A new route to N-aromatic heterocycles from the hydrogenation of diesters in the presence of anilines

Article abstract of DOI:10.1039/c7sc01718a

The hydrogenation of dicarboxylic acids and their esters in the presence of anilines provides a new synthesis of heterocycles. [Ru(acac)₃] and 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos) gave good to excellent yields of the cyclic amines at 220 °C. When aqueous ammonia was used with dimethyl 1,6-hexadienoic acid, ?-caprolactam was obtained in good yield. A side reaction involving alkylation of the amine by methanol was suppressed by using diesters derived from longer chain and branched alcohols. Hydrogenation of optically pure diesters (dimethyl (R)-2-methylbutanedioate and dimethyl (S)-2-methylbutanedioate) with aniline afforded racemic 3-methyl-1-phenylpyrrolidine in 78% yield.

Full text of DOI:10.1039/c7sc01718a

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A new route to N-aromatic heterocycles from the hydrogenation
of diesters in the presence of anilines
Yiping Shi,a Paul C. J. Kamer,a David J. Cole-Hamilton,a* and (in part) Michelle Harvie,a Emma F.
Received 00th January 20xx,
Accepted 00th January 20xx
Baxter,a Kate J. C. Lima and Peter Pogorzeleca
DOI: 10.1039/x0xx00000x
The hydrogenation of dicarboxylic acids and their esters in the presence of anilines provides a new synthesis of heterocycles.
[Ru(acac)3] and 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos) gave good to excellent yields of the cyclic amines at
220 °C. When aqueous ammonia was used with dimethyl 1,6-hexadienoic acid, -caprolactam was obtained in good yield. A
side reaction involving alkylation of the amine by methanol was suppressed by using diesters derived from longer chain and
branched alcohols. Hydrogenation of optically pure diesters (dimethyl (R)-2-methylbutanedioate and dimethyl (S)-2-
methylbutanedioate) with aniline afforded racemic 3-methyl-1-phenylpyrrolidine in 78 % yield.
www.rsc.org/
route involving the hydrogenation of dicarboxylic acid
derivatives in the presence of an amine (Scheme 1) would
represent a step change in the synthesis of N-heterocycles.
To our knowledge the only report of a reaction of this kind gives
lactams rather than saturated N-heterocycles. Thus
hydrogenation of maleic or 1,6-hexanedioic acids in the
presence of methylamine and Ru/triphos gives respectively N-
Introduction
Catalytic hydrogenation of amides has emerged as an
environmentally attractive route to amines. The groups of
Crabtree,1 Cole-Hamilton,2-5 Leitner6 and Beller7 have reported
that amides can by successfully hydrogenated to amines using
Ru/triphos catalysts and that, in contrast to reactions using
heterogeneous catalysts,8 aromatic rings in the substrates
remain untouched. Other catalysts for amide hydrogenation
generally lead to C-N rather than C-O cleavage products giving
alcohols from the carboxylate reside9-14 or to partial
reduction.15, 16
methylpyrrolidone or N-methyl--caprolactam with > 80 %
selectivity. The related N-heterocycles were obtained as side
products in small amounts (< 10 %).21 Using dimethyl 1,6-
hexanedioate and liquid ammonia in a fluorinated solvent gave
1,6-hexanediamide as the major product, but -caprolactam
was also obtained (17 %).22 Pyrrolidones can be produced from
levulinic acid and primary amines in the presence of hydrogen23,
24
or silanes,25, 26 but pyrrolidines can only be formed if silanes
are the reducing agents.25, 26 These reactions introduce the
amine via a Schiff base condensation with the ketone function
in levulinic acid.
Sch. 1 Proposed route to heterocycles from hydrogenation of dicarboxylic
acid derivatives in the presence of amines.
Following this successful development, we now report the use
of diesters as substrates, since they have the potential to
produce saturated N-heterocycles, which are highly important
building blocks for pharmaceuticals and notoriously difficult to
synthesise.17 Common routes involve constructing an amine
with a chain terminated by a group with which the amine can
cyclise such as a halide or double bond (hydroamination),
transformations of previously formed rings or C-H aminations
using azides.17 Recently, partial hydrogenation of quinolines has
been shown to give tetrahydroquinolines.18 Hydrogenation of
NH lactams can give N-heterocycles,14, 19 with alkylation of the
N atom if the reactions are carried out in alcohols.20 A simple
Results
Our initial studies were centred around 1,6-hexanedioate esters
for two reasons. Firstly, 1,6-hexanedioate esters can be easily
and sustainably obtained, either from biomass, such as
glucose by catalytic or enzymatic methods,14, 15 or from 1,3-
butadiene by palladium catalysed alkoxycarbonylation
reactions.27-29 The second reason for us to use 1,6-hexanedioate
esters is because our initial reactions focussed on
caprolactam, which can be used as a precursor for the synthesis
of Nylon-6. -Caprolactam is industrally generated by the
Beckmann rearrangement from cyclohexanone.30 However,
cyclohexanone is produced by oxidation of cyclohexane, with
high selectivity only being obtained at 10-12 % conversion per
pass.31 Concentrated sulfuric acid is involved in the reaction and
ammonium sulfate is produced as the major waste product,
making this route costly and environmentally unattractive.32
.
-

a. EaStCHEM, School of Chemistry, University of St. Andrews, St. Andrews, KY16 9ST,
Scotland, UK.
† *Correspondence to: David J. Cole-Hamilton, djc@st-andrews.ac.uk
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 1. Cyclisation of dimethyl 1,6-hexanedioate in the presence of aqueous ammonia.a
Entry
R
t (h)
20
70
Conv.(%)
100
100
Sel. 2 (%)
Sel. 3 (%)
Sel. 4 (%)
Sel. 5 (%)
1
2
3
Me
Me
H
1
5.2
33
60
46
45
16
19.8
-
7.2
28.5
-
88
100
aReagents and conditions: [Ru(acac)3] (1 mol %), triphos (2 mol %), MSA (1 mol %), 35% aq. NH3 (5 mL), dioxane (15 mL), H2 (10 bar), 220 °C; Yield by calibrated GC-FID.
The previous report21 of the attempted
from dimethyl 1,6- hexanedioate used liquid ammonia and only be discussed later. When 1.5 equivalents of aniline were used,
produced low yields of the desired product (<18 %). Crabtree et the selectivity to compound increased to 69 % and the

-caprolactam synthesis produced, the importance of this known33-35 side reaction will
6
al showed that these types of hydrogenation reactions proceed conversion was increased to 90.6 % (Table 2, Entry 2). However,
better in the presence of water1 and we have shown2 that water further increasing the amount of aniline did not improve the
and small amounts of acid are essential for high conversions in yield of 6, rather leading to a significant loss of selectivity (Table
amide hydrogenation to amines., We, therefore, reacted 2, Entry 5). When 5 equivalents of aniline were used, the
dimethyl 1,6-hexanedioate with aqueous ammonia in the formation of linear difunctionalised products dominated. The
presence of Ru/triphos and acid (Table 1) using the conditions linear diamine,
that had been optimised for the hydrogenation of amides to monomethylated diamine
amines in our previous studies,2 where we also reported details Scheme 3 in the Discussion section).
7
, was further methylated to give a mixture of
8
and dimethylated diamine (see
9
of the complexes present in solution during and after the To gain a better understanding of the reaction, it was monitored
reactions. We used aqueous ammonia for these reactions over time (Figure 1) using the optimised conditions (1.5
because our previous studies4, which we have since confirmed, equivalent of aniline, 220 °C). Dimethyl 1,6-hexanedioate,
1,
gave much better conversions in simple amide hydrogenations and aniline are quickly consumed to give the monoester
when using aqueous ammonia rather than liquid ammonia. monoamine 12, which slowly produces the N-heterocycle,
After 20 hours, -caprolactam was obtained in 60% yield without any further detectible intermediates. After about 66 h,
(Table 1, Entry 1), a considerable improvement on the previous no more aniline is left so is no longer formed. The incomplete
report.22 Azepane
, N-methyl azepane and N-methyl conversion for this cyclisation was mainly because of the side
caprolactam were also observed. Methylated products and reactions occurring between produced methanol and aniline.
were formed by methylation of or , the methyl groups
being derived from methanol. Methanol is the side product
from the hydrogenation of dimethyl 1,6-hexanedioate . Longer
reaction time (Table 1, Entry 2) led to an increased amount of
methylated products, and . Using the diacid in place of the
diester, rather similar results were obtained, but with increased
6
,

3
6
2
4
5
4
5
2
3
1
4
5
amounts of
1, Entry 3).
2. No N-methylated products were observed (Table
We next turned our attention to using aniline instead of
aqueous ammonia. Interestingly, when reacting with aniline,
the corresponding lactam was not formed. Instead, N-phenyl
azepane, , was predominately produced. Using one equivalent
of aniline (Table 2, Entry 1), was obtained in 59 % selectivity,
and no N-phenyl -caprolactam was observed after the
reaction. However, the conversion was only 82 %. This low
conversion could be explained by a side reaction between the
aniline and the methanol formed during the hydrogenation of
methyl esters as mentioned earlier reducing the availability of
aniline. Mono- and di-substituted N-methyl anilines were both
1
6
6

Figure 1. Monitoring of the hydrogenation of dimethyl 1,6-
hexanedioate in the presence of aniline against time.
Conditions: [Ru(acac)3] (1 mol%), triphos (2 mol%), MSA (1
mol%), dioxane (45 mL), dimethyl 1,6-hexanedioate (1 equiv.
7.5 mmol), aniline (1.5 equiv.), H2 (10 bar), 220 °C
2 | J. Name., 2012, 00, 1-3
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Table 2. Hydrogenation of dimethyl 1,6-hexanedioate with aniline.a
Entry
Equiv. aniline
Conv. (%)
81.5
90.6
94.1
91.9
Sel. 6 (%)
59.0
69.0
51.8
54.0
1
2
3
4
5
1
1.5
2
3
5
86.7
12.5
aReagents and conditions: [Ru(acac)3] (1 mol %), triphos (2 mol %), MSA (1 mol %), aniline (1-5 equiv.), dimethyl adipate (2.5 mmol), dioxane (15 mL), H2 (10 bar), 70 h,
220 °C; Yields by calibrated GC-FID
In an attempt to improve the selectivity, other 1,6- No amination between aniline and the corresponding alcohol
hexanedioate esters were studied to avoid the introduction of was observed when using tert-buyl or phenyl esters, which
methyl groups. Initially, a sterically bulky ester, diisobutyl 1,6- could be explained if the hydrogen borrowing mechanism
hexanedioate, was studied (Table 3, Entry 2). Pleasingly, the proposed by Beller’s group7 for the amination between alcohols
yield (defined as conversion x selectivity) of
6 was improved to and amines (Scheme 2) operates rather than direct attack of the
94 % (95 % conversion) with 1.5 equivalent of aniline. An amine on the protonated alcohol. Tertiary alcohols and phenols
increased amount of aniline in this case did not significantly cannot form the corresponding aldehyde; therefore, no
influence either the conversion or the yield (Table 3, Entry 3). amination reaction occurred. The alkylation of aniline proved
The rate of the reaction could be increased by increasing the only to be severely detrimental to the yield of
6 when using the
catalyst loading to 2 mol%. The yield of the desired cyclic amine dimethyl ester, presumably because methanol is more effective
reached 80 % after 24 h, and improved to 93 % after 42 h using in the hydrogen borrowing reactions than the other alcohols.
diisobutyl 1,6-hexanedioate as the substrate (Table 3, entry 8).
With these optimised conditions, the effect of different 1,6-
hexanedioate esters was studied in more detail (Table 3).
A wide range of diesters, both aliphatic and aromatic, was
successfully cyclised to N-phenyl azepane 6 in good to excellent
Sch 2. Proposed hydrogen borrowing mechanism for the
7
alkylation between alcohol and amine.
yields. Short linear or branched alkyl chains increased the yield
(Table 3, Entries 2, 3, 4 and 8), but longer chains (Table 3, Entries
7, 10 and 11) or further branching (Table 3, Entry 9) led to a
slight decrease in selectivity. When di-tert-butyl 1,6-
hexanedioate was used as the substrate (Table 3, Entry 9), N-
phenylcaprolactam was also obtained in 10 % yield which was
not observed in other cases. Diphenyl 1,6-hexanediaote gave
Although in principle, the problem of competing amine
alkylation should be entirely eliminated by using 1,6-
hexanedioic acid as the substrate, reactions under the same
conditions as for the diesters gave poor selectivity to
with the N-phenyl- -caprolactam being the major side product
(30 %, Table 3, Entry 14).
6 (40 %),

excellent yields of
6 (Table 3, Entry 12), but the selectivity was
reduced (71 %) when using the dibenzyl diester.
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Table 3. Study of different 1,6-hexanedioate ester substrates.a
Entry
1b
2b
3c
R
Conv. (%)
91
Yield (%)
62
Me
2-methylpropyl
95
94
2-methylpropyl
96
95
4
Et
98
95
5
Prn
99
93
6
Pri
92
88
7
Bun
2-methylpropyl
But
97
63
8
99
93
9
100
100
100
100
100
100
80
10
11
12
13
14
2-ethylhexyl
8-methylnonyl
Ph
80
59
92
PhCH2
71
H
13
a[Ru(acac)3] (2 mol%), triphos (4 mol %), MSA (2 mol %), dioxane (15 mL), substrate (2.5 mmol), aniline (1.5 equiv.), H2 (10 bar),
b
220 °C, 42 h; [Ru(acac)3] (1 mol%), triphos (2 mol %), MSA (1 mol %), dioxane (15 mL), substrate (1 equiv., 2.5 mmol), aniline (1.5
equiv.), H2 (10 bar), 220 °C, 70 h; c as b but aniline (2 equiv.).Yields by calibrated GC-FID
Five, six and eight membered N-heterocycles could also be To test if a mechanism involving alcohol intermediates could
prepared in good to excellent yields (Table 4, Entries 1-3). Chiral also be viable under our conditions, 1,6-hexan-diol, 13, was
dimethyl 2-methylbutanedioate esters were studied, the
reacted with aniline under the same conditions as used for the
corresponding cyclic products being obtained in good yield (78 carboxylic acid eaters. Hydrogen was included although it is not
%, Table 4, Entries 4-6). However, the optical purity was lost necessary because we wished to use identical conditions to
after the reaction. Carrying out the reaction over only 3 h, N- those used in the heterocycle forming reactions. When one
phenyl 3-methylpyrrolidine was again the major product and equivalent of aniline was used, 92 % yield of N-phenyl azepane
the two ester amides were produced only in trace amounts,
suggesting that the second hydrogenation and ring closing are 1). With 5 equivalents of aniline, the diol, 13, was mainly
much faster for the 5 than for the 7 membered ring. converted to the corresponding diamine (88 %), with less than
Beller has shown by sampling a reaction over time that amide 10 % yield of the azepane (Table 5, Entry 2). This result is
hydrogenations using Ru/triphos and Lewis acids, preferably consistent with the lower selectivity to and the formation of
6 was obtained without formation of the lactam (Table 5, Entry
7
6
6
Yb(OTf)3.H2O, occur via initial formation of the free alcohol linear products when larger amounts of aniline are used (Table
followed by amination by a hydrogen borrowing mechanism.7 2, Entry 5) in reactions starting from dimethyl 1,6-hexanedioate
The amination of alcohols by this system has been reported and suggests that 1,6-diaminohexane does not cyclise to
6
separately.36
under the reaction conditions.
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Table 4. Cyclisation with various substrates.a
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DOI: 10.1039/C7SC01718A
Entry
Substrate
Conv. (%)
Product
Yieldb (%)
1
2
3
89
66
92
66
100
96
4
100
100
78 (75)c
5
6
78
100
39
79
35
7
aConditions as in Table 3; bNMR yield; cIsolated yield
When ester amine 12 was used as the starting material, in the leading to catalyst decomposition in the case of 2,6-
absence of aniline, 62 % yield of was obtained after 20 hours dinitroaniline. 2,6-Dimethyl aniline gives 54 % yield at 100 %
6
under the normal catalytic conditions. When heating the ester conversion whilst 1,4-dibenzodioxan-6-amine performs well
amine in the absence of catalysts at 220 °C, N-phenyl lactam, (100 % conversion, 96 % yield). The reaction is less successful
14, was observed. 14 could also be hydrogenated to
6 under with alkyl and allyl amines (ESI Table S1), the best result being
similar conditions, but the conversion (39 %) and yield (35 %) of obtained with benzylamine, which gives 53 % yield of N-
the hydrogenation was lower, suggesting that it is not an benzylazepane at 92.4 % conversion when starting from bis(2-
intermediate since it does not build up during the methylpropyl) 1,6-hexanedioate.
hydrogenation of hexanedioate esters.
As shown in ESI Table S1 the reaction works well with 2 or 4-
fluoroaniline. More strongly electron withdrawing nitro groups
in the 4 or the 2,6-positions completely inhibit the reaction
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Table 5. Hydrogenation 1,6-hexan-diol 13 with aniline.a
Entry
1
2b
Equiv. aniline
Conv.(%)
100
100
Yield. 6 (%)
Yield. 7(%)
1
5
92
9.5
0
88
a Conditions as Table 1a but 16 h; Yields by calibrated GC-FID, b NMR yield.
Discussion
The simplest mechanism that is consistent with our
Summarising the results described above, N-phenyl observations is that shown in Scheme 3, Steps A-D. It involves
heterocycles such as can be formed in high yield by the hydrogenation of the diester, , to the ester aldehyde, 15
6
1
Ru/triphos catalysed hydrogenation of diesters in the presence (Scheme 3, Step A), which is trapped by aniline to give an imine
of aniline. The only observable intermediate is the amino ester, (not shown), which in turn is hydrogenated in to the observed
12. In the absence of catalyst, 12 converts to N-phenyl

-
ester amine, 12 (Scheme 3, Step B). 12 is then hydrogenated to
, but more the amino aldehyde, 16, (Scheme 3, Step C) which ring closes
but gives and is hydrogenated to (Scheme 3, Step D).
caprolactam, 14, which can also be hydrogenated to
slowly than . Diol, 13, is converted smoothly to
linear diamine,
the products (
6
6
1
6
7
, in the presence of excess aniline. A number of Also shown in Scheme 3 are the possible side reactions leading
and 20) are formed by N-methylation if the to the diol, 13, which also gives under the reaction conditions
(dotted box); the formation of N-phenyl
Beller and co-workers have shown by sampling the reaction from 12 in the absence of catalyst and its hydrogenation to
8
,
9
6
substrate is a dimethyl diester.

-caprolactam, 14
,
,
6
over time that amide hydrogenations using Ru/triphos and a when catalyst is present, which is rather inefficient; the
Lewis acid in place of a Brønsted acid proceed via the formation formation of diamine, from 13 when excess aniline is used and
of an alcohol which then undergoes amination by a hydrogen the methylation of various products and intermediates to give
borrowing mechanism.7 In our experiments using methane
and 20
sulfonic acid, we do not see the formation of free alcohol during The intermediacy of aldehydes in the formation of 12 from
the reaction. DFT calculations on the hydrogenation of methyl and of from 12 is consistent with the results of reactions using
7
8
,
9
.
1
6
benzoate to benzyl alcohol suggest that free benzaldehyde is an (S) or (R)-dimethyl 1,4-butanedioate (Table 4, Entries 5 and 6),
intermediate.6 The hydrogen borrowing mechanism proposed which both give racemic N-phenyl 3-methypyrolidine. This
for the transformation of an intermediate alcohol into an amide result implies that the chiral carbon atom becomes planar
involves the formation of the same aldehyde as is intermediate during the reaction and this is most likely to be as a result of
in the amide hydrogenation reaction. We cannot, therefore, enolisation of the intermediate aldehydes, which is highly likely
distinguish in our system whether ester alcohol, 17, is at 220 °C in the presence of amine and added acid.
intermediate or whether aldehyde 15 is trapped by the amine Dimethyl 1,4-butanedioate can form two amino esters (Scheme
before hydrogenation. Which occurs will depend on the relative 4). In one the chiral carbon is to the carbonyl in the aldehyde
rates of hydrogenation and reaction with aniline of 15. We do so will racemise in this step, whilst in the other it is
know that diol, 13, transforms to under the reaction carbonyl so should be configurationally stable. The observation
conditions so it cannot be ruled out as an intermediate on that that the final product is racemic strongly suggests that the final
 to the
6
basis.
ring closing step also involves an enolisable aldehyde since this
will racemise the chiral centre that remained stable during the
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first step (Scheme 4). Unfortunately, the ester amides in this times so it is not possible to measure their optical purity nor
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DOI: 10.1039/C7SC01718A
case are only formed in trace amounts even after short reaction absolute configuration.
Sch. 3. Proposed reaction pathway for diester,
1, hydrogenation in the presence of aniline to give 6. The main mechanism is
proposed to proceed by steps 1-4. The dotted box shows the hydrogenation of 13 to
6
. The origin of side products is also shown
methyl esters,
a competing methylation of the aniline
compromises the conversion, but other esters give excellent
conversion and selectivity. The reaction is believed to undergo
hydrogenation of the diester to the corresponding ester
aldehyde, followed by reductive amination, hydrogenation of
the second ester again to an aldehyde and cyclisation to the
corresponding heterocycle. The presence of enolisable
aldehyde intermediates in both steps explains the racemisation
at the chiral C atom when starting from enantiopure dimethyl
2-methyl-1,4-butanedioate. In the presence of aqueous
ammonia,
-caprolactam was obtained in 60 % yield from
dimethyl 1,6-hexanedioate.
Sch. 4. Proposed steps in which racemisation of the chiral centre
originally in 2-methylsuccinic acid occurs during hydrogen
borrowing steps in the formation of 2-methyltetrahydropyrrole.
Acknowledgements
We Thank Dr. Alan Pettman for the original suggestion that led
to this work, the EPSRC for the critical mass grant 'Clean
Catalysis for Sustainable Development' (EP/J018139/1), Sasol
Technology, UK for a case studentship (Y. S.) and the EPSRC UK
National Mass Spectrometry Facility at Swansea University for
mass spectrometric analysis.
Conclusions
We have developed a new simple and selective route to N-
phenyl heterocycles from the hydrogenation of diesters in the
presence of aniline and a Ru/triphos catalyst. When using
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27. E. Drent, R. Ernst, W. W. Jager and C. A. Krom, 2006,
WO084892.
Notes and references
1. M. Kilner, D. V. Tyers, S. P. Crabtree and M. A. Wood, 2003,
WO03093208.
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Green Chem., 2006, 8, 296.
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34. T. T. Dang, B. Ramalingam and A. M. Seayad, Acs Catalysis,
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