Development of a solvent selection guide for aldehyde-based direct reductive amination processes

Article abstract of DOI:10.1039/c3gc40359a

A range of alternative, more environmentally conservative solvents have been evaluated for use within the direct reductive amination reactions of aldehydes using borane-based reductants. The data generated has been used to develop a guide to facilitate replacement of less desirable chlorinated solvents, such as DCE, from these widely used synthetic processes.

Full text of DOI:10.1039/c3gc40359a

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Development of a solvent selection guide for
aldehyde-based direct reductive amination processes†
Cite this: Green Chem., 2013, 15, 1159
Received 19th February 2013,
Accepted 9th April 2013
Fiona I. McGonagle,a Donna S. MacMillan,a Jane Murray,b Helen F. Sneddon,c
Craig Jamiesona and Allan J. B. Watson*a
DOI: 10.1039/c3gc40359a
www.rsc.org/greenchem
A range of alternative, more environmentally conservative sol- picoline–borane complex (pic–BH3),6 NaBH4/Mg(ClO4)2,7
vents have been evaluated for use within the direct reductive NaBH4/ Ti(Oi-Pr)4,8 borohydride exchange resin,9 Zn/AcOH,10
amination reactions of aldehydes using borane-based reductants. Zn(BH4)2/ZnCl2,11 Zn(BH4)2/SiO2,12 Bu3SnH/SiO2,13 and
The data generated has been used to develop a guide to facilitate PhSiH3/Bu2SnCl2.14 Of these, NaBH3CN and NaBH(OAc)3 are
replacement of less desirable chlorinated solvents, such as DCE, perhaps the most widely employed while pic–BH3 has emerged
from these widely used synthetic processes.
as a highly promising reagent and, indeed, a safer alternative
to pyr–BH3.6 In terms of the solvent media conventionally
used for these processes, while a variety of solvents have been
used, chlorinated solvents feature heavily with CH2Cl2 and 1,2-
dichloroethane (DCE) among the most common with DMF
also widely used: a SciFinder survey revealed that 25% of
241 324 reductive amination reactions employed chlorinated
solvents (CH2Cl2 and DCE).15
In this context, a key emerging consideration as part of the
sustainability drive within pharmaceutical research and devel-
opment is the use of green solvents as replacements for those
that are less sustainable, pose adverse health and safety issues
or demonstrate a detrimental environment impact. Indeed,
replacement of less desirable solvents has been designated a
key research area16 with several reports recently emerging from
leading pharmaceutical companies detailing their efforts
towards a more benign solvent selection as part of their overall
sustainability programmes.2a,17 In particular, based on high
concerns over safety and environmental impact, chlorinated
solvents have been earmarked as a primary category for re-
placement in both reaction and purification settings.
As part of our continuing interests in the area of sustain-
able organic synthesis, we recently reported our efforts towards
enabling replacement of less desirable solvents, in particular
CH2Cl2 and N,N-dimethylformamide, within both chromato-
graphic purification and amidation processes with the aim of
providing fundamental data to assist in the adoption of more
sustainable solvent alternatives.18 Here we wish to report our
findings in relation to the replacement of less desirable sol-
vents within direct reductive amination reactions of aldehydes
using borane-based reductants. The reactivity profiles gener-
ated have been used to construct a guide to facilitate employ-
ment of alternative solvents for this key transformation.
The reductive amination of carbonyl compounds is a highly
useful, robust, and broadly employed transformation for the
synthesis of further functionalised amines and has become a
workhorse of synthetic medicinal chemistry.1,2 There are two
distinct approaches generally adopted for reductive amination
reactions: the indirect or stepwise approach in which an imine
is pre-formed between an amine and a suitable carbonyl sub-
strate, which is then exposed to a suitable hydride source (e.g.,
NaBH4, metal catalyst/H2), and the direct method in which the
amine and carbonyl substrates are mixed together with a mild
hydride reagent that selectively reduces the in situ generated
imine. This latter one-pot method is perhaps the most straight-
forward and is therefore widely practised.
In terms of the reductants employed for direct reductive
amination, the choice of reducing agent can have a profound
effect on the outcome of the reaction and a wide range of
reducing agents have been explored.1 Borane-based reagents
feature heavily in this area and a number of reagents and
reagent systems have been developed. These include sodium
cyanoborohydride (NaBH3CN),3 sodium triacetoxyboro-
hydride (NaBH(OAc)3),1f,4 pyridine–borane complex (pyr–BH3),5
aDepartment of Pure and Applied Chemistry, WestCHEM, University of Strathclyde,
Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, UK.
E-mail: allan.watson.100@strath.ac.uk; Fax: +44 (0)141 548 4822;
Tel: +44 (0)141 548 2439
bSigma-Aldrich, The Old Brickyard, New Road, Gillingham, Dorset, SP8 4XT, UK
cGreen Chemistry Performance Unit, GlaxoSmithKline, Medicines Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, analytical data, charts of conversion vs. time for all substrates in all sol-
vents and for all reducing agents. See DOI: 10.1039/c3gc40359a
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variation on reactivity and overall conversion. The 12 reactions
comprised of both alkyl and aryl aldehydes in combination
with a range of amines that consisted of representative
Results and discussion
Methods
For our study, we elected to use two of the most widely members of (i) primary and secondary, (ii) alkyl and aryl, and
employed borane-based reducing agents (sodium cyanoboro- (iii) acyclic and cyclic (Fig. 1). In terms of solvent selection,
hydride (NaBH3CN)19 and sodium triacetoxyborohydride and as stated above, the most common solvents for direct alde-
(NaBH(OAc)3) as well as the picoline–borane complex (pic– hyde reductive amination reactions were found to be CH2Cl2,
BH3) based on the emerging utility of this reagent as a promis- DCE, dimethylformamide (DMF), and THF. To compare
ing replacement for pyr–BH3 (Fig. 1). While NaBH3CN is typi- directly with these less desirable solvents, we selected emer-
cally disfavoured in the context of green synthesis, especially ging or existing alternatives including tert-butyl methyl ether
in industry,4c,6 the frequency with which this reagent is (TBME), cyclopentylmethyl ether (CPME), dimethylcarbonate
employed, particularly within a discovery chemistry setting, (DMC), ethyl acetate (EtOAc), iso-propyl alcohol (IPA), and
compelled us to include it in our study. These reagents would 2-methyltetrahydrofuran (2-MeTHF) (Fig. 1).20 Other potential
be evaluated in a series of 12 benchmark aldehyde reductive alternative solvents such as MeOH, EtOH, and acetone were
amination reactions in order to establish the effect of substrate discounted based on unfavourable potential side reactions –
carbonyl reduction (MeOH and EtOH) and competing reduc-
tive amination (acetone). Reactions were monitored by HPLC
at a range of time points (0 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h)
to give a temporal profile of conversion, which could be
directly compared across the solvent selection. Reactions and
aliquots were repeated and analysed up to a maximum of three
times to ensure reliability.† Overall, this would generate a com-
prehensive dataset of 360 reactions to lay the foundations of
the survey.
Analysis
An illustrative example chart of conversion vs. time for Reac-
tion 1 using NaBH(OAc)3 is shown in Fig. 2. As anticipated, the
choice of solvent has a significant effect on the reaction per-
formance. Of the 10 solvents, two failed to register conversion
above 40% (DMF and THF), the remaining eight solvents deli-
vered greater than 70% conversion with three of these (CH2Cl2,
DCE, and IPA) providing quantitative conversion. A compari-
son of reducing agent performance for a particular reaction in
a specific solvent could also be extracted for an alternative
view of the data. Fig. 3 displays the conversion vs. time data for
Reaction 10 in DMC using the three reducing agents where,
for this example, all three reactions proceed to completion
in 2–4 h. A summary of the overall analysis is provided in
Fig. 1 Reducing agents, solvents, and representative reactions for the reductive
amination survey.†
Fig. 2 Representative example of conversion data: reductive amination Reac-
tion 1 using NaBH(OAc)3 with the range of solvents.†
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Aryl aldehydes (Table 1). Considering the frequency with
which NaBH3CN is employed in reductive amination reactions,
we were surprised at the very poor performance throughout
this reaction class and this was not a function of solvent
employed. Indeed, with the exception of reactions of acyclic
primary alkyl amines (Reaction 3), NaBH3CN provided gener-
ally low levels of conversion to the desired products (<50%). It
should be noted that these reactions included AcOH as an
additive and that in the absence of AcOH conversions were
considerably lower. Pic–BH3 demonstrated good performance
for acyclic aryl and acyclic alkyl amines (Reactions 1 and 3)
and moderate utility for acyclic secondary alkyl and cyclic
secondary aryl amines (Reactions 7 and 9) but was signi-
ficantly less useful for acyclic secondary alkyl and cyclic
secondary alkyl amines (Reactions 5 and 11). In accordance
with previous studies,1f,4c the most successful reductant was
NaBH(OAc)3 which was generally useful for all amine classes.
In terms of solvent, as expected, the commonly used chlori-
nated solvents performed robustly, particularly with NaBH-
(OAc)3, while DMF was surprisingly inconsistent. However,
pleasingly, when used in conjunction with NaBH(OAc)3, most
of the alternative solvents were effective providing a range of
Fig. 3 Representative example of conversion data: reductive amination Reac-
tion 10 with the three reducing agents in DMC.†
Tables 1 and 2.† A cursory analysis at this stage clearly shows
the utility of EtOAc and DMC as viable alternatives to chlori-
nated solvents.
From consideration of the overall data set (see ESI†), a
series of general observations could be made.
Table 1 Illustrative representation of the reductive amination dataset for aryl aldehydesa
a Key: red = <50% conv., orange = 50–70% conv., green = >70% conv. *Indicates 100% conv. within 4 h. **Indicates 100% conv. within 1 h. SCB =
NaBH3CN, STAB = NaBH(OAc)3, Pic-B = picoline–borane complex.
Table 2 Illustrative representation of the reductive amination dataset for alkyl aldehydesa
a Key: red = <50% conv., orange = 50–70% conv., green = >70% conv. *Indicates 100% conv. within 4 h. **Indicates 100% conv. within 1 h. SCB =
NaBH3CN, STAB = NaBH(OAc)3, Pic-B = picoline–borane complex.
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Table 3 Assessment of alternative solvents in a range of aldehyde reductive amidations using NaBH(OAc)3 as the preferred reducing agenta
Conversionb,c
Entry
Product
DCE
TBME
CPME
DMC
EtOAc
IPA
2-MeTHF
1
2
100% (1 h)
100% (2 h)
85% (24 h)
100% (2 h)
86% (24 h)
100% (1 h)
85% (24 h)
100% (2 h)
80% (24 h)
100% (1 h)
100% (4 h)
100% (2 h)
80% (24 h)
100% (1 h)
3
4
5
100% (2 h)
0% (24 h)
100% (4 h)
100% (4 h)
0% (24 h)
89% (24 h)
73% (24 h)
0% (24 h)
87% (24 h)
100% (1 h)
0% (24 h)
87% (24 h)
100% (4 h)
0% (24 h)
72% (24 h)
100% (2 h)
0% (24 h)
17% (24 h)
74% (24 h)
14% (24 h)
73% (1 h)
6
7
100% (1 h)
100% (4 h)
100% (2 h)
100% (1 h)
100% (2 h)
100% (1 h)
100% (1 h)
100% (4 h)
100% (1 h)
100% (4 h)
100% (1 h)
100% (1 h)
100% (2 h)
100% (4 h)
8
9
100% (2 h)
79% (24 h)
100% (1 h)
74% (24 h)
100% (1 h)
81% (24 h)
100% (2 h)
64% (24 h)
94% (24 h)
60% (24 h)
100% (2 h)
28% (24 h)
100% (1 h)
77% (24 h)
10
11
100% (2 h)
100% (2 h)
100% (2 h)
100% (2 h)
100% (2 h)
100% (1 h)
100% (2 h)
100% (2 h)
100% (2 h)
100% (2 h)
100% (1 h)
100% (2 h)
100% (1 h)
100% (1 h)
12
13
100% (1 h)
100% (2 h)
100% (4 h)
43% (24 h)
100% (1 h)
100% (2 h)
100% (4 h)
100% (2 h)
100% (1 h)
100% (2 h)
100% (1 h)
100% (2 h)
100% (1 h)
100% (2 h)
14
15
100% (2 h)
100% (2 h)
43% (24 h)
100% (2 h)
39% (24 h)
100% (2 h)
46% (24 h)
100% (2 h)
100% (4 h)
100% (2 h)
59% (24 h)
100% (2 h)
27% (24 h)
100% (2 h)
16
17
100% (2 h)
63% (24 h)
100% (2 h)
75% (24 h)
100% (2 h)
80% (24 h)
100% (2 h)
70% (24 h)
100% (2 h)
67% (24 h)
90% (24 h) 100% (2 h)
66% (24 h)
70% (24 h)
18
77% (24 h)
68% (24 h)
57% (24 h)
58% (24 h)
56% (24 h)
15% (24 h)
50% (24 h)
19
20
100% (5 min)c 100% (4 h)
100% (4 h)
20% (24 h)
57% (24 h)
37% (24 h)
64% (24 h)
34% (24 h)
68% (24 h)
5% (24 h)
67% (24 h)
11% (24 h)
73% (24 h)
11% (24 h)
21
100% (5 min)c 100% (5 min)c 100% (5 min)c 100% (5 min)c 100% (5 min)c 100% (2 h)
100% (5 min)c
Average
90%
80%
82%
81%
82%
74%
78%
a Reaction conditions: aldehyde (1 equiv., 0.2 mmol), amine (1.1 equiv., 0.22 mmol), NaBH(OAc)3 (1.2 equiv., 0.24 mmol), solvent (1 mL, 0.2 M),
RT. b Determined by HPLC analysis. See ESI. c Taken at 0 h time point, represents first data point sampled.
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viable substitutes for CH2Cl2, DCE, and DMF. This suggests
that application of NaBH(OAc)3 in conjunction with the
replacement solvents examined would be effective for this
reagent class. Specifically, DMC and EtOAc emerged as the
most promising solvents for this reaction subset.
Alkyl aldehydes (Table 2). Within this substrate class, the
performance of NaBH3CN was again generally poor, with
limited utility across the range of reactions and did not corre-
late to solvent choice. Pic–BH3 demonstrated improved efficacy
for this alkyl aldehyde survey as compared to aryl aldehydes
(see above) while NaBH(OAc)3 continued to be the superior
reagent in a general sense. A particularly significant obser-
vation was that the reaction with acyclic primary alkyl amines
(Reaction 4) delivered very poor conversion to desired product
under the majority of reaction conditions surveyed. This was
found to be due to over alkylation, i.e., further reductive ami-
nation of the in situ generated secondary amine. However,
interestingly, pic–BH3 provided access to this product class in
up to 78% conversion, depending on the selected solvent.
From the range of solvents evaluated, the alternative solvents
generally performed well across the reaction classes with
several opportunities for practical replacements for CH2Cl2,
DCE, and DMF, with EtOAc once again demonstrating the
most robust overall profile.
The conversions for benchmark Reactions 1–12 using
NaBH(OAc)3 in the range of alternative solvents are shown in
Table 3, entries 1–12, with DCE (the most successful conven-
tional solvent used in this study) given for comparison. Entries
9–21 in Table 4 show the outcomes of a further assessment
phase with an extended range of aldehydes and amines. As
can be seen from Table 3, with the exception of entry 20, the
conversions to the desired products using alternative solvents
were broadly comparable to those achieved using DCE.
Fig. 4 Performing three representative reactions on gram scale.
Accordingly, based on this analysis, we suggest EtOAc is likely
to be the optimal replacement for DCE.
To further refine our analysis of suitable replacements for
DCE, we sought to rank the alternative solvents based on three
criteria (Table 4): (i) the average conversions established in
Table 3 as a measure of synthetic applicability; (ii) the out-
comes of the calculations of Pearson’s correlation vs. DCE; and
(iii) the green credentials of each solvent based on the analysis
of Henderson et al.17e This ranking process one again demon-
strated that EtOAc would be the most promising replacement
for DCE for this reaction type.
Based on all of the above, to further assess the practical
synthetic applicability of EtOAc as an alternative medium
for direct aldehyde reductive amination with NaBH(OAc)3, we
performed the gram scale (20 mmol) synthesis of three com-
pounds from our substrate scope evaluation (Fig. 4). Pleas-
ingly, these three representative reactions proceeded smoothly
to deliver the desired compounds in high yield.
Calculating the average reaction mass efficiency (RME)21 of
the reactions in Fig. 4 delivered an RME of 40%. While this
is lower than the benchmark for amination established by
Curzons (54%),21 there is no indication of the specific reagents
employed for this established value which precludes a true
comparison. Clearly, if the same chemical yield for these reac-
tions could be obtained using NaBH3CN and pic–BH3, the
theoretical RMEs from these processes would be superior, due
to the lower molecular weight of these as compared to the pre-
ferred reagent. However, and as discussed above, the synthetic
performance of NaBH3CN and pic–BH3 were consistently con-
siderably lower than that of NaBH(OAc)3 and as such, it is
unlikely that a superior RME could be achieved using these
alternative reagents.
The mean yields across each of the solvents suggest that
IPA is an outlier in that its average yield is lower. Performing a
t-test comparing the yields for each of the reactions in Table 3
at the 24 h time point for DCE and IPA suggests that the differ-
ence between the two sets is statistically significant (p < 0.05).
Based on this, IPA is considered to be less suitable as a repla-
cement for DCE. In addition, calculation of Pearson’s corre-
lation between DCE and the replacement solvents for each of
the reactions suggests that EtOAc and DMC have the strongest
correlation with values of 0.87 and 0.81, respectively.
Conclusions
Table 4 Ranking the alternative solvents according to assessment criteria
In summary, we have evaluated a range of alternative solvents
as potential replacements for CH2Cl2, DCE, and DMF as the
medium for 12 classes of aldehyde reductive amination
using common borane-based reducing agents. These studies
revealed that, especially when using NaBH(OAc)3 as the redu-
cing agent, CH2Cl2, DCE, and DMF could potentially be readily
replaced with alternatives that exhibit less harmful and environ-
mentally damaging effects. We subsequently assessed the
utility of these solvents in a range of reactions using a variety
of aldehydes and amines with NaBH(OAc)3 as the preferred
Synthetic
Correlation
to DCEb
Green
Overall
rank
Solvent
applicabilitya
credentialsc
TBME
CPME
DMC
EtOAc
IPA
4
2
3
1
6
5
4
3
2
1
5
6
4
5
1
2
3
6
5
3
2
1
4
6
2-MeTHF
a Based on average conversion from Table 3. b Based on calculation of
Pearson’s correlation. c Based on the GSK solvent selection guide.17e
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reductant, which indicated that conversions were broadly com-
parable to those observed in conventional media (DCE) with
EtOAc offering considerable potential as a functional replace-
ment. Overall, we believe that the data presented here will
assist in the selection of more environmentally acceptable
media for aldehyde reductive amination reactions.
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Acknowledgements
We thank the EPSRC National Mass Spectrometry Service
Centre, Swansea University, for analyses. We are grateful to
GlaxoSmithKline and Sigma-Aldrich for the kind donation of
consumables. FIM wishes to thank the EPSRC for postdoctoral
funding. DSM wishes to thank the University of Strathclyde
Knowledge Transfer Account for postdoctoral funding.
Graham Inglis and Dr Simon MacDonald (GSK) are thanked
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