Ruthenium-Catalyzed Chemoselective N-Allyl Cleavage: Novel Grubbs Carbene Mediated Deprotection of Allylic Amines

Article abstract of DOI:10.1002/chem.200305236

A novel application of the Grubbs carbene complex has been discovered. The first examples of the catalytic deprotection of allylic amines with reagents other than palladium catalysts have been achieved through Grubbs carbene mediated reaction. Significantly, the catalytic system directs the reaction toward the selective deprotection of allylic amines (secondary as well as tertiary) in the presence of allylic ethers. A variety of substrates, including enantiomerically pure multifunctional piperidines, are also usable. The new method is more convenient, chemoselective, and operationally simple than the palladium-catalyzed method. The current mechanistic hypothesis invokes a nitrogen-assisted ruthenium-catalyzed isomerization, followed by hydrolysis of the enamine intermediate. We believe that the reactive species involved in the reaction may be an Ru-H species rather than the Grubbs carbene itself. Thus, the isomerization may occur according to the hydride mechanism. The synthetic utility of this ruthenium-catalyzed allyl cleavage is illustrated by the preparation of indolizidine-type alkaloids.

Full text of DOI:10.1002/chem.200305236

FULL PAPER
Ruthenium-Catalyzed Chemoselective N-Allyl Cleavage: Novel Grubbs
Carbene Mediated Deprotection of Allylic Amines
Benito Alcaide,*[a] Pedro Almendros,*[b] and Jose M. Alonso[a]
Abstract: A novel application of the
Grubbs carbene complex has been dis-
covered. The first examples of the cata-
lytic deprotection of allylic amines with
reagents other than palladium catalysts
have been achieved through Grubbs
carbene mediated reaction. Significant-
ly, the catalytic system directs the reac-
tion toward the selective deprotection
of allylic amines (secondary as well as
tertiary) in the presence of allylic
ethers. A variety of substrates, includ-
ing enantiomerically pure multifunc-
tional piperidines, are also usable. The
new method is more convenient, che-
moselective, and operationally simple
than the palladium-catalyzed method.
The current mechanistic hypothesis in-
vokes a nitrogen-assisted ruthenium-
catalyzed isomerization, followed by
hydrolysis of the enamine intermediate.
We believe that the reactive species in-
volved in the reaction may be an RuÀ
H species rather than the Grubbs car-
bene itself. Thus, the isomerization
may occur according to the hydride
mechanism. The synthetic utility of this
ruthenium-catalyzed allyl cleavage is il-
lustrated by the preparation of indolizi-
dine-type alkaloids.
Keywords: amines
cleavage reactions
groups ¥ ruthenium
¥
carbenes
protecting
¥
¥
Introduction
tion, primarily due to the high catalytic activity of phosphine
and imidazolidine ruthenium carbene complexes in olefin
metathesis. Olefin metathesis is a catalytic reaction in which
alkenes are converted into new products through the rup-
ture and reformation of CÀC double bonds. Depending on
the starting material (cyclic or acyclic alkenes) and the reac-
tion parameters, ring-closing metathesis (RCM), acyclic
diene metathesis (ADMET), or ring-opening metathesis pol-
ymerization (ROMP) proceed. The most useful ruthenium
carbene complex in the series is the Grubbs catalyst,
[(PCy3)2Cl2Ru=CHPh](Cy =cyclohexyl), which bears a ben-
zylidene unit.[5] Being highly active and remarkably tolerant
to common functional groups, this compound has found
many applications in both organic and polymer chemistry.
On the other hand, neither improvements in selectivity nor
the invention of new reactions have abated the dependence
of modern organic chemistry on protecting groups.[6] The
allyl moiety is a protecting group that permits orthogonal
protection strategies with a wide range of protecting groups,
a property that allows its use in multistep synthetic schemes.
The removal of allylic protecting groups through catalytic p-
allyl palladium methodology has recently received growing
attention,[7] especially in the field of peptide chemistry. Allyl
carboxylates, carbonates, carbamates, ethers, and amines
have been successfully deallylated. However, this methodol-
ogy requires the presence of both the palladium catalyst and
a nucleophilic compound as an allyl group scavenger. In this
contribution, we present full details of a novel, simple, che-
moselective, and general ruthenium-catalyzed deprotection
As the coordination chemistry of ruthenium complexes has
progressed, the characteristic features of ruthenium (for ex-
ample, high electron transferability, low redox potentials,
stability of reactive metallic species, metallacycles, and
metal carbenes) have opened the way for a broad variety of
catalytic transformations. These include olefin metathesis,[1]
Kharasch addition reactions,[2] hydrosilylation of carbonyls,[3]
and enol ester synthesis.[4] The chemistry of late-transition-
metal carbene complexes has recently received much atten-
[a]Prof. Dr. B. Alcaide, Dipl.-Chem. J. M. Alonso
Departamento de QuÌmica Orgµnica I
Facultad de QuÌmica
Universidad Complutense de Madrid
28040 Madrid (Spain)
Fax : (+34)913-944-103
E-mail: alcaideb@quim.ucm.es
[b]Dr. P. Almendros
Instituto de QuÌmica Orgµnica General
Consejo Superior de Investigaciones CientÌficas
Juan de la Cierva 3
28006 Madrid (Spain)
Fax : (+34)915-644-853
E-mail: iqoa392@iqog.csic.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author and contains com-
pound characterization data and experimental procedures for com-
pounds 1a k, 2a, 2d, 2e, 2g k, 3a c, 4a, 5a g, (+)-6b, (+)-6d, (+)-
6 f, (À)-6g, (+)-7c, (À)-7e, 10d, 10h, and 10j.
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DOI: 10.1002/chem.200305236
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FULL PAPER
of tertiary allylic amines,[8] together with its extension to sec-
ondary allylic amines. In addition, the utility of the N-allyl
cleavage is demonstrated by a process leading to indolizi-
dines. To our knowledge, there are no other examples for
the catalytic deprotection of allylic amines that do not use a
palladium catalyst.[9] In addition, reactions providing a
straightforward rupture of CÀN bonds are rare.[10]
efficient catalyst for the deprotection of allylic amines.
Among the various solvents and conditions tested, we found
that toluene at reflux temperature gave the best yields of N-
deprotected products. The Grubbs catalyst is known to be
moderately thermally unstable,[13] with the thermolytic half-
life having been reported to be eight days at 558C.[13a] To cir-
cumvent this problem, the Grubbs carbene was added in
small portions every twenty minutes (5 mol% is the overall
amount of all the portions). Thus, the catalytic species is
continuously being renewed by fresh Grubbs carbene. Expo-
sure of the tertiary allyl amines 1 to the ruthenium catalyst
[(PCy3)2Cl2Ru=CHPh]under our standard reaction condi-
tions (5 mol% catalyst, 0.03m substrate, toluene, 1108C) re-
sulted in clean formation of the secondary amines 2 in good
yields (62 81%) after chromatographic purification
(Table 1, Scheme 2). Attempts to effect the reaction at tem-
Results and Discussion
In our ongoing project directed toward the asymmetric syn-
thesis of natural products and derivatives of biological inter-
est,[11] we observed that in some cases isomerization to the
internal double bond in an N-allyl b-lactam is favored over
ring-closing metathesis (Scheme 1).[12] The higher stability of
Scheme 2. Grubbs carbene catalyzed deprotection of tertiary allylic
amines. a) 5 mol% [(PCy3)2Cl2Ru=CHPh], toluene, 110 8C.
Scheme 1. Grubbs catalyst promoted isomerization of N-allyl-b-lactams.
peratures lower than 508C slowed the reaction considerably.
Incomplete conversion was observed on decreasing the
amount of catalyst. On the contrary, increasing the catalyst
loading from 5 to 10 mol% did increase the conversion (typ-
ically from 95% to quantitative) but the yield of deallylated
amine increased very little. Tertiary allylic amines, many of
which bear pendant functionalities, were efficiently and cat-
alytically deallylated by the Grubbs carbene. Aromatic as
well as aliphatic amines were amenable to this novel deally-
lation reaction. As a good example, the strained four-mem-
bered cyclic amine (+)-1b smoothly yielded the enantiomer-
ically pure azetidine (À)-2b (entry 2, Table 1). Treatment of
compounds (+)-1 f and (À)-1g with the Grubbs carbene
forms the piperidines (+)-2 f and (À)-2g, bearing two chiral
centers, in 78 and 69% yield, respectively (entries 6 and 7,
Table 1). Piperidines (+)-2 f and (À)-2g showed a single set
enamides in comparison with enamines favors the double-
bond isomerization and thereby prevents N-allyl cleavage.
On the basis of these principles, it was to be expected that
successful catalytic CÀN cleavage from an enamine inter-
mediate could be attained by using allylic amines as sub-
strates.
The highly selective properties of various transition-
metal-derived reagents would seem to recommend their ap-
plication to the removal of the allyl protecting group in
amines, but only palladium complexes have been probed as
useful catalysts.[7] However, such catalysts do not distinguish
between O-allyl ethers and N-allyl amines. Therefore we
were interested in the development of an alternative catalyt-
ic N-deallylation method that can smoothly provide free
amines. Fortunately, an investigation of the chemistry of the
Grubbs ruthenium carbene led to the discovery that it is an
1
of signals in their H NMR spectra, thus proving again that
this transformation proceeds without erosion of stereochem-
ical integrity. The ability of the Grubbs carbene to selective-
ly deprotect allylic amines in the presence of allylic ethers
(entry 3, Table 1) deserves special mention, as it competes
favorably with the p-allyl palladium deallylation methodolo-
gy. Conjugation of the new double bond with the lone pair
of the nitrogen atom is believed to promote the enamine in-
termediate formation in allyl amines, with this ability being
minimized in allyl ethers.[14] In addition to this exquisite che-
moselectivity, the extraordinary functional group tolerance
of the ruthenium-based catalyst [(PCy3)2Cl2Ru=CHPh]cou-
pled with its commercial availability makes it a very conven-
ient catalyst.
Abstract in Spanish: Se ha descubierto un mÿtodo de desali-
laciÛn de aminas catalizado por el carbeno de Grubbs, lo que
constituye el primer ejemplo de desalilaciÛn catalÌtica en el
que no participan complejos de paladio. El sistema catalÌtico
lleva a cabo la desprotecciÛn selectiva de alilaminas (tanto se-
cundarias como terciarias) en presencia de ÿteres alÌlicos. Se
han utilizado una gran variedad de sustratos, como por ejem-
plo piperidinas enantiopuras altamente funcionalizadas. Este
nuevo mÿtodo es mµs Çtil y versµtil que el mÿtodo que utiliza
paladio. Creemos que se produce una isomerizaciÛn alil
amina-enamina, seguida de hidrÛlisis. La especie catalÌtica
activa puede ser un hidruro de rutenio derivado del carbeno
de Grubbs. La utilidad sintÿtica de esta desalilaciÛn catalÌtica
se ha puesto de manifiesto en la preparaciÛn de indolizidinas.
As recently outlined, ligand modification in the Grubbs
carbene improves its excellent application profile even fur-
ther.[15] We thought that it would be of significant interest to
see if the same chemistry occurs with these second-genera-
tion catalysts. Deallylation of some of the amines was effect-
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Grubbs Carbene Mediated Deprotection of Allylic Amines
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Table 1. Grubbs carbene mediated N-deallylation of tertiary allylic amines.[a]
[b]
Substrate
t [h]Product
Yield [%]
1
1a
5
2a
81
2
3
4
(+)-1b
1c
1
1
5
(À)-2b
2c
49
68
77
1d
2d
5
6
7
1e
(+)-1 f
(À)-1g
4.5
4.5
2
2e
(+)-2 f
(À)-2g
75
78
69
8
1h
1i
3.5
1.5
3.5
3
2h
2i
77
78
71
62
9
10
11
1j
1k
2j
2k
[a]All reactions were carried out on the 1 mmol scale. [b]Yield of pure product with correct analytical and spectral data.
ed with the more stable second-generation ruthenium-based
catalyst [Cl2(Im)(Cy3P)Ru=CHPh](Im =1,3-dimesityl-4,5-
dihydroimidazol-2-ylidene), which led to essentially identical
results to those observed with the Grubbs carbene. As re-
Scheme 3. Grubbs carbene catalyzed deprotection of secondary allylic
placement of the first-generation Grubbs catalyst with its
second-generation analogue neither accelerated the reaction
rate nor improved the yield of N-deallylated amines 2, we
chose the less expensive first-generation Grubbs carbene for
our study.
Extrapolation of the deprotection of tertiary allyl amines
to secondary allyl amines is not obvious, since free bases are
claimed to be ineffective for RCM mediated by the Grubbs
catalyst because of poisoning of the catalyst by the amine
functionality due to coordination of the amine group to the
ruthenium.[16] Scheme 3 and Table 2 illustrate several exam-
ples of deprotection of nitrogen on secondary allylic amines
amines. a) 5 mol% [(PCy3)2Cl2Ru=CHPh], toluene, 110 8C.
3. All substrates reacted efficiently to afford high yields of
the corresponding primary amines 4. Noteworthy cases in-
clude a chemoselective N-deallylation in presence of an O-
allyl ether moiety, which remains unchanged (entry 2,
Table 2), and a pyrrolidino quinoline (entry 3, Table 2), the
parent system of which is of known utility in pharmacolo-
gy.[17] Because of the yield of the deprotection reaction, ap-
parently the primary and secondary amine products have no
inhibiting effect.
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B. Alcaide, P. Almendros and J. M. Alonso
FULL PAPER
Table 2. Grubbs carbene mediated N-deallylation of secondary allylic amines.[a]
[b]
Substrate
t [h]Product
Yield [%]
1
2
3a
3b
5
1
4a
4b
81
57
3
(+)-3c
0.5
(+)-4c
52
[a]All reactions were carried out on the 1 mmol scale. [b]Yield of pure product with correct analytical and spectral data.
Several of the above examples provide interesting and
useful structural motifs. For example, piperidines (+)-2 f and
(À)-2g can be converted into derivatives of pipecolic acid, a
nonproteinogenic amino acid present in several natural
products, some of which are of important pharmaceutical in-
terest.[18] A further synthetic application of the present reac-
tion is demonstrated in the following synthesis of indolizidi-
nones. Piperidine-b-lactams can serve in the construction of
indolizidine alkaloids, natural products with diverse and
potent biological activities.[19] However, we have noticed dif-
ficulties in the elimination of nitrogen protecting groups on
N-protected piperidine-b-lactams. As an example, on route
to indolizidine (À)-7e, cerium ammonium nitrate (CAN)
promoted oxidative cleavage of an N-4-methoxyphenyl sub-
stituent provided the key intermediate piperidine-b-lactam
(À)-6g in low yield (approximately 40%).[20] In addition, the
CAN-mediated deprotection was incompatible with the
ketone group. Taking into consideration all these drawbacks,
we tested the Grubbs carbene catalyzed N-deallylation on
the series of compounds 5. In the event, differently function-
alized deprotected piperidine-b-lactams were achieved in
good yields (Scheme 4). Again, the deprotection reactions
show excellent chemoselectivity. In compounds (+)-5c and
(+)-5d the b,g-unsaturated ethers remained unreacted. In
addition, (+)-5e and (+)-5 f show that a selective N-deally-
lation can be achieved in presence of g,d-unsaturated or d,e-
unsaturated amines. However, it should be noted that in the
Grubbs carbene promoted reaction with compounds (+)-5e
and (+)-5 f, in addition to the N-deallylated products (+)-6e
and (+)-6 f, the corresponding RCM products were isolated
as minor products (approximately 30% yield). Piperidine-2-
azetidinones 6 were easily converted into indolizidinones 7
in excellent yields (87 100%). Thus, the ruthenium-cata-
lyzed synthesis of piperidines 6 gives a novel improved
Scheme 4. Grubbs carbene catalyzed deprotection of N-allyl piperidines
and its application to the synthesis of enantiopure indolizidines.
a) 5 mol% [(PCy3)2Cl2Ru=CHPh], toluene, 110 8C; b) MeONa, MeOH,
room temperature. TBS=tert-butyldimethylsilyl, Tol=tolyl.
access to indolizidine-type alkaloids 7 (Scheme 4).
It may be reasonable to postulate that a nitrogen-assist-
ed ruthenium-catalyzed isomerization to a more stable
olefin took place, followed by hydrolysis under chromato-
graphic workup of the enamine intermediate to the free
amine. In order to probe this assumption we must show that
an allylic amine does give the corresponding enamine inter-
mediate 8 in the presence of a catalytic amount of the
Grubbs carbene. This informative result was provided by
monitoring the reactions of 1d and 1h with [(PCy3)2Cl2Ru=
CHPh]by 1H NMR spectroscopy. Indeed, we observed dis-
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Grubbs Carbene Mediated Deprotection of Allylic Amines
5793 5799
appearance of the terminal vinyl group and a comparable
rate of appearance of a methyl group. Not unexpectedly, en-
amines 8d and 8h were characterized by the H NMR spec-
tra of the crude reaction products as a mixture of two iso-
mers.
lyzed deallylation of allylamines), it is general, selective, and
operationally simple. The new method is more convenient
than the conventional palladium-catalyzed method because
Grubbs carbene is able to achieve a chemoselective depro-
tection of allyl amines in the presence of allyl ethers. In ad-
dition, the p-allyl palladium deallylation methodology re-
quires the presence of both the palladium catalyst and a nu-
cleophilic compound as an allyl group scavenger. We believe
that this CÀN bond cleavage involves a ruthenium-catalyzed
isomerization to a more stable olefin, followed by hydrolysis
of the resulting enamine. The specific ruthenium catalyst re-
sponsible for the isomerization is still in question. However,
it is plausible that the reactive species involved in the reac-
tion may be an RuÀH species rather than the Grubbs car-
bene itself. Taken together, these observations have the po-
tential to significantly extend the scope of the allyl protect-
ing group in synthesis. Application of the present efficient
ruthenium catalytic cleavage to other moieties such as
amides and lactams is currently underway in our group.
1
One piece of hypothesis that should be taken into ac-
count is that, due to the reaction conditions, it may be possi-
ble that there is not much catalyst left and the active species
might well be a decomposition product derived from the
Grubbs catalyst. In this case, the active catalyst is probably
the corresponding hydrido derivative formed in situ under
the reaction conditions rather than the Grubbs carbene.
Thus, the isomerization may occur according to the hydride
mechanism, by hydrometallation followed by b elimination,
analogously to the double-bond migration of allyl ethers
promoted by related ruthenium complexes.[21] This metal hy-
dride mechanism for the deprotection of allylic amines is
shown in Scheme 5. Precoordination of the substrate nitro-
gen atom directs subsequent coordination of the olefin to
the metal center, with the metal-hydride addition to the
Experimental Section
General methods: 1H and 13C NMR spectra were recorded on a Bruker
Avance-300, Varian VRX-300S, or Bruker AC-200 instrument. NMR
spectra were recorded in CDCl3 solutions unless otherwise stated. Chemi-
cal shifts (d) are given in ppm relative to tetramethylsilane (1H, 0.0 ppm)
or CDCl3 (13C, 76.9 ppm). Low- and high-resolution mass spectra were
taken on a HP5989A spectrometer by using the chemical ionization
mode (CI) unless otherwise stated. Specific rotation [a]D is given in
degdmÀ1 at 208C and the concentration (c) is expressed in g per 100 mL.
All commercially available compounds were used without further purifi-
cation.
Scheme 5. Mechanistic explanation for the ruthenium-catalyzed deprotec-
tion of N-allyl amines.
General procedure for the deallylation reaction of secondary and tertiary
allylic amines: [(PCy3)2Cl2Ru=CHPh](0.01 mmol) was added in portions
to a solution of the allylic amine 1, 3, or 5 (0.20 mmol) in anhydrous tolu-
ene (6 mL) protected from the sunlight and under argon. The resulting
mixture was heated at reflux until complete disappearance of the starting
material (as monitored by thin-layer chromatography (TLC)) and was
then concentrated under reduced pressure. Chromatography of the resi-
due by eluting with hexanes/ethyl acetate mixtures gave analytically pure
N-deallylated amines 2, 4, or 6. Spectroscopic and analytical data for
some representative pure forms of 2, 4, and 6 follow.[22]
olefin occurring in a Markovnikov fashion to afford a secon-
dary metal alkyl. Subsequent b-hydride elimination gives
the enamine which decomplexes and hydrolyzes to the deal-
lylated amine. The formation of the ruthenium-hydride may
arise from traces of impurities present in the commercial
Grubbs carbene as well as the basic amine media under the
reaction conditions.
Secondary amine (À)-2b: From N-allyl azetidine (+)-1b (60 mg,
0.264 mmol) and after flash chromatography by eluting with hexanes/
ethyl acetate (2:1 containing 1% triethylamine), azetidine (À)-2b
(25 mg, 49%) was obtained as a colorless oil. [a]D =À10.3 (c=1.0 in
Unfortunately, the ruthenium species derived from the
Grubbs carbene and responsible for this activity is unclear,
1
1
as 31P and H NMR studies are inconclusive.[14a,d] However,
CHCl3); H NMR (300 MHz, CDCl3, 258C): d=4.41 (m, 1H), 4.27 (t, J=
6.2 Hz, 1H), 4.00 (m, 2H), 3.49 (m, 4H), 3.16 (s, 3H), 1.09, 1.06 (s, each
3H) ppm; 13C NMR (75 MHz, CDCl3, 258C): d=73.4, 72.3, 72.0, 69.6,
68.6, 55.9, 51.0, 22.1, 22.0 ppm; MS (ES): m/z (%): 210 (11) [M+Na]+,
188 (100) [M+H]+ ; elemental analysis calcd (%) for C9H17NO3 (187.2):
C 57.73, H 9.15, N 7.48; found: C 57.83, H 9.18, N 7.45.
at the present time, we suggest that the reactive species in-
volved in the reaction may be an RuÀH species rather than
1
the Grubbs carbene itself. The H NMR experiments of the
reaction mixtures did not reveal whether the carbene frag-
ment is a spectator ligand or disappears in the course of the
reaction, because we were not able to observe neither a new
ruthenium-hydride, nor a change in the ruthenium-alkyl-
idene signal.
Secondary amine 2c: From allyl (4-allyloxyphenyl)ethylamine 1c (40 mg,
0.184 mmol) and after flash chromatography by eluting with hexanes/
ethyl acetate (5:1), (4-allyloxyphenyl)ethylamine 2c (22 mg, 68%) was
1
obtained as a pale yellow oil. H NMR (300 MHz, CDCl3, 258C): d=6.74
(m, 2H), 6.54 (m, 2H), 6.00 (m, 1H), 5.21 (m, 2H), 4.39 (m, 2H), 3.05
(q, J=7.0 Hz, 2H), 1.18 (t, J=7.0 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3, 258C): d=151.6, 143.7, 134.1, 117.5, 116.3, 114.7, 69.9, 39.9,
14.9 ppm; MS (EI): m/z (%): 178 (100) [M]+ ; elemental analysis calcd
(%) for C11H15NO (177.2): C 74.54, H 8.53, N 7.90; found: C 74.48, H
8.50, N 7.88.
Conclusion
In conclusion, the Grubbs carbene complex efficiently cata-
lyzes the deprotection of allylic amines. In addition to the
novelty of the method (offering the first ruthenium-cata-
Secondary amine (+)-2 f: From tertiary allylic amine (+)-1 f (110 mg,
0.46 mmol) and after flash chromatography by eluting with ethyl acetate,
piperidine (+)-2 f (71 mg, 78%) was obtained as a colorless oil. [a]D =
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B. Alcaide, P. Almendros and J. M. Alonso
FULL PAPER
+27.6 (c=0.7 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=3.93 (m,
2H), 3.68 (m, 1H), 3.36 (m, 1H), 2.85 (m, 2H), 2.38, 2.27 (m, each 2H),
2.02 (brs, 1H), 1.36, 1.29 (s, each 3H) ppm; 13C NMR (75 MHz, CDCl3,
258C): d=207.8, 109.4, 78.3, 66.2, 59.7, 45.2, 42.4, 26.5, 25.1 ppm; IR
(CHCl3): n˜ =3347, 1714 cmÀ1; MS (CI): m/z (%): 200 (100) [M+H]+, 199
(17) [M]+ ; elemental analysis calcd (%) for C10H17NO3 (199.3): C 60.28,
H 8.60, N 7.03; found: C 60.36, H 8.62, N 7.01.
then water was added (0.5 mL). The methanol was concentrated under
reduced pressure, the aqueous residue was extracted with ethyl acetate
(5î3 mL), the organic layer was dried over MgSO4, and the solvent was
removed under reduced pressure. Chromatography of the residue by
eluting with hexanes/ethyl acetate mixtures gave analytically pure fused
bicycles 7.
Indolizidine (+)-7a: From piperidine-b-lactam (+)-6a (50 mg,
0.173 mmol), compound (+)-7a (49 mg, 98%) was obtained as an orange
oil. [a]D =+11.0 (c=0.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C):
d=7.01, 6.59 (m, each 2H), 4.43 (m, 1H), 3.82 (d, J=4.0 Hz, 1H), 3.76
(t, J=4.0 Hz, 1H), 3.64 (s, 3H), 3.54 (m, 1H), 3.11 (m, 1H), 2.75 (dd, J=
14.3, 2.7 Hz, 1H), 2.50 (m, 3H), 2.26 (s, 3H), 1.25 (brs, 1H) ppm;
13C NMR (75 MHz, CDCl3, 258C): d=205.1, 169.9, 143.5, 130.0, 128.4,
113.9, 83.4, 69.2, 60.5, 60.4, 47.1, 39.7, 37.9, 20.3 ppm; IR (CHCl3): n˜ =
3440, 1725, 1715 cmÀ1; MS (ES): m/z (%): 289 (100) [M+H]+, 288 (15)
[M]+ ; elemental analysis calcd (%) for C16H20N2O3 (288.3): C 66.65, H
6.99, N 9.72; found: C 66.76, H 7.02, N 9.68.
Primary amine 4b: From secondary allylic amine 3b (63 mg, 0.33 mmol)
and after flash chromatography by eluting with hexanes/ethyl acetate
(2:1), 4-allyloxyphenylamine 4b (28 mg, 57%) was obtained as a yellow
oil. 1H NMR (300 MHz, CDCl3, 258C): d=6.72 (m, 2H), 6.58 (m, 2H),
5.96 (m, 1H), 5.27 (m, 2H), 4.40 (m, 2H), 3.39 (brs, 2H) ppm; 13C NMR
(75 MHz, CDCl3, 258C): d=153.7, 139.8, 133.9, 117.4, 116.8, 116.1,
69.7 ppm; MS (EI): m/z (%): 150 (7) [M+H]+, 149 (100) [M]+ ; elemental
analysis calcd (%) for C9H11NO (189.3): C 72.46, H 7.43, N 9.39; found:
C 72.57, H 7.46, N 9.43.
Primary amine (+)-4c: From secondary allylic amine (+)-3c (55 mg,
0.153 mmol) and after flash chromatography by eluting with ethyl ace-
tate, the amino tetracycle (+)-4c (25 mg, 52%) was obtained as a color-
less oil. [a]D =+11.3 (c=0.8 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.95 (d, J=8.9 Hz, 1H), 7.03 (d, J=2.5 Hz, 1H), 6.79 (dd, J=
8.9, 2.5 Hz, 1H), 4.94 (d, J=5.6 Hz, 1H), 3.74 and 3.71 (s, each 3H), 3.60
(m, 4H), 3.21 (d, J=10.0 Hz, 1H), 2.36 (m, 1H), 1.41 (m, 4H) ppm;
13C NMR (75 MHz, CDCl3, 258C): d=169.8, 157.6, 129.5, 128.3, 122.6,
114.1, 112.2, 86.2, 72.6, 61.2, 59.3, 55.7, 55.6, 53.2, 32.9, 24.7, 20.6 ppm; IR
(CHCl3): n˜ =3330, 1712 cmÀ1; MS (ES): m/z (%): 341 (11) [M+Na]+, 319
Indolizidine (+)-7b: From piperidine-b-lactam (+)-6c (20 mg,
0.058 mmol), compound (+)-7b (20 mg, 100%) was obtained as an
orange oil. [a]D =+83.2 (c=0.4 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=6.73, 6.50 (m, each 2H), 5.87 (m, 1H), 5.24 (m, 2H), 4.47 (m,
2H), 4.26 (dd, J=12.7, 6.1 Hz, 1H), 4.04 (m, 3H), 3.69 (s, 3H), 2.98 (m,
1H), 2.33 (m, 4H), 1.19 (brs, 1H) ppm; 13C NMR (75 MHz, CDCl3,
258C): d=205.9, 168.2, 139.9, 137.2, 134.1, 118.5, 115.3, 114.7, 79.5, 71.4,
56.6, 55.9, 55.6, 42.3, 40.1, 38.4 ppm; IR (CHCl3): n˜ =3442, 1723,
1712 cmÀ1; MS (ES): m/z (%): 353 (9) [M+Na]+, 331 (100) [M+H]+, 330
(7) [M]+ ; elemental analysis calcd (%) for C18H22N2O4 (330.4): C 65.44,
H 6.71, N 8.48; found: C 65.36, H 6.75, N 8.52.
(100) [M+H]+, 318 (18) [M]+
; elemental analysis calcd (%) for
C17H22N2O4 (318.4): C 64.13, H 6.97, N 8.80; found: C 64.24, H 7.00, N
8.84.
Indolizidine (+)-7d: From piperidine-b-lactam (+)-6e (20 mg,
0.079 mmol), compound (+)-7d (20 mg, 100%) was obtained as an
orange oil. [a]D =+101.2 (c=0.7 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=5.69 (m, 1H), 4.99 (m, 2H), 4.39 (m, 1H), 3.80 (m, 1H), 3.76
(d, J=7.4 Hz, 1H), 3.63 (s, 3H), 3.37 (t, J=7.4 Hz, 1H), 2.91 (m, 1H),
2.60 (m, 2H), 2.39 (m, 6H), 1.19 (brs, 1H) ppm; 13C NMR (75 MHz,
CDCl3, 258C): d=206.5, 170.3, 135.5, 116.8, 81.9, 58.9, 58.5, 56.3, 47.2,
42.7, 40.3, 38.3, 34.0 ppm; IR (CHCl3): n˜ =3447, 1721, 1710 cmÀ1; MS
(ES): m/z (%): 253 (100) [M+H]+, 252 (9) [M]+ ; elemental analysis
calcd (%) for C13H20N2O3 (252.3): C 61.88, H 7.99, N 11.10; found: C
61.77, H 7.96, N 11.06.
Piperidine-b-lactam (+)-6a: From N-allyl piperidine (À)-5a (130 mg,
0.396 mmol) and after flash chromatography by eluting with ethyl acetate
(containing 1% triethylamine), piperidine (+)-6a (100 mg, 88%) was ob-
tained as a colorless oil. [a]D =+116.1 (c=0.5 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.24, 7.06 (m, each 2H), 4.60 (d, J=5.4 Hz,
1H), 4.17 (dd, J=5.4, 5.1 Hz, 1H), 3.62 (s, 3H), 3.32 (m, 2H), 2.72 (m,
1H), 2.34 (m, 4H), 2.24 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3, 258C):
d=207.9, 164.8, 134.5, 134.4, 129.6, 117.9, 82.8, 59.7, 57.1, 45.7, 42.9, 42.8,
20.8 ppm; IR (CHCl3): n˜ =3352, 1738, 1717 cmÀ1; MS (ES): m/z (%): 289
(100) [M+H]+, 288 (11) [M]+
; elemental analysis calcd (%) for
C16H20N2O3 (288.3): C 66.65, H 6.99, N 9.72; found: C 66.74, H 7.02, N
9.68.
Piperidine-b-lactam (+)-6c: From N-allyl piperidine (+)-5c (30 mg,
0.078 mmol) and after flash chromatography by eluting with ethyl acetate
(containing 1% triethylamine), piperidine (+)-6c (20 mg, 74%) was ob-
Acknowledgments
Support for this work by the DGI-MCYT (Project: BQU2000 0645) is
gratefully acknowledged. J.M.A. thanks the Universidad Complutense de
Madrid for a fellowship.
tained as
a
colorless oil. [a]D =+21.4 (c=0.6 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.28, 6.80 (m, each 2H), 5.88 (m, 1H), 5.25
(m, 2H), 4.77 (d, J=5.4 Hz, 1H), 4.28 (m, 3H), 3.73 (s, 3H), 3.42 (m,
2H), 2.78 (m, 1H), 2.28 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3, 258C):
d=208.3, 165.1, 156.7, 133.2, 129.8, 119.2, 118.4, 114.6, 80.9, 72.5, 58.9,
57.6, 55.5, 45.9, 44.6, 43.0 ppm; IR (CHCl3): n˜ =3350, 1740, 1715 cmÀ1
;
MS (CI): m/z (%): 331 (100) [M+H]+, 330 (18) [M]+ ; elemental analysis
calcd (%) for C18H22N2O4 (330.4): C 65.44, H 6.71, N 8.48; found: C
65.31, H 6.69, N 8.51.
[1]For some reviews on olefin metathesis, see: a) R. H. Grubbs, T. M.
Trnka, Acc. Chem. Res. 2001, 34, 18; b) A. F¸rstner, Angew. Chem.
2000, 112, 3140; Angew. Chem. Int. Ed. 2000, 39, 3012; c) M. R.
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36, 2036. For recent theoretical studies of the mechanism of the
ruthenium-catalyzed olefin metathesis, see: i) L. Cavallo, J. Am.
Chem. Soc. 2002, 124, 8965; j) S. F. Vyboishchikov, M. B¸hl, W.
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Chem. 2002, 114, 4668; Angew. Chem. Int. Ed. 2002, 41, 4484.
[2]For the unexpected reactivity of the Grubbs catalyst for Kharasch
addition, see: J. A. Tallarico, L. A. Malnick, M. L. Snapper, J. Org.
Chem. 1999, 64, 344.
Piperidine-b-lactam (+)-6e: From N-allyl piperidine (+)-5e (65 mg,
0.223 mmol) and after flash chromatography by eluting with ethyl acetate
(containing 1% triethylamine), piperidine (+)-6e (27 mg, 49%) was ob-
tained as
a
colorless oil. [a]D =+88.4 (c=0.5 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=5.67 (m, 1H), 5.07 (m, 2H), 4.41 (d, J=
5.2 Hz, 1H), 3.67 (dd, J=6.0, 5.2 Hz, 1H), 3.51 (m, 4H), 3.31 (m, 1H),
3.14 (m, 2H), 2.85 (m, 1H), 2.32 (m, 6H), 1.86 (brs, 1H) ppm; 13C NMR
(75 MHz, CDCl3, 258C): d=207.8, 167.7, 134.6, 117.2, 83.1, 59.6, 59.2,
57.5, 45.7, 45.5, 42.9, 40.6, 31.8 ppm; IR (CHCl3): n˜ =3352, 1739,
1714 cmÀ1; MS (ES): m/z (%): 253 (100) [M+H]+, 252 (12) [M]+ ; ele-
mental analysis calcd (%) for C13H20N2O3 (252.3): C 61.88, H 7.99, N
11.10; found: C 61.99, H 8.02, N 11.06.
General procedure for the sodium methoxide promoted preparation of
indolizidines 7: Sodium methoxide (0.6 mmol) was added in portions to a
solution of the appropriate piperidine-b-lactam (0.15 mmol) in methanol
(3 mL) at 08C. The reaction was stirred at room temperature until com-
plete disappearance of the starting material (as monitored by TLC) and
[3]For the Grubbs carbene promoted activation of silanes in the pres-
ence of carbonyls, see: S. V. Maifeld, R. L. Miller, D. Lee, Tetrahe-
dron Lett. 2002, 43, 6363.
5798
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 5793 5799

Grubbs Carbene Mediated Deprotection of Allylic Amines
5793 5799
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a
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[22]Full spectroscopic and analytical data for compounds not included
in this Experimental Section are described in the Supporting Infor-
mation.
Received: June 16, 2003 [F5236]
5799
Chem. Eur. J. 2003, 9, 5793 5799
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim