Transamidation of primary amides with amines catalyzed by zirconocene dichloride

Article abstract of DOI:10.1039/c2cc37427g

Zirconocene dichloride (Cp₂ZrCl₂) has been shown to be an effective catalyst for the transamidation of primary amides with amines in cyclohexane at 80°C in 5-24 hours. For favourable substrates, the reaction can be performed at temperatures as low as 30°C.

Full text of DOI:10.1039/c2cc37427g

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Transamidation of primary amides with amines catalyzed by
zirconocene dichloride†
Benjamin N. Atkinson, A. Rosie Chhatwal, Helen V. Lomax, James W. Walton and Jonathan M. J.
Williams*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
amides 1 with benzylamine 2 to give secondary amides 3. Using
toluene as a solvent, many Lewis acids showed at least some
50 catalytic activity,† although Cp2ZrCl2 and Cp2HfCl2 stood out as
catalysts capable of achieving close to full conversion in only 5
hours at reflux.
Zirconocene dichloride (Cp2ZrCl2) has been shown to be an
effective catalyst for the transamidation of primary amides
with amines in cyclohexane at 80 oC in 5-24 hours. For
10 favourable substrates, the reaction can be performed at
temperatures as low as 30 oC.
Table 1 Acylation of benzylamine with amides
Amides are one of the most important functional groups, being
widely found in natural products, pharmaceuticals and materials.1
In order to avoid the use of stoichiometric activating agents,
15 many catalytic methods for amide synthesis have been developed
in recent years.2 Amines can react directly with carboxylic acids,
most often catalyzed by boronic acid derivatives,3 although metal
catalysts, including our own recent work using zirconocene
dichloride, can also be used.4 There have been several reports of
20 the oxidative coupling of alcohols with amines to give amides,5
along with metal-catalyzed rearrangement reactions of oximes
which usually only give primary amides.6
Amides are relatively inert in comparison with other acyl
donors and therefore uncatalyzed transamidation reactions require
25 forcing reaction conditions.7 The reaction has been catalyzed by
imidazole,8 at least for formamide synthesis and by
hydroxylamine hydrochloride.9 Other non-metal catalysts include
boric acid10 and related compounds.11 Stahl and co-workers have
identified several catalysts,12 including zirconium13 and
30 aluminium-based14 catalysts, where the main focus has been on
achieving equilibration between amides. Other catalysts include
cerium oxide15 and Beller’s recent report of the use of copper
acetate.16 All of the reported catalysts have some drawback; the
need for high temperatures, reversibility or high catalyst loading.
35 Myers has reported that transamidation can be achieved
catalytically under mild conditions, but the protocol requires
derivatization of the amide with a stoichiometric activating
agent.17
Conversiona Isolated
Entry
1
Amide Product
Time (h)
5
(%)
Yield (%)
100
83
2
3
4
5
6
7
5
100
96
88
84
93
76
84
86
8
18
18
18
18
100
89
100
100
8
9
24
18
5
87
91
73
84
92
Further to our report of hydroxylamine hydrochloride acting as
40 a catalyst for transamidation, we chose to investigate the use of
metal catalysts for this process, with the reaction of primary
10
100
a Conversions were determined by analysis of the crude 1H NMR spectra.
University of Bath, Claverton Down, Bath, BA2 7AY, UK. Email:
j.m.j.williams@bath.ac.uk
55
45 †Electronic supplementary information (ESI) available: Full
experimental details, product characterization and selected NMR
spectra are provided. See DOI: 10.1039/b000000x/
A solvent screen† identified commercially available anhydrous
cyclohexane as a particularly good solvent. The reagent grade
solvent performed less well, indicating that the presence of
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adventitious water is slightly detrimental to the reaction. 20 although the less nucleophilic amines, p-methoxyaniline and 2-
Complete conversion was achieved when a small excess of amine
2 was used. The optimized reaction conditions allowed the
reaction to be performed at only 80 oC in 5 hours.
aminothiazole (Table 2, entries 8 and 9) required a higher
temperature. Remarkably, trifluoroacetamide underwent catalytic
transamidation with (S)-(-)-α-methylbenzylamine at 30 oC and
with retention of stereochemistry (Table 2, entry 10). Formamide
5
Having established a viable catalytic transamidation under
relatively mild conditions, we explored the reaction scope. We 25 was also converted into the corresponding secondary and tertiary
were pleased to find that benzylamine reacted with a range of
primary amides at 80 C (Table 1). Longer reaction times were
required for less reactive amides such as benzamide and related
10 aromatic amides (Table 1, entries 4-7). N-Boc prolinamide
amides at the same temperature (Table 2, entries 11 – 13).
Notable limitations† include the use of bulky amines (H2NtBu
with butyramide) and amides (tBuCONH2 with benzylamine),
which each gave less than 10% conversion into the desired
o
(Table 1, entry 8) was found to be less reactive, perhaps due to its 30 secondary amides in their respective reactions. The
chelating ability, but we were pleased to see that stereochemistry
was fully retained in the secondary amide product.
transamidation of secondary amides and ureas, along with
amidation of simple esters, were found to be less effective under
the optimized reaction conditions.
Table 2 Further transamidation reactions
Carbamates, however, were found to be good substrates for
35 conversion into the corresponding mono-substituted ureas – the
most convenient substrate was ethyl carbamate and the reaction
was successful with primary amines, anilines and with piperidine
(Table 3). Heptane was used as solvent in order to accommodate
the higher temperature required.
Time (h)/ Conversiona Isolated
Entry
Amide product
Temp (oC)
(%)
Yield (%)
40 Table 3 Reaction of amines with ethyl carbamate
1
2
3
5/80
100
78
5/80
5/80
100
100
81
69
Conversiona
(%)
Isolated
yield (%)
Entry
Mono-substituted urea
1
2
100
100
96
87
80
92
4
18/80
95
86
5
6
5/80
5/80
100
100
91
89
3
4
100
100
89
84
7
8/80
100
90
5
8
18/100b
18/100b
5/30
81
80
54
68
88
95
90
a Conversions were determined by analysis of the crude 1H NMR spectra.
9
Although it seemed unlikely that the amide was attacking the
amine, we confirmed this with an isotope labeling study. The
45 reaction of 15N-labeled benzamide with unlabeled benzylamine
led to the exclusive formation of unlabeled secondary amide
product (Scheme 1), indicating that the amine adds to the amide.
10
11
12
100
100
100
5/30
5/30
13
5/30
100
89
15 a Conversions were determined by analysis of the crude 1H NMR spectra.
b These reactions were performed in n-heptane.
A range of other amines was used successfully (Table 2).
Most substrates underwent conversion into product at 80 oC
Scheme 1 Mechanistic studies

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In a second experiment, a small amount of H/D exchange was
Commun., 2012, 48, 666-668; (b) M. Hosseini-Sarvari and H. Sharghi,
J. Org. Chem., 2006, 71, 6652-6654; (c) T. H. T. Ogawa, T. Ikegami,
N. Ono, H. Suzuki, J. Chem. Soc. Perkin Trans. 1., 1994, 3473-3478;
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Lundberg, F. Tinnis and H. Adolfsson, Chem. Eur. J., 2012, 18, 3822-
3826.
observed when acetamide-d3 was converted into the secondary
amide. It is unlikely that a ketene mechanism plays any
significant role in the reaction, as this would be expected to lead
to a greater level of H/D exchange (D/H ~ 67/33).
5
50
55
60
Analysis of the 1H NMR spectra of Cp2ZrCl2 in the presence of
varying concentrations of either benzamide or benzylamine
revealed that the cyclopentadienyl ligands were not displaced and
that both substrates bound fairly weakly (Ka = 0.4 M-1 for
5. (a) C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007, 317,
790-792; (b) L. U. Nordstrøm, H. Vogt and R. Madsen, J. Am. Chem.
Soc., 2008, 130, 17672-17673 ; (c) T. Zweifel, J.-V. Naubron and H.
Grützmacher, Angew. Chem. Int. Ed., 2009, 48, 559-563; (d) A. J. A.
Watson, A. C. Maxwell and J. M. J. Williams, Org. Lett., 2009, 11,
2667-2670;
10 benzylamine and 1.5 M-1 for benzamide).
A kinetic analysis of the reaction established that the reaction
was first order in both Cp2ZrCl2 and benzamide. However, the
reaction was found to be second order in benzylamine. One
explanation for this might be that the amine is used as a base as
15 well as a nucleophile in the reaction, but the reaction rate was
found to be zero order with respect to tertiary amine when
iPr2NEt was added (in fact the rate decreased slightly).
6. For recent examples see; (a) C. L. Allen, R. Lawrence, L. Emmett and
J. M. J. Williams, Adv. Synth. Catal., 2011, 353, 3262-3268;
(b).Gnanamgari and R. H. Crabtree, Organometallics., 2009, 28, 922-
924; (c) M. A. Ali and T. Punniyamurthy, Adv. Synth. Catal., 2010,
352, 288-292; (d a n Bosson e - on le
Marion and S. P. Nolan, J. Org. Chem., 2010, 75, 1197-1202;
One possible mechanism which is consistent with the data is
presented in Scheme 2. Reaction of the zirconium catalyst with
20 the amine leads to formation of a zirconium amide (i.e. Zr-NHR). 65 7. (a) A. Galat and G. Elion, J. Am. Chem. Soc., 1943, 65, 1566-1567.
Complexation of the carboxamide to the catalyst would be
followed by addition of the amine to the carboxamide as shown
in Scheme 2, intermediate 4. We speculate that this addition may
be assisted by the zirconium amide (Zr-NHR), which would
25 rationalize why the reaction is second order in amine. After loss
of ammonia from intermediate 6, secondary amide would be
exchanged from intermediate 7 to complete the catalytic cycle.
For an example of a reactive amide, see; (b) M. Hutchby, C. E.
Houlden, M. F. Haddow, S. N. G. Tyler, G. C. Lloyd-Jones and K. I.
Booker-Milburn, Angew. Chem. Int. Ed., 2012, 51, 548-551.
8. uch , A. A. H. Elmehriki and R. H. E. Hudson, Org. Lett.,
2011, 13, 3952-3955.
70
9. C. L. Allen, B. N. Atkinson and J. M. J. Williams, Angew. Chem. Int.
Ed., 2012, 51, 1383-1386.
10. T. B. Nguyen, J. Sorres, M. Q. Tran, L. Ermolenko and A. Al-
Mourabit, Org. Lett., 2012, 14, 3202-3205.
75 11. (a) P. Starkov and T. D. Sheppard, Org. Biomol. Chem., 2011, 9,
1320-1323; (b) S. Çalimsiz and M. A. Lipton, J. Org. Chem., 2005,
70, 6218-6221; (c) A. Klapars, S. Parris, K. W. Anderson and S. L.
Buchwald, J. Am. Chem. Soc., 2004, 126, 3529-3533; (d) A.
Vasudevan, C. I. Villamil and S. W. Djuric, Org. Lett., 2004, 6, 3361-
80
85
90
95
3364; (e) J. Lasri, M. E. González-Rosende and J. Sepúlveda-Arques,
Org. Lett., 2003, 5, 3851-3853.
12. (a) S. E. Eldred, D. A. Stone, S. H. Gellman and S. S. Stahl, J. Am.
Chem. Soc., 2003, 125, 3422-3423; (b) D. A. Kissounko, I. A. Guzei,
S. H. Gellman and S. S. Stahl, Organometallics, 2005, 24, 5208-5210;
(c) D. A. Kissounko, J. M. Hoerter, I. A. Guzei, Q. Cui, S. H. Gellman
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13. N. A. Stephenson, J. Zhu, S. H. Gellman and S. S. Stahl, J. Am. Chem.
Soc., 2009, 131, 10003-10008.
Scheme 2 Possible mechanism for transamidation
30
In summary, we have identified zirconocene dichloride as an
effective catalyst for transamidation reactions of primary amides
under milder conditions than previously reported.
We thank the EPSRC (BNA) and the Doctoral Training Centre
in Sustainable Chemical Technology (HVL) for funding. We
14. (a) J. M. Hoerter, K. M. cui, S. H. Gellman, Q. Cui and S. S. Stahl, J.
Am. Chem. Soc., 2007, 130, 647-654; (b) J. M. Hoerter, K. M. Otte, S.
H. Gellman and S. S. Stahl, J. Am. Chem. Soc., 2006, 128, 5177-5183.
See also; (c) E. Bon, D. C. H. Bigg and G. Bertrand, J. Org. Chem.,
1994, 59, 4035-4036.
35 thank the University of Bath for further support.
Notes and references
15.M. Tamura, T. Tonomura, K.-I. Shimizu and A. Satsuma, Green
Chem., 2012, 14, 717-724.
1. Many recent reviews including (a) E. Valeur and M. Bradley, Chem.
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16. Zhangꢀ I Bähn L eubert H eu ann and Beller
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45 4. (a) C. L. Allen, A. R. Chhatwal and J. M. J. Williams, Chem.

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Zirconocene dichloride (Cp2ZrCl2) has been shown to be an effective catalyst for the transamidation
of primary amides with amines in cyclohexane at 80 oC in 5-24 hours. For favourable substrates, the
reaction can be performed at temperatures as low as 30 oC.