Chemo-selective Rh-catalysed hydrogenation of azides into amines

Article abstract of DOI:10.1016/j.carres.2020.107948

Rh/Al₂O₃ can be used as an effective chemo-selective reductive catalyst that combines the mild conditions of catalytic hydrogenation with high selectivity for azide moieties in the presence of other hydrogenolysis labile groups such as benzyl and benzyloxycarbonyl functionalities. The practicality of this strategy is exemplified with a range of azide-containing carbohydrate and amino acid derivatives.

Full text of DOI:10.1016/j.carres.2020.107948

Journal Pre-proof
Chemo-selective Rh-catalysed hydrogenation of azides into amines
Mattia Ghirardello, Helene Ledru, Abhijit Sau, M. Carmen Galan
PII:
S0008-6215(20)30022-7
DOI:
https://doi.org/10.1016/j.carres.2020.107948
CAR 107948
Reference:
To appear in: Carbohydrate Research
Received Date: 17 January 2020
Revised Date: 4 February 2020
Accepted Date: 5 February 2020
Please cite this article as: M. Ghirardello, H. Ledru, A. Sau, M.C. Galan, Chemo-selective Rh-catalysed
hydrogenation of azides into amines, Carbohydrate Research (2020), doi: https://doi.org/10.1016/
j.carres.2020.107948.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

TOC
Chemo-selective Rh-catalysed Hydrogenation of Azides into Amines.
N3
NH2
O
H2, 1 atm, Rh/Al2O3
O
BnO
BnO
OR
NHCbz
OR
NHCbz
toluene/EtOAc
6:1

Chemo-selective Rh-catalysed Hydrogenation of Azides
into Amines.
Mattia Ghirardello, Helene Ledru, Abhijit Sau and M. Carmen Galan*
School of Chemistry, University of Bristol, Cantock’s Close, BS8 3TS (UK)
*Corresponding author: M.C.Galan@bristol.ac.uk
Abstract
Rh/Al2O3 can be used as an effective chemo-selective reductive catalyst that combines the
mild conditions of catalytic hydrogenation with high selectivity for azide moieties in the
presence of other hydrogenolysis labile groups such as benzyl and benzyloxycarbonyl
functionalities. The practicality of this strategy is exemplified with a range of azide-containing
carbohydrate and amino acid derivatives.
Keywords
Rhodium catalysis, Azide reduction, Chemo-selective reduction, Protecting groups
manipulation, aminoglycosides
Introduction
Amines are common functional groups present in many organic compounds. In multistep
organic synthesis, reactive amine groups often require temporary protection [1]. Azides are
often used to mask amines, their chemical stability and orthogonal reactivity towards other
common protecting groups makes them exceedingly versatile. [2]. The use of azides in
carbohydrate synthesis is also very prevalent since glycosyl azides are highly useful
precursors for N-linked glycans [3].
One of the most common ways to introduce azides in chemical synthesis consists in the
displacement of halogens or other leaving groups (e.g. tosyl and triflyl) by NaN3, other
common protocols include acid-catalysed addition of trimethylsilyl azide, amine substitution
via sulfonylazides or the use of diazonium salts among others [4,5]. Reduction of the azide
moiety to an amine is also a synthetically important step, since many azides can be
prepared with regio- and stereocontrol, their subsequent reduction permits controlled
introduction of the amine group. To that end, the most common protocols for the reduction of
azides into amines involve Pd/C or PtO2-promoted catalytic hydrogenation [6], Staudinger
reaction [7], or hydride reduction [8] (e.g. LiAlH4, PhSeH,
tris(trimethylsilyl)silane,
dithiol/Et3N), among many others [2].
Despite the numerous methods available for the reduction of the N3 group, selectivity
issues often arise due to the presence of other non-orthogonal protecting groups or labile
moieties on the same molecule which can’t withstand the reaction conditions. While Pd-
catalysed hydrogenation is often non-selective for benzyl ethers and olefins, previous
examples of selective Pd-catalysed hydrogenation of azides in presence of benzyl ethers
have been reported.[9] Nonetheless, the method does not allow for selective reduction of
azides in the presence of the more labile benzyloxycarbonyl (Cbz) protecting group. On the
other hand, the Staudinger reaction requires the use of water, which is often incompatible
with hydrolytically labile groups; hydride-mediated reductions (e.g. LiAlH4) are not selective
towards N3 groups in the presence of aldehydes or esters and in some instances the
1

methods involve the use of toxic or/and malodourous reagents (e.g. selenols, thiols, tin
hydrides) [2].
Rh complexes have been successfully and extensively employed in organometallic
chemistry in for example metathesis reactions [10,11], hydrosilylation reactions [12],
hydrogenation of olefins [13] and for reduction of nitriles to amines [14]. Rh-catalysed
hydrogenation represents an alternative to the aforementioned azide reduction strategies,
which has the potential to offer several advantages over more traditional methods, in terms
of chemical orthogonality.
Herein we report the use of Rh as an effective and selective catalyst for the
hydrogenolysis of azides. The applicability of the method is exemplified with a range of
azide-containing carbohydrate and amino acid derivatives. We demonstrate that Rh/Al2O3
may be used as an effective reductive catalyst that combines the mild conditions used in
catalytic hydrogenation with high selectivity for azide moieties in the presence of other labile
groups. To the best of our knowledge there are no reported applications of the use of Rh or
its complexes for the catalytic reduction of azides in biological chemistry.
Results and Discussion
Initial studies were aimed at evaluating the effectiveness of Rh as a mild hydrogenation
catalyst for the chemo-selective reduction of azides in the presence of benzyl ethers, which
are typically labile under Pd-catalysed hydrogenolysis conditions [15]. To that end, glycosyl
azide 1 was chosen as a model substrate (Scheme 1a) and reacted with 10 mol%
commercially available Rh/Al2O3 in presence of an excess of acetic acid to help stabilise the
resulting amine product as the acetate salt [16]. Pleasingly, the reduction of 1 to amine 2
was achieved in an excellent yield of 90% using mild conditions (H2, 1 atm, balloon and
room temperature) without affecting the surrounding benzyl groups.
To determine the efficiency of this reduction under different catalyst loadings, a
preliminary rate determination screen was performed using 10, 5 and 1 mol% of Rh/Al2O3
under the same reaction conditions as before. Under these conditions and for each catalyst
loading, the conversion between azide 1 to amine 2 was monitored by taking aliquots of the
reaction at different time intervals and analysed via NMR spectroscopy (Scheme 1b). The
reduction at 10 mol% of Rh reached > 90% completion after 6 h. Similar results were
achieved at 5 mol% of Rh after 13 h, while at 1 mol% load of Rh the reaction was slower and
gave a 17 % conversion after 24 h.
Solvent effects were then explored and the outcome of the model reaction in different
solvents was monitored in order to evaluate if the nature of the solvent would influence the
efficiency of the reduction. The Rh-catalysed hydrogenation of 1 into 2 was tested in toluene,
EtOAc, MeOH, THF, and CHCl3 under the same conditions (5 mol% catalytic load, H2 1 atm,
5 h, room temperature). No significant difference was observed between the different
solvents (Scheme 1c), except for CHCl3 that gave a much lower conversion probably due to
the lower solubility of H2 in halogenated solvents [17]. Consequently, It was decided to carry
out the Rh-catalysed hydrogenations in a 6:1 toluene/EtOAc mixture, providing optimal
solubility conditions for both reagents and products.
2

(a)
(b)
(c)
Relative conversion
after 5 h
Solvent
100
80
60
40
20
0
MeOH
Toluene
THF
1.00
1.00
0.95
0.78
0.19
1.00
EtOAc
CHCl3
Toluene/EtOAc
(6:1)
0
5
10
15
20
25
Time (h)
Scheme 1. (a) Rh-catalysed hydrogenation of 1, reagent and conditions: H2 1 atm, Rh/Al2O3 10
mol%, AcOH, toluene 6 h, room temperature, 90 %. (b) Plot of conversion of 1 into 2 at 1 mol% (blue
▲), 5 mol% (red ●) and 10 mol% (grey ■) of Rh/Al2O3 over time. (c) Relative conversion rates
between 1 into 2 in different solvent at 5 mol% Rh/Al2O3, H2 1 atm, AcOH, after 5h.
Encouraged from these initial results, the scope of the Rh-catalysed azide reduction was
then explored on a range of glucosides containing either primary, secondary or anomeric
azides and bearing both acetyl and benzyl ether protecting groups (Scheme 2) using the
optimized catalytic conditions and toluene/EtOAc (6:1) as the reaction solvent.
In most cases the reductions proceeded smoothly in moderate to good yields at room
temperature. In brief, glycosides bearing azide-groups at C2 as in 3 and 4 afforded the
respective perbenzylated and peracetylated 2-aminoglycosides 5 and 6 in good yields of
63% and 86% yield, after 3 and 6 h, respectively, at room temperature. Rh-catalysed
reduction of 1-azido acetyl-protected glucoside 7 resulted in the corresponding 1-amino
glycoside 9 in 69% with no anomerization by-products observed. In the case of 1-azido
benzyl-protected glucoside 8, a complex mixture of amino-containing derivatives including
α/β anomeric mixtures of the 1-amino derivative were obtained under this conditions, likely
due to the electron donating nature of the benzyl protecting groups which makes the
resulting hemiaminal product more reactive and thus more susceptible to anomerization
and/or degradation [18]. We, therefore resolved the product mixture via acetylation of the
resulting reduced product using acetic acid and pyridine which lead to the isolation of the
major product, β-1-N-acetyl glycoside 10 in 36% yield after 2 steps. On the other hand,
reduction of glucoside 11, bearing a primary azide at C6, underwent reduction to the amine
within 8 h with concomitant acetate migration of the acetyl group at C4 to afford acetamide
derivative 12 in a 83% yield. This was confirmed by the proton shift associated for H4 (from
δ 4.97 in 11 to δ 3.33 ppm for acetamide 12) and to the presence of a cross-peak in the
COSY spectrum corresponding to the broad OH signal and H4. To ascertain whether other
H2-cleavable protecting groups were amenable to the mild Rh reaction conditions, CbzN-
3

protected glucoside 13 was also screened. Compound 13 was reduced to amide 14 in 63%
yield, without loss of the carbamate protecting group. Similarly to the outcome observed for
11, the primary amine undergoes intramolecular transacetylation affording the corresponding
acetamide and leaving a free hydroxyl at position C4 of the sugar. In order to elucidate
whether the transacetylation reaction occurs only for amines at position C6 of glycosides
featuring OAc groups at adjacent positions (e.g. C4) of the sugar moiety or due to the
general stronger nucleophilicity of primary amines over secondary or anomeric ones, the
reduction of acetate containing glycosides 15 and 17, bearing a primary azide at different
positions on the sugar, were performed. Amino-derivatives 16 and 18 were obtained in good
yields of 73% and 94%, respectively, without the formation of transacetylated derivatives.
These results confirm that the observed acetate migration appears to be a specific feature of
C6-amine containing glycosides where acetate groups are present at C4 and can undergo
intramolecular rearrangement via a 6-membered transition state giving the corresponding
acetamide, which is a common problem in carbohydrate chemistry [19].
Scheme 2. Reagent and conditions: i) H2 1 atm, Rh/Al2O3 10 mol%, AcOH, toluene/EtOAc (6:1), room
temperature. ii) H2 1 atm, Rh/Al2O3 10 mol%, AcOH, toluene/EtOAc (6:1), 6 h, room temperature, then
Py/Ac2O 1:1 16 h, room temperature.
4

To evaluate the chemical selectivity and efficiency of Rh-catalysed hydrogenation in the
presence of different protecting and functional groups, orthogonally protected glycoside 19,
thioglycoside 21, nucleosides 23 and 25 and amino acid derivatives 27 and 29 containing
free amino and carboxylic acid groups, were subjected to the Rh-catalysed reduction
(Scheme 3).
Scheme 3. Reagent and conditions: i) H2 1 atm, Rh/Al2O3 10 mol%, AcOH, MeOH, 5 h, room
temperature. ii) H2 1 atm, Rh/Al2O3 10 mol%, AcOH, toluene/EtOAc (6:1), 24 h, room temperature. iii)
H2 1 atm, Rh/Al2O3 10 mol%, AcOH, MeOH, 5 h, room temperature. iv) H2 1 atm, Rh/Al2O3 10 mol%,
AcOH, MeOH, 2.5 h, room temperature.
Reduction of 19 gave amine 20 cleanly in 74% yield without cleavage of the benzylidene
acetal protecting group and without the need for anhydrous conditions. On the other hand,
Rh-catalysed reduction of sulphur-bearing glycoside 21 only yielded starting material,
5

despite of long reaction times (24 h) with a 10 mol% of Rh, likely due to catalyst poisoning by
the thioether [10,21]. Our reduction conditions were then applied to azido-containing uridine
derivative 23 and adenosine 25 as model pyrimidine and purine nucleoside substrates. In
the case of 23, complete reduction of the azido and double bond in the nucleobase afforded
dihydrouridine amine 24 as the major product. The lack of chemo-selectivity in this instance
is not completely unexpected as previous work has demonstrated the applicability of Rh in
the reduction of uridine bases [22-24]. However, selective azido reduction in adenosine 27
was successful and amine 28 was obtained in 65% yield without affecting the nucleobase, in
virtue of a stronger aromaticity compared to the pyrimidine model 25. Finally, we also
demonstrated that Rh-catalysed hydrogenation of azides is compatible with the presence of
free acid or basic amine functions such as those found in amino acid derivatives 27 and 29,
which furnished the corresponding amines 28 and 30 in excellent yields of 92% and 86%
respectively, after subjecting the parent substrates to the Rh-catalysed conditions in
methanol as the solvent for solubility purposes.
Conclusions
In conclusion, we have demonstrated that Rh/Al2O3 can be used as an effective and chemo-
selective catalyst for the reduction of azides in the presence of other hydrogen-labile
functional groups such as O-Bn and N-Cbz protecting groups The method is mild and offers
an orthogonal alternative to Pd- or Pt- catalysed hydrogenation where high specificity for the
azide moiety is required. Although the presence of thiols as in thioglycosides appears to be
incompatible with the protocol, in a similar way to hydrogenations carried out with Pd or Pt
catalysts where the catalysts are inactivated, the versatility of the protocol is exemplified in a
range of glycosides and amino acid derivatives demonstrating its compatibility with other
commonly used orthogonal functional groups, setting the stage for novel applications of Rh-
catalysed azide reduction in organic synthesis.
Acknowledgments
This project has been funded by the Industrial Biotechnology Catalyst (Innovate UK,
BBSRC, EPSRC) to support the translation, development and commercialisation of
innovative Industrial Biotechnology processes (BB/M028976/1). We also thank the
European Research Council (ERC-COG: 648239).
References
[1]
[2]
[3]
[4]
Wuts, P. G. M.; Greene, T. W. Protecting Groups in Organic Synthesis, 4th ed.; John Wiley &
Hoboken, New Jersey, 2007.
Scriven, E. F. V.; Turnbull, K., Azides - Their Preparation and Synthetic Uses. Chem. Rev. 88, (1988) 297-
368. https://doi.org/10.1021/cr00084a001.
H. S. G. Beckmann and V. Wittmann, V. Azides in Carbohydrate Chemistry. In Organic Azides: Syntheses
and Applications; Bräse, S.; Banert, K., Eds.; John Wiley & Sons, Ltd: Chichester, UK, 2009; pp 469–491.
Z. Györgydeák, J. Thiem, in Advances in Carbohydrate Chemistry and Biochemistry, Vol. 60 (Ed.: D.
Horton), Academic Press, 2006, pp. 103-182.
Sons:
[5]
[6]
E. D. Goddard-Borger, R. V. Stick, Org. Lett. 9 (2007) 3797-3800. https://doi.org/10.1021/ol701581g.
Catalytic Reduction in Organic Synthesis 2, 2018 ed. (Ed.: J. G. de Vries), Georg Thieme Verlag,
Stuttgart, 2018.
[7]
a)
H.
Staudinger,
J.
Meyer,
Helvetica
Chimica
Acta,
2
(1919)
635-646.
https://doi.org/10.1002/hlca.19190020164. b) S. Liu, K. J. Edgar, Biomacromolecules 16 (2015) 2556-
2571. https://doi.org/10.1021/acs.biomac.5b00855. c) M. Ghirardello, I. Delso, T. Tejero, P. Merino, Asian
J. Org. Chem. 5 (2016) 1525-1534. https://doi.org/10.1002/ajoc.201600497.
6

[8]
[9]
a) R. Zhang, K. J. Edgar, Carbohydr. Pol. 122 (2015) 84-92. https://doi.org/10.1016/j.carbpol.2014.12.020.
b) H. Bayley, D. N. Standring and J. R. Knowles, J. R. Tetrahedron Lett. 19 (1978), 3633-3634.
https://doi.org/10.1016/S0040-4039(01)95015-4.
H. Sajiki, Tetrahedron Letters, 36 (1995) 3465-3468. https://doi.org/10.1016/0040-4039(95)00527-J.
[10] Y.
Wang,
Z.-X.
Yu,
Acc.
Chem.
Res.
48,
(2015)
2288-2296.
https://doi.org/10.1021/acs.accounts.5b00037.
[11] T. Kan, T. Asakawa, M. Inai, Heterocycles 92 (2016) 31-43. https://doi.org/10.3987/REV-15-829.
[12] A. S. Henderson, J. F. Bower, M. C. Galan, Org. Biomol. Chem. 12 (2014) 9180-9183.
https://doi.org/10.1039/C4OB02056A
[13] a) A. M. Geer, C. Tejel, J. A. López, M. A. Ciriano, Angew. Chem. Int. Ed. 53 (2014) 5614-5618.
https://doi.org/10.1002/anie.201400023. b) S. Kraft, K. Ryan, R. B. Kargbo, J. Am. Chem. Soc. 139 (2017)
11630-11641. https://doi.org/10.1021/jacs.7b07188.
[14] L. Xu, A.K. Farthing, J.F. Dropinski, P.T. Meinke, C. McCallum, E. Hickey, K. Liu, Bioorganic & Medicinal
Chemistry Letters, 23 (2013) 366-369. https://doi.org/10.1016/j.bmcl.2012.10.065
[15] S. Vidal, Protecting Groups: Strategies and Applications in Carbohydrate Chemistry. Wiley-VCH, Georg
Thieme Verlag, Stuttgart, (2019).
[16] The reaction in the absense of acetic acid was significantly slower.
[17] E. B. Maxted, V. Stone, J. Chem.Soc. (1938) 454-455. http://dx.doi.org/10.1039/JR9380000454
[18] A.
D.
Dorsey,
J.
E.
Barbarow,
D.
Trauner,
Org.
Lett.
5
(2003)
3237-3239.
https://doi.org/10.1021/ol035111s.
[19] T. C. Baddeley, J. L. Wardell, J. Carbohydr. Chem. 28 (2009), 198-221.
https://doi.org/10.1080/07328300902887672.
[20] N. S. Nasri, J. M. Jones, V. A. Dupont, A. Williams, Energy & Fuels. 12 (1998), 1130-1134.
https://doi.org/10.1021/ef980104j.
[21] D. L. Boger, S. H. Kim, Y. Mori, J.-H. Weng, O. Rogel, S. L. Castle, J. J. McAtee, J. Am. Chem. Soc. 123
(2001) 1862-1871. https://doi.org/10.1021/ja003835i.
[22] W. E. Cohn, D. G. Doherty, D. G., J. Am. Chem. Soc. 78 (1956) 2863-2866.
https://doi.org/10.1021/ja01593a063.
[23] J. Kremser, E. Strebitzer, R. Plangger, M. A. Juen, F. Nußbaumer, H. Glasner, K. Breuker, C. Kreutz,
Chem. Commun. 53 (2017) 12938-12941. https://doi.org/10.1039/C7CC06747J
[24] N. P. J. Price, M. A. Jackson, K. E. Vermillion, J. A. Blackburn, T. M. Hartman, Carbohydr. Res. 471
(2019) 43-55. https://doi.org/10.1016/j.carres.2018.10.007
7

Highlights:
•
Rh/Al2O3 can be used as a mild and effective chemo-selective reductive catalyst
for azide moieties in the presence of other hydrogenolysis labile groups such as
benzyl and benzyloxycarbonyl functionalities.
•
The reactions proceed cleanly and the method works well across a range of
reactivity profiles including carbohydrate and amino acid derivatives.

Chemo-selective Rh-catalysed Hydrogenation of Azides into Amines.
The authors declare no conflict of interest.