Efficient intramolecular hydroamination of unactivated alkenes catalysed by butyllithium

Article abstract of DOI:10.1002/ejoc.200300058

In this communication, we wish to report some preliminary results demonstrating, for the first time, that intramolecular hydroamination of unactivated alkenes can be performed efficiently using small quantities of nBuLi as the pre-catalyst. Wiley-VCH Verl

Full text of DOI:10.1002/ejoc.200300058

SHORT COMMUNICATION
Efficient Intramolecular Hydroamination of Unactivated Alkenes Catalysed by
Butyllithium
Ali Ates*[a] and Coralie Quinet[a]
Keywords: Alkenes / Amination / Cyclization / Lithium
In this communication, we wish to report some preliminary
results demonstrating, for the first time, that intramolecular
hydroamination of unactivated alkenes can be performed ef-
ficiently using small quantities of nBuLi as the pre-catalyst.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003
Introduction
ditions[6,8] or with transition metals.[7,9] A breakthrough in
the metal-catalysed[3,4] intramolecular hydroamination of
unfunctionalised alkenes was achieved about ten years ago
by the use of lanthanide complexes.[5] Unfortunately, the
extraordinarily high sensitivity of these catalysts towards
both moisture and oxygen precludes their general use with-
out specialised equipment.
The hydroamination of alkenes (Figure 1) — the addition
of an NH unit to a carbon-carbon double bond to form the
corresponding amines — is of paramount importance in
organic chemistry. This transformation, which is ideal from
the viewpoint of atom economy as both reactants combine
to afford a single product, generates the desired nitrogen
derivative in only one step from readily available starting
materials.
Results and Discussion
During some investigations directed towards the develop-
ment of novel catalytic systems for the intramolecular hy-
droamination of unactivated alkenes, rigorously dry 1-am-
ino-2,2-dimethylpent-4-ene (1) was required, and therefore
it was stirred over sodium-potassium amalgam. Much to
our surprise, the corresponding hydroaminated product 2
(entry 1, Table 1) was obtained, although in a modest yield
of 10% (GC yield).[10] This result attracted our attention[11]
and we decided to study in detail the base-catalysed cyclis-
ation of amines such as 1. In this communication, we wish
to report some preliminary results demonstrating, for the
Figure 1. Hydroamination of unactivated alkenes
However, despite an enormous amount of work, only
limited success has been obtained so far in the establish-
ment of a mild and efficient procedure for the hydroamin-
ation of unactivated alkenes.[1] In 1954, Howk[2a] reported
that ammonia and ethylene react in the presence of alkali
metals under forcing conditions (temperature of up to 180
°C and pressures of up to 800 bar) to produce a mixture of
ethyl-, diethyl- and triethylamine. More substituted alkenes,
such as propene or 1-hexene, are less reactive under these
conditions[2] (yields and/or conversions Ͻ30%). Only styr-
ene and some substituted derivatives, as well as 1,3-dienes,
which can be considered as slightly activated olefins, have
been successfully hydroaminated under alkaline con-
Table 1. Solvent and pre-catalyst effect on intramolecular hydro-
amination of substrate 1
[a]
´
´
Universite catholique de Louvain, Departement de Chimie,
´
´
ˆ
Unite de Chimie Organique et Medicinal, Batiment Lavoisier,
Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Fax: (internat.) ϩ32-10/472-788
[a]
[c]
[b]
Ratio determined by GC analysis.
nBuLi (1.6  in hexanes).
nBuLi (1.6  in hexanes), THF, substrate concentration 0.5 ,
E-mail: atesa@chim.ucl.ac.be
room temp.
Eur. J. Org. Chem. 2003, 1623Ϫ1626
DOI: 10.1002/ejoc.200300058
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A. Ates, C. Quinet
SHORT COMMUNICATION
first time, that intramolecular hydroamination of unacti- cyclised and isomerised products 8:9 in a ratio of 75:25 after
vated alkenes can be performed efficiently using small more than 95% conversion at 50 °C.[12] Clearly, the substi-
quantities of nBuLi as the pre-catalyst.
tution along the chain linking the amine and the olefin
Initial experiments, using catalytic amounts of a variety functions is responsible for the observed preference between
of bases such as nBuLi in the neat amines, produced only the hydroamination and the isomerisation of the double
traces of the desired cyclised product 2 (Table 1, entry 2). bond. The ThorpeϪIngold effect, generated by the 2,2-di-
However, addition of nBuLi to the dry aminoolefin 1 in methyl substituent in substrate 1, is sufficient to suppress
tetrahydrofuran (0.5  concentration), at room temperature, the isomerised product 3 completely (entry 3, Table 2).
smoothly led to the formation of the corresponding pyrroli- However, amine 4 or 7, which do not possess such a similar
dine 2 in excellent yield (95%. GC yield, Table 1, entry 3) ThorpeϪIngold effect, gave some isomerised product 6 or
accompanied by trace amounts of the starting material 1 9 beside the hydroaminated product 5 or 8 (entries 1 and
and the isomerised alkene 3.
2, Table 2).
This remarkable result prompted us to investigate in
The synthetic utility of this novel, catalytic hydroamin-
greater detail the scope and limitations of this novel cata- ation protocol is further exemplified by the smooth ring
lytic system. Various olefins bearing a primary amine func- closure of amine 10 to afford the spiro-bicyclic system 11
tion were thus prepared and reacted under our optimised in 91% isolated yield (Table 2, entry 4). Only minute
conditions: nBuLi as pre-catalyst (5Ϫ16 mol %) in tetra- amounts of the isomerisation product 12 could be detected
hydrofuran at 50 °C or room temperature. Some selected by GC and NMR analysis. Having successfully demon-
results are collected in Table 2. When amine 4 was used, a strated that primary amines could be cyclised using small
fast reaction occurred at 50 °C and more than 95% conver- quantities of nBuLi (5Ϫ16 mol %), we next turned our at-
sion was observed after 2 hours of reaction (entry 1, tention to the intramolecular hydroamination of disubsti-
Table 2). However, a mixture of the cyclised product 5 and tuted amines. When various secondary amines were sub-
the isomerised alkene 6 was generated in a ratio of 32:68 jected to our standard base-catalysed conditions, a remark-
(GC ratio). On the other hand, when 1-amino-2,2-dimeth-
ylpent-4-ene (1; entry 3, Table 2) was reacted under the
same conditions, adduct 2 was formed in a quantitative
yield and no isomeric amine 3 could be detected either by
GC or NMR analysis. Compound 7, possessing a single
methyl substituent (entry 2, Table 2) also gave a mixture of
Table 3. Intramolecular hydroamination of secondary amines.
Table 2. Intramolecular hydroamination of primary amines.
[a] nBuLi (16 mol %), THF or [D8]THF, room temp., substrate con-
[a]
[b]
[c]
nBuLi (1.6  in hexanes; for reasons of simplicity 16 mol % of
centration 0.5 .
Isolated yield, conversion Ͼ95%.
Yield in
pre-catalyst was used), THF or [D8]THF, 50 °C, substrate concen- brackets determined by GC analysis or NMR spectroscopy in
tration 0.5 . [b] Determined by GC analysis or NMR spectroscopy
[D8]THF. [d] Ͻ2% isomerisation of the double bond. [e] The amount
[d]
in [D8]THF. [c] Isolated yield, conversion Ͼ95%. The amount of
of pre-catalyst could be reduced to 5 mol % without any significant
[f]
pre-catalyst could be reduced to 5 mol % without any significant change in the yield of the hydroaminated product. 5% isomeris-
change in the yield of the hydroaminated product. [e] Reaction per-
ation of the double bond. [g] 20% isomerisation of the double bond
[h]
formed at room temp. instead of 50 °C.
Reaction performed at 50 °C.
1624
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Eur. J. Org. Chem. 2003, 1623Ϫ1626

Efficient Intramolecular Hydroamination of Unactivated Alkenes
SHORT COMMUNICATION
ably rapid formation of the desired pyrrolidines ensued double bond of unactivated alkenes to form intermediate
(Table 3). In most cases, only five hours were required, at 30. This lithiated carbanion is then protonated by the excess
room temperature, for the quantitative conversion of the amine 27, giving pyrrolidine 31 and regenerating amide 28,
aminoolefin into the corresponding five-membered hetero- which initiates a new catalytic cycle (Figure 2). In parallel,
cycle (entries 1Ϫ4, Table 3).
amine 29 might be formed competitively at room tempera-
As can be seen from Table 3, N-ethyl (entry 1 and 3, ture by an intramolecular allylic-deprotonation/repro-
Table 3) and N-benzyl (entries 2 and 4, Table 3) substituents tonation sequence (Figure 2). At higher temperature (50
can be used equally successfully despite their important °C), the isomerisation equilibrium between 28 and 29 ap-
steric and electronic differences. Furthermore, no by-prod- pears to be reversible and intramolecular cyclisation of am-
uct originating from metallation at the benzylic position ine 28 displaces this equilibrium, ultimately affording ad-
could be detected. It is noteworthy that the ThorpeϪIngold duct 31.
effect, which favours to some extent the hydroamination of
In summary, we have developed an efficient, catalytic
primary amines, appears to play a much weaker role in the protocol for the intramolecular hydroamination of unacti-
cyclisation of disubstituted amines. For example, intramol- vated double bonds. To the best of our knowledge, this is
ecular ring closure of substrates 21 (no methyl substituent) the first report that the use of inexpensive nBuLi (5Ϫ16
proceeded smoothly, affording the desired pyrrolidines 22 mol %) allows the expeditious high yielding intramolecular
in excellent yield (compare entry 5, Table 3 with entry 1, cyclisation of primary and secondary amines onto unacti-
Table 2). However, the presence of another substituent on vated alkenes. This novel catalytic procedure opens exciting
nitrogen does not completely suppress the isomerisation avenues for the rapid assembly of a variety of pyrrolidines,
and, besides amine 22, 5% of the by-product originating piperidines and derivatives. Further work is now directed at
from isomerisation of the terminal double bond to the 1,2- delineating the full scope of this protocol, establishing an
disubstituted alkene was observed. Similarly, the secondary enantioselective version and applying it to the synthesis of
N-benzyl-amine 23, possessing a methyl substituent at C-1, related natural products.
gave the two pyrrolidines 24 in 75% isolated yield with a
cis:trans ratio of 78:22 (entry 6, Table 3) accompanied by
some isomerised product (Ͻ20%).
It is noteworthy that our base-catalysed protocol allows
Experimental Section
not only the synthesis of various pyrrolidines but also the
assembly of piperidines (entry 7, Table 3). Indeed, when
amine 25 was treated with 16 mol % of nBuLi, at room tem-
perature in tetrahydrofuran, the hydroaminated product 26
was observed, along with the isomerised alkene, in a ratio of
30:70 (determined by GC analysis and NMR spectroscopy).
Interestingly, when this 30:70 mixture of compounds was
reacted under the same base-catalysed conditions, but at 50
°C instead of room temperature, the isomerised product dis-
appeared completely in favour of the hydroaminated adduct
26. Similarly, heating 25 with catalytic amounts of nBuLi,
at 50 °C, resulted in the sole production of 26 (isolated yield
95%, entry 7, Table 3).
nBuLi (1.6 /hexane, 358 µL, 16 mol %) was added at room tem-
perature to a stirred solution of 1-amino-2,2-dimethylpent-4-ene (1;
405 mg, 3.58 mmol) in tetrahydrofuran (0.5 , 7 mL). The solution
was stirred for 24 hours at room temperature. Diethyl ether (25 mL)
and water (3 mL) were then added; the mixture was decanted and
the aqueous phase extracted with diethyl ether (3 ϫ 5 mL). The
organic extracts were dried over MgSO4 and the solvent removed
carefully in vacuo at 0 °C to give 346 mg (85%) of 2 as a colourless
1
oil. H NMR (300 MHz, CDCl3, 20 °C, TMS): δ ϭ 1.04 (s, 3 H,
CH3), 1.07 (s, 3 H, CH3), 1.12 (dd, 2JH,H ϭ 12.45, 3JH,H ϭ 3.35 Hz,
1 H, CH2), 1.15 (d, 3JH,H ϭ 6.22 Hz, 3 H, CH3), 1.69 (dd, 2JH,H ϭ
3
2
12.44, JH,H ϭ 6.7 Hz, 1 H, CH2), 2.72 (A part of AB, JH,H
ϭ
2
11.0 Hz, 1 H, CH2), 2.59 (B part of AB, JH,H ϭ 11.01 Hz, 1 H,
CH2), 3.18Ϫ3.33 (m, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3,
20 °C) 21.9, 28.1, 29.0, 39.9, 49.7, 54.4, 61.1 ppm. IR (KBr): ν˜ ϭ
1100 cmϪ1, 1152, 1198, 1280, 1366, 1377, 1463, 1649, 2866, 2955,
3298. MS (70 eV): m/z (%) ϭ 113 (5) [M·ϩ], 98 (40), 57 (100).
Based upon these observations, a plausible mechanism
for the nBuLi-catalysed hydroamination of olefins can be
proposed (Figure 2).
Acknowledgments
The author would like to express his appreciation and his deep
´
respect to I. E. Marko for his generous support, encouragement
and many suggestions. We thank the Fonds National de la Recher-
che Scientifique (FNRS) for financial support.
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SHORT COMMUNICATION
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