funded B. S. N. H.’s PhD studies. NSERC of Canada is thanked
Scheme 6 Investigation of amine autocatalysis.
for a Discovery Grant.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
11 (a) M. Arrowsmith, M. S. Hill and G. Kociok-Köhn, Chem. –
Eur. J., 2013, 19, 2776; (b) K. Manna, P. Ji, F. X. Greene and
W. Lin, J. Am. Chem. Soc., 2016, 138, 7488.
Notes and references
1 C. C. Chong and R. Kinjo, ACS Catal., 2015, 5, 3238.
2 F. Schömberg, Y. Zi and I. Vilotijevic, Chem. Commun., 12 (a) M. R. Adams, C. H. Tien, B. S. N. Huchenski,
2018, 54, 3266.
M. J. Ferguson and A. W. H. Speed, Angew. Chem., Int. Ed.,
2017, 56, 6268; (b) M. R. Adams, C. H. Tien, R. McDonald and
A. W. H. Speed, Angew. Chem., Int. Ed., 2017, 56, 16660;
(c) Y.-C. Lin, E. Hatzakis, S. M. McCarthy, K. D. Reichl,
T.-Y. Lai, H. P. Yennawar and A. T. Radosevich, J. Am. Chem.
Soc., 2017, 139, 6008; (d) C. H. Tien, M. R. Adams,
M. J. Ferguson, E. R. Johnson and A. W. H. Speed, Org. Lett.,
2017, 19, 5565.
3 (a) I. P. Query, P. A. Squier, E. M. Larson, N. A. Isley and
T. B. Clark, J. Org. Chem., 2011, 76, 6452; (b) Z. Zhu, X. Wu,
X. Xu, Z. Wu, M. Xue, Y. Yao, Q. Shen and X. Bao, J. Org.
Chem., 2018, 83, 10677.
4 H. Stachowiak, J. Kaźmierczak, K. Kuciński and
G. Hreczycho, Green Chem., 2018, 20, 1738.
5 R. T. Baker, J. C. Calabrese and S. A. Westcott, J. Organomet.
Chem., 1995, 498, 109.
6 (a) D. Enders, A. Rembiak and M. Seppelt,
Tetrahedron Lett., 2013, 54, 470; (b) D. Enders, A. Rembiak
and B. A. Stöckel, Adv. Synth. Catal., 2013, 355,
1937.
7 C. E. Tucker, J. Davidson and P. Knochel, J. Org. Chem.,
1992, 57, 3482.
13 (a) L. Koren-Selfridge, H. N. Londino, J. K. Vellucci,
B. J. Simmons, C. P. Casey and T. B. Clark, Organometallics,
2009, 28, 2085; (b) A. Kaithal, B. Chatterjee and
C. Gunanathan, J. Org. Chem., 2016, 81, 11153;
(c) R. Arévalo, C. M. Vogels, G. A. MacNeil, L. Riera, J. Pérez
and S. A. Westcott, Dalton Trans., 2017, 46, 7750; (d) J. Wu,
H. Zeng, J. Cheng, S. Zheng, J. A. Golen, D. R. Manke and
G. Zhang, J. Org. Chem., 2018, 83, 9442.
8 P. Eisenberger, A. M. Bailey and C. M. Crudden, J. Am.
Chem. Soc., 2012, 134, 17384.
9 (a) M. K. Bisai, S. Pahar, T. Das, K. Vanka and S. S. Sen,
14 E. A. Romero, J. L. Peltier, R. Jazzar and G. Bertrand, Chem.
Commun., 2016, 52, 10563.
Dalton Trans., 2017, 46, 2420; (b) V. A. Pollard, 15 L. S. Bleicher, N. D. P. Cosford, A. Herbaut, J. S. McCallum
M. Á. Fuentes, A. R. Kennedy, R. McLellan and and I. A. McDonald, J. Org. Chem., 1998, 63, 1109.
R. R. Mulvey, Angew. Chem., Int. Ed., 2018, 57, 16 C. S. Wei, C. A. Jiménez-Hoyos, M. F. Videa, J. F. Hartwig
10651. and M. B. Hall, J. Am. Chem. Soc., 2010, 132, 3078.
10 (a) Q. Yin, Y. Soltani, R. L. Melen and M. Oestreich, 17 K. Vukics, T. Fodor, J. Fischer, I. Fellegvári and S. Lévai,
Organometallics, 2017, 36, 2381; (b) J. R. Lawson, Org. Process Res. Dev., 2002, 6, 82.
L. C. Wilkins and R. L. Melen, Chem. – Eur. J., 2017, 23, 18 S. Li, G. Li, W. Meng and H. Du, J. Am. Chem. Soc., 2016,
10997.
138, 12956.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018