A simple Ru catalyst for the conversion of aldehydes or oximes to primary amides

Article abstract of DOI:10.1016/j.ica.2009.08.022

Ru(DMSO)₄Cl₂ is catalytically active for converting aldehydes to primary amides via oxime intermediates. This catalyst is readily available, and requires no additional ligands, a great simplification compared to previous work. A Ru(II)/(IV) mechanism is proposed.

Full text of DOI:10.1016/j.ica.2009.08.022

Inorganica Chimica Acta 363 (2010) 1243–1245
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A simple Ru catalyst for the conversion of aldehydes or oximes to primary amides
,1
*
Jonathan F. Hull, Sheena T. Hilton, Robert H. Crabtree
Yale University, Department of Chemistry, 225 Prospect St., New Haven, CT 06511, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Ru(DMSO)4Cl2 is catalytically active for converting aldehydes to primary amides via oxime intermediates.
This catalyst is readily available, and requires no additional ligands, a great simplification compared to
previous work. A Ru(II)/(IV) mechanism is proposed.
Received 28 May 2009
Accepted 16 August 2009
Available online 19 August 2009
Ó 2009 Elsevier B.V. All rights reserved.
Dedicated by Prof. Johnathan R. Dilworth.
Keywords:
Beckmann rearrangement
Aldoxime
1. Introduction
achieve equally high yields. In a further simplification of this reac-
tion, we now report that Ru(DMSO)4Cl2, having only dimethylsulf-
Amides, which are valuable intermediates in organic synthesis
and in industrial applications such as detergents, lubricants and
pharmaceuticals [1], are commonly prepared from the stoichiome-
tric reaction of amines with acyl chlorides, acid anhydrides, and es-
ters [2]. However, the toxicity and waste formation involved in
these methods has made the atom-economical synthesis of amides
a high priority, especially in the pharmaceutical industry.
oxide (DMSO) and Clꢀ as ligands, provides
a much simpler
precatalyst for the conversion of aldehydes and aldoximes to
amides. Ru(DMSO)4Cl2 is known to be active for b-alkylation and
coupling of ketones to alcohols [11–13]; we now find that Ru(II)
can indeed also rearrange oximes to amides via H migration. The
metal precatalyst can easily be synthesized in high yield by reflux-
ing RuCl3 hydrate in DMSO for a short time [14]. Our catalyst does
not require additives, and gives high yields with no nitrile
formation.
ð1Þ
2. Results and discussion
One approach is the Beckmann rearrangement, in which an acid as-
sists in migration of the R group anti to N–OH to give the rearranged
amide (Eq. (1)) [3]. Alkyl and aryl groups readily migrate while H
generally does not, making ketoximes favored over aldoximes [4].
Traditionally, acids such as PCl5 are used in the Beckmann rear-
rangement, but transition metal catalysts containing nickel [5], pal-
ladium [6], iridium [7] and rhodium [8] have also been reported. In
a recent advance, Williams and coworkers reported a ruthenium
catalyst for this reaction with high selectivity, yield and low catalyst
loading [9]. However, additives like p-toluenesulfonic acid (p-TsOH)
and other ligands are required, and nitriles are frequently found in
addition to the amide (abnormal Beckmann rearrangement). Gna-
namgari and Crabtree [10] found that additives and product mix-
tures can be avoided with a ruthenium terpyridine catalyst to
In the initial screening phase, we looked only at the conversion
of preformed oximes to amides in toluene (Eq. (2)). As shown in
Table 1, aromatic aldoxime substrates such as (E)- and (Z)-benzal-
dehyde oxime (Table 1, Entries 1 and 2), and a heterocyclic aldox-
ime (R = furaldehyde, Table 1, Entry 7) are quantitatively converted
to benzaldamide within 8 h in refluxing toluene.
ð2Þ
Because acid and basic additives have been reported to increase the
yield in prior systems [7, 9], we also ran reactions with 1 equivalent
of p-TsOH, (Table 1, Entry 3), and 1 equivalent of sodium bicarbon-
ate (Table 1, Entry 4). The addition of acid resulted in complete con-
version but to an uncharacterizable mixture of products, while
added base had no influence on yield or reaction time. We therefore
excluded these additives in subsequent reactions. Running the reac-
tions open to the air had no influence for benzylic aldehydes, but
* Corresponding author.
E-mail address: robert.crabtree@yale.edu (R.H. Crabtree).
We would like to congratulate Professor Jonathan R. Dilworth on his many
1
contributions.
0020-1693/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2009.08.022

1244
J.F. Hull et al. / Inorganica Chimica Acta 363 (2010) 1243–1245
Table 1
consistent with the presence of traces of oxime found in the MeCN
Results for the conversion of aldoximes to amides.
reactions in Table 2, suggesting that MeCN enables good conversion
to the oxime, but slower conversion to the amide; toluene is good
for the amide conversion, but not great for the oxime formation.
The mechanism is still under investigation, however several
points are clear. If Ru(II) acted merely as Lewis acid we would ex-
pect to see product from the classical Beckmann rearrangement,
such as secondary amides from ketoximes. If Ru(II)/(IV) conversion
is possible in this system, an alternative mechanism (Scheme 1)
can be proposed: oxidative addition of the aldoxime N–OH bond
to Ru(II), followed by nucleophilic attack on the co-ordinated imine
in 2, then b-elimination of cyclometallated 3, and finally reductive
elimination to give the amide. Notably, water cannot eliminate
from 2, and no nitrile is observed. This explains the absence of ni-
trile products in this system.
Entry Aldoxime R= Time (h) Solvent
Conversion (%) Yielda (%)
1
2
3
4
5
6
7
8
9
10
(E)-C6H5
(Z)-C6H5
(E)-C6H5
(E)-C6H5
(4-NO2)C6H4
C6H5CH@CH
2-furyl
C3H7
(4-NO2)C6H4
2-furyl
8
8
8
8
6
6
6
6
6
6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
>99
>99
>99
>99
>99
71
>99
>99
nd
>99
48
b
c
71
>99
>99
>99
49
acetonitrile 31
acetonitrile 48
31
38
Reaction conditions: 0.164 mmol oxime, 5 mol% Ru(DMSO)4Cl2, and 1 mL of solvent
at refluxed (110 °C, Toluene; 82 °C MeCN) under N2 atmosphere.
Yields determined by 1H NMR using 1,3,5-trimethoxybenzene as internal
a
standard.
b
1 equiv. p-toluenesulfonic acid added.
1 equiv. potassium tert-butoxide added.
c
3. Experimental
gave decreased yields and unknown product mixtures were found
for substrates with easily oxidizable C–H bonds, such as for cinne-
maldehyde oxime. Aldoximes with electron withdrawing groups
such as 4-nitrobenzaldehydeoxime (Table 1, Entry 5) reacted com-
pletely, but gave slightly lower yields. Consistent with other Ru cat-
alysts [9,10], ketoximes were inert under our conditions.
Except where noted, all the reactions were conducted using
standard Schlenk techniques under nitrogen, using dry glassware
and solvents. Toluene and acetonitrile were passed through an
activated alumina column before use. NMR spectra were recorded
at room temperature using CDCl3 and DMSO-d6 on 400 and
500 MHz Bruker spectrometers and referenced to the internal stan-
dard peak (d in ppm and J in Hz). All organic reagents were pur-
chased from Sigma Aldrich and Alfa Aesar, and ruthenium
trichloride from Pressure Chemicals Company. Ru(DMSO)4Cl2 was
synthesized according to literature methods [14].
ð3Þ
Having established the conversion of aldoximes to amides, we
investigated the more useful conversion of aldehydes to amides
(Eq. (3) and Table 2). We were initially discouraged to find poor
conversions and yields under the same conditions, even after 48 h
(Table 2, Entries 1–4). In most of these cases, large amounts of alde-
hyde starting material and traces of the oxime intermediate re-
mained at the end of the reaction. Therefore the formation of the
oxime was the problem, not the later oxime to aldehyde conversion.
Switching to a more polar solvent, MeCN, we found better conver-
sion and yield at shorter times and lower temperatures (Table 2, En-
tries 5–10). For example, with cinnemaldehyde as substrate after 6
and 48 h in refluxing toluene, we saw 74% of the cinnemaldehyde
remained, and only 9% of the corresponding amide was found (En-
try 4). However, in MeCN 80% of the product was now formed after
only 6 h: only cinnemaldehyde oxime, and no aldehyde remained,
supporting our hypothesis that the reaction between the hydroxyl-
amine hydrochloride, base, and the aldehyde limited the reaction in
toluene. This prompted us to reevaluate the reactions in Table 1
with MeCN as solvent. Interestingly, yields were lower after 6 h
indicating that the solvent effects are not straightforward. This is
3.1. Representative procedure for the rearrangement of aldoximes to
amides
To a flame-dried Schlenk tube equipped with a magnetic stirbar
were added oxime (0.164 mmol) and catalyst (4 mg, 1.64 lmol).
After filling the tube with N2 using three vacuum-N2 cycles, dry
and degassed toluene (1 mL) was added with a syringe, and the
mixture was refluxed for the time indicated in the tables. After
cooling, 1,3,5-trimethoxybenzene (9 mg, 55 lmol) and 1 mL meth-
anol were added to the mixture. The contents were transferred to a
round bottom flask, and all solvent was removed under reduced
pressure. The resulting solid was dissolved in DMSO-d6, and fil-
tered through Celite into an NMR tube for analysis. NMR data were
found to be identical to literature values, and are reported below.
Table 2
Results for the conversion of aldehydes to amides.
Entry Aldehyde R=
Time (h) Solvent
Conversion (%) Yielda (%)
1
2
3
4
5
6
7
8
9
10
Ph
6
toluene
toluene
toluene
toluene
acetonitrile 78
acetonitrile 79
acetonitrile 75
acetonitrile 35
acetonitrile 83
acetonitrile 60
>99
17
nd
9
24
17
nd
9
30
79
68
35
80
60
(4-NO2)C6H4
(4-Me)C6H4
C6H5CH@CH
Ph
(4-NO2)C6H4
(4-CF3O)C6H4
(4-Me)C6H4
C6H5CH@CH
2-furyl
48
48
48
6
6
6
6
6
6
Reaction conditions: 0.164 mmol oxime, 0.164 mmol sodium bicarbonate,
0.164 mmol hydroxylamine hydrochloride, 5 mol% Ru(DMSO)4Cl2, and 1 mL of
solvent were refluxed (110 °C, toluene; 78 °C MeCN).
a
Yields determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal
Scheme 1. Proposed mechanism for the Ru(II) catalyzed rearrangement of
aldoximes.
standard.

J.F. Hull et al. / Inorganica Chimica Acta 363 (2010) 1243–1245
1245
3.2. Representative procedure for the conversion of aldehydes to
amides
3.7. Butyramide (Table 1, Entry 8)
(49%). 1H NMR (500 MHz, CDCl3): d 5.50 (2H, s), 2.18 (2H, t, J,
7.46 Hz), 1.64 (2H, m), 0.95 (3H, t, J, 7.37 Hz). 13C NMR
(100 MHz, CDCl3): d 175.9, 38.0, 19.1, 13.9.
To a flame-dried Schlenk tube equipped with a magnetic stirbar
were added oxime (0.164 mmol), hydroxylamine hydrochloride
(0.164 mmol, 11.3 mg), NaHCO3 (0.164 mmol, 13.6 mg) and cata-
lyst (4 mg, 1.64
lmol). After filling the tube with N2 using three
3.8. 4-(Trifluoromethoxy)benzamide (Table 2, Entry 7)
vacuum-N2 cycles, dry and degassed toluene or acetonitrile
(1 mL) was added with a syringe, and the mixture was refluxed
for the time indicated in the tables. After cooling, 1,3,5-trimethoxy-
(68% from the aldehyde). 1H NMR (400 MHz, DMSO-d6): d 8.08
(1H, s), 7.99 (2H, m), 7.51 (1H, s), 7.45 (2H, m). 13C NMR (100 MHz,
DMSO-d6): d 166.7, 150.3, 133.4, 129.8, 121.7, 120.6.
benzene (9 mg, 55 lmol) and 1 mL methanol were added to the
mixture. The contents were transferred to a round bottom flask,
and all solvent was removed under reduced pressure. The resulting
solid was dissolved in DMSO-d6, and filtered through Celite into an
NMR tube for analysis.
3.9. Toluamide (Table 2, Entry 8)
(35%). 1H NMR (400 MHz, CDCl3): d 7.69 (2H, d, J, 8.20 Hz), 7.23
(2H, m), 6.04 (2H, br s), 2.38 (3H, s). 13C NMR (400 MHz, CDCl3): d
169.5, 142.8, 130.7, 129.5, 127.6, 21.7.
3.3. Benzamide (Table 1, Entries 1–4)
(>99%). 1H NMR (500 MHz, CDCl3): d 7.79 (2H, m), 7.52 (1H, t, J,
7.4 Hz), 7.44 (2H, t, J, 7.6 Hz), 5.85 (2H, br s, NH2). 13C NMR
(100 MHz, CDCl3): d 169.8, 133.5, 132.21, 128.8, 121.53.
Acknowledgments
R.H.C. thanks the DOE (Gant Number DE-FGO2-84ER13297) for
funding, S.T.H. thanks Yale University for a STARS II Fellowship.
3.4. 4-Nitrobenzamide (Table 1, Entry 5)
References
(>99%). 1H NMR (500 MHz, DMSO-d6): d 8.29 (3H, m), 8.09 (2H,
d, J, 8.8 Hz), 7.72 (1H, NH). 13CNMR (100 MHz, DMSO-d6): d 166.2,
149.1, 139.9, 128.9, 123.4.
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3.5. Cinnamide (Table 1, Entry 6)
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(71%). 1H NMR (500 MHz, CDCl3): d 7.59 (1H, d, J, 15.7 Hz), 7.49
(2H, m), 7.36 (3H, m), 6.44 (1H, d, J, 15.7 Hz), 5.69 (2H, s). 13C NMR
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3.6. 2-Furamide (Table 1, Entry 7)
(>99%). 1H NMR (500 MHz, CDCl3): d 7.45 (1H, m), 7.15 (1H, d, J,
3.50 Hz), 6.50 (1H, dd, J, 3.46 Hz, 1.73 Hz), 5.89 (2H, br s). 13CNMR
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