Iron-catalysed tandem isomerisation/hydrosilylation reaction of allylic alcohols with amines

Abstract

An iron(0)-catalysed cascade synthesis of N-alkylated anilines from allylic or homoallylic alcohols and primary and secondary anilines under hydrosilylation conditions has been developed. Notably, a simple Fe(cod)(CO)₃ complex (cod = cycloocta-1,5-diene) was used as a precatalyst under visible light activation in ethanol in the presence of the inexpensive and non-toxic PMHS (polymethylhydrosiloxane) as the hydrosilane source. This methodology is based on a three step-one sequence process involving isomerisation of allylic alcohols/condensation with anilines/reduction reactions.

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The production of alkylated anilines is an important economic area in agrochemical, dye, and pharmaceutical industries.¹ Classically, their syntheses are based on N-alkylation of primary aniline derivatives with alkyl halides and transition metal catalysed cross coupling reactions,² hydroamination of unsaturated C–C bonds,³ or condensation of anilines with carbonyl derivatives such as aldehydes and ketones followed by reduction with borohydride type reducing reagents.⁴ In the latter field, catalytic reductive amination reaction of carbonyl derivatives via transition metal catalysed hydrogenation, hydrogen transfer or hydrosilylation of the in situ formed imines is rising as a major way in molecular synthesis to obtain amines.⁵ As inexpensive, abundant and environmentally benign metal, iron is a particularly valuable alternative to precious transition metals, thus intense research on its catalytic potential has emerged during the past decade.⁶ Up to now, iron catalysts were only used scarcely to perform reductive amination.^7,8

On another hand, in the quest for eco-friendly and atom economic protocols, cascade and tandem procedures have attracted significant attention as efficient synthetic methodologies providing powerful alternatives to classical multistep sequences. Furthermore, one efficient and atom economical way to generate in situ saturated carbonyl derivatives is the redox isomerization of allylic alcohols usually promoted by transition metal such as Ru, Rh and Ir.⁹ Iron Fe(CO)_x type complexes have also been described as useful catalysts for allylic alcohol isomerization under irradiation conditions,^10,11 and few examples of tandem isomerization–aldolization reactions were reported.¹²

In the present contribution, in the continuation of our research interest on iron-catalysed reduction,^13–15 the iron(0)-catalysed synthesis of N-alkylated anilines from both allylic and homoallylic alcohols and primary and secondary anilines under hydrosilylation conditions has been developed. Notably, a simple Fe(cod)(CO)₃ complex (cod = cycloocta-1,5-diene) was used as the precatalyst under visible light activation in ethanol using the inexpensive and non-toxic PMHS (polymethylhydrosiloxane) as the hydrosilane source (eqn (1)).

We started our investigation by the model reaction of (E)-hex-2-en-1-ol 1a with N-ethylaniline using 3 equiv. of PMHS as the hydrosilane in ethanol under visible light irradiation (Table 1).‡

Table 1 Optimization of the parameters for the reaction of (E)-hex-2-en-1-ol with N-ethylaniline and PMHS^a

Entry	Cat. (mol%)	1a/2a	Temp. (°C)	Conv.^b (%)
a Aniline 2a (0.25 mmol), allylic alcohol 1a (1.1–2 equiv.), PMHS (45 μL, 0.75 mmol, 3 equiv.), iron complex (1.7–5 mol%), EtOH (1 mL), at 50 °C for 20 h in the presence of visible light activation (24 watt compact fluorescent lamp).b Conversion determined by GC.c Without light activation.
1	Fe(CO)5 (5)	1.5	50	68
2	Fe2(CO)9 (2.5)	1.5	50	31
3	Fe3(CO)12 (1.7)	1.5	50	83
4	Fe(PBO)(CO)3 (5)	1.5	50	83
5	Fe(cot)(CO)3 (5)	1.5	50	0
6	Fe(IMes)(CO)4 (5)	2	40	0
7	Fe(cod)(CO)3 (5)	1.5	50	95
8	Fe(cod)(CO)3 (5)	1.5	40	88
9	Fe(cod)(CO)3 (5)	2	40	88
10	Fe(cod)(CO)3 (5)	1.1	50	76
11	Fe(cod)(CO)3 (2.5)	1.5	50	78
12^c	Fe(cod)(CO)3 (5)	1.5	50	64

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With the commercially available Fe(CO)₅ (5 mol%), Fe₂(CO)₉ (2.5 mol%) and Fe₃(CO)₁₂ (1.7 mol%) complexes, at 50 °C for 20 h, using 1.5 equiv. of the allylic alcohol 1a, moderate to good conversions were obtained (31–83%), and the tertiary aniline 3a was obtained selectively (Table 1, entries 1–3). These results show that under the mild reaction conditions (50 °C), the isomerisation of the allylic C=C bond took place leading to the corresponding aldehyde which reacted faster with the secondary aniline 2a than with PMHS leading to the corresponding imines which can be then reduced. Using Fe(PBO)(CO)₃ (5 mol%) (PBO = 4-phenylbut-3-en-2-one) which was the catalyst of choice for the selective hydrosilylation of carboxylic acids to aldehydes,^15b under the same conditions, similar conversion was obtained (83%, entry 4). With Fe(cot)(CO)₃ (cot = cyclooctatetraene) and (IMes)Fe(CO)₄ (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene),^15a the starting materials were recovered quantitatively (entries 5 and 6). Interestingly, using Fe(cod)(CO)₃ (5 mol%), under similar conditions led to 95% conversion and the N-ethyl-N-hexylaniline 3a was isolated with 86% yield (entry 7). When the temperature was lowered to 40 °C, even with 2 equiv. of the allylic alcohol 1a, the conversion decreased (88%, entries 8 and 9). Similarly, when decreasing the amount of alcohol 1a to 1.1 equiv., or the loading of the Fe(cod)(CO)₃ complex (2.5 mol%) slightly lower conversions were observed (76 and 78%, respectively, entries 10 and 11). Notably the visible light activation seems important as in its absence a drastic decrease of the conversion was observed (64% versus 95%, entries 12 and 7).

Hence, we selected the Fe(cod)(CO)₃ complex as the precatalyst for further investigation of the scope of the reaction (Table 2). Using N-ethylaniline (1 equiv.) as the amine partner, the condensation with several allylic alcohols (1.5 equiv.) were investigated. (E)- and (Z)-hex-2-en-1-ols similarly led to the N-ethyl-N-hexylaniline with 86 and 80% yields, respectively (entries 1 and 2). With allylic alcohols bearing a geminated or a tri-substituted olefinic moiety, the tandem reaction proceeded also nicely as the corresponding tertiary anilines were obtained with good isolated yields (entries 4 and 5). Starting from cinnamyl alcohol, 75% of the isolated aniline could be obtained (entry 6). Interestingly, starting from (Z)-but-2-ene-1,4-diol, the 4-(N-ethyl-N-phenyl-amino)butan-1-ol was isolated with 89% yield (entry 7). By reaction with phytol, a linear diterpene allylic alcohol, the corresponding N-ethyl-N-phytylaniline was obtained in 65% yield for a conversion of 75%.

Table 2 Scope of the iron-catalysed reaction of allylic and homoallylic alcohols with secondary amines^a

Entry	Alcohol	Product	Conv.^b (%)	Yield^c (%)
a Amine (0.25 mmol), allylic alcohol (0.375 mmol, 1.5 equiv.), PMHS (45 μL, 0.75 mmol, 3 equiv.), Fe(cod)(CO)3 (0.0125 mmol, 5 mol%), EtOH (1 mL), at 50 °C for 20 h in the presence of visible light activation (24 watt compact fluorescent lamp).b Conversion determined by GC.c Isolated yield.d Yield determined by ^1H-NMR with 1,3,5-trimethoxybenzene as an internal standard.
1			95	86
2			>95	80^d
3			>98	95
4			>95	82
5			>95	95
6			83	75
7			>98	89
8	Phytol		75	65
9			>95	81
10			>95	86^d
11			>95	80
12			>95	81
13			78	70
14			>95	95
15			50	31

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Notably, this transformation works well also with homoallylic alcohols leading to the corresponding tertiary anilines with 80–86% yields (entries 9–11). Furthermore, starting from allylic alcohols such as (E)-hex-2-en-1-ol and cinnamyl alcohol, several secondary anilines such as indoline and 1,2,3,4-tetrahydroquinoline could be coupled successfully leading to the corresponding tertiary amino compounds with good to excellent isolated yields (70–95%, entries 12–14). In contrast, the reaction of cinnamyl alcohol with N-benzylaniline led to only 50% conversion and 31% yield (entry 15).

The substrate scope of amine was then extended to primary aniline derivatives 4. The optimization of the reaction conditions are summarized in the Table 3. In the presence of 1.5 equiv. of (E)-hex-2-en-1-ol 1a and 3 equiv. of PMHS in ethanol at 70 °C for 20 h, the aniline 4a was fully converted and a mixture 90 : 10 of the monoalkylated and dialkylated anilines was obtained (entry 1). The decrease of the temperature to 50 °C, even if it permitted to increase the selectivity to 95 : 5, has a deleterious effect on the conversion (67%, entry 2). By contrast, working at 70 °C for 20 h but decreasing the quantity of allylic alcohol 1a used to 1.25 equiv. permitted to obtained an excellent selectivity towards the monoalkylation (5a/6a = 97 : 3) at high conversion (91%, entry 4).

Table 3 Optimization of the parameters for the reaction of (E)-hex-2-en-1-ol with aniline and PMHS^a

Entry	1a/4	Temp. (°C)	Conv.^b (%)	5a : 6a^b
a Aniline 4a (0.25 mmol), allylic alcohol 1a (1.25–1.5 equiv.), PMHS (45 μL, 0.75 mmol, 3 equiv.), Fe(cod)(CO)3 (5 mol%), EtOH (1 mL), at 50–70 °C for 20 h in the presence of visible light activation (24 watt compact fluorescent lamp).b Determined by GC.
1	1.5	70	>98	90 : 10
2	1.5	50	67	95 : 5
3	1.5	rt	50	90 : 10
4	1.25	70	91	97 : 3

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The scope of the selective preparation of secondary aniline derivatives starting from the corresponding primary anilines was then evaluated and the results are summarized in Table 4. By reaction with p-methoxyaniline, (E)-hex-2-en-1-ol 1a led to the N-(n-hexyl)-p-methoxyaniline with 72% yield (entry 2). Similarly, good results were obtained with cinnamyl alcohol affording the alkylated aniline derivatives in 66–91% isolated yields (entries 3–5 and 7–11). Notably there is no strong influence of the electronic or steric parameters of the para-substituent of the aniline partner on the performance of the catalytic system. Furthermore, it is noticeable that when the p-iodoaniline was used, even if the conversion reached 40%, no desired alkylated aniline derivative can be identified (entry 6). The reaction of α-substituted allylic alcohols such as but-3-en-2-ol with p-toluidine under similar conditions led to the N-isobutyl-p-toluidine with 91% isolated yield (entry 12).

Table 4 Scope of the iron-catalysed reaction of allyl alcohols with primary amines^a

Entry	Alcohol	Product	Conv.^b (%)	Yield^c (%)
a Amine (0.25 mmol), allylic alcohol (0.31 mmol, 1.25 equiv.), PMHS (45 μL, 0.75 mmol, 3 equiv.), Fe(cod)(CO)3 (0.0125 mmol, 5 mol%), EtOH (1 mL), at 70 °C for 20 h in the presence of visible light activation (24 watt compact fluorescent lamp).b Determined by GC.c Isolated yield.d Conversion determined by ^1H-NMR with 1,3,5-trimethoxybenzene as an internal standard.e Less than 10% of dialkylated aniline derivative detected in the crude mixture.f Reaction at 100 °C for 20 h instead of 70 °C for 20 h.
1			95	88
2			>95	72
3			95	81
4			95	68
5			90	76
6			40^d	—
7			>95^e	91
8			82^e	66
9			80	74
10			>95	71
11			82	76
12			>95^f	91
13			>95	71
14			>95	72
15			>95	92
16			78	61
17			80	64

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Interestingly anilines featuring a hydroxylated N-substituent can be prepared with moderate yields (61–92%) by reaction of (Z)-but-2-ene-1,4-diol with various substituted primary aniline compounds (entries 13–17).

The first step in this tandem reaction is the isomerisation of the (homo)allylic alcohol to the corresponding aldehyde. This is now well established with iron carbonyl based catalysts,¹¹ light activation helping to generate the Fe(CO)₃ active species by decoordination of the cod ligand from the starting Fe(cod)(CO)₃ pre-catalyst.¹⁶ After which the condensation of aldehydes with anilines led to the formation of imines and iminium as the intermediates which can be reduced under hydrosilylation conditions with PMHS. The iron catalysed reduction of imines⁷ and more particularly with PMHS was already reported recently.⁸

In summary, Fe(cod)(CO)₃ complex was efficiently used as a precatalyst for the selective synthesis of tertiary and secondary anilines derivatives starting from allylic and homoallylic alcohols and secondary and primary anilines, respectively, under hydrosilylation conditions using cheap and abundant PMHS reagent as the hydrosilane reagent. It must also be pointed out that this reaction was performed in ethanol under mild conditions (50–70 °C under visible light activation). This process correspond to a formal reductive amination of (homo)allyllic alcohols via a tandem isomerisation/condensation/hydrosilylation reaction.

Acknowledgements

We are grateful to the University of Rennes 1, CNRS, Rennes Métropole and the Britanny council for financial support. H.L. thanks the foundation Rennes 1 for a Grant.

Notes and references

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8. Representative papers on iron-catalysed reductive amination via hydrosilylation, see: (a) H. Jaafar, H. Li, L. C. Misal Castro, J. Zheng, T. Roisnel, V. Dorcet, J.-B. Sortais and C. Darcel, Eur. J. Inorg. Chem., 2012, 3546; (b) S. Enthaler, ChemCatChem, 2010, 2, 1411.
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16. Example of Fe(cod)(CO)₃ catalysed alkene isomerisation: H. Fleckner, F.-W. Grevels and D. Hess, J. Am. Chem. Soc., 1984, 106, 2027.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental section, spectral data and ¹H and ¹³C NMR spectra of all compounds are provided. See DOI: 10.1039/c4ra04037f

‡ Representative experimental conditions: A 20 mL oven dried Schlenk tube containing a stirring bar, was charged with Fe(cod)(CO)₃ (3.1 mg, 0.0125 mmol) and then purged with argon/vacuum three times. Ethanol (1 mL), amine (0.25 mmol, 1 equiv.), (homo)allylic alcohol (0.313 mmol, 1.25 equiv.), PMHS (45 μL, 3 equiv.) were added under argon. The reaction mixture was stirred in a preheated oil bath at 50–70 °C for 20 h under light irradiation (using 24 watt compact fluorescent lamp). Then the reaction mixture was condensed under reduced pressure. The residue was then purified by silica gel column chromatography using a mixture of diethylether/petroleum ether as the eluent to afford the desired product.

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