Ru(iv)-catalyzed isomerization of allylamines in water: A highly efficient procedure for the deprotection of N-allylic amines

Article abstract of DOI:10.1039/b506788j

A general and efficient method for the deprotection of N-allylic substrates in aqueous media, using catalytic amounts of the bis(allyl)-ruthenium(iv) complexes [Ru(η³ : η² : η³-C ₁₂H₁₈)Cl₂] (1) and [{Ru(η³ : η-C₁₀H₁₆)(μ-Cl)Cl}₂] (2), has been developed. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b506788j

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Ru(IV)-catalyzed isomerization of allylamines in water: A highly
efficient procedure for the deprotection of N-allylic amines
Victorio Cadierno,* Sergio E. Garc´ıa-Garrido, Jose´ Gimeno* and Noel Nebra
Received (in Cambridge, UK) 13th May 2005, Accepted 22nd June 2005
First published as an Advance Article on the web 13th July 2005
DOI: 10.1039/b506788j
allylic deprotection of a large variety of secondary and tertiary
allylamines.5 These catalysts belong to the class in which the active
species are hydride complexes able to undergo isomerization of the
CLC bond to give enamines (Scheme 1; path b).6 The final N–C
bond cleavage to give the deprotected amines is only achieved after
acidic hydrolysis5 or oxidation7 of the enamines.
A general and efficient method for the deprotection of N-allylic
substrates in aqueous media, using catalytic amounts of the
bis(allyl)-ruthenium(IV) complexes [Ru(g3 : g2 : g3-C12H18)Cl2]
(1) and [{Ru(g3 : g3-C10H16)(m-Cl)Cl}2] (2), has been developed.
Among the most important strategies in organic synthesis the
search for efficient protecting groups and subsequent deprotection
methodologies is a crucial issue.1 These processes are particularly
relevant in the chemistry of amines since they generally constitute
unavoidable steps in a great variety of organic transformations
including the synthesis of natural products and other polyfunc-
tional complex molecules.1 The use of allyl moieties as protecting
groups in amines is becoming more and more popular since, in
contrast to more classical protecting groups, they remain inert in
both acidic and basic media.1 In addition, due to the presence of
an orthogonal p-bond, the final deprotection step can be easily
achieved in the presence of transition metals via appropriate
coordination.
We have recently reported that the bis(allyl)-ruthenium(IV)
complexes [Ru(g3 : g2 : g3-C12H18)Cl2] (C12H8 5 dodeca-2,6,10-
triene-1,12-diyl) (1) and [{Ru(g3
:
g3-C10H16)(m-Cl)Cl}2]
(C10H16 5 2,7-dimethylocta-2,6-diene-1,8-diyl) (2) (see Fig. 1)8
are able to promote CLC migrations in water and perform
catalytic isomerizations of allylic alcohols.9 Taking advantage of
this ability, herein we report that they are also efficient catalysts for
the deprotection of secondary as well as tertiary N-allylic amines in
water with tolerance of common functional groups. This is the
first synthetic procedure which is performed in pure aqueous
media and proceeds in a one-pot manner (Scheme 1; path c). Up to
now, the CLC isomerization step had only been performed in
organic solvents.5 In addition, these catalysts act selectively
towards the deprotection of N,N-diallylamines in marked contrast
to the Grubbs’ type catalysts which lead to complex mixtures of
products due probably to their competitive activity in RCM
transformations.10
In this regard, transition-metal catalyzed reactions are currently
one of the most efficient and selective strategies for the
deprotection of N-allylamines.1,2 Nevertheless, the number of
active metal catalysts is till now very scarce, showing most of them
a range of limitations affecting both to the substrates as well as the
reaction conditions.1 Thus, the methodology using palladium(0)
complexes, which are among the most efficient catalysts, requires
the presence of stoichiometric amounts of
a nucleophilic
scavenger.3 This important drawback arises from the transient
formation of p-allylamine complexes which undergo the extrusion
of the allyl group and elimination of the free amine via reaction
with a nucleophile (Scheme 1; path a).4
Recently, it has been reported that Grubbs’ carbene complexes
[RuCl2(5CHPh)(L)(PCy3)] (L 5 PCy3, IMes) also catalyze the
Fig. 1 Structure of the bis(allyl)-ruthenium(IV) complexes 1 and 2.
Firstly, we have checked the activity of complexes 1 and 2 in the
deprotection of N-allylaniline as a model reaction. Thus, we have
found that, under optimized conditions (3 mol% of Ru; 0.1 M
solution of the substrate in water, 90 uC), both complexes are
efficient catalysts for this transformation affording deallylated
aniline in 96% yield after ca. 3 h (entry 1 in Table 1).{ The use of
lower temperatures and/or catalyst loadings slows down the
reaction considerably.11 In this reaction the allyl unit is selectively
transformed into propionaldehyde (detected by GC) confirming
the intermediate formation of an enamine which, due to the
aqueous media, is readily hydrolyzed.
Scheme 1 Strategies used for the catalytic deprotection of N-allylamines.
Under these optimal reaction conditions, catalysts 1 and 2 are
also active in the deprotection of a large number of secondary
N-allylic substrates (entries 2–13 in Table 1).12 Thus, as observed
for N-allylaniline, its ortho-, meta- and para-substituted derivatives
undergo a fast (¡3 h) and efficient removal of the allyl unit
Departamento de Qu´ımica Orga´nica e Inorga´nica, Instituto
Universitario de Qu´ımica Organometa´lica ‘‘Enrique Moles’’ (Unidad
Asociada al C.S.I.C.), Universidad de Oviedo, 33071, Oviedo, Spain.
E-mail: jgh@uniovi.es (Jose´ Gimeno); vcm@uniovi.es (Victorio
Cadierno); Fax: +34985103446; Tel: +34985103461
4086 | Chem. Commun., 2005, 4086–4088
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Table 1 Ru(IV)-catalyzed deprotection of N-allylamines in watera
Entry
1
Substrate
Catalyst
Time
Yieldb
Entry
12
Substrate
Catalyst
Time
Yieldb
1
2
3.5 h
3 h
96%
96%
1
2
3 h
1.5 h
99%
99%
2
3
4
5
6
7
1
2
2 h
2 h
.99%
.99%
13
14
15
16
17
18
1
2
6 h
7 h
95%
97%
1
2
45 min
15 min
.99%
.99%
1
2
1 h
1 h
.99%
.99%
1
2
15 min
15 min
.99%
.99%
1
2
3.5 h
3.5 h
99%
95%
1
2
15 min
30 min
97%
.99%
1
2
1 h
1.5 h
97%
95%
1
2
1.5 h
2 h
.99%
.99%
1
2
1.2 h
2 h
.99%
.99%
1
2
45 min
5 min
.99%
.99%
1
2
22 h
8 h
81%
98%
8
9
1
2
30 min
1.5 h
96%
.99%
19
20
21
1
2
1 h
3 h
.99%
98%
1
2
2 h
1.5 h
98%
97%
1
2
45 min
2 h
.99%
96%
10
1
2
3 h
2 h
.99%
.99%
1
2
7 h
7 h
90%
.99%
11
1
2
20 min
20 min
.99%
.99%
22
1
2
6 h
4.5 h
99%
99%
a
b
Reactions performed under N2 atmosphere at 90 uC using 1 mmol of the corresponding N-allylamine (0.1 M in water). Yields determined
by GC.
(¢96% yield) regardless of the presence of electron-withdrawing or
electron-donating groups (entries 2–11). Different functionalities at
the aryl ring, such as halides (entries 2–6), nitro (entry 7), alkoxy
(entry 9), ketone (entry 10) and ester (entry 11), are tolerated
in this transformation. Special mention deserves the ability
shown by complexes 1 and 2 for the selective deprotection of
halide-substituted anilines (entries 2–6) since, using the classical
Pd(0) deallylation methodology, competitive oxidative addition of
the halide–Caryl bond to the metal could be envisaged. Secondary
alkyl–allylamines (entries 12–13), as well as tertiary diaryl- (entry
14), aryl–alkyl- (entries 15–16) and dialkyl–allylamines (entries 17–
18), can also be efficiently deprotected (¢95% yield within 1–8 h),13
assessing the generality of this catalytic methodology.{ It is
interesting to note that no epimerization reaction takes place
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deallylated products was assessed by comparison with commercially
available pure samples (Aldrich Chemical Co. or Acros Organics) and by
their fragmentation in GC-MS.
during the deallylation of (S)-N-allyl-N-benzyl-a-methylbenzyl-
amine (entry 18).14 Thus, this method can be applied in the
preparation of optically active compounds.
{ We note that all these reactions can be performed in a preparative scale.
Representative example: Under
a nitrogen atmosphere,
It is also worth noting that this deallylation procedure can be
applied to substrates of synthetic interest serving as crucial
intermediates for the preparation of a large variety of both natural
products and pharmacologic agents. Thus, we have found that
N-allyl-1,2,3,4-tetrahydroquinoline (entry 19), N-allylindoline
(entry 20), N-allylindole (entry 21) and N-allylimidazolidine-2-
thione (entry 22) can be easily deallylated in high yields (¢90%).
Of particular significance is the chemoselectivity observed in the
reaction of N-allylimidazolidine-2-thione (entry 22) containing a
free NH unit and a thiocarbonyl group.
N-allylcyclohexylamine (3 g, 21.5 mmol), complex 2 (0.199 g, 0.324 mmol)
and water (200 mL) were introduced in a Schlenk flask and the reaction
mixture stirred at 90 uC for 3 h (quantitative conversion by GC). The
resulting aqueous solution was then saturated with NaCl and extracted
with dichloromethane (3 6 50 mL). The combined organic extracts were
dried over MgSO4, concentrated and purified by column chromatography
over silica gel, using diethyl ether as eluent, to give 1.96 g (19.8 mmol) of
analytically pure cyclohexylamine (92% yield).
1 (a) P. J. Kocienski, Protecting Groups, Thieme Verlag, Stuttgart, 3rd
edn., 2003; (b) T. W. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, Wiley-Interscience, New York, 3rd edn., 1999.
t
Remarkably, N,N-diallylaniline and N,N-diallyl-p-nitroaniline
can also be completely deallylated to give the corresponding
primary anilines in excellent yields (¢96%) after 7–9 h (see
Scheme 2). No RCM products have been detected by GC-MS. As
far as we know these are the first ruthenium catalysts which are
able to perform chemoselectively the deprotection of N,N-diallylic
amines.10
2 For examples of stoichiometric deprotections see: (a) BuOK/DMSO:
J. A. Montgomery and H. J. Thomas, J. Org. Chem., 1965, 30, 3235; (b)
Cp2Zr: H. Ito, T. Taguchi and Y. Hanzawa, J. Org. Chem., 1993, 58,
774; (c) OsO4/NaIO4: P. I. Kitov and D. R. Bundle, Org. Lett., 2001, 3,
t
2835; (d) BuLi: J. Barluenga, F. J. Fan˜ana´s, R. Sanz, C. Marcos and
J. M. Ignacio, Chem. Commun., 2005, 933; (e) Thiyl radicals:
S. Escoubet, S. Gastaldi, V. I. Timokhin, M. P. Bertrand and D. Siri,
J. Am. Chem. Soc., 2004, 126, 12343.
3 See for example: F. Guibe´, Tetrahedron, 1998, 54, 2967 and references
therein.
4 The use of nickel catalysts, which also require the presence of a
nucleophilic scavenger, has been reported: T. Taniguchi and
K. Ogasawara, Tetrahedron Lett., 1998, 39, 4679.
5 (a) C. Cadot, P. I. Dalko and J. Cossy, Tetrahedron Lett., 2002, 43,
1839; (b) B. Alcaide, P. Almendros and J. M. Alonso, Chem. Eur. J.,
2003, 9, 5793.
6 Formation of an active hydride intermediate by decomposition of the
Grubbs’ carbenes has been proposed but no experimental evidence has
been provided (see ref. 5b). Nevertheless, it should be noted that
isomerization of N-allylic substrates to give the corresponding enamines
catalyzed by Ru-hydride complexes has been extensively studied in
organic media: S. Krompiec, M. Pigulla, N. Kuz´nik, M. Krompiec,
B. Marciniec, D. Chadyniak and J. Kasperczyk, J. Mol. Catal. A:
Chem., 2005, 225, 91 and references therein.
7 (a) S. Kamijo, T. Jin, Z. Huo and Y. Yamamoto, J. Am. Chem. Soc.,
2003, 125, 7786; (b) B. Alcaide, P. Almendros and J. M. Alonso,
Tetrahedron Lett., 2003, 44, 8693.
8 Complexes 1 and 2 are easily prepared by reacting ethanolic solutions of
RuCl3?nH2O with butadiene and isoprene, respectively. See: (a)
J. K. Nicholson and B. L. Shaw, J. Chem. Soc. A, 1966, 807; (b)
L. Porri, M. C. Gallazzi, A. Colombo and G. Allegra, Tetrahedron
Lett., 1965, 4187.
Scheme 2 Deprotection of N,N-diallylamines catalyzed by 1 and 2.
In summary, an operationally simple, inexpensive and efficient
procedure for the removal of the allyl protecting group in amines
has been developed. This one-pot catalytic transformation using
the readily available bis(allyl)-ruthenium(IV) complexes [Ru(g3 : g2
: g3-C12H18)Cl2] (1) and [{Ru(g3 : g3-C10H16)(m-Cl)Cl}2] (2) is based
on their ability to promote CLC migrations in water, allowing the
direct hydrolysis of the initially formed enamines. It represents a
new chemoselective methodology which provides a competitive
route for the deprotection of N-allylic amines, allowing the
limitations of the other previously reported approaches to be
overcome and the double deprotection of N,N-diallylamines to be
performed. In addition, by the first time these transformations
have been performed in water. Providing that organic reactions in
water are of primary interest specially when they proceed under
catalytic conditions,15 the chemoselective deallylation methodology
presented herein is of interest in organic synthesis with potential
industrial applications. Further studies on the scope and limita-
tions of this catalytic reaction, as well as detailed mechanistic
investigations, are now in progress.
9 Complexes 1 and 2 are efficient catalysts for the isomerization of allylic
alcohols into carbonyl compounds in both organic and aqueous media.
See: V. Cadierno, S. E. Garc´ıa-Garrido and J. Gimeno, Chem.
Commun., 2004, 232.
10 B. Alcaide, P. Almendros, J. M. Alonso and A. Luna, Synthesis, 2005,
668.
11 Yields up to 95% were obtained, after 26 h at 90 uC, using a catalyst
loading of 2 mol% of Ru. Yields up to 81% were obtained, after 24 h at
70 uC, using a catalyst loading of 3 mol% of Ru.
12 Close examination revealed that the reaction mixtures are in most of the
cases emulsions rather than homogeneous solutions.
13 The presence of a benzyl substituent seems to promote slower
transformations (entries 13 and 18). A clear example of this situation
is the deprotection of (S)-N-allyl-N-benzyl-a-methylbenzylamine cata-
lyzed by complex 1 in which only 81% of conversion was attained after
22 h (entry 18). At present, no explanation for this particular behaviour
can be provided.
This work was supported by the MCyT of Spain (Project
BQU2003-00255). S.E.G.-G. and V.C. thank the MCyT for the
award of a PhD grant and a Ramo´n y Cajal contract, respectively.
14 Confirmed by GC, using a Supelco Beta-Dex2 120 (30 m, 250 mm)
chiral column, by comparison with a commercially available pure
sample of (S)-N-benzyl-a-methylbenzylamine.
Notes and references
{ General procedure for the deallylation reactions: Under a nitrogen
atmosphere, the corresponding N-allylic substrate (1 mmol), the ruthenium
catalyst precursor 1 or 2 (3 mol% of Ru) and water (10 mL) were
introduced in a Schlenk flask and the reaction mixture stirred at 90 uC for
the indicated time. The course of the reaction was monitored by regular
sampling and analysis by gas chromatography. The identity of the resulting
15 (a) C. J. Li and T. H. Chan, Organic Reactions in Aqueous Media, John
Wiley & Sons, New York, 1997; U. M. Lindstro¨m, Chem. Rev., 2002,
102, 2751 and references therein; (b) For a recent review on ruthenium-
catalyzed reactions in aqueous media see: M. Wang and C. J. Li, in
Ruthenium Catalysts and Fine Chemistry, ed. C. Bruneau and P. H.
Dixneuf, Springer-Verlag, Berlin, 2004.
4088 | Chem. Commun., 2005, 4086–4088
This journal is ß The Royal Society of Chemistry 2005