Conversion of aldimines to secondary amines using iron-catalysed hydrosilylation

Article abstract of DOI:10.1039/c8ob01262h

Iron-catalyzed hydrosilylation of imines to amines using a well-defined iron complex is reported. This method employs relatively mild conditions, by reaction of imine, (EtO)₃SiH in a 1 : 2 ratio in the presence of 1 mol% precatalyst ([BIAN]Fe(η⁶-toluene), 3, BIAN = bis(2,6-diisopropylaniline)acenaphthene) at 70 °C. A broad scope of imines was readily converted into the corresponding secondary amines without the need for precatalyst activators.

Full text of DOI:10.1039/c8ob01262h

Organic &
Biomolecular Chemistry
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Conversion of aldimines to secondary amines
using iron-catalysed hydrosilylation†
Cite this: Org. Biomol. Chem., 2018,
16, 9368
Anu Saini,‡ Cecilia R. Smith,‡ Francis S. Wekesa, Amanda K. Helms and
Received 29th May 2018,
Accepted 29th November 2018
Michael Findlater
*
DOI: 10.1039/c8ob01262h
rsc.li/obc
Iron-catalyzed hydrosilylation of imines to amines using a well- behind the development of non-toxic and abundant replace-
defined iron complex is reported. This method employs relatively ments; iron has emerged as a leading candidate in the context
mild conditions, by reaction of imine, (EtO)3SiH in a 1 : 2 ratio in of first-row metal catalysis.8
the presence of 1 mol% precatalyst ([BIAN]Fe(η6-toluene), 3, BIAN
The iron-catalysed hydrosilylation of alkenes, aldehydes,
= bis(2,6-diisopropylaniline)acenaphthene) at 70 °C. A broad scope and ketones has been studied extensively; surprisingly, only a
of imines was readily converted into the corresponding secondary handful of reports exist detailing the iron-catalyzed hydrosilyl-
amines without the need for precatalyst activators.
ation of imines.9 Thus, in 2012, Darcel and coworkers10
reported the first general and efficient catalytic system for the
hydrosilylation of imines using a well-defined iron complex
(Fig. 1). Recently Mandal and coauthors have employed a
The amine functional group represents an important com-
ponent of a variety of biologically relevant compounds: amino
acids, vitamins, and commonly used analgesics such as mor-
phine and demerol.1 The reductive amination of carbonyl
derivatives employing primary amines remains one of the
most commonly utilized methods to synthesize amines; this is
now a well-established and practical approach.2 The direct
reduction of amides is another common route found in amine
synthesis, generally using metal catalyzed processes, but its
use is still limited owing to the lower electrophilicity of the
carbonyl group in amides.3a–c The generic metal catalyzed
reduction of imines (encompassing hydrogenation,4 hydrogen
transfer5 and hydrosilylation6) is a direct and efficient method
for accessing amines. Among these catalytic methods, hydro-
silylation has emerged as a convenient route as it employs
readily available silanes as the source of hydrogen, which are
easy to handle, activated under mild conditions, and provide
excellent chemoselectivity in functional group-rich molecular
settings. Many groups have now used this strategy, yet the
most efficient catalysts developed to date are usually based on
precious metal elements such as ruthenium, iridium and
rhodium.7 The high cost and toxicity of precious metals
imposes limits on their potential industrial use, i.e., in the syn-
thesis of amine based compounds with pharmacological rele-
vance. These limitations provide just some of the driving force
Department of Chemistry & Biochemistry, Texas Tech University, Lubbock,
Texas 79409-1061, USA. E-mail: michael.findlater@ttu.edu
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob01262h
Fig. 1 Recent examples of iron-based complexes capable of the cata-
‡These authors contributed equally.
lytic hydrosilylation of imines.
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closely related iron catalyst (Fig. 1).11 A low catalyst loading of vious work and in an effort to enhance the knowledge of well-
0.05 mol% afforded turnovers of 17 000, demonstrating defined Fe complexes of the BIAN ligands, herein we describe
remarkable efficiency when compared to previous catalyst the hydrosilylation of imines using iron complex 3 as the pre-
systems in imine hydrosilylation.
catalyst (Table 1).
Common to both structures is the presence of a carbene
We examined the catalytic hydrosilylation of imines using
ancillary ligand, and although such moieties have been exten- N-benzylideneaniline (8a) as our model substrate using
sively used in designing base-metal catalysts, recent interest 1 mol% of precatalyst 3. Precatalyst 3 is readily prepared fol-
has shifted more toward the use of redox active ligands in iron lowing the literature procedure.16 A range of silane reagents
catalysis; such iron complexes have been shown to mimic were explored, and we observed that Ph3SiH, Ph2SiH2 and
some of the catalytic properties of noble metals.12 Among the (EtO)3SiH were effective in the hydrosilylation of the imine
most prominent classes of redox-active ligands are the di- moiety. Neither of the trialkylsilanes explored, triethyl- or
imines. Specifically, the late transition metal complexes of the triisopropylsilane, were competent reagents for hydrosilylative
bis(arylimino)acenaphthene (BIAN) have been extensively reduction of the imine bond. Triethoxysilane is a more elec-
studied by many research groups.13 Moreover, BIAN ligands tron-rich and sterically less congested silane source, which
are known to undergo multiple, successive electron-accepting may have an impact on its success relative to trialkylsilanes.
redox events, making them an attractive ligand to deploy in The progress of the hydrosilylation reaction was monitored
redox non-innocent applications in catalysis.14 Surprisingly, using GCMS analysis. At 1 mol% catalyst loading and within
iron-based BIAN complexes are relatively scarce. Most reports 4 hours (70 °C), our model substrate was converted quantitat-
on BIAN-Fe complexes comprise an ‘extra’ donor arm in ively to the corresponding secondary amine. Subsequently, we
addition to the two nitrogen atoms of the diimine.15
decided to explore the scope of imine substrates amenable to
This virtual absence from the literature of BIAN-Fe com- our reaction conditions using the inexpensive triethoxysilane
plexes motivated us to study their preparation and potential as our preferred silane reductant (Table 2).
applications in catalysis.16 In our initial report we disclosed
A broad substrate scope was observed; a diverse set of
the synthesis, molecular structure and catalytic application of imines is readily accessible from commercially available alde-
complex 3 in the hydrosilylation of aldehydes and ketones.16 hydes and (aryl)amines. Imines that are derived from combi-
Notable progress has been made in this area since then, as nations of (aryl)aldehydes and (aryl)amines typically under-
several studies have been reported investigating similar cata- went hydrosilylation in high yield. Introduction of either elec-
lytic systems in the last two years (Fig. 2). Recently, Lei and co- tron-releasing (8b and 8d) or electron-withdrawing (8c and 8e)
workers17a demonstrated sterically hindered BIAN-FeCl2 (5) substituents in the para-position of the aldehyde-derived aro-
complexes as precatalysts for hydrosilylation of carbonyl com- matic ring did not result in diminished yields (81–92%).
pounds and olefins. Further, Hoyt and coworkers17b have Similarly, no erosion in product yield was observed upon intro-
investigated closely related analogues (6) using Mössbauer duction of electronically diverse substituents to the para-posi-
spectroscopy, solution state magnetic measurements and DFT tion of the (aryl)amine-derived ring (8g–8j; 81–90%).
quantum-chemical calculations. These studies were also Combinations of mixed electronic effects, “push–push”,
applied to complex 3 and strongly suggest a 1-electron transfer “push–pull”, and “pull–pull”, via use of appropriately substi-
has occurred from metal to the BIAN ligand; an oxidation state
of +1 would thus seem to be a more appropriate description of
the electronic state of the iron center in 3. In collaboration
with our group, Long and co-authors17c successfully employed
Table 1 Optimization of reaction conditions using model substrate
N-benzylideneaniline (8a)a
4 as precatalyst in the ring opening polymerization of L-lactide.
Finally, Wangelin and co-workers17d reported the synthesis
and electrochemical properties of several (R-BIAN)FeCl2 (7)
complexes using cyclic voltammetry. Building upon our pre-
Entry
Silane
Yieldb (%)
1
2
3
PhSiH3
Ph2SiH2
Et3SiH
100
100
0
4
5
(iPr)3SiH
(EtO)2MeSiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
0
0
100
100
0
6
7c
8d
a Reaction conditions: 8a (0.5 mmol), 3 (3 mg, 1 mol%), silane
(1 mmol), methylene chloride (1 mL), 70 °C. b As determined by
GC-MS analysis. c Neat conditions, no solvent. d No added 3.
Fig. 2 Examples of BIAN-based iron complexes capable of catalytic
hydrosilylation and ring-opening polymerization chemistry.
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Table 2 Scope of the Fe-catalyzed hydrosilylative reduction of aldiminesa
a Yield. b Calculated using GCMS analysis by adding mesitylene as internal standard; response factors were not determined. c Catalyst loading
5 mol%.
tuted pairs of (aryl)aldehyde/(aryl)amine precursors, were also groups were also tolerated as substituents on imine substrates in
explored. In all cases (8n–8r), good to excellent yields of either the (aryl)aldehyde or (aryl)amine rings. Disappointingly,
reduced products were obtained (86–95%). Taken together, the presence of hydroxyl- or bromo-substituents (8f and 8k,
there appears to be no clear-cut electronic influence on the respectively) on imine substrates was not tolerated. We have pre-
performance of imine substrates in hydrosilylative reduction viously shown that alcohols react with complex 3 to afford (as
chemistry.
yet) unidentified paramagnetic species.17c In an extension from
In contrast to the aryl-derivatives, imines derived from aldimines 8a–8r, we attempted reduction of more hindered inda-
either aliphatic amines (8l) or aliphatic aldehydes (8m) give none-derived imine, 8s. Secondary amine, 9s was obtained in
lower yields, even after extended reaction times (24 h). Ester excellent yield (94%). Moreover, 9s, is a precursor to the mono-
(8j), amine (8d, 8p and 8r) and ether (8b, 8g, 8n, 8p and, 8q) amine oxidase inhibitor rasagiline.18
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S. Pisiewicz, K. Kiersch, D. Michalik, F. Gallou, K. Junge
and M. Beller, Angew. Chem., Int. Ed., 2015, 54, 12389.
4 (a) F. Spindler, Handbook of Homogeneous Hydrogenation,
Wiley-VCH, Weinheim, 2007; (b) T. Nugent and M. El-
Shazly, Adv. Synth. Catal., 2010, 352, 753; (c) M. Ruping,
E. Sugiono and F. R. Schoepke, Synlett, 2010, 852;
(d) S. Fleischer, S. Werkmeister, S. Zhou, K. Junge and
M. Beller, Chem. – Eur. J., 2012, 18, 9005; S. Fleischer,
S. Zhou, S. Werkmeister, K. Junge and M. Beller, Chem. –
Eur. J., 2013, 19, 4997; (e) D. S. Mérel, M. Elie, J. F. Lohier,
S. Gaillard and J. L. Renaud, ChemCatChem, 2013, 5, 2939;
(f) S. Chakraborty, W. W. Brennessel and W. D. Jones,
J. Am. Chem. Soc., 2014, 136, 8564.
5 (a) C. Zhu, K. Saito, M. Yamanaka and T. Akiyama, Acc.
Chem. Res., 2015, 48, 388; (b) B. Xiong, Y. Li, W. Lv, Z. Tan,
H. Jiang and M. Zhang, Org. Lett., 2015, 17, 4054;
(c) S. Zhou, S. Fleischer, K. Junge, S. Das, D. Addis and
M. Beller, Angew. Chem., Int. Ed., 2010, 49, 8121;
(d) A. A. Mikhailine, M. I. Maishan and R. H. Morris, Org.
Lett., 2012, 14, 4638; (e) H.-J. Pan, T. W. Ng and Y. Zhao,
Org. Biomol. Chem., 2016, 14, 5490.
Scheme 1 Hydrosilylation of ketone-derived ketimine 10.
Finally, imine substrates comprising heterocycles were also
studied (8t–8w). Gratifyingly, both pyridine- and thiophene-
based imines were amenable to our optimized hydrosilylation
conditions and were converted to corresponding amine pro-
ducts in good to excellent yields (80–98%); in the case of thio-
phene-derived imine 8w, slightly extended reaction times were
necessary to afford good yields of the amine product.
To extend our methodology to ketimines, we attempted the
hydrosilylation of substrate 10 (Scheme 1). Disappointingly,
the ketimine proved to be a poor substrate for hydrosilylation
using catalyst 3. Moderate yield (42%) was only obtained after
increasing catalyst loading to 5 mol%.19
In summary, we have isolated a well-defined BIAN-based
iron complex (3) and shown it to be an efficient precatalyst
system for hydrosilylation of imines to secondary amines.
Further derivatization of the ligand and their use in reducing
more challenging substrates such as amides are in progress.
Details of the hydrosilylation mechanism are currently being
explored in our group.
6 (a) L. D. Field, B. A. Messerle and S. L. Rumble, Eur. J. Org.
Chem., 2005, 2881; (b) Y. Nishibayashi, I. Takei, S. Uemura
and M. Hidai, Organometallics, 1998, 17, 3420.
7 (a) H. Hashimoto, I. Aratani, C. Kabuto and M. Kira,
Organometallics, 2003, 22, 2199–2201; (b) C. Cheng and
M. Brookhart, J. Am. Chem. Soc., 2012, 134, 11304–11307.
8 (a) B. H. Lipshutz and H. Shimizu, Angew. Chem., Int. Ed.,
2004, 43, 2228–2230; (b) L. Wang, H. Sun and X. Li,
Eur. J. Inorg. Chem., 2015, 2732–2743; (c) I. Bauer and
H.-J. Knolker, Chem. Rev., 2015, 115, 3170–3387;
(d) A. Fürstner, ACS Cent. Sci., 2016, 2, 778–789.
Conflicts of interest
There are no conflicts to declare.
9 (a) B. M. Park, S. Mun and J. Yun, Adv. Synth. Catal., 2006,
348, 1029–1032; (b) A. Bezlada, M. Szewczyk and
J. Mlynarski, J. Org. Chem., 2016, 81, 336–342; (c) T. Ireland,
F. Fontanet and G. G. Tchao, Tetrahedron Lett., 2004, 45,
4383–4387.
Acknowledgements
The authors thank the National Science Foundation (Grant
CHE-1554906) for financial support.
10 L. C. M. Castro, J. B. Sortais and C. Darcel, Chem.
Commun., 2012, 48, 151.
11 M. Bhunia, P. K. Hota, G. Vijaykumar, D. Adhikari and
S. K. Mandal, Organometallics, 2016, 35, 2930.
12 (a) P. J. Chirik and K. Wieghardt, Science, 2010, 327, 794–
795; (b) P. J. Chirik, Inorg. Chem., 2011, 50, 9737–9740.
Notes and references
1 (a) R. C. Larock, Comprehensive Organic Transformations: a
Guide to Functional Group Preparation, Wiley-VHC, 13 (a) N. J. Hill, I. Vargas-Baca and A. H. Cowley, Dalton Trans.,
New York, 1989; (b) A. Ricci, Modern Amination Method,
Wiley-VCH, New York, 2000; (c) S. A. Lawrence, Amines:
Synthesis, Properties and Applications, Cambridge University
Press, Cambridge, 2004; (d) Amino Group Chemistry:
Synthesis to the Life Sciences, ed. A. Ricci, Wiley-VCH,
Weinheim, 2008.
2008, 240–253; (b) J. L. Rhinehart, N. E. Mitchell and
B. K. Long, ACS Catal., 2015, 4, 2501–2504; (c) C. Chen,
S. Luo and R. Jordan, J. Am. Chem. Soc., 2010, 132, 5273–
5284; (d) S. B. Williams, M. Leatherman, P. White and
M. Brookhart, J. Am. Chem. Soc., 2005, 127, 5132–5146;
(e) D. H. Camacho and Z. Guan, Chem. Commun., 2010,
7879–7893; (f) X. L. Sui, C. W. Hong, W. M. Pang and
C. L. Chen, Mater. Chem. Front., 2017, 1, 2487–2494.
2 (a) T. C. Nugent and M. El-Shazly, Adv. Synth. Catal., 2010,
352, 753; (b) V. L. Tararov and A. Borner, Synlett, 2005, 203.
3 (a) A. A. Nunez Magro, G. R. Eastham and D. J. Cole- 14 (a) I. L. Fedushkin, A. A. Skatova, V. A. Chudakova,
Hamilton, Chem. Commun., 2007, 3154; (b) S. Das,
B. Wendt, K. Möller, K. Junge and M. Beller, Angew. Chem.,
Int. Ed., 2012, 51, 1662; (c) S. Das, Y. Li, C. Bornschein,
V. K. Cherkasov, G. K. Fukin and M. A. Lopatin, Eur. J. Inorg.
Chem., 2004, 338–393; (b) M. M. Khusniyyarov, K. Harms,
O. Burghaus and J. Sundermeyer, Eur. J. Inorg. Chem., 2006,
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9368–9372 | 9371

View Article Online
Communication
Organic & Biomolecular Chemistry
2985–2996; (c) R. V. Asselt, C. J. Elsevier, C. Amatore and
A. S. Bogomyakov and V. M. Makarov, Russ. Chem. Bull.,
2013, 62, 2122–2131.
A.
Jutand,
Organometallics,
1997,
16,
317–328;
(d) I. L. Fedushkin, A. A. Skatova, V. A. Chudakova and 16 F. S. Wekesa, R. Arias-Ugarte, L. Kong, Z. Sumner,
G. K. Fukin, Angew. Chem., Int. Ed., 2003, 42, 3294–3298;
(e) B. E. Cole, J. P. Wolbach, W. G. Dougherty, N. A. Piro,
G. P. McGovern and M. Findlater, Organometallics, 2015,
34, 5051.
W. S. Kassel and C. R. Graves, Inorg. Chem., 2014, 53, 3899– 17 (a) X. Yu, F. Zhu, D. Bu and H. Lei, RSC Adv., 2017, 7,
3906; (f) I. L. Fedushkin, A. A. Skatova, A. N. Lukoyanov,
N. M. Khvoinova, A. V. Piskunov, A. S. Nikipelov, G. K. Fukin,
K. A. Lysenko, E. Irran and H. Schumann, Dalton Trans.,
2009, 4689–4694; (g) W. C. Anderson Jr., J. L. Rhinehart and
B. K. Long, J. Am. Chem. Soc., 2016, 138, 774–777;
(h) W. C. Anderson Jr. and B. K. Long, ACS Macro Lett., 2016,
5, 1029–1033; (i) W. Gao, L. Xin, Z. Hao, G. Li, J. H. Su,
L. Zhou and Y. Mu, Chem. Commun., 2015, 7004.
15321; (b) M. J. Supej, A. Volkov, L. Darko, R. A. West,
J. M. Darmon, C. E. Schulz, K. A. Wheeler and H. M. Hoyt,
Polyhedron, 2016, 114, 403–414; (c) L. A. Brown,
F. S. Wekesa, D. K. Unruh, M. Findlater and B. K. Long,
J. Polym. Sci., Part A: Polym. Chem., 2017, 55, 2824–2830;
(d) M. Villa, D. Miesel, A. Hildebrandt, F. Ragaini,
D. Schaarschmidt and A. Jacobi von Wangelin,
ChemCatChem, 2017, 9, 3203–3209.
15 (a) A. Paulovicova, U. El-Ayaan, K. Umezawa, C. Vithana, 18 D. Brenna, M. Pirola, L. Raimondi, A. J. Burke and
Y. Ohashi and Y. Fukuda, Inorg. Chim. Acta, 2002, 339, 209– M. Benaglia, Bioorg. Med. Chem., 2017, 25, 6242–6247.
214; (b) I. L. Fedushkin, A. A. Skatova, M. Khvoinova, 19 Complete separation of amine product from imine starting
A. N. Lukoyanov, G. K. Fukin, S. Y. Ketkov, M. O. Maslov,
material could not be achieved, see ESI† for spectra.
9372 | Org. Biomol. Chem., 2018, 16, 9368–9372
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