Multifaceted catalysis approach to nitrile activation: Direct synthesis of halogenated allyl amides from allylic alcohols

Article abstract of DOI:10.1039/c3ob41692e

Allyl amides were synthesised from the reaction of allyl alcohols and halogenated nitriles using a platinum multifaceted catalysis approach in which both the nucleophilic addition and subsequent [3,3]-sigmatropic rearrangement steps of the process were catalysed by the same complex. Additionally, ¹H/¹³C{¹H} NMR and GC studies provided the first insights into the mechanism of this transformation.

Full text of DOI:10.1039/c3ob41692e

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BiomolecularChemistry
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Volume 11 | Number 43 | 21 November 2013 | Pages 7437–7632
ISSN 1477-0520
PAPER
Jason E. Camp et al.
Multifaceted catalysis approach to nitrile activation: direct synthesis of
halogenated allyl amides from allylic alcohols
1477-0520(2013)11:43;1-4

Organic &
Biomolecular Chemistry
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Multifaceted catalysis approach to nitrile activation:
direct synthesis of halogenated allyl amides from allylic
alcohols†
Cite this: Org. Biomol. Chem., 2013, 11,
7472
Roy P. Lester, Jay J. Dunsford and Jason E. Camp*‡
Received 18th August 2013,
Accepted 3rd September 2013
Allyl amides were synthesised from the reaction of allyl alcohols and halogenated nitriles using a plati-
num multifaceted catalysis approach in which both the nucleophilic addition and subsequent [3,3]-
sigmatropic rearrangement steps of the process were catalysed by the same complex. Additionally,
1H/13C{1H} NMR and GC studies provided the first insights into the mechanism of this transformation.
DOI: 10.1039/c3ob41692e
www.rsc.org/obc
Nitriles are used extensively in synthetic chemistry due to their nucleophilic addition, they are also relatively harsh, wasteful
chemical versatility.1 Traditionally they are activated for and incompatible with a number of important functional
nucleophilic addition by strong acids (Pinner reaction) or groups (Fig. 1a).2,3 Stoichiometric use of transition metals has
stoichiometric use of transition metals (Fig. 1a/b). While also been shown to activate nitriles towards nucleophilic
the acidic conditions are able to activate nitriles towards addition (Fig. 1b).4 For example, reaction of a nitrile with plati-
num(IV) chloride initially forms a platinum–nitrile complex,
which after isolation can be treated with an alcoholic solvent
at room temperature to form a platinum–imidate. These reac-
tions can proceed under mild conditions, but stoichiometric
amounts of the metal are necessary. Liberation of the imidate
from the metal can also be problematic, requiring ligand
exchange with an additional reagent or very high tempera-
tures,5 thus making the overall process impractical for cata-
lysis. One potential solution to this turnover problem would be
to utilise a multifaceted catalysis (MFC) approach (Fig. 1c).6,7
Multifaceted catalysis has been defined as the ability of one
species to catalyse multiple mechanistically distinct steps in a
synthetic sequence. The key to this approach is that the final
product of the reaction sequence binds poorly to the catalyst
and is therefore exchangeable with the starting material under
the reaction conditions. The related terms, auto-tandem cata-
lysis,8 single-pot catalysis,9 domino-catalysis and dual catalysis10
have also been used to describe this mode of catalysis. Herein,
is described the development of a platinum multifaceted cata-
lysis (Pt-MFC) approach to nitrile activation for the direct for-
mation of allyl amides from halogenated nitriles in which the
metal catalyses both the addition of the allylic alcohol to the
Fig. 1 Comparison of acidic, transition metal and multifaceted catalysis (MFC)
nitrile as well as the subsequent [3,3]-sigmatropic rearrange-
ment of the in situ formed imidate under mild conditions.
To probe the feasibility of a multifaceted catalysis process
for nitrile activation a synthetic probe was sought in which the
platinum species could activate multiple mechanistically dis-
tinct steps. A synthetic sequence that converts a limited
number of strongly activated nitriles into halogenated allyl
amides was reported by Overman et al. in the late 1970s.11,12
approaches to nitrile activation.
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
†Electronic supplementary information (ESI) available: Experimental details and
full spectroscopic data for all compounds. See DOI: 10.1039/c3ob41692e
‡Present address: School of Biological and Chemical Sciences, Queen Mary Uni-
versity of London, Mile End Road, London, E1 4NS, UK. jason.camp@qmul.ac.
uk. Tel: +44 (0)20 7882 5389.
7472 | Org. Biomol. Chem., 2013, 11, 7472–7476
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Trichloroallyl amides are highly useful building blocks of (Table 1, entries 1–3). An increased yield of the desired allyl
more complex structures13 that are used extensively in the syn- amide 3a was achieved by running the reaction for a longer
thesis of biologically active compounds.14 Traditionally, the period of time at room temperature or heating the reaction
Overman process is a two-step sequence involving the syn- mixture to 60 °C (Table 1, entries 4–6). Changing to the homo-
thesis and isolation of a trichloroimidate followed by an geneous catalyst, bis(triphenylphosphine)-platinum(II) dichlo-
overall [3,3]-sigmatropic rearrangement.15,16 The requisite ride, did not afford any of the desired product 3a (Table 1,
imidate is formed via addition of an allyl alcohol to haloge- entries 7–9). Whilst increasing the cationic nature of the cata-
nated nitriles in the presence of a strong base.17 Subjection of lysts via the addition of 10 or 20 mol% AgBF4 afforded imidate
the isolated imidate to either heat or metal catalysis affords 2a in moderate isolated yield, the species was no longer able to
the desired allyl amide.18–20 In particular, noble metals are catalyse the [3,3]-sigmatropic rearrangement to form 3a in sig-
increasingly used to catalyse this process21 because they allow nificant yield. Importantly, control experiments at either room
for relatively mild reaction conditions as well as the redox neu- temperature or 60 °C, in which the platinum catalyst was
trality, chemoselectivity and functional group compatibility of omitted, did not afford any of the desired allyl amide 3a and
the catalyst.22 Some major limitations of this overall process only the starting material was recovered (Table 1, entries 10
are the use of a strong base and the workup and isolation of and 11).24 Finally, it was found that the catalyst loading could
the imidate intermediate.
be decreased, though this lead to a significant increase in reac-
Our goal was to develop a multifaceted catalysis approach tion times to reach the same level of conversion.23 The use of
in which the metal would act as a catalyst for both the acti- harsh thermal conditions5 with a decreased catalyst loading
vation of the nitrile and the subsequent [3,3]-sigmatropic lead exclusively to decomposition of the starting materials.
rearrangement (cf. Fig. 1c). Thus, the reaction between tri-
Next the scope of the platinum multifaceted catalysis
chloroacetonitrile and (E)-2-butenol (1a) to directly form halo- process for the formation of allyl amides was investigated
genated allyl amide 3a was used to assess the feasibility of this (Scheme 1). It was found that primary allylic alcohols 1 were
approach (Table 1). Due to the known ability of platinum(II) smoothly converted to allyl amides 3a–l in dichloromethane at
chloride to activate nitriles towards alcoholic nucleophiles4 60 °C in the presence of 10 mol% platinum(II) chloride. The
and catalyse [3,3]-sigmatropic rearrangements20 it was reaction can also be run at room temperature, though this lead
employed in an initial solvent screen in which dichloro- to increased reaction times and decreased yields in some of
methane gave the highest yield of allyl amide 3a.23 A number the more challenging substrates that were investigated (e.g.
of other metals were also investigated as potential catalysts, 1g–k). Several features of the platinum-catalysed method are
but none of these were able to both form and rearrange noteworthy. In addition to varying the alkane chain length,
imidate 2a in synthetically useful yields.23 The stoichiometry 3a–f, cinnamyl and allyl derivatives also afforded the corres-
of the reaction with respect to trichloroacetonitrile was investi- ponding allyl amides 3g–j in moderate yield. Interestingly,
gated and it was found that 2.2 equiv. gave a good yield of the trans-2-hexen-1-ol (1ca) gave the desired allyl amide 3c in a
desired allyl amide after stirring the reaction at rt for 20 h similar yield to the corresponding cis-alcohol 1cb at room
temperature, in contrast to previous reports on the rearrange-
ment of cis-allyl imidates.25 Allyl amide 3k, which contains an
Table 1 Optimisation of the Pt-MFC process
Cl3CCN
(equiv.)
Time
(h)
Temp
(°C)
Yield
(%) 3a
Entry
Catalyst
1
2
3
4
5
6
7
8
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
[Pt(PPh3)2Cl2]
[Pt(PPh3)2Cl2]a
[Pt(PPh3)2Cl2]b
None
1.1
2.2
5.0
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
20
20
20
30
40
20
20
20
20
20
20
rt
rt
rt
rt
rt
60
rt
rt
rt
rt
60
56
80
80
91
99
86
0
(20, 2a)
(26, 2a)
0
0
9
10
11
None
Scheme 1 art for 40 h. btrans-2-Hexen-1-ol 1ca was used. ccis-2-Hexen-1-ol
1cb was used. drt for 20 h. e80 °C.
a 10 mol% AgBF4 was added. b 20 mol% AgBF4 was added.
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α-quaternary centre could also be synthesised via the standard hypothesis, the reaction of (E)-2-butenol (1a) with trichloroaceto-
method. Synthesis of allyl amide 3l, which contains a BOC pro- nitrile at room temperature in CD2Cl2 was monitored by 1H
tecting group, proceeded in good overall yield without the loss and 13C{1H} NMR over 19 hours.23 While the production of
of the protecting group that would occur under thermal con- allyl amide 3a was easily monitored, we were unable to unam-
ditions.26 Finally, the corresponding dichloroallyl amide 4a biguously assign either proton or carbon signals to an in situ
was synthesised by reacting the less activated dichloroaceto- formed platinum–imidate 6 or imidate 2. Based on this obser-
nitrile with allyl alcohol 1a at 80 °C, though in significantly vation we tentatively suggest that the lack of unambiguous evi-
lower yield than trichloroallyl amide 3a. This result is most dence for any free or Pt bound imidate species in the reaction
likely due to the initial nitrile activation step (vide infra), as mixture infers that the subsequent [3,3] rearrangement in the
platinum(II) chloride was shown to efficiently catalyse the [3,3]- reaction sequence is rapid and that imidate formation is there-
sigmatropic rearrangement of dichloroimidate 5a to dichloro- fore rate limiting. Interestingly, low temperature 13C{1H} NMR
allyl amide 4a in 70% yield.27 Less activated nitriles, such as and HRMS analysis indicated that amide acetal 8 may be a
chloroacetonitrile and acetonitrile, were unreactive under transient species in the reaction mixture. If the reaction pro-
these conditions. In all of these reactions none of the products ceeds through amide acetal 8, this would explain the futility of
from the known [1,3]-rearrangement were observed.28
the Pt-MFC processes when the steric bulk is increase around
To better understand the Pt-MFC process and to allow for allylic alcohol 1. The rapid rearrangement of imidate 2/6 was
its further development, a preliminary mechanistic investi- confirmed by subjecting aliquots from various time points of
gation was undertaken. In contrast to the well studied stoichio- the reaction to analysis by gas-chromatography, which showed
metric addition of nucleophiles to platinum bound nitriles,4,29 a persistent trace amount of free imidate 2 throughout the
little mechanistic work has been conducted on the gold or course of the reaction.22,32 Thus, the platinum was acting as a
platinum metal-catalysed [3,3]-sigmatropic rearrangement of multifaceted catalysis in the formation and rearrangement of
allyl imidates to allyl amides.30 We offer the following mechan- allyl imidate 2.33 Additionally, a catalyst poisoning experiment
ism for the Pt-MFC process that is based on the ability of was conducted by adding various amounts of acetonitrile,
simple platinum salts to (1) form Pt–imidate complexes and which is not sufficiently activated to allow for addition of the
(2) catalyse the Overman rearrangement (Fig. 2).10 Initial allylic alcohol under these conditions, to the reaction of allyl
addition of allylic alcohol 1 to an in situ formed platinum– alcohol 1a and trichloroacetonitrile in order to quench the
nitrile adduct would give the platinum–imidate species 6. This reaction and allow for isolation of the intermediate imidate
is in contrast to the traditional stepwise formation of related 2a.23 No imidate 2/6 was observed in this study, further sup-
Pt–imidate complexes via isolated Pt–nitrile species.4 The porting the supposition that its rearrangement is rapid under
imidate adduct 6 could (i) rearrange directly via 9 to amide 3, the reaction conditions.
(ii) break up to give the free imidate 2, which could be in equi-
In conclusion, a multifaceted catalysis approach to the syn-
librium with adduct 731 or (iii) act as an electrophile13a to thesis of allyl amides directly from halogenated nitriles was
form amide acetal 8. Platinum-catalysed [3,3]-sigmatropic developed using simple platinum salts. These added-value
rearrangement of allyl imidate 2, via a cyclisation induced substrates were synthesised in a convergent, one-pot process
rearrangement10 (adduct 9), affords allyl amide 3 after elimi- that maximised the catalytic potential of the platinum species.
nation of the platinum. To probe the validly of the mechanistic Additionally, 1H/13C{1H} NMR and GC studies provided the
Fig. 2 Proposed mechanism of the Pt-MFC method of direct allyl amide synthesis.
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first insights into the mechanism of the direct formation of
allyl amides from allylic alcohols and halogenated nitriles.
This research demonstrates that nitriles can be catalytically
activated by a noble metal for processes other than simple
hydration or amination. The further extension of this approach
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concept to other important synthetic transformations is cur-
rently in progress.
This work was supported by the School of Chemistry at the
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the starting materials.
7476 | Org. Biomol. Chem., 2013, 11, 7472–7476
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