A simple amine protection strategy for olefin metathesis reactions

Article abstract of DOI:10.1039/c0cc03716h

Acyclic diamines are valuable feedstocks for polyamide synthesis. Ruthenium-alkylidene catalysed cross metathesis of amino alkenes is problematic and acyl derivatisation can result in less efficient syntheses, poor catalyst turnover and isomerisation. Tem

Full text of DOI:10.1039/c0cc03716h

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A simple amine protection strategy for olefin metathesis reactionsw
Clint Peter Woodward, Nicolas Daniel Spiccia, William Roy Jackson and
Andrea Jane Robinson*
Received 8th September 2010, Accepted 27th October 2010
DOI: 10.1039/c0cc03716h
Acyclic diamines are valuable feedstocks for polyamide synthesis.
Ruthenium-alkylidene catalysed cross metathesis of amino alkenes
is problematic and acyl derivatisation can result in less efficient
syntheses, poor catalyst turnover and isomerisation. Temporary
amine masking via stable and soluble ammonium salts delivers
cyclic and acyclic aminoalkenes in high yield and purity.
Table 1 CM of 3-butenyl ammonium salts
Entry Counterion X Conditions
Product Yield
1
2
3
4
5
6
Free amine
4a, Cl
CH2Cl2, D
80 1C in HCl satd toluene 5a
CH2Cl2, D
CH2Cl2, D
CH2Cl2, D
CH2Cl2, D
—
0a
Advances in homogeneous catalysts have led to their wide-
spread use in organic synthesis.1 The recent rise in popularity
of olefin metathesis can be directly attributed to the commercial
availability of the catalysts 1–3, the ease in which they can be
handled, and the broad variety of olefins and functional
groups that these catalysts accommodate (Fig. 1).2 These
catalyst systems however, are susceptible to poisoning by
substrates containing moieties that act as strong donor
ligands. Amines, for example, can result in inhibition of the
catalytic cycle by competitively binding to the ruthenium
metal centre.3 This phenomenon may be avoided by masking
the problematic functional group with a protecting group,
reducing the donating capabilities of the relevant heteroatom.
Unfortunately, protection can lead to competing olefin
isomerization4 and unproductive catalytic cycles due to
deleterious protecting group chelation.5 Hence, finding
alternate methods to mask strong donors such as amines
remains a challenge and an important endeavour.
38a
4b, OTfb
4b, OTfc
4c, BF4
5b
5b
5c
5d
8a
83d
91a
c
4d, OTsc
92d, 95d,e
Conditions: catalyst = 3, substrate concentration = B0.1 mol LÀ1
24 h, under N2.a % Conversion determined by 1H NMR spectroscopy
,
b
in D2O. Salt metathesis preformed in situ with AgOTf. Preformed
c
d
e
ammonium salt. Isolated yield. Microwave heating used, 2 h,
100 1C, 100 W.
amines in organic media therefore began by investigating
3-butenyl ammonium salts 4a–d (Table 1). While cross
metathesis of unadultered 3-butenylamine was unsuccessful
(entry 1, 0%), metathesis of 4a in HCl-saturated toluene gave
reasonable conversion (38%) to the target homodimer 5a
(Table 1, entry 2). The observed incomplete reaction was
attributed to poor substrate solubility in toluene. We therefore
sought to rectify this problem by solubilising the ammonium
chloride salt of 3-butenylamine in situ by the addition of
AgOTf. The resultant triflate salt 4b was immediately treated
with Hoveyda Grubbs’ catalyst (3, 5 mol%). Unfortunately,
only poor conversion to the desired product 5b was obtained
(Table 1, entry 3, 8%). The low cross metathesis conversion
was attributed to the deleterious coordination of the AgCl
by-product to the butenyl olefin resulting in a non-reactive
olefinic substrate. In light of this result it was deemed
important to preform the ammonium salts and completely
remove the AgCl prior to olefin cross metathesis (entries 4–6).
The ammonium salts 4b–d, prepared by a standard silver
chloride salt elimination reaction, were subjected to cross
metathesis to generate their respective homodimers 5b–d
(entries 4–6). Solubility tests revealed that the tosylate adduct
4d readily dissolved in dichloromethane at room temperature,
whereas the triflate 4b and tetrafluoroborate 4c salts displayed
only partial solubility at ambient temperature but became
soluble upon heating. The results of the cross metathesis of
the AgCl-free olefinic ammonium salts 4b–d are displayed in
Table 1 (entries 4–6) and show high conversions (83–95%) for
all three salts. The tosylate analogue marginally out performed
the other two salts screened. The homodimer products 5b–d
were readily separated from the reaction mixture by selective
precipitation. Conveniently, the crude products were simply
Towards this end, in situ deactivation of the amino group,
via Brønsted6 or Lewis acid addition,7 has been used to affect
ring closing metathesis (RCM) of dienes containing secondary
and tertiary amines. Our investigations, however, sought to
enable cross metathesis (CM) of unprotected amine-containing
substrates, with a particular emphasis on primary amines as
they have previously proven to be particularly difficult metathesis
substrates.8 Our attempts to homodimerise salt-masked
Fig. 1 Olefin metathesis catalysts.
School of Chemistry, Wellington Road, Clayton 3800, Victoria,
Australia. E-mail: andrea.robinson@monash.edu;
Fax: +61 3 9905 4597; Tel: +61 3 9905 4553
w Electronic supplementary information (ESI) available: Spectral data
for compounds 4a–m and 5a–m. See DOI: 10.1039/c0cc03716h
c
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Chem. Commun., 2011, 47, 779–781 779

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Table 2 CM and RCM of olefinic ammonium salts (4e–m)
Yielda
Conv.
Producte
MW
74
Entry
1
Substrate
40
2
3
23c
46
95
92
4
0
0
5
6
92
90
—
94b
7
8
92d
88d
81
82
9
495c
495c
10
11
495c
495c
495c
9c
Conventional conditions: catalyst = 3, substrate concentration = B0.1 mol LÀ1, catalyst loading 5 mol%, 24 h, 40 1C, under N2. Microwave
a
b
conditions: substrate concentration = B0.1 mol LÀ1, 2 h, 100 1C 100 W, under N2. Isolated yield. Salt formation performed
in situ. Conversion determined by H NMR spectroscopy in d4-MeOH. Olefin isomerisation products observed by ESI-MS. Stereochemical
assessment of acyclic products was examined by NMR spectroscopy and GC analysis of derivative diacetates.
c
1
d
e
washed with solvent to remove catalyst and ruthenium residues.
Homodimerisation of the tosylate adduct 4d could be further
improved to 495% by the use of microwave heating.
Importantly, no olefin isomerisation was observed in any of
these reactions. This was a significant result as exposure of
carbamate protected 3-butenylamine (Fmoc or Boc) to
ruthenium-alkylidene catalyst 2 results in significant isomerisation
of the starting amine and poor conversion (o30%) to the
c
780 Chem. Commun., 2011, 47, 779–781
This journal is The Royal Society of Chemistry 2011

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target homodimer. Given the success of this approach in
providing a temporary and expedient mask of amines during
CM we decided to extend this methodology to additional
amine-containing substrates (Table 2). To remove the
likelihood of AgCl contamination we applied an alternative
method to preparing the starting olefinic ammonium salts by
direct proton exchange of an olefinic amine with anhydrous
p-toluenesulfonic acid. The tosylate salts 4d–m were found to
possess excellent solubility in dichloromethane and their low
hygroscopic nature facilitated easy handling.
Lastly, to show the general applicability of the approach, we
examined three ring closing metathesis reactions involving
primary, secondary and quaternary amines (entries 9–11).
Under conventional and microwave heating conditions, the
tosylate salts of 4k and 4l underwent near quantitative
(495%) conversion to the expected aminocyclopentene
analogues (entries 9 and 10). Quaternary amine 4m, however,
resisted RCM when heated at reflux in DCM in the presence of
Hoveyda Grubbs’ catalyst 3. This result is consistent with a
report by Grubbs and Hong where only low RCM conversion
(o5%) of the analogous chloride salt derivative was observed
using a specialised water soluble metathesis catalyst.9 Significantly,
under microwave irradiation, the amine salt 4m underwent
smooth RCM to provide the target pyrrolidine analogue in
excellent yield (495%, entry 11).
In conclusion, we have developed a method to directly and
temporarily mask primary amines as stable and soluble
ammonium salt derivatives to enable olefin metathesis to
proceed in good to excellent yields without olefin isomerization.
The bis-ammonium tosylate products 5e–l can be readily used
in subsequent chemical transformations by ‘deprotecting’ the
ammonium salt pair with a base, such as triethylamine or
potassium carbonate. This approach therefore provides an
efficient strategy for the metathesis of substrates containing
amine functionality. It is also applicable to the synthesis of a
broad range of diamines and could therefore find widespread
use in polyamide and pharmaceutical production.
The silver-free olefinic ammonium salts were subjected to
both the conventional and microwave reaction conditions used
for 4d, with the results shown in Table 2. In most cases pure
target homodimer 5 was obtained by precipitation from
solution using cold dichloromethane, acetone or hexane, and
washing the filtered product with the same solvent. The
tosylate salt of propenylamine 4e underwent smooth
homodimerisation under microwave conditions (entry 1).
Notably, Miller et al. showed that homodimerisation of
N-acyl derivatives of propenylamine are unsuccessful: in
all cases, a complex mixture of isomerised starting material/
product resulted and the target homodimer could not be
isolated.9 Gratifyingly, the N-benzyl derivative of propenyl-
amine 4f, a secondary amine, also underwent cross metathesis
without isomerization (entry 2), although the use of
microwave heating was required to achieve a respectable yield.
The tosylate salt of butenylamine underwent near quantitative
homodimerisation without isomerization (entry 3). Poor
solubility of the zwitteric allylglycine 4g in DCM prevented
homodimerisation (entry 4), however the tosylate salt of the
methyl ester derivative 4h underwent smooth cross metathesis
to generate the target dimer 5h as a mixture of geometric
isomers and in excellent yield (entry 5). Conveniently, we also
found that the tosylate salts of these substrates could be
generated in situ prior to addition of the metathesis catalyst
by direct proton exchange without affecting yield. This is
exemplified by homodimerisation of 4h in 94% yield under
conventional heating conditions (entry 6).
We acknowledge the provision of an Australian Postgraduate
Research Award (to N.S.) and thank the Australian Research
Council for financial assistance.
Notes and references
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T. M. Champagne, R. L. Pederson and S. H. Hong, Clean: Soil,
Air, Water, 2008, 36, 669; (c) A. H. Hoveyda and A. R. Zhugralin,
Nature, 2007, 450, 243; (d) X. Bei, D. P. Allen and R. L. Pederson,
Pharm. Technol., 2008, s18.
2 (a) A. K. Chatterjee, T. L. Choi, D. P. Sanders and R. H. Grubbs,
J. Am. Chem. Soc., 2003, 125, 11360; (b) T. M. Trinka and
R. H. Grubbs, Acc. Chem. Res., 2001, 34, 19; (c) G. C.
Vougioukalakis and R. H. Grubbs, Chem. Rev., 2010, 110, 1746.
3 P. Compain, Adv. Synth. Catal., 2007, 349, 1829.
4 (a) B. R. McNaughton, K. M. Bucholtz, A. Camaano-Moure and
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J. H. G. Steinke and R. Vilar, J. Org. Chem., 2005, 70, 8235.
5 (a) B. R. Maughon and R. H. Grubbs, Macromolecules, 1997, 30,
3459; (b) A. Furstner, O. R. Thiel and C. W. Lehmann, Organo-
metallics, 2001, 21, 331.
6 (a) A. Furstner and A. Leitner, Angew. Chem., Int. Ed., 2003, 42,
308; (b) A. Furstner, J. Grabowski and C. W. Lehmann, J. Org.
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J. P. Harrity, Chem. Commun., 2002, 1542; (e) V. Gracias,
A. F. Gasiecki, J. D. Moore, I. Akritopoulou-Zanze and
S. W. Djuric, Tetrahedron Lett., 2006, 47, 8977; (f) E. Prusov and
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An interesting relationship between alkyl chain length of the
ammonium salts and the yield of homodimer was also
observed (entries 7 and 8). Short chain homodimers, such as
those derived from 4d and 4e, 3-butenyl and allylamine,
respectively, immediately precipitate from solution reducing
the chance of concomitant isomerization. As the alkyl chain
length is increased however, to undecenylamine for example,
the dimerised product can remain soluble for an extended
period of time potentiating the chance for secondary reaction
(Table 2, entry 7). The mass spectrum of the bis-tosylate
product 5i showed molecular ion peaks separated by m/z
14 a.m.u. suggesting that isomerization processes were operating.
By switching the counterion from tosylate 4i to chloride 4j
however, the solubility of the dichloride homodimer product
5j was decreased to promote early precipitation and eliminate
undesired olefin isomerisation (Table 2, entry 8). Hence, the
point at which the dimerisation product precipitates can be
tuned via modification of the counterion, making product
purification straightforward. Significantly, this feature also
appears to minimise, and in some cases prevent, trans–cis
isomerisation of the acyclic homodimers.
7 Q. Yang, W. J. Xiao and Z. Yu, Org. Lett., 2005, 7, 871.
8 S. J. Connon and S. A. Blechert, Bioorg. Med. Chem. Lett., 2002, 12,
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9 S. H. Hong and R. H. Grubbs, J. Am. Chem. Soc., 2006, 128, 3508.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 779–781 781