Transamidation of primary amides with amines using hydroxylamine hydrochloride as an inorganic catalyst

Article abstract of DOI:10.1002/anie.201107348

Metal-free catalysis: A method for the transamidation of primary amides with primary or secondary amines provides access to secondary and tertiary amides, by utilizing catalytic quantities of hydroxylamine hydrochloride to activate the chemically robust primary amide group (see scheme). A mechanism of primary amide activation through a hydrogen-bonding complex is proposed. Copyright

Full text of DOI:10.1002/anie.201107348

Angewandte
Chemie
DOI: 10.1002/anie.201107348
Catalytic Transamidation
Transamidation of Primary Amides with Amines Using Hydroxylamine
Hydrochloride as an Inorganic Catalyst**
C. Liana Allen,* Benjamin N. Atkinson, and Jonathan M. J. Williams
Amide bonds are among the most important linkages in
industrial and medicinal chemistry today.[1] While the most
common way to make an amide bond is still by using a
stoichiometric amount of a coupling reagent, with growing
focus on green chemistry, this method is becoming increas-
ingly impractical.[2] Recently, in our group and others, there
has been high interest in developing catalytic methods of
amide bond formation which avoid using these coupling
reagents.[3]
Transamidation is potentially a synthetically useful reac-
tion, but is hindered by the high stability of the carboxamide
group. Due to this stability they are rarely used as acylating
agents. There are several reports of thermal transamidation
reactions,[4] typically requiring very high temperatures
(> 1808C), thus having a very limited substrate range. The
use of the yeast Candidia cylindracea lipase has been reported
by Gotor et al. to promote transamidations between N-
trifluoroethyl-2-chloropropionamide and various amines[5]
and intramolecular transamidations have been reported by
Langlois and Buchwald et al.[6]
Several metal complexes have been reported to promote
transamidation reactions in the last two decades, including
AlCl3,[7] Sc(OTf)3,[8] Ti(NMe2)4[9] and polymer-bound HfCl4.[10]
Lanthanide catalysts have been reported to promote trans-
amidation between Fmoc protected lactams and various
amines.[11] A report by Myers et al. in 2006 described the
in situ activation of primary amides using N,N-dialkylform-
amide dimethyl acetals, however 1.3 equivalents of the
activating reagent were required, along with a lanthanide
catalyst to effect the full transformation.[12] Borate esters have
recently been reported to be effective reagents for trans-
amidation reactions between primary amides and amines,
however two equivalents of the boron reagent are required
for the reaction.[13] Stahl et al. have found some metal
complexes will facilitate the equilibration between a secon-
dary amide and an amine when the reaction is thermoneu-
tral.[14]
quantities of hydroxylamine hydrochloride to activate the
primary carboxamide and promote a transamidation reaction.
During the course of our on-going efforts into developing
catalytic syntheses of amide bonds,[15] we envisioned that a
catalytic method of primary amide activation and subsequent
irreversible transamidation with an amine would be not only
an exceptionally atom efficient and clean reaction (with the
only by product being ammonia) but also highly synthetically
useful due to the primary carboxamide groups inertness in the
presence of many other catalysts and common organic
reagents. We initially screened a number of catalysts we
reasoned may activate the primary amide towards nucleo-
philic attack (Table 1).
Pleasingly, simple hydroxylamine salts gave the best
conversion into secondary amide after 18 h. Although several
other hydroxylamine derivatives showed promise as catalysts,
we were intrigued by the possibility of using hydroxylamine
hydrochloride as a purely inorganic, metal-free catalyst. The
free base of hydroxylamine is only available in water or
ethanol, so a direct comparison between the hydrochloride
salt and free base is not possible (Table 1, entries 4 and 5). The
Table 1: Screen of catalysts.
Entry
Catalyst
Conversion
into 1 [%][a]
1
2
3
4
n-butyraldoxime
benzaldoxime
hydroxylamine sulfate
hydroxylamine hydrochloride
hydroxylamine
N-methylhydroxylamine hydrochloride
O-methylhydroxylamine hydrochloride
N,N-diethylhydroxylamine hydrochloride
O-benzylhydroxylamine
O-benzylhydroxylamine hydrochloride
hydrazine monohydrate
N,N’-diphenylthiourea
benzylamine hydrochloride
hydrochloric acid
36
30
100
100
0
5[b]
6
96
91
71
13
73
23
13
46
51
43
43
37
10
7
8
9
Clearly, there is a lack of an efficient, catalytic procedure
for transamidation reactions between simple primary amides
and amines to form secondary and tertiary amides irrever-
sibly. Herein, we report such a procedure utilizing catalytic
10
11
12
13[c]
14
15
16
17
18
nitric acid
triethylamine hydrochloride
ammonium chloride
[*] C. L. Allen, B. N. Atkinson, Prof. J. M. J. Williams
Department of Chemistry, University of Bath
Claverton Down, Bath, BA2 7AY (UK)
E-mail: ca221@bath.ac.uk
no catalyst
[a] Conversions determined by 1H NMR spectroscopy. [b] Reaction run in
ethanol, H2NOH cannot be extracted into toluene. [c] Added as addi-
tional 10 mol% benzylamine hydrochloride salt.
[**] We thank the EPSRC for the award of a studentship to C.L.A.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107348.
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Table 2: Range of primary amides or primary amide equivalents and
complete lack of activity when hydroxylamine free base was
used could be explained by the use of ethanol as a solvent, as
when hydroxylamine hydrochloride was used as catalyst in
ethanol no activity was observed. The use of O-benzyl-
hydroxylamine free base in toluene compared with O-benzyl-
hydroxylamine hydrochloride in toluene shows the presence
of the acid salt has a positive effect on the conversion into
secondary amide (Table 1, entries 9 and 10). Interestingly, the
use of just acid as a catalyst (Table 1, entries 13–15) showed
some activity in all cases, although they were not as effective
as hydroxylamine hydrochloride.
Next, different solvents and temperatures were screened
using hydroxylamine hydrochloride as the catalyst. Toluene at
1058C with a varying amount of H2NOH·HCl (depending on
the substrates used) was found to be the optimal combination,
so a range of primary amides and amines was screened under
these conditions to test the tolerance of this new reaction
(Table 2).
A wide range of functional groups has been shown to be
tolerated by the reaction conditions, including halogens
(Table 2, entries 3, 11, 22), free phenolic hydroxy groups
(entry 9), heterocycles (entries 5, 7, 13), alkenes (entry 2), and
alkynes (entry 18). Aliphatic amides generally gave the
highest conversions, with some substrates requiring only 10
mol% hydroxylamine hydrochloride to reach complete con-
version in 16 h (entries 1, 2, 17).
Other notable observations from this substrate screening
are that Boc protecting groups are unaffected in the reaction
(entries 7 and 14), allowing for selective acylation of one
nitrogen atom in a mono-protected diamine, or selective
coupling of a Boc-protected amino amide to an amine. Ester
protected amino acids can also be N-acylated without any loss
of the ester functionality. Monosubstituted ureas can be
selectively acylated, yielding unsymmetrical ureas (entry 15).
Formamide can be used as a formylating agent in this
reaction, giving N-formyl products, including [N-formyl(O-
benzyl)]glycinate (entries 16–19). Slight racemization at the
a-position to the carbonyl was observed when 1-Boc-l-
prolinamide was used as a starting material (entry 7).
In the interest of atom efficiency, we have run these
reactions at a temperature of 1058C, allowing for the use of a
catalytic amount of hydroxylamine hydrochloride to activate
the primary amide group. However, several aliphatic amide
substrates gave good conversions into secondary amide at
lower temperatures when an increased amount of hydroxyl-
amine hydrochloride was used (Table 3). The benzoic primary
amide, however, was very slow to react at 808C, even with 1
equivalent of hydroxylamine hydrochloride present (Table 3,
entry 8).
amines used in the transamidation reaction.[a]
Entry
Product
Mol%
H2NOH·HCl
t
[h]
Conv.
[%][b]
Yield
[%]
1
2
3
4
5
10
10
10
20
20
16
16
20
20
20
100
100
100
100
95
81
86
91
83
90
6
7
50
50
20
24
63
98
–
87
8
50
50
50
24
24
24
62
83
90
–
9
76
81
10
11
12
13
50
50
50
24
24
24
88
70
63
71
59
–
14
50
50
22
22
79
69
71
–
15[c]
16
10
22
100
91
17
18
10
10
16
20
100
98
86
87
Most notable in Table 3 are the examples using form-
amide. At room temperature (208C), the uncatalyzed reac-
tion gave < 1% conversion. Addition of just 30 mol%
hydroxylamine hydrochloride increased this to 100%
(entries 2 and 3). This is a remarkable result when compared
with other catalytic formylation reactions which generally use
much more active formylating agents (formic acid, formalde-
hyde) and are run at higher temperatures.[3]
19
20
10
50
20
24
100
86
82
74
To understand this chemistry further, we conducted a
series of experiments to gain an insight into possible
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Table 2: (Continued)
by the hydroxylamine hydrochloride. In the absence of acid, a
marked decrease in conversion is seen (Table 1, entries 9 and
10), suggesting the acid is participating in the reaction
mechanism in some way.
Entry
Product
Mol%
H2NOH·HCl
t
[h]
Conv.
[%][b]
Yield
[%]
1H NMR experiments run in [D8]toluene showed a clear
interaction between the NH amide protons and O-methyl-
hydroxylamine hydrochloride (Table 4), suggesting a hydro-
gen bonding interaction between the two species in the
21
50
50
22
24
68
79
–
22[d]
70
[a] All reactions 1m in PhMe, 1:1 amide:amine, unless stated otherwise.
[b] Conversions determined by 1H NMR spectrsocopy. [c] Starting
materials were N-[(trimethylsilyl)methyl]urea and benzylamine. [d] Run
at 1508C in xylenes.
Table 4: Chemical shift of amide protons is affected by the presence of
O-methylhydroxylamine hydrochloride.
Entry
Conditions[a]
NH shifts [ppm]
1
2
3
4
5
6
0.05m butyramide
0.1m butyramide
0.2m butyramide
0.05m butyramide-MeONH2·HCl
0.1m butyramide-MeONH2·HCl
0.2m butyramide-MeONH2·HCl
4.37, 4.70
4.40, 5.25
4.37, 5.23
4.40, 4.68
4.37, 5.53
4.53, 5.86
Table 3: Representative examples of primary amides and amines used in
the transamidation reaction at lower temperatures.
Entry
Product
T [8C]
Mol%
H2NOH·HCl
Conv.
[%][b]
[a] In [D8]toluene, 558C.
1
2
3
50
20
20
10
30
0
94
100
<1
reaction solvent (Figure 1). In the presence
and absence of O-methylhydroxylamine
hydrochloride, different effects on chemical
shift are observed as the concentration is
increased.[16]
4
5
80
50
50
100
100
78
6
7
80
50
50
100
80
64
Figure 1. Pro-
posed method of
primary amide
activation
through hydro-
gen bonding.
It is also possible that the hydroxyl-
amine attacks the “activated” primary
8
80
100
25
amide,
generating
an
intermediate
hydroxamic acid. Indeed, when hydroxyl-
amine hydrochloride and acetamide (in a
1:1 ratio) were subjected to the reaction
conditions, complete conversion into the
hydroxamic acid was observed within 4 h.
[a] All reactions run for 16 h, 1:1 amide:amine, 1m in PhMe. [b] Con-
versions determined by 1H NMR spectroscopy.
mechanisms by which this reaction may be operating. It
became clear to us that once the reaction reaches the
secondary or tertiary amide product, it is irreversible. Run-
ning a secondary amide in the presence of an amine under the
same reaction conditions did not lead to a crossover
(Scheme 1). Even increasing the ratio of amine to five
Furthermore, when acetohydroxamic acid and benzylamine
were subjected to the reaction conditions, complete conver-
sion into the secondary amide was observed within 45 min,
suggesting that, if the hydroxamic acid is formed, trans-
formation into the product (and thus regeneration of the
catalyst) is very rapid (Scheme 2).
Kinetic studies were then performed by following the
reaction of butyramide and benzylamine (with varying
amounts of hydroxylamine hydrochloride present) over time
(see Supporting Information). The results show an approx-
Scheme 1. Crossover with a secondary amide not observed under the
reaction conditions.
equivalents (compared with the secondary amide) did not
result in a crossover reaction. This feature of the reaction is
highly synthetically useful, as even in the presence of an
excess of another nucleophile, no breakdown of the secondary
amide product is observed.
In the absence of catalyst, only 10% conversion into
secondary amide was observed after 18 h (Table 1, entry 18),
therefore the primary amide must be activated in some way
Scheme 2. Hydroxamic acid reactions.
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evaporator and 20 mL dichloromethane added. The reaction mixture
was then washed with water (2 ꢀ 30 mL) to remove the hydroxyl-
amine hydrochloride, and the resulting organic layer was dried over
MgSO4. The solution was concentrated in vacuo and then analyzed by
their 1H NMR and 13C NMR spectroscopy and mass spectrometry
data. Purification by column chromatography and recrystallization
was carried out as necessary.
imate first-order relationship between concentration of
hydroxylamine hydrochloride and the initial rate of reaction.
Therefore, as one equivalent of hydroxylamine is involved in
the rate-determining step of the reaction, the slow step of the
mechanism could be either initial activation of the primary
amide (formation of the hydrogen-bonded complex) or attack
of this complex (Scheme 3). The relative pKa of the amine and
Received: October 18, 2011
Revised: November 28, 2011
Published online: December 30, 2011
Keywords: amines · metal-free catalysis · hydroxylamines ·
.
primary amides · transamidation
[1] J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol.
Chem. 2006, 4, 2337 – 2347.
[2] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L.
Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman,
A. Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9, 411 – 420.
[3] C. L. Allen, J. M. J. Williams, Chem. Soc. Rev. 2011, 40, 3405 –
3415.
[4] a) M. E. Smith, H. Adkins, J. Am. Chem. Soc. 1938, 60, 657 – 663;
b) L. F. Beste, R. C. Houtz, J. Polym. Sci. 1952, 8, 395 – 407;
c) I. K. Miller, J. Polym. Sci. Part A 1976, 14, 1403 – 1417; d) F.
Zaragoza-Dçrwald, G. von Kiedrowski, Synthesis 1988, 917 –
918.
[5] V. Gotor, R. Brieva, C. Gonzalez, F. Rebolledo, Tetrahedron
1991, 47, 9207 – 9214.
[6] a) N. Langlois, Tetrahedron Lett. 2002, 43, 9531 – 9533; b) A.
Klapars, S. Parris, K. W. Anderson, S. L. Buchwald, J. Am. Chem.
Soc. 2004, 126, 3529 – 3533.
Scheme 3. Proposed reaction pathways.
hydroxylamine dictate that the amine is more basic and thus
more nucleophilic towards the carbonyl—the opposite order
of reactivity seen in SN2 reactions at saturated centers.
Therefore we propose the major pathway to be attack of
the amine onto the hydrogen bonded primary amide–
hydroxylamine complex and that this is the rate-determining
step.[17]
[7] E. Bon, D. C. H. Bigg, G. Bertrand, J. Org. Chem. 1994, 59,
4035 – 4036.
In conclusion, we have reported a novel method for the
transamidation of primary carboxamides with primary or
secondary amines to give secondary or tertiary amides,
utilizing catalytic quantities of hydroxylamine hydrochloride
to activate the usually chemically robust primary amide
group. A proposed mechanism of primary amide activation
through a hydrogen-bonding complex is also presented with
initial H NMR and kinetics studies. Further investigations
into improving the efficiency of the catalyst and the room
temperature formylations are on-going in our laboratory.
[8] S. E. Eldred, D. A. Stone, S. H. Gellman, S. S. Stahl, J. Am.
Chem. Soc. 2003, 125, 3422 – 3423.
[9] D. A. Kissounko, J. M. Hoerter, I. A. Guzei, Q. Cui, S. H.
Gellman, S. S. Stahl, J. Am. Chem. Soc. 2007, 129, 1776 – 1783.
[10] M. Shi, S.-C. Cui, Synth. Commun. 2005, 35, 2847 – 2858.
[11] S. C¸ alimsiz, M. A. Lipton, J. Org. Chem. 2005, 70, 6218 – 6221.
[12] T. A. Dineen, M. A. Zajac, A. G. Myers, J. Am. Chem. Soc. 2006,
128, 16406 – 16409.
[13] P. Starkov, T. D. Sheppard, Org. Biomol. Chem. 2011, 9, 1320 –
1323.
[14] a) J. M. Hoerter, K. M. Otte, S. H. Gellman, Q. Cui, S. S. Stahl, J.
Am. Chem. Soc. 2008, 130, 647 – 654; b) N. A. Stephenson, J.
Zhu, S. H. Gellman, S. S. Stahl, J. Am. Chem. Soc. 2009, 131,
10003 – 10008.
1
Experimental Section
[15] C. L. Allen, S. Davulcu, J. M. J. Williams, Org. Lett. 2010, 12,
5096 – 5099.
[16] L. P. McIntosh, E. Brun, L. E. Kay, J. Biomol. NMR 1997, 9,
306 – 312.
The primary amide species (2 mmol) was added to an oven-dried
Radleys carousel tube, followed by toluene (2 mL) and the amine
species (2 mmol, see Table 2). Hydroxylamine hydrochloride was
then added and the carousel tube was sealed before the reaction
mixture was heated at 1058C. After being allowed to cool to room
[17] W. P. Jencks, J. Carriuolo, J. Am. Chem. Soc. 1960, 82, 675 – 681.
temperature, the solvent was removed in vacuo on
a rotary
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