Base-catalysed intramolecular hydroamination of vinyl sulfiies

Article abstract of DOI:10.1002/ejoc.200900009

Small amounts of n-butyllithium catalyse the highly efficient hydroamination of a large variety of vinyl sulfides. This novel methodology offers an easy access to a wide range of nitrogen heterocycles, including simple pyrrolidines and piperidines, as well as more complex bicyclic compounds. Subsequent transformations of the sulfur group led to the formation of functionalised alkaloid-like substructures. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900009

FULL PAPER
DOI: 10.1002/ejoc.200900009
Base-Catalysed Intramolecular Hydroamination of Vinyl Sulfides
Coralie Quinet,[a] Laetitia Sampoux,[a] and István E. Markó*[a]
Dedicated to Professor Alain Krief
Keywords: Heterocycles / Alkaloids / Hydroamination / Sulfur
Small amounts of n-butyllithium catalyse the highly efficient
hydroamination of a large variety of vinyl sulfides. This novel
methodology offers an easy access to a wide range of nitro-
gen heterocycles, including simple pyrrolidines and piperi-
dines, as well as more complex bicyclic compounds. Subse-
quent transformations of the sulfur group led to the formation
of functionalised alkaloid-like substructures.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
and intramolecular[9] addition of amines to somewhat acti-
vated substrates such as alkynes,[10] vinyl arenes and
dienes.[11] These initial results, employing “activated” ac-
ceptors have undergone dramatic improvements over the
years. Nowadays, the base-catalysed hydroamination of
myrcene forms the basis of an important industrial process:
the menthol synthesis by Takasago.[12] In stark contrast, the
base-catalysed intramolecular hydroamination of nonacti-
vated alkenes has received considerably less attention.[2k] An
early contribution to this area was due to Evans and co-
workers, who described the preparation of various bridge-
head-substituted dibenzo[a,d]cycloalkenimines by transan-
nular addition of amines to olefins in the presence of cata-
lytic amounts of nBuLi or LDA.[13] However, the observed
regioselectivity, coupled with the special structure of their
substrates, led them to suggest a radical transfer mecha-
nism. To the best of our knowledge, the first report of a
“true”, base-catalysed intramolecular addition of an amine
to a nonactivated alkene was due to Suginome and cowork-
ers.[9a] In 1992, among several examples of intramolecular
hydroamination of styrene derivatives, they described the
addition of a secondary lithium amide to a terminal olefin.
Unfortunately, this reaction proceeded with moderate yields
and went essentially unnoticed.
In 2003, our laboratory accidentally rediscovered the
nBuLi-catalysed intramolecular hydroamination of nonacti-
vated olefins and developed it into a simple and efficient
method for the transformation of several ω-unsaturated
amines into the corresponding pyrrolidines and piperidines
in moderate to good yields.[14] This methodology has sub-
sequently been applied as a key step in several synthetic
ventures by various research groups[15] and enantioselective
variants have also been published.[16] More recently, we
have improved on our initial protocol and devised optimal
conditions to enable the competent synthesis of cyclic
Introduction
The hydroamination of alkenes, the addition of an N–H
bond across a carbon–carbon double or triple bond, is a
highly atom economical method for the preparation of sub-
stituted amines. These are attractive targets for organic syn-
thesis and for the pharmaceutical industry. Though the hy-
droamination reaction is generally a thermodynamic pro-
cess at room temperature,[1] it is plagued by a high acti-
vation barrier due to electronic repulsions between the elec-
tron-rich substrate and the amine nucleophile. Moreover,
this reaction also displays a highly negative entropy, making
it unfavourable at high temperatures. Consequently, cataly-
sis is a prerequisite for this transformation to proceed.[2]
Substantial efforts have resulted in the development of
catalytic systems able to promote the hydroamination of
nonactivated alkenes. Whilst stoichiometric quantities of
transition-metal complexes were initially required,[3] excit-
ing breakthroughs have recently been reported on the inter-
and intramolecular hydroamination of alkenes using alkali
metals,[4] lanthanides[5] and late-transition metals.[6] How-
ever, many of these catalysts suffer from a number of short-
comings (air sensitivity, difficult preparation and/or high
cost). Moreover, the efficiency of these organometallic spe-
cies often applies to substrates benefiting from the Thorpe–
Ingold effect and, hence, already primed to undergo ring
closure, or to specific nitrogen nucleophiles.
Whereas elevated temperatures (up to 180 °C) and high
pressures (up to 800 bar) have been employed with alkali
metals,[7] milder conditions have only enabled the inter-[8]
[a] Université catholique de Louvain, Département de Chimie,
Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Fax: +32-10-472788
E-mail: istvan.marko@uclouvain.be
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Base-Catalysed Intramolecular Hydroamination of Vinyl Sulfides
amines, its application to the assembly of more complex adducts 2 was achieved in only 5 min in every case
bicyclic amines and the synthesis of alkaloid-like natural (Scheme 3). Pyrrolidines 6–15 were obtained in good to ex-
products.[17] Unfortunately, all these hydroamination reac- cellent yields and diastereoisomeric ratios. Only the major
tions only generate the corresponding nitrogen heterocycles diastereoisomer is presented in Scheme 3.
bearing an α-methyl substituent. As was the case previously
in radical chemistry, the cyclic adduct is less functionalised
than the substrate. In order to raise this stringent limitation,
we wondered if the hydroamination of vinyl sulfides such
as 1, using our base-catalysed protocol, would lead to the
desired sulfur-containing ring system 2. In this article, we
wish to report some of our results on the successful imple-
mentation of this novel approach towards functionalised
five- and six-membered nitrogen heterocycles (Scheme 1).
Scheme 1. Proposed hydroamination of vinyl sulfides.
Results and Discussion
Scheme 3. Efficient preparation of pyrrolidines.
At the onset of our work, several amine-containing vinyl
sulfides had to be assembled. An efficient and flexible
As can be seen in Scheme 3, the intramolecular hydro-
method for their preparation is displayed in Scheme 2.
amination of vinyl sulfides offers one of the easiest accesses
Thus, addition of various nitro compounds to the appropri-
to the synthesis of functionalised pyrrolidines. Moreover,
ate acrylates provided nitroester adducts 3. Chemoselective
this methodology is well suited to a large variety of primary
and secondary substrates and tolerates substituents at every
position in the starting material. It is interesting to note
that the use of a secondary amine leads sometimes to the
corresponding pyrrolidine with opposite stereochemical
control (compare structures 7 and 12, 13). In all cases ex-
reduction of the ester function to the corresponding alde-
hyde 4, followed by a Wittig reaction with methylthio- or
phenylthiomethylene triphenylphosphorane led to the de-
sired vinyl sulfides 5 as mixtures of E/Z isomers (up to
2.6:1). Subsequent reduction of the nitro function com-
pleted the efficient formation of primary amines 1 (R =
cept one (i.e., 14), the addition of the secondary amines on
H). Acetylation or benzoylation of these primary amines,
the carbon–carbon double bond is always more diastereo-
selective than the primary amines. Moreover, the Thorpe–
Ingold effect is no longer indispensable for these hydro-
amination reactions to be successful. It thus transpires that
followed by LiAlH4 treatment of the intermediate amides,
provided the corresponding secondary amines 1 in good
yields.
phenyl vinyl sulfides appear to be particularly attractive
substrates for the efficient synthesis of pyrrolidines by base-
catalysed intramolecular hydroamination.
The initial hydroamination reactions employed sulfides 1
as mixtures of E/Z isomers. In order to delineate the role
played by each olefinic isomer in the establishment of the
cis/trans ratio of stereoadducts, the E/Z isomers of substrate
1 (R = H, RЈ = 2-Me, RЈЈ = Ph) were separated. Unfortu-
nately, the Z isomer proved to be unstable and its E coun-
terpart provided 7 in a ratio similar to that observed when
an E/Z mixture was employed.
In order to broaden the scope of this methodology and
to delineate the key role played by the phenyl sulfide sub-
stituent, it was decided to explore the reactivity of two
Scheme 2. Synthesis of the sulfur-containing substrates.
methyl vinyl sulfides 16 and 18. In the presence of a cata-
With a variety of vinyl sulfides in hand, the study of their lytic amount of nBuLi, both 16 and 18 smoothly cyclised,
reactivity in the presence of nBuLi (16 mol-%), in THF at providing the corresponding pyrrolidines 17 and 19 in high
room temperature, was undertaken.[18] Gratifyingly, under yields (Scheme 4). Though the rate of cyclisation of 18 did
these mild conditions, quantitative formation of the desired not differ too much from that of its –SPh counterpart, 16
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underwent hydroamination much more slowly, requiring up Much to our pleasure, the corresponding piperidines 23,
to 72 h to reach completion. Interestingly, the ring closure 25 and 27 were obtained in excellent yields, either at room
of vinyl sulfide 16 proved to be more diastereoselective temperature or at 50 °C (Table 1). Even though the reaction
(compare 9 and 17).
times were longer (1–10 h at 25 °C) than those required for
the synthesis of pyrrolidines (5 min), gentle heating pro-
vided the desired piperidines in 5 min or less. Finally, it is
interesting to note that secondary amines, such as 26, are
significantly more reactive than their primary counterparts,
such as 22.
Table 1. Efficient synthesis of piperidines.
Scheme 4. Influence of the sulfur substituent.
It thus transpires that a phenyl substituent on the sulfur
atom of the vinyl sulfide substrates probably exerts an elec-
tron-withdrawing effect that might help in stabilising a
putative carbanionic intermediate. In this regard, the role
played by the sulfur group on the rate enhancement of these
hydroamination reactions (as compared with the corre-
sponding terminal olefins[14,17]) is less than obvious. Indeed,
due to the electron-donating ability of the sulfur atom, the
carbon–carbon double bond of a vinyl sulfide is more elec-
tron-rich than that of a terminal alkene.[19] Therefore, the
presence of sulfur should considerably slow down the ad-
dition of lithiated amide 20 (Scheme 5). However, a sulfur
atom is also polarisable and well known to stabilise a carb-
anion at the α position.[20] Even though the initial approach
of the negatively charged nitrogen atom on the vinyl sulfide
double bond should be significantly disfavoured, the capa-
bility of the sulfur substituent to stabilise the developing
negative charge in the transition state should lower the en-
ergy of activation of the hydroamination process, thereby
increasing the rate of addition.[21]
[a] All yields are for pure, isolated compounds. All the conversions
were quantitative and the reactions were performed by using nBuLi
(1.6  in hexanes, 16 mol-%) in THF (0.5  solutions). [b] dr = 1:1.
With a rapid and efficient access to both five- and six-
membered nitrogen heterocycles in hand, the assembly of
bicyclic structures akin to the pyrrolizidine, indolizidine
and quinolizidine alkaloids, using this novel hydroamin-
ation protocol, was next investigated. As can be seen from
Table 2, divinyl sulfides 28 and 30 underwent smooth cycli-
sation in the presence of catalytic quantities of nBuLi in
THF, affording fused bicyclic adducts 29 and 31 in excellent
yields. As for the synthesis of pyrrolidines, only 5 min were
required to reach full conversion at room temperature.
These results stand in sharp contrast to the hydroamination
of the corresponding sulfur-free terminal alkenes, which re-
quired prolonged reaction times at elevated temperature
(110 °C, THP/toluene, 24–48 h).[14,17] Such dramatic differ-
ences clearly highlight the importance of the sulfur substit-
Scheme 5. Possible mechanistic hypothesis.
Though at this stage, an intermediate such as 21 might uent. Much more surprising was the successful cascade hy-
look plausible, we have not yet been able to substantiate its droamination of amine 32, which, upon exposure to small
existence. Moreover, and quite unexpectedly, full metalla- amounts of nBuLi, exclusively produced quinolizidine de-
tion of 1 with quantitative generation of 20 does not lead rivative 33 in good yield. This double cyclisation proved to
to cyclic derivative 21 (Scheme 5).[14,17] Instead, either no be one of the most difficult to realise and required up to
reaction took place or complete decomposition was ob- 8 h at 50 °C to reach full completion.[23] Interestingly, pyr-
served.[22]
rolizidine 31 was obtained as a mixture of only two dia-
The exciting results obtained in the assembly of pyrrol- stereoisomers, suggesting an excellent stereocontrol during
idines by intramolecular hydroamination of the precursors the double ring-closure process.
vinyl sulfides prompted us to study the application of this
The intramolecular hydroamination of vinyl sulfides has
new methodology to the synthesis of the homologous six- provided us with a variety of adducts bearing a sulfur sub-
membered ring heterocycles. Accordingly, vinyl sulfides 22, stituent that can readily be converted into a range of useful
24 and 26 were readily assembled and then submitted to functionalities. Initially though, the reductive cleavage of
the nBuLi-catalysed hydroamination protocol (Table 1). the C–S bond to obtain the corresponding methyl-substi-
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Base-Catalysed Intramolecular Hydroamination of Vinyl Sulfides
Table 2. Tandem hydroaminations.
Further functionalisation of these nitrogen heterocycles
by transformation of the sulfur group into an aldehyde moi-
ety was next investigated (Scheme 7). After several attempts,
it was found that oxidation of the sulfur atom of compound
34, by treatment with an aqueous solution of hydrogen per-
oxide in hexafluoro-2-propanol (HFIP),[24] quantitatively
afforded the desired sulfoxide 40, with no trace of the corre-
sponding sulfone, even in the presence of an excess amount
of hydrogen peroxide. Pummerer reaction then produced
Boc-protected prolinal 41 in good overall yields.
Scheme 7. Pummerer reaction of sulfur-containing pyrrolidine.
[a] All yields are for pure, isolated compounds. All the conversions
were quantitative and the reactions were performed by using nBuLi
(1.6  in hexanes, 16 mol-%) in THF (0.5  solutions). [b] A single
diastereoisomer was obtained.
Conclusions
In summary, the base-catalysed hydroamination of vinyl
sulfides opens up new vistas for the efficient and concise
synthesis of a variety of nitrogen-containing substructures
present in numerous natural products. Compared with the
hydroamination of terminal olefins, this methodology re-
quires much milder conditions and needs far shorter reac-
tion times. Our method provides an efficient access to a
large variety of substituted pyrrolidines and piperidines, as
well as to a range of fused bicyclic amine derivatives akin to
the pyrrolizidine and quinolizidine alkaloid families. These
cascade hydroamination reactions occur smoothly and pro-
ceed generally with excellent levels of diastereocontrol. The
hydroamination of vinyl sulfides also offers an efficient ac-
cess to a large variety of functionalised nitrogen heterocy-
cles. Indeed, subsequent transformation of the sulfur group
of the final adducts, for example through a Pummerer reac-
tion, provided the corresponding aldehyde from which a
range of other structural modifications can be envisioned.
Ongoing efforts are now aimed at broadening the scope of
this methodology, applying it to the efficient synthesis of
several relevant natural products and understanding its
mechanism in its most intimate details.
tuted pyrrolidines was investigated. Indeed, simple nitrogen
heterocycles, such as pyrrolidines 38 and 39, are difficult
to access by the intramolecular hydroamination of terminal
olefins, and the combination of hydroamination of vinyl
sulfides followed by desulfurisation might prove to be an
expedient and reliable alternative. Moreover, the generation
of 38 (a known compound) from 34 will help us in the
structural assignment of adduct 34.
At the onset, Raney nickel desulfurisation was attempted
on amines 6 and 9, alas to no avail. Whilst the starting
material was consumed quite readily, only trace amounts of
pyrrolidines 38 and 39 could be obtained, even after exten-
sive processing of the catalyst. It soon became evident that
these basic nitrogen heterocycles remain strongly adsorbed
on the Raney nickel and our efforts to isolate them in good
yields proved to be fruitless. Recourse to a protecting group
became mandatory and Boc-substituted 34 and 35 were
prepared by standard procedures. The reductive cleavage of
the C–S bond of 34 and 35 occurred smoothly in refluxing
methanol, affording pyrrolidines 36 and 37 in good yields.
Finally, the protecting group was removed under acidic
conditions (TFA), leading to amines 38 and 39, identical in
all respects to previously prepared authentic samples
(Scheme 6).
Experimental Section
Representative Procedure for the Hydroamination Reaction. Prepa-
ration of 2-[(phenylthio)methyl]pyrrolidine (6): To a stirred solution
of vinyl sulfide 45 (400 mg, 2.07 mmol, 1 equiv.) dissolved in tetra-
hydrofuran (4 mL, 0.5 ) in a Schlenk tube maintained under an
argon atmosphere was added nBuLi (1.6  in hexanes, 210 µL,
16 mol-%). The solution was stirred at room temperature for 5 min.
Diethyl ether (5 mL) and water (5 mL) were added and the layers
were separated. The aqueous phase was extracted with diethyl ether
(2ϫ). The pooled organic extracts were washed with water and then
with brine. After drying with MgSO4, the solid was filtered and
the solvent was removed in vacuo. Bulb-to-bulb distillation under
reduced pressure (110 °C, turbo pump 3ϫ10–3 mbar) afforded pure
Scheme 6. Removal of the sulfur substituent.
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C. Quinet, L. Sampoux, I. E. Markó
FULL PAPER
6 (374 mg, 93%). H NMR (300 MHz, CDCl3): δ = 7.41–7.13 (m,
1
[5]
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5 H, Ph), 3.28 [quint (tt), J = 6.8 Hz, 1 H, 2-H], 3.09–2.96 (m, 3
H, 1-H and 5a-H), 2.96–2.82 (m, 1 H, 5b-H), 2.01–1.88 (m, 1 H,
3a-H), 1.88–1.67 (m, 3 H, 4-H and 6-H), 1.55–1.40 (m, 1 H, 3b-H)
ppm. 13C NMR (75 MHz, APT, CDCl3): δ = 136.8 (–, C-7), 129.4
and 129.1 (+, C-8 and C-9), 126.1 (+, C-10), 57.8 (+, C-2), 46.6
(–, C-5), 40.3 (–, C-1), 31.3 (–, C-3), 25.5 (–, C-4) ppm. MS (APCI,
70 eV): m/z (%) = 194 (59) [M + 1], 177 (10), 149 (15), 135 (11),
123 (66), 116 (11), 96 (10), 84 (100) [M + 1 – PhSH]. IR (film): ν
˜
= 3333 (w, N–H); 3055 (w, =C–H); 2961–2868 (s, C–H); 1620 (w),
1583 (m, C=C); 1479 (s), 1437 (s), 1393 (s), 1339 (m, C–N); 1088
(s), 1024 (s), 812 (m), 737 (s), 691 (s, C–S) cm–1. CAS: [106865–52–
5].
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details and spectroscopic data.
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Acknowledgments
Financial support for this work by the Université catholique de
Louvain and Merck Sharp and Dohme (Merck Academic Develop-
ment Program Award to IEM) is gratefully acknowledged.
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[21] Theoretical calculations are currently underway to determine
the importance of the anion-stabilising contribution offered by
the sulfur moiety.
[22] The involvement of a true carbanion in the hydroamination of
terminal, nonactivated alkenes appears rather improbable in
view of the enormous difference in pKa values between the N-
centred and C-centred anion. This is reflected by the inability
to capture such a putative carbanion by using a variety of elec-
trophiles (see also ref.[9a]). Such is not the case for the intramo-
lecular addition of an amide onto an “activated” styrene-type
olefin. The stabilisation provided by the aromatic nucleus leads
to the generation of a “true” carbanion, which can be inter-
cepted intramolecularly (S. Tsuchida, A. Kaneshige, T. Ogata,
H. Baba, Y. Yamamoto, K. Tomioka, Org. Lett. 2008, 10,
3635). The situation of the vinyl sulfides is far from being clear-
cut, as the pKa value of amide 20 is rather close to that of
carbanion 21. That no reaction took place when stoichiometric
quantities of nBuLi were used tends to suggest the noninvolve-
ment of a “real” carbanion. More work is needed to shed light
on this important mechanistic problem.
[23] Despite numerous attempts, quinolizidine synthesis by double
hydroamination of the sulfur-free analogue of 32 never af-
forded even a trace amount of the desired bicyclic nitrogen
derivative. C. Quinet, I. E. Markó, unpublished observation.
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Received: January 7, 2009
Published Online: February 26, 2008
Eur. J. Org. Chem. 2009, 1806–1811
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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