A general approach to aza-heterocycles by means of domino sequences driven by hydroformylation

Article abstract of DOI:10.1002/chem.200801795

The development of hydroformylative domino reactions of easily accessible vinyl acetamides is described. Extremely regioselective hydroformylation of terminal double bounds provides a transient N-acyliminium that can be trapped by various nucleophiles to give several aza-heterocylic scaffolds in a diastereoselective manner.

Full text of DOI:10.1002/chem.200801795

DOI: 10.1002/chem.200801795
A General Approach to Aza-Heterocycles by Means of Domino Sequences
Driven by Hydroformylation
Etienne Airiau,[a] Thomas Spangenberg,[a] Nicolas Girard,[a] Angꢀle Schoenfelder,[a]
Jessica Salvadori,[b] Maurizio Taddei,[b] and Andrꢁ Mann*[a]
Dedicated to Dr. C. Mioskowski
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Chem. Eur. J. 2008, 14, 10938 – 10948

FULL PAPER
Abstract: The development of hydroformylative domino reactions of easily acces-
sible vinyl acetamides is described. Extremely regioselective hydroformylation of
terminal double bounds provides a transient N-acyliminium that can be trapped by
various nucleophiles to give several aza-heterocylic scaffolds in a diastereoselective
manner.
Keywords: cyclohydrocarbonyla-
tion · diastereoselectivity · domino
reactions · heterocycles · hydrofor-
mylation
Introduction
The sequence of forming successively two or more new
chemical bonds in a single transformation without the isola-
tion of the intermediate has been defined as a domino se-
quence.[1–4] Originally fuelled by the quest of step- and
atom-economy in the syntheses of complex targets from nat-
ural sources,[5–7] domino reactions have found large applica-
tions in the synthesis of new cyclic or heterocyclic structures
from open-chain substrates.[8] The optimal design of domino
reactions should deliver complex compounds starting from
easily available reagents and implementing simple reactions.
Hydroformylation of alkenes is a powerful example of ef-
ficient C C bond formation.[9–12] This reaction, by carbon ac-
Scheme 1. The hydroformylation of linear vinylacetamides (A) to termi-
nal aldehydes (B) is triggering domino reactions with appended nucleo-
philes (Nu) via a transient N-acyliminium (C) towards complex heterocy-
cles (D).
À
tivation, introduces an aldehyde onto a double bond, provid-
ing a new functional group suitable for multistep sequences.
The application of hydroformylation in domino processes
has been investigated as a strategy to prepare different het-
erocycles, and several creative applications have been re-
ported.[13–17]
ucts D. The structure of the products obtained with this
strategy will be subordinated to the nature of the three reac-
tive centers (vinyl, amide, and nucleophile) and their rela-
tive locations.
Based on our previous experiences in the preparation of
aldehydes by hydroformylation,[18–19] we ambitioned to
expand the concept of carbonylative-based domino reac-
tions[20] in designing new synthetic routes. In this work, a
general approach to aza-heterocycles by domino sequences
driven by hydroformylation is disclosed. Our strategy is il-
lustrated in Scheme 1: the key substrate (A) features a ter-
minal double bond and a nucleophile linked through an
amide group working itself as an additional nucleophile.
Indeed, upon hydroformylation, the amide NH will react
with the newly formed aldehyde yielding a highly activated
N-acyliminium ion C.[21–22] Then, a second nucleophilic
attack, completing the sequence of the domino cyclohydro-
carbonylation (CHC)[14b] delivers the final polycyclic prod-
Results and Discussion
The starting substrates were easily prepared by a one-step
coupling reaction between 3-butenoic acid (1) and several
amines (Scheme 2). Indeed by using different chiral amino
alcohols, products 3a–d were obtained with an OH as
second nucleophile suitable for cyclization to give bicyclic
oxazole derivatives. When phenethylamine derivatives,
tryptamine or tryptophan methyl ester were coupled with 1,
compounds 4–9 were produced as ideal substrates for
domino CHC Pictet–Spengler reactions. Finally the amide
10 derived from 5-bromopent-2-enyltrimethylsilane was em-
ployed to test the feasibility of a domino CHC/aza-Sakurai–
Hosomi reaction.
Initially, the optimization work was done by using com-
pound 2. All the possible products (11–16) that can be
formed during the hydroformylation of 2 are reported in
Table 1. As the clean generation of the linear aldehyde 11
by hydroformylation is crucial for the domino sequence, dif-
ferent variables, such as the solvent, the ligand for RhI, the
temperature, acid additives, and the nature of the conditions
needed for the domino sequence were addressed. The ratios
of 11–16 were easily quantified by 1H NMR spectroscopy
and the data are summarized in Table 1.
[a] E. Airiau, T. Spangenberg, Dr. N. Girard, A. Schoenfelder,
Dr. A. Mann
Facultꢁ de Pharmacie, Universitꢁ Louis Pasteur de Strasbourg
Laboratoire de Pharmacochimie de la Communication Cellulaire
UMR 7175/LC1, 74, route du Rhin
BP 60024, 67401 Illkirch (France)
Fax : (+33)390-244-310
E-mail: andre.mann@pharma.u-strasbg.fr
[b] J. Salvadori, Prof. M. Taddei
Dipartimento Farmaco Chimico Tecnologico
Universitꢂ degli Studi di Siena
Via A. Moro 2, 53100 Siena (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801795.
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A. Mann et al.
nation. But at 708C, the catalytic cycle is set for hydrofor-
mylation: the linear aldehyde 11 is produced as the major
adduct, and the corresponding branched aldehyde 12 is the
minor one. These results suggest that, at 708C, the presence
of electron-rich heteroatoms (N, O) in substrate 2 does nei-
ther compete with the complexation of biphephos to RhI
nor to the ligation of the alkene. Thus, biphephos was select-
ed as the ligand of choice in further experiments.
From this prelude, it appears that the optimal hydrofor-
mylation conditions of 2 are achieved by using biphephos as
the ligand for RhI in THF at 708C and that the presence of
acid additives does not compromise the RhI-promoted cata-
lytic cycle.
The application of these conditions to amide 3a with acid
additives gave similar results and the oxazolopiperidone 21a
was obtained as a mixture of two diastereomers (21a/21a’
91:9) separable by chromatography (Table 2, entry 1).
This result confirmed that the linear hydroformylation
was the predominant pathway in the domino cyclohydrocar-
bonylation. The main diastereomer was identified as the
trans adduct by comparison with reported data.[27,28] Indeed,
compound 21a (trans adduct) has already been prepared by
different routes. Furthermore, the reactivity of the latent
iminium in 21a to various organometallic reagents was used
towards the synthesis of natural compounds. According to
Bosch,[28] the trans diastereomer is the most valuable for fur-
ther chemical transformations.
Scheme 2. General procedure for peptide couplings: a) 1, DCC, HOBt,
CH2Cl2, RT, 24 h; b) 1, EDC, HOBt, CH2Cl2, RT, 24 h; Substrates for
peptide couplings: (1R)-2-methoxy-1-phenylethanamine 32 for 2, (R)-
(À)-2-amino-2-phenylethanol for 3a, (R)-2-amino-3-phenyl-1-propanol
for 3b, (S)-(+)-2-amino-3-methyl-1-butanol for 3c, d-(+)-norephedrine
for 3d, 2-(3-methoxyphenyl)ethylamine for 4, 2-(3,4-dimethoxyphenyl)-
ethylamine for 5, (S)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propa-
noate 33 for 6, tryptamine for 7, 5-bromotryptamine for 8, (S)-methyl 2-
amino-3-(1H-indol-3-yl)propanoate 34 for 9, and 5-(trimethylsilyl)pent-3-
en-1-amine 36 for 10. DCC= N,N’-dicyclohexylcarbodiimide; EDC=N’-
(3-dimethylaminopropyl)-N-ethyl-carbodiimide; HOBt=1-hydroxyben-
zotriazole.
This seminal example of
a hydroformylation-based
domino reaction proved to be of general use, as oxazolopi-
peridones derived from phenylalaninol 3b, valinol 3c, and
norephedrine 3d were converted into bicyclic 21b–21b’,
21c–21c’, and 21d–21d’ adducts in good yields with compa-
rable diastereoselectivities (ca. 90:10).
Our approach towards the oxazolopiperidones 21a–d has
some advantages relative to the existing methods as the es-
sential aldehyde function is generated in situ from an inex-
pensive alkene 1. As many other similar alkenes are avail-
able from the feedstock, extensions of this domino CHC/
heteroatoms addition are conceivable.
The syngas (H2/CO 1:1) pressure was fixed at 5 bar and
[RhACHTUNGTRENNUNG
(acac)(CO)2] was chosen as the precatalyst.[9] All the li-
gands (PPh3 (17), xantphos (18), 6-DPPon (19),[23] biphephos
(20))[24,25] produced full conversions to linear or branched al-
dehydes 11 or 12, with some amounts of the fully reduced
adduct 13 (Table 1, entries 1–4). As expected, the bulky di-
phosphite biphephos favored the formation of the linear al-
dehyde, whereas xantphos, PPh3, or 6-DPPon gave higher
amounts of the branched aldehyde.
Next, the influence of Brønsted or Lewis acids (pTSA,
PPTS, BF3·Et2O, and ZnACHTUNTRGNEUNG(OTf)2) were examined. The stabili-
Next, we decided to examine if an electron-rich aromatic
ring could be used as the nucleophile partner in a domino
CHC/Pictet–Spengler sequence.[29] Phenethylamine deriva-
tives (Table 3) and indole derivatives (Table 4) were pre-
pared for that purpose and submitted to the standard hydro-
formylative conditions in presence of Brønsted or Lewis
acids.
The expected adducts 22–27 were isolated in good to very
good yields. They result from a linear hydroformylation of
4–9 and a subsequent quenching of the transient N-acylimi-
nium with the electron-rich aromatic ring. Depending on the
substrates, various quantities of acid additives were necessa-
ry to obtain good yields. The domino CHC/Pictet–Spengler
reaction works well with Brønsted or Lewis acid (Table 3,
entries 1–6) and provides benzo[a]quinolizidine-type prod-
ucts in very good yields and with good diastereoselectivity
for 24. With indole derivatives 7 and 8, BF3·Et2O gave
better results (Table 4, entries 1–4) and indoloquinolizidines
ty of biphephos in acidic media was questionable as a water
molecule will be released during the cyclohydrocarbonyla-
tion step. Interestingly, no notable changes were detected in
the conversion balance (Table 1, entries 5–10), except that
now the major adducts are enamides 15 or 16, and the
chemistry went a step forward. The transient aminals, de-
rived from aldehydes 11 and 12, respectively, underwent de-
hydration to enamides 15 and 16, which, in this particular
case, results from further p-isomerization. The stability of
our catalytic system (RhI and biphephos) was proved by
31P NMR spectroscopic experiments.[26] Moreover, biphe-
phos, either in THF, toluene, or CH2Cl2 favors the formation
of linear aldehyde (Table 1, entries 5, 6, and 7). A point to
note is that at room temperature the major pathway is the
conversion of
2 to 14 by double-bond isomerization
(entry 11), as a result of a rhodium hydride addition–elimi-
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A General Approach to Aza-Heterocycles
FULL PAPER
Table 1. Optimization of the experimental conditions for the hydroformylation of 2.[a]
the nature of the acid additive
has a great influence on the dia-
stereoselectivity of the reaction.
Indeed, in presence of pTSA
(Table 4, entry 5), a mixture of
27 and 27’, separable by chro-
matography, was obtained with
95% yield with a good diaste-
reoselectivity (88:12: the con-
figuration of the major diaste-
reomer was confirmed by X-ray
diffraction analysis[30]). Where-
as, with BF3·Et2O (entry 6), a
1:1 mixture of the two diaste-
reomers was obtained.[31] As ex-
pected, the in situ formation of
the linear aldehyde gave the
domino sequence CHC/Pictet–
Spengler reaction, allowing a
very straightforward access to
N-containing polycyclic com-
pounds starting from carefully
designed starting materials. To
the best of our knowledge, this
represents the first application
of a domino CHC/Pictet–Spen-
gler reaction applied to elec-
tron-rich aromatic rings or in-
doles nucleus.
Entry
Additive (10 mol%)
Ligand
Hydroformylation ([%])
Regioselectivity
1
2
3
4
–
–
–
–
17
18
19
20
20
20
20
20
20
20
20
11+12 (95)
11+12 (94)
11+12 (95)
11+12 (93)
15+16 (94)
15+16 (90)
15+16 (85)
15+16 (93)
15+16 (94)
15+16 (94)
15+16 (15)[e]
11/12 67:33
11/12 72:28
11/12 67:33
11/12 92:8
15/16 96:4
15/16 91:9
15/16 86:14
15/16 96:4
15/16 96:4
15/16 96:4
n.d.
5
pTSA
pTSA
pTSA
PPTS
BF3·Et2O
6[b]
7[c]
8
9
10
Zn
pTSA
ACHTUNGTRENNUNG(OTf)2
11[d]
[a] [Rh(CO)2acac]/ligand/2 1:2:50, [2]=0.04m, THF (3 mL), 5 bar H2/CO 1:1, 708C, 12 h. Ratios were deter-
mined by 1H NMR spectroscopic analysis on the crude reaction mixtures. Full conversion was observed in
each case [b] Reaction in toluene. [c] Reaction in CH2Cl2 at 508C. [d] Reaction at room temperature. [e] 85%
of 14 was isolated. n.d.=not determined. PPTS=pyridinium tosylate; pTSA=p-toluenesulfonic acid.
Finally, we decided to investi-
gate the nucleophilic reactivity
of allylsilane in the context of
cyclohydrocarbonylation.
For
that purpose, we prepared sub-
strate 10 in four steps passing
through bromallylsilane 28 by
cross-metathesis (Scheme 3).[32]
Table 2. Domino CHC/hetero nucleophilic addition on 3a–d.[a]
We expected that a chemose-
lective hydroformylation would
operate to produce the linear
aldehyde leaving intact the
double bound of the allylsilane.
Then, the CHC to the amidic
nitrogen atom should produce
an N-acyliminium ready for an
aza-Sakurai–Hosomi reaction.
The newly formed vinyl alkene
30 could be again hydroformy-
lated regioselectively to pro-
duce the terminal aldehyde in
adduct 31 (Scheme 3).
Entry
Substrate
Additive [mol%]
Yield [%][b]
Products (trans/cis)
1
2
3
4
3a
3b
3c
3d
pTSA (10)
pTSA (10)
pTSA (10)
PPTS (5)
94
90
78
91
21a/a’ 91:9
21b/b’ 90:10
21c/c’ 91:9
21d/d’ 86:14
Thus several conditions were
[a] [RhACHTUNGTRENNUNG(acac)(CO)2]/20/3a–d 1:2:100, [3a–d]=0.04m, THF, 5 bar H2/CO 1:1, 708C, 12 h. [b] Isolated yield.
acac=acetylacetonate.
tested (Table 5). Depending on
the solvent and the acid addi-
tives, three different adducts 29,
30, and 31, corresponding to each singular step could be iso-
lated. Enamide 29 (entry 1) is obtained in 78% yield in
25 and 26 were obtained with 85 and 73% yields, respective-
ly. Surprisingly, with tryptophan methyl ester derivative 9,
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A. Mann et al.
Table 3. Domino CHC/Pictet–Spengler reaction on 4–6.[a]
Entry
Substrate
Additive [mol%]
Product
Yield [%][b]
1
2
3
4
5
6
4
4
5
5
6
6
pTSA (50)
BF3·Et2O (20)
pTSA (20)
BF3·Et2O (20)
pTSA (10)
BF3·Et2O (10)
22
22
23
23
24
24
90
85
88
95
67[c]
84[c]
[a] [RhACHTUNGTRENNUNG(acac)(CO)2]/20/4–6 1:2:100, [4–6]=0.04m, THF, 5 bar H2/CO 1:1,
708C, 12 h. [b] Isolated yield. [c] Only one diastereomer was isolated.
Scheme 3. Access to indolizinones by means of CHC/aza-Sakurai–
Hosomi/hydroformylation.
THF with PPTS (5 mol%), which establishes that the hydro-
formylation is selective for the terminal double bound. No
hydroformylation of the internal alkene (allylsilane) was ob-
served, that left room for the subsequent aza-Sakurai–
Hosomi reaction.
When compound 29 was isolated and treated with four
equivalents of trifluoroacetic acid (TFA) in CH2Cl2, adducts
30 were obtained as a mixture of two diastereomers (cis/
trans 90:10) in 89% yield.[33] It was also possible to isolate
30 in a one-pot operation if the hydroformylation was car-
ried out without acid additive, and after the autoclave had
been cooled and degassed, TFA was added at room temper-
ature to give 30 in 82% yield (entry 2) with the same diaste-
reoselectivity. Then, hydroformylation of 30 in classical con-
ditions (without acid additive) gave 31 with 78% yield.
Now, we decided to produce 31 in a domino reaction.
When allylsilane 10 was mixed in CH2Cl2 with one equiva-
lent of TFA and submitted to hydroformylation conditions,
after 12 h at 558C, adduct 31 could be isolated in 63% yield
(entry 3). Use of a Lewis acid additive in CH2Cl2 (entry 4)
does not improve the yield of the reaction. The best result
was obtained by using 0.5 equivalents of BF3·Et2O in THF
(entry 5) to give 31 with 69% yield as a mixture of two dia-
stereomers (cis/trans 90:10).
This result confirms that four reactions were involved in
the domino sequence involving selective hydroformylation
of the terminal alkene, cyclization, aza-Sakurai–Hosomi re-
action on the transient N-acyli-
minium, and a final regioselec-
Table 4. Domino CHC/Pictet–Spengler reaction on 7–9.[a]
tive hydroformylation. In this
sequence, from the linear
adduct 10, two cycles and nine
new bounds are formed in the
same chemical operation.
A
domino sequence that included
hydroformylation was described
by Hoffmann in which an allyl-
borane was involved.[8] The ad-
vantage of the process depicted
in Scheme 3 is a straightforward
access to the allylsilane deriva-
tive 10. Additionally, upon cer-
tain reaction conditions, com-
pounds 29, 30, and 31 can be
obtained separately allowing
further potential transforma-
tions into biomolecules. We be-
lieve that the elaboration of
other allylsilanes for the
Entry
Substrate
Additive [mol%]
Product
Yield [%][b]
1
2
3
4
5
6
7
7
8
8
9
9
pTSA (10)
BF3·Et2O (10)
pTSA (20)
BF3·Et2O (10)
pTSA (10)
BF3·Et2O (10)
25
25
26
26
27+27’
27+27’
66
85
70
73
95[c]
85[d]
[a] [RhACHTUNGTRENNUNG(acac)(CO)2]/20/7–9 1:2:100, [7--9]=0.04m, THF, 5 bar H2/CO 1:1, 708C, 12 h. [b] Isolated yield. [c] 27/
27’ 88:12; the structure of 27 was confirmed by X-ray diffraction analysis.[30d] 27/27’ 54:46.
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A General Approach to Aza-Heterocycles
FULL PAPER
Table 5. Domino CHC/aza-Sakurai–Hosomi/hydroformylation on 10.[a]
compounds 2, 3a, 3b, 3c, 3d, and 4) or EDC (1.1 equiv, for compounds
5, 6, 7, 8, 9, and 10) and HOBt (1 equiv) were added and the solution
was stirred at room temperature for 24 h. The suspension was filtered off
and the organic layer was washed with saturated aqueous NaHCO3 solu-
tion, dried (Na2SO4), filtered, and concentrated to give a yellow oil.
Entry
Solvent (T [8C])
Additive [equiv]
Product
Yield [%][b]
1
2
3
4
5
THF (70)
PPTS (0.05)
TFA (1)
TFA (1)
BF3·Et2O (0.5)
BF3·Et2O (0.5)
29
30
31
31
31
78
CH2Cl2 (55)
CH2Cl2 (55)
CH2Cl2 (55)
THF (70)
82[c]
63
General procedure B for hydroformylation: In a stainless steel autoclave
under an inert atmosphere, a solution of dicarbonylacetylacetonato rho-
dium (1 mol%) and biphephos (2 mol%) in anhydrous degassed solvent
(3 mL), prepared in a Schlenk glassware under inert atmosphere, was
added to a solution of the desired olefin (1 equiv) and acid if necessary
in anhydrous degassed solvent to reach a final concentration of 0.04m.
The autoclave was flushed with H2/CO (1:1) three times. Then, the auto-
clave was filled with 5 atm. of H2/CO (1:1) and was heated at the desired
temperature with stirring for 12 h. Then, the autoclave was cooled to
room temperature and gases were slowly and carefully released. The re-
action mixture was then concentrated under reduced pressure to give an
oil. The residue was purified by flash chromatography.
61
69
[a] [RhACHTUNGTRENNUNG(acac)(CO)2]/20/10 1:2:100, [10]=0.04m, 5 bar H2/CO 1:1, 12 h.
cis/trans ratios were 90:10 in all cases. Determined by 1H NMR spectros-
copy for 30 and GCMS analyses for 31. [b] Isolated yield. [c] Reaction
for 4 h, then TFA (1 equiv), 12 h, RT.
domino cyclohydrocarbonylation/aza-Sakurai–Hosomi/hy-
droformylation may lead to series of analogues of 29, 30, or
31.
N-[(1R)-2-Methoxy-1-phenylethyl]but-3-enamide (2): Compound 2 was
prepared by following the general procedure A as described above from
32 (1.88 g, 12.4 mmol). The residue was purified by flash chromatography
(70:30 to 60:40 pentane/EtOAc) to give 2 as a white solid (2.29 g, 84%).
[a]2D0 =À30.1 (c=1.0 in CHCl3); m.p. 39–408C; IR (neat): n˜ =3297, 2871,
Conclusion
We have developed new domino reactions for the synthesis
of aza-heterocycles by using hydroformylation as the trigger.
Our strategy allows full control over product formation: by
fine-tuning of the reaction conditions, various heterocycles
can be obtained from simple, readily available materials
from the feedstock. Moreover, complex, aza-polycyclic sys-
tems can be efficiently built in a diastereoselective fashion.
Our present work has shown that domino reactions based
on hydroformylation have a great potential in organic syn-
thesis, the combination of RhI and biphephos is ideal for
linear hydroformylation even in the presence of multiple
components in the reaction mixture. Work is in progress by
our group to experiment with other domino sequences in as-
sociation with the hydroformylation reaction.
1
1640, 1537 cmÀ1; H NMR (CDCl3, 200 MHz): d=7.35–7.25 (m, 5H), 6.36
(br d, J=7.7 Hz, 1H), 5.97 (m, 1H), 5.28 (m, 1H), 5.22 (m, 1H), 5.17 (dt,
J=7.8, 4.7 Hz, 1H), 3.65 (d, J=4.7 Hz, 2H), 3.35 (s, 3H), 3.06 ppm (dt,
J=7.0, 1.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 170.1 (C), 139.9 (C),
131.4 (CH), 128.6 (CH), 127.6 (CH), 126.8 (CH), 119.8 (CH2), 75.0
(CH2), 59.2 (CH3), 52.6 (CH), 41.7 ppm (CH2); HRMS-ESI: m/z: calcd:
220.1332 [M+H]+; found: 220.1332 (D=0.2 ppm).
N-[(1R)-2-Hydroxy-1-phenylethyl]but-3-enamide (3a): Compound 3a
was prepared by following the general procedure A as described above
from (R)-(À)-2-amino-2-phenylethanol (1.00 g, 7.29 mmol). The residue
was purified by flash chromatography (98:2 CH2Cl2/MeOH) to give 3a as
a white solid (1.14 g, 76%). [a]2D0 =À42.1 (c=1.0 in CHCl3); m.p. 105–
1068C; IR (neat): n˜ =3307, 1644, 1632, 1493, 1454 cmÀ1
;
1H NMR
(CDCl3, 200 MHz): d=7.45–7.26 (m, 5H), 6.39 (brd, J=7.2 Hz, 1H),
6.10–5.89 (m, 1H), 5.32–5.23 (m, 2H), 5.09 (dt, J=7.2, 4.7 Hz, 1H), 3.90
(d, J=4.7 Hz, 2H), 3.1 (dt, J=7.2, 1.1 Hz, 2H), 2.52 ppm (brs, 1H);
13C NMR (CDCl3, 75 MHz): d=171.4 (C), 139.1 (C), 131.2 (CH), 129.0
(CH), 127.9 (CH), 126.7 (CH), 120.0 (CH2), 66.3 (CH2), 55.9 (CH),
41.5 ppm (CH2); HRMS-ESI: m/z: calcd: 206.1176 [M+H]+; found:
206.1175 (D=0.2 ppm).
Experimental Section
N-[(2R)-1-Hydroxy-3-phenylpropan-2-yl]but-3-enamide (3b): Compound
3b was prepared by following the general procedure A as described
above from (R)-2-amino-3-phenyl-1-propanol (800 mg, 5.29 mmol). The
residue was purified by flash chromatography (98:2 CH2Cl2/MeOH) to
give 3b as a white solid (798 mg, 69%). [a]2D0 =+33.8 (c=1.0 in CHCl3);
General: All reagents were used as purchased from commercial suppliers
without further purification. The reactions were carried out in oven-dried
or flamed vessels and performed under argon. Solvents were dried and
purified by conventional methods prior use. Et2O and THF were freshly
distilled from sodium/benzophenone and dichloromethane was distilled
from CaH2. Toluene was distilled from sodium. Flash column chromatog-
raphy was performed with Merck silica gel 60, 0.040–0.063 mm (230–400
mesh). Merck aluminum-backed plates pre-coated with silica gel 60
(UV254) were used for TLC and were visualized by staining with KMnO4.
1H, 13C, and 31P NMR spectra were recorded on Bruker (300/75/
121 MHz) or (200/50/81 MHz) spectrometers. Conditions are specified
for each spectrum (temperature 258C unless specified). Splitting patterns
are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
sext, sextuplet; br, broad. Chemical shifts (d) are given in ppm relative to
the resonance of their respective residual solvent peak, CHCl3 (1H: d=
7.27, 13C: 77.16 ppm, the middle peak). IR spectra were taken with a
Nicolet 380 FTIR spectrometer. HR and LRMS analyses were conducted
by the Institut Fꢁdꢁratif de Recherche 85 at the Louis Pasteur University,
Strasbourg. Melting points were determined on a Bꢃchi Melting Point B-
540 apparatus in open capillary tubes and are uncorrected. Specific rota-
tions were measured with a Perkin–Elmer apparatus by using a 10 cm
m.p. 69–708C; IR (neat): n˜ =3286, 1645, 1549, 1450, 1428 cmÀ1 1H NMR
;
(CDCl3, 200 MHz): d=7.37–7.21 (m, 5H), 6.02 (brd, J=7.4 Hz, 1H),
5.96–5.75 (m, 1H), 5.24–5.12 (m, 2H), 4.26–4.10 (m, 1H), 3.70 (dd, J=
11.0, 3.7 Hz, 1H), 3.60 (dd, J=11.0, 5.1 Hz, 1H), 3.24 (brs, 1H), 2.98
(brd, J=7.1 Hz, 2H), 2.90 ppm (dd, J=7.3, 3.1 Hz, 2H); 13C NMR
(CDCl3, 50 MHz): d=171.4 (C), 137.6 (C), 131.1 (CH), 129.4 (CH), 128.7
(CH), 126.8 (CH), 120.1 (CH2), 64.1 (CH2), 53.1 (CH), 41.7 (CH2),
37.0 ppm (CH2); HRMS-ESI: m/z: calcd: 220.1332 [M+H]+; found:
220.1328 (D=2.0 ppm).
N-[(2S)-1-Hydroxy-3-methylbutan-2-yl]but-3-enamide (3c): Compound
3c was prepared by following the general procedure A as described
above from (S)-(+)-2-amino-3-methyl-1-butanol (300 mg, 2.91 mmol).
The residue was purified by flash chromatography (98:2 CH2Cl2/MeOH)
to give 3c as a yellow oil (318 mg, 64%). [a]2D0 =À50.0 (c=1.0 in CHCl3);
IR (neat): n˜ =3292, 2960, 1632, 1545 cmÀ1 1H NMR (CDCl3, 300 MHz):
;
d=6.02–5.85 (m, 2H), 5.24–5.18 (m, 2H), 3.72–3.58 (m, 4H), 3.02 (brd,
J=7.0 Hz, 2H), 1.92–1.81 (m, 1H), 0.93 (d, J=6.8 Hz, 3H), 0.89 ppm (d,
J=6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d=171.8 (C), 131.4 (CH),
120.0 (CH2), 63.7 (CH2), 57.2 (CH), 41.8 (CH2), 29.1 (CH), 19.6 (CH3),
18.8 ppm (CH3); LRMS-ESI: m/z: 194 [M+Na], HRMS-ESI: m/z: calcd:
172.1332 [M+H]+; found: 172.1328 (D=2.4 ppm).
cell with a Na 589 nm filter: values are given in 10À1 8cm2 gÀ1
.
General procedure A for the formation of products 2–10: But-3-enoic
acid (1 equiv) was added to a solution of the desired substrate (1 equiv)
in anhydrous CH2Cl2 (0.3m) in an ice bath. Then, DCC (1.05 equiv, for
Chem. Eur. J. 2008, 14, 10938 – 10948
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10943

A. Mann et al.
N-[(1R,2S)-2-Hydroxy-1-methyl-2-phenylethyl]but-3-enamide (3d): Com-
pound 3d was prepared by following the general procedure A as de-
scribed above from d-(+)-norephedrine (500 mg, 2.66 mmol). The residue
was purified by flash chromatography (98:2 CH2Cl2/MeOH) to give 3d as
a white solid (497 mg, 85%). [a]2D0 =+88.4 (c=1.0 in CHCl3); m.p. 78–
N-[2-(5-Bromo-1H-indol-3-yl)ethyl]but-3-enamide (8): Compound 8 was
prepared by following the general procedure A as described above from
5-bromotryptamine (300 mg, 1.25 mmol). The residue was purified by
flash chromatography (50:50 pentane/EtOAc) to give 8 as a white solid
(347, 90%). M.p. 104–1058C; IR (neat): n˜ =3277, 1618, 1560, 1436,
1188 cmÀ1 1H NMR (CDCl3, 300 MHz): d=8.42 (brs, 1H), 7.71 (d, J=
;
798C; IR (neat): 3304, 2921, 2850, 1646, 1540 cmÀ1 1H NMR (CDCl3,
;
1.1 Hz, 1H), 7.30–7.23 (m, 2H), 7.02 (d, J=1.5 Hz, 1H), 5.86 (ddt, J=
17.3, 10.0, 7.1 Hz, 1H), 5.77 (brs, 1H), 5.20–5.13 (m, 2H), 3.56 (td, J=
6.8, 6.2 Hz, 2H), 2.98 (dt, J=7.1, 1.0 Hz, 2H), 2.92 ppm (t, J=6.8 Hz,
2H); 13C NMR (CDCl3, 75 MHz): d=170.9 (C), 135.1 (C), 131.3 (CH),
129.3 (C), 125.1 (CH), 123.4 (CH), 121.4 (CH), 120.2 (CH2), 112.9 (CH),
112.85 (C), 112.80 (C), 41.8 (CH2), 40.2 (CH2), 25.2 ppm (CH2); HRMS-
ESI: m/z: calcd: 307.0441 [M+H]+, 309.0421; found: 307.0433, 309.0419
(D=2.4 ppm).
300 MHz): d=7.34–7.27 (m, 5H), 5.89 (ddt, J=17.2, 10.5, 7.0 Hz, 1H),
5.88 (brs, 1H), 5.23–5.16 (m, 2H), 4.83 (d, J=3.0 Hz, 1H), 4.29 (dqd, J=
8.2, 6.9, 2.9 Hz, 1H), 3.77 (brs, 1H), 2.99 (dt, J=7.1, 1.2 Hz, 2H),
0.99 ppm (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 171,4 (C),
140.8 (C), 131.2 (CH), 128.3 (CH), 127.6 (CH), 126.4 (CH), 120.0 (CH2),
76.5 (CH), 51.1 (CH), 41.6 (CH2), 14.6 ppm (CH3); HRMS-ESI: m/z:
calcd: 226.1414 [M+Li]+; found: 226.1415 (D=0.6 ppm).
N-[2-(3-Methoxyphenyl)ethyl]but-3-enamide (4): Compound 4 was pre-
pared by following the general procedure A as described above from 2-
(3-methoxyphenyl)-ethylamine (500 mg, 3.31 mmol). The residue was pu-
rified by flash chromatography (60:40 to 50:50 pentane/EtOAc) to give 4
as a white solid (677 mg, 93%). M.p. 40–418C; IR (neat): n˜ =3249, 3077,
(S)-Methyl 2-(but-3-enamido)-3-(1H-indol-3-yl)propanoate (9): Com-
pound 9 was prepared by following the general procedure A as described
above from 34 (1.62 g, 7.45 mmol). The residue was purified by flash
chromatography (50:50 pentane/EtOAc) to give 9 as a waxy solid (1.99 g,
93%). [a]2D0 =+44.6 (c=1.0 in CHCl3); IR (neat): n˜ =3293, 2951, 1734,
2942, 1637, 1553, 1486 cmÀ1 1H NMR (CDCl3, 300 MHz): d=7.25–7.20
;
1652, 1515, 1434, 1204 cmÀ1 1H NMR (CDCl3, 300 MHz): d=8.41 (brs,
;
(m, 1H), 6.79–6.72 (m, 3H), 5.87 (ddt, J=17.0, 10.3, 7.2 Hz, 1H), 5.73
(brs, 1H), 5.21–5.13 (m, 2H), 3.79 (s, 3H), 3.50 (dt, J=6.6, 6.6 Hz, 2H),
2.96 (dt, J=7.0, 1.1 Hz, 2H), 2.78 ppm (t, J=7.0 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d=170.6 (C), 159.9 (C), 140.5 (C), 131.4 (CH), 129.7
(CH), 121.2 (CH), 119.8 (CH2), 114.5 (CH), 112.0 (CH), 55.3 (CH3), 41.7
(CH2), 40.7 (CH2), 35.8 ppm (CH2); HRMS-ESI: m/z: calcd: 220.1332
[M+H]+; found: 220.1336 (D=1.8 ppm).
1H), 7.55–7.51 (m, 1H), 7.39–7.34 (m, 1H), 7.24–7.07 (m, 2H), 6.96 (d,
J=2.2 Hz, 1H), 6.16 (d, J=7.9 Hz, 1H), 5.84 (ddt, J=16.8, 10.5, 7.1 Hz,
1H), 5.18–5.07 (m, 2H), 4.95 (dt, J=7.9, 5.3 Hz, 1H), 3.70 (s, 3H), 3.33
(dt, J=5.4, 0.7 Hz, 2H), 2.98 ppm (dt, J=7.1, 1.2 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d=172.4 (C), 170.4 (C), 136.2 (C), 130.8 (CH), 127.8
(C), 122.9 (CH), 122.3 (CH), 120.0 (CH2), 119.7 (CH), 118.7 (CH), 111.4
(CH), 109.9 (C), 53.2 (CH3), 52.5 (CH), 41.4 (CH2), 27.6 ppm (CH2);
HRMS-ESI: m/z: calcd: 287.1390 [M+H]+; found: 287.1397 (D=
2.4 ppm).
N-(3,4-Dimethoxyphenethyl)but-3-enamide (5): Compound 5 was pre-
pared by following the general procedure A as described above from 2-
(3,4-dimethoxyphenyl)ethylamine (400 mg, 2.21 mmol). The residue was
purified by flash chromatography (50:50 pentane/EtOAc) to give 5 as a
yellow solid (522 mg, 95%). M.p. 75–768C; IR (neat): n˜ =3246, 3077,
N-[5-(Trimethylsilyl)pent-3-enyl]but-3-enamide (10): Compound 10 was
prepared by following the general procedure A as described above from
36 (500 mg, 3.18 mmol). The residue was purified by flash chromatogra-
phy (85:15 pentane/EtOAc) to give 10 as a colorless oil (615 mg, 86%).
2938, 1633, 1568, 1512, 1256, 1136, 1022 cmÀ1
;
1H NMR (CDCl3,
200 MHz): d=6.81–6.77 (m, 1H), 6.72–6.69 (m, 2H), 5.87 (ddt, J=16.8,
10.3, 7.3 Hz, 1H), 5.74 (brs, 1H), 5.20–5.10 (m, 2H), 3.84 (s, 6H), 3.47
(td, J=7.0, 5.8 Hz, 2H), 2.95 (dt, J=7.0, 1.3 Hz, 2H), 2.74 ppm (t, J=
7.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=170.6 (C), 149.1 (C), 147.8
(C), 131.4 (CH), 131.3 (C), 120.7 (CH), 119.7 (CH2), 112.0 (CH), 111.5
(CH), 56.0 (CH3), 41.7 (CH2), 40.9 (CH2), 35.3 ppm (CH2); HRMS-ESI:
m/z: calcd: 250.1438 [M+H]+; found: 250.1431 (D=2.8 ppm).
IR (neat): n˜ =3292, 3081, 2953, 1648, 1552, 1247 cmÀ1 1H NMR (CDCl3,
;
300 MHz): d=5.98–5.84 (m, 1H), 5.67 (brs, 1H), 5.56–5.42 (m, 1H),
5.23–5.12 (m, 3H), 3.28–3.22 (m, 2H), 2.99–2.96 (m, 2H), 2.23–2.14 (m,
2H), 1.48–1.41 (m, 2H), 0.00 (s, 2.7H), À0.01 ppm (s, 5.7H); 13C NMR
(CDCl3, 75 MHz): major isomer: d=170.5 (C), 131.6 (CH), 129.5 (CH),
124.8 (CH), 119.6 (CH2), 41.7 (CH2), 39.4 (CH2), 32.7 (CH2), 22.9 (CH2),
À1.9 ppm (CH3); HRMS-ESI: m/z: calcd: 226.1622 [M+H]+; found:
226.1626 (D=2.1 ppm).
(S)-Methyl 2-(but-3-enamido)-3-(3,4-dimethoxyphenyl)propanoate (6):
Compound 6 was prepared by following the general procedure A as de-
scribed above from 33 (634 mg, 2.65 mmol). The residue was purified by
flash chromatography (50:50 pentane/EtOAc) to give 6 as a white solid
(749 mg, 92%). [a]2D0 =+69.2 (c=1.0 in CHCl3); m.p. 122–1238C; IR
4-Formyl-N-[(R)-2-methoxy-1-phenylethyl]butanamide (11) (regioiso-
meric mixture, diagnostic peak only): Compound 11 was prepared by fol-
lowing the general procedure B as described above from 2 (50 mg,
0.023 mmol) in THF. 1H NMR (CDCl3, 300 MHz): d=9.78 (t, J=1.3 Hz,
1H), 3.66 (d, J=4.9 Hz, 2H), 3.38 (s, 3H), 2.56–2.51 (m, 2H), 2.34–2.29
(m, 2H), 1.99 ppm (t, J=7.1 Hz, 2H).
(neat): n˜ =3311, 1748, 1642, 1540, 1521, 1270, 1162 cmÀ1 1H NMR
;
(CDCl3, 200 MHz): d=6.80–6.76 (m, 1H), 6.64–6.60 (m, 2H), 6.05 (brd,
J=7.4 Hz, 1H), 5.89 (ddt, J=16.7, 10.6, 7.1 Hz, 1H), 5.25–5.15 (m, 2H),
4.85 (dt, J=7.8, 5.8 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.73 (s, 3H), 3.07
(brd, J=5.8 Hz, 2H), 3.01 ppm (dt, J=7.1, 1.3 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d=172.1 (C), 170.1 (C), 149.0 (C), 148.2 (C), 130.9
(CH), 128.2 (C), 121.4 (CH), 120.0 (CH2), 112.4 (CH), 111.3 (CH), 55.92
(CH3), 55.89 (CH3), 53.2 (CH), 52.4 (CH3), 41.5 (CH2), 37.5 ppm (CH2);
HRMS-ESI: m/z: calcd: 308.1492 [M+H]+; found: 308.1489 (D=
1.1 ppm).
3-Formyl-N-[(R)-2-methoxy-1-phenylethyl]butanamide (12) (diastereo-
meric mixture, diagnostic peak only): Compound 12 was prepared by fol-
lowing the general procedure B as described above from 2 (50 mg,
0.023 mmol) in THF. 1H NMR (CDCl3, 300 MHz): d=9.74 (d, J=0.9 Hz,
0.5H), 9.71 (d, J=0.9 Hz, 0.5H), 1.21 (d, J=7.4 Hz, 1.5H), 1.17 ppm (d,
J=7.4 Hz, 1.5H).
N-[(1R)-2-Methoxy-1-phenylethyl]butanamide (13): Compound 13 was
prepared by following the general procedure B as described above from
2 (50 mg, 0.023 mmol) in THF. Purification conditions: 50:50 pentane/
EtOAc; slightly yellow oil; [a]2D0 =À61.7 (c=0.67 in CHCl3); IR (neat):
N-[2-(1H-Indol-3-yl)ethyl]but-3-enamide (7): Compound 7 was prepared
by following the general procedure A as described above from trypta-
mine (753 mg, 4.70 mmol). The residue was purified by flash chromatog-
raphy (60:40 to 50:50 pentane/EtOAc) to give 7 as an off-white solid
(843 mg, 78%). M.p. 68–698C; IR (neat): n˜ =3384, 3254, 3081, 1633,
n˜ =3292, 2961, 2928, 2873, 1640, 1540 cmÀ1 1H NMR (CDCl3, 300 MHz):
;
d=7.34–7.26 (m, 5H), 6.19 (d, J=6.6 Hz, 1H), 5.19 (dt, J=7.9, 4.8 Hz,
1H), 3.66 (d, J=4.8 Hz, 2H), 3.36 (s, 3H), 2.22 (t, J=7.5 Hz, 2H), 1.69
(sext, J=7.5 Hz, 2H), 0.95 ppm (t, J=7.5 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d=172.6 (C), 140.1 (C), 128.6 (CH), 127.5 (CH), 126.9 (CH),
75.1 (CH2), 59.2 (CH3), 52.4 (CH), 38.8 (CH2), 19.3 (CH2), 13.9 ppm
(CH3); HRMS-ESI: m/z: calcd: 222.1489 [M+H]+; found: 222.1485 (D=
1.5 ppm).
1557, 1455, 1341, 1217 cmÀ1 1H NMR (CDCl3, 300 MHz): d 8.37 (brs,
;
1H), 7.61 (d, J=7.9 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.25–7.11 (m, 2H),
7.02 (d, J=2.2 Hz, 1H), 5.87 (ddt, J=16.9, 10.3, 7.2 Hz, 1H), 5.75 (brs,
1H), 5.18–5.11 (m, 2H), 3.60 (dt, J=6.6, 6.5 Hz, 2H), 3.00–2.95 ppm (m,
4H); 13C NMR (CDCl3, 50 MHz): d 170.7 (C), 136.5 (C), 131.4 (CH),
127.4 (C), 122.24 (CH), 122.20 (CH), 119.8 (CH2), 119.5 (CH), 118.8
(CH), 112.9 (C), 111.4 (CH), 41.8 (CH2), 40.0 (CH2), 25.3 ppm (CH2);
HRMS-ESI: m/z: calcd: 229.1335 [M+H]+; found: 229.1338 (D=
1.1 ppm).
(2E)-N-[(1R)-2-Methoxy-1-phenylethyl]but-2-enamide (14): Compound
14 was prepared by following the general procedure B as described
above from 2 (50 mg, 0.023 mmol) in THF. Purification conditions: 50:50
10944
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10938 – 10948

A General Approach to Aza-Heterocycles
FULL PAPER
pentane/EtOAc; white solid; [a]2D0 =À74.3 (c=1.0 in CHCl3); m.p. 86–
(dd, J=11.6, 6.5 Hz, 1H), 2.26–2.16 (m, 1H), 1.89 (ddtd, J=13.9, 6.6, 3.8,
2.0 Hz, 1H), 1.62 (tddd, J=13.8, 11.5, 6.0, 2.6 Hz, 1H), 1.39 ppm (dddd,
J=13.7, 12.5, 9.1, 3.2 Hz, 1H); 13C NMR (CDCl3, 50 MHz): d=168.7 (C),
136.9 (C), 129.6 (CH), 128.6 (CH), 126.7 (CH), 87.3 (CH), 69.3 (CH2),
55.1 (CH), 37.8 (CH2), 31.4 (CH2), 28.2 (CH2), 17.2 ppm (CH2); HRMS-
ESI: m/z: calcd: 232.1332 [M+H]+; found: 220.1330 (D=0.8 ppm).
878C; IR (neat): n˜ =3275, 2882, 1669, 1633, 1556 cmÀ1 1H NMR (CDCl3,
;
300 MHz): d=7.25–7.15 (m, 5H), 6.78 (dq, J=15.1, 6.9 Hz, 1H), 6.18
(brd, J=7.6 Hz, 1H), 5.79 (dq, J=15.1, 1.6 Hz, 1H), 5.16 (dt, J=7.6,
4.9 Hz, 1H), 3.60 (m, 2H), 3.27 (s, 3H), 1.77 ppm (dd, J=6.9, 1.5 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 165.5 (C), 140.4 (CH), 140.0 (C),
128.6 (CH), 127.5 (CH), 126.9 (CH), 125.0 (CH), 75.0 (CH2), 59.1 (CH3),
52.5 (CH), 17.8 ppm (CH3); HRMS-ESI: m/z: calcd: 220.1332 [M+H]+;
found: 220.1328 (D=1.7 ppm).
AHCTUNGTERNN(GUN 3R,8aR)-3-Benzylhexahydro-5H-[1,3]oxazoloACTHUNGTREN[NNUG 3,2-a]pyridin-5-one (21b’)
1
(nonisolated, diagnostic peak only): H NMR (CDCl3, 300 MHz): d=4.68
(dd, J=9.9, 3.4 Hz, 2H), 4.24 (ddd, J=9.4, 6.5, 3.2 Hz, 2H), 3.78–
3.73 ppm (m, 2H).
1-[(1R)-2-Methoxy-1-phenylethyl]-3,4-dihydropyridin-2(1H)one
(15):
Compound 15 was prepared by following the general procedure B as de-
scribed above from 2 (50 mg, 0.023 mmol) in THF. Purification condi-
tions: 50:50 pentane/EtOAc; slightly yellow oil; [a]2D0 =À89.0 (c=1.0 in
ACHUTNGRENU(NG 3S,8aR)-3-Isopropylhexahydro-5H-[1,3]oxazoloCAHTUNGTRENN[UGN 3,2-a]pyridin-5-one
(21c): Compound 21c was prepared by following the general procedure
B as described above from 3c (100 mg, 0.58 mmol) in THF. The residue
was purified by flash chromatography (98:2 CH2Cl2/MeOH) to give 21c
as a yellow oil (76 mg, 71%). [a]2D0 =+3.2 (c=1.0 in CHCl3) (lit.:[34]
CHCl3); IR (neat): n˜ =2894, 1662 cmÀ1 1H NMR (CDCl3, 200 MHz): d=
;
7.37–7.29 (m, 5H), 6.07 (dt, J=8.0, 1.5 Hz, 1H), 6.05 (t, J=6.7 Hz, 1H),
5.15 (dt, J=8.0, 4.2 Hz, 1H), 3.89 (m, 2H), 3.43 (s, 3H), 2.63 (m, 2H),
2.33 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d=169.7 (C), 137.7 (C),
128.7 (CH), 127.7 (CH), 127.6 (CH), 126.6 (CH), 106.3 (CH), 72.1 (CH2),
59.0 (CH3), 53.6 (CH), 31.7 (CH2), 20.0 ppm (CH2); HRMS-ESI: m/z:
calcd: 232.1332 [M+H]+; found: 232.1335 (D=1.1 ppm).
[a]2D0 =+13 (c=1.1 in EtOH)); IR (neat): n˜ =2957, 2873, 1648, 1464 cmÀ1
;
1H NMR (CDCl3, 300 MHz): d=4.73 (dd, J=8.6, 4.7 Hz, 1H), 4.19 (brdt,
J=7.3, 6.9 Hz, 1H), 4.03 (dd, J=8.3, 8.0 Hz, 1H), 3.66 (dd, J=8.6,
6.9 Hz, 1H), 2.49 (brddt, J=17.9, 5.8, 1.9 Hz, 1H), 2.34–2.10 (m, 3H),
1.95–1.85 (m, 1H), 1.75–1.60 (m, 1H), 1.49–1.37 (m, 1H), 0.92 (d, J=
6.5 Hz, 3H), 0.89 ppm (d, J=6.5 Hz, 3H); 13C NMR (CDCl3, 50 MHz):
d=169.3 (C), 87.7 (CH), 66.6 (CH2), 59.2 (CH), 31.7 (CH2), 30.1 (CH),
28.5 (CH2), 19.1 (CH2), 17.0 ppm (CH3); HRMS-ESI: m/z: calcd:
184.1332 [M+H]+; found: 184.1328 (D=2.4 ppm).
1-[(1R)-2-Methoxy-1-phenylethyl]-4-methyl-1,5-dihydro-2H-pyrrol-2-one
(16): Compound 16 was prepared by following the general procedure B
as described above from 2 (50 mg, 0.023 mmol) in THF. Purification con-
ditions: 50:50 pentane/EtOAc; slightly yellow oil; [a]2D0 =À60.5 (c=1.0 in
CHCl3); IR (neat): n˜ =2922, 1672 cmÀ1 1H NMR (CDCl3, 300 MHz): d=
;
ACHUTNGRENU(NG 3S,8aS)-3-Isopropylhexahydro-5H-[1,3]oxazoloCAHTUNGTRENN[UGN 3,2-a]pyridin-5-one
(21c’) (nonisolated, diagnostic peak only): 1H NMR (CDCl3, 300 MHz):
d=4.65 (dd, J=9.6, 3.2 Hz, 1H), 3.97–3.94 (m, 1H), 2.86–2.75 (m, 1H),
0.76 ppm (d, J=7.0 Hz, 3H).
7.28–7.18 (m, 5H), 5.78 (m, 1H), 5.44 (dd, J=6.9, 5.6 Hz, 1H), 3.89 (d,
J=19.5 Hz, 1H), 3.88 (dd, J=10.2, 2.8 Hz, 1H), 3.75 (dd, J=10.2, 5.4 Hz,
1H), 3.57 (d, J=19.5 Hz, 1H), 3.32 (s, 3H), 1.93 ppm (d, J=1 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d 172.3 (C), 155.8 (C), 138.1 (C), 128.7
(CH), 127.7 (CH), 127.6 (CH), 122.6 (CH), 72.5 (CH2), 58.9 (CH3), 53.2
(CH2), 53.0 (CH), 15.4 ppm (CH3); HRMS-ESI: m/z: calcd: 232.1332
[M+H]+; found: 232.1337 (D=2.2 ppm).
(2S,3R,8aS)-3-Methyl-2-phenylhexahydro-5H-[1,3]oxazoloACTHNUTRGNE[UNG 3,2-a]pyridin-
5-one (21d): Compound 21d was prepared by following the general pro-
cedure B as described above from 3d (150 mg, 0.68 mmol) in THF. The
residue was purified by flash chromatography (30:70 to 0:100 pentane/
EtOAc) to give 21d as a colorless oil (123 mg, 78%). [a]2D0 =+77.3 (c=
ACHTUNGTRENNUNG(3R,8aS)-3-Phenyltetrahydro-2H-oxazoloACHTUNTGREN[NUGN 3,2-a]pyridin-5(3H)one (21a):
Compound 21a was prepared by following the general procedure B as
described above from 3a (150 mg, 0.73 mmol) in THF. The residue was
purified by flash chromatography (98:2 CH2Cl2/MeOH) to give 21a as
pale-yellow solid (135 mg, 85%). [a]2D0 =À87.5 (c=0.6 in CH2Cl2) (lit.:[27]
[a]2D2 =À88.0 (c=0.6 in CH2Cl2); m.p. 87–888C (lit.:[28] m.p. 88–908C); IR
1.0 in CHCl3); IR (neat): n˜ =2958, 1628, 1448, 1329 cmÀ1 1H NMR
;
(CDCl3, 300 MHz): d=7.38–7.26 (m, 5H), 5.28 (dd, J=9.3, 4.2 Hz, 1H),
5.14 (d, J=6.1 Hz, 1H), 4.87 (dq, J=6.6, 6.6 Hz, 1H), 2.53–2.44 (m, 1H),
2.41–2.29 (m, 2H), 1.99–1.90 (m, 1H), 1.78–1.63 (m, 1H), 1.61–1.48 (m,
1H), 0.81 ppm (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 50 MHz): d=167.6
(C), 137.4 (C), 128.4 (CH), 127.8 (CH), 126.1 (CH), 86.0 (CH), 80.0
(CH), 53.4 (CH), 30.9 (CH2), 29.3 (CH2), 16.7 (CH2), 14.1 ppm (CH3);
HRMS-ESI: m/z: calcd: 232.1332 [M+H]+; found: 232.1330 (D=
1.0 ppm).
(neat): n˜ =2930, 2871, 1650, 1443, 1307, 996, 698 cmÀ1 1H NMR (CDCl3,
;
200 MHz): d=7.40–7.23 (m, 5H), 5.28 (t, J=7.9 Hz, 1H), 5.03 (dd, J=
8.9, 4.6 Hz, 1H), 4.50 (dd, J=8.9, 7.8 Hz, 1H), 3.77 (dd, J=8.9, 7.8 Hz,
1H), 2.54 (ddm, J=18.0, 6.0 Hz, 1H), 2.38 (m, 1H), 2.34 (ddd, J=18.0,
11.4, 6.4 Hz, 1H), 1.98 (m, 1H), 1.75 (m, 1H), 1.55 ppm (dddd, J=13.0,
12.2, 9.0, 3.6 Hz, 1H); 13C NMR (CDCl3, 50 MHz): d=168.9 (C), 139.6
(C), 128.8 (CH), 127.5 (CH), 126.1 (CH), 88.7 (CH), 72.4 (CH2), 58.1
(CH), 31.3 (CH2), 28.4 (CH2), 17.1 ppm (CH2); LRMS-ESI: m/z: 218
[M+H]+, 240 [M+Na]; HRMS-ESI: m/z: calcd: 218.1176 [M+H]+;
found: 218.1169 (D=3.0 ppm).
(2S,3R,8aR)-3-Methyl-2-phenylhexahydro-5H-[1,3]oxazolo
5-one (21d’): Colorless oil; yield: 20 mg, 13%; [a]2D0 =+59.2 (c=1.0 in
CHCl3); IR (neat): n˜ =2953, 1635, 1442, 1399, 1328 cmÀ1 1H NMR
ACHTUNGTREN[NGNU 3,2-a]pyridin-
;
(CDCl3, 200 MHz): d=7.39–7.30 (m, 5H), 5.11 (d, J=6.2 Hz, 1H), 4.93
(dd, J=9.4, 3.2 Hz, 1H), 4.33 (dq, J=6.3, 6.2 Hz, 1H), 2.44–2.33 (m,
3H), 2.10–1.96 (m, 1H), 1.85–1.60 (m, 2H), 0.88 ppm (d, J=6.3 Hz, 3H);
13C NMR (CDCl3, 50 MHz): d=168.2 (C), 135.7 (C), 128.4 (CH), 128.0
(CH), 126.2 (CH), 88.2 (CH), 81.5 (CH), 55.0 (CH), 31.1 (CH2), 28.9
(CH2), 17.5 (CH2), 14.5 ppm (CH3); HRMS-ESI m/z: calcd: 232.1332
[M+H]+; found: 232.1335 (D=1.2 ppm).
ACHTUNGTRENNUNG(3R,8aR)-3-Phenyltetrahydro-2H-oxazoloACHTUNTGREN[NUGN 3,2-a]pyridin-5(3H)one (21a’):
Purification conditions: 98:2 CH2Cl2/MeOH; waxy solid (13 mg, 8%);
[a]2D0 =À52.2 (c=0.6 in CH2Cl2) (lit.:[3] [a]2D2 =À51.0 (c=2.2 in CH2Cl2));
IR (neat): n˜ =2956, 2872, 1651, 1467 cmÀ1 1H NMR (CDCl3, 200 MHz):
;
d=7.33–7.22 (m, 5H), 4.92 (dd, J=6.4, 1.0 Hz, 1H), 4.84 (dd, J=9.3,
3.5 Hz, 1H), 4.15 (dd, J=9.0, 6.7 Hz, 1H), 4.01 (dd, J=9.0, 1.2 Hz, 1H),
2.43–2.26 (m, 3H), 2.03 (m, 1H), 1.82–1.73 ppm (m, 2H); 13C NMR
(CDCl3, 50 MHz): d=167.5 (C), 141.6 (C), 128.7 (CH), 127.6 (CH), 126.5
(CH), 89.0 (CH), 73.9 (CH2), 58.9 (CH), 31.2 (CH2), 28.4 (CH2),17.9 ppm
(CH2); HRMS-ESI: m/z: calcd: 218.1176 [M+H]+; found: 218.1170 (D=
2.5 ppm).
1,2,3,6,7-Hexahydro-9-methoxy-4H-benzo[a]quinolizin-4-one (22): Com-
pound 22 was prepared by following the general procedure B as de-
scribed above from 4 (100 mg, 0.46 mmol) in THF. The residue was puri-
fied by flash chromatography (20:80 to 0:100 pentane/EtOAc) to give 22
as a yellow oil (94 mg, 90%). IR (neat): n˜ =2929, 2837, 1606, 1503, 1464,
1
1237 cmÀ1; H NMR (CDCl3, 300 MHz): d=7.12 (d, J=8.4 Hz, 1H), 6.79
(dd, J=8.4, 2.7 Hz, 1H), 6.67 (d, J=2.7 Hz, 1H), 4.81–4.75 (m, 1H), 4.61
(dd, J=10.3, 4.6 Hz, 1H), 3.79 (s, 3H), 2.97–2.87 (m, 2H), 2.75–2.68 (m,
1H), 2.59–2.48 (m, 2H), 2.36 (ddd, J=17.6, 11.4, 6.4 Hz, 1H), 1.99–1.80
(m, 2H), 1.74–1.61 ppm (m, 1H); 13C NMR (CDCl3, 75 MHz): d=169.5
(C), 158.2 (C), 136.5 (C), 129.7 (C), 126.1 (CH), 113.5 (CH), 112.8 (CH),
56.6 (CH), 55.4 (CH3), 39.8 (CH2), 32.3 (CH2), 30.7 (CH2), 29.3 (CH2),
19.7 ppm (CH2); HRMS-ESI: m/z: calcd: 232.1332 [M+H]+; found:
232.1328 (D=1.7 ppm).
ACHTUNGTRENNUNG(3R,8aS)-3-Benzylhexahydro-5H-[1,3]oxazoloACHUTNGTREN[NUGN 3,2-a]pyridin-5-one (21b):
Compound 21b was prepared by following the general procedure B as
described above from 3b (200 mg, 0.91 mmol) in THF. The residue was
purified by flash chromatography (98:2 EtOAc/MeOH) to give 21b as a
white solid (172 mg, 82%). [a]2D0 =À30.7 (c=1.0 in CHCl3); m.p. 65–
668C; IR (neat): n˜ =1637, 1450, 1412, 999, 702 cmÀ1 1H NMR (CDCl3,
;
300 MHz): d=7.32–7.17 (m, 5H), 4.54–4.45 (m, 2H), 4.01 (dd, J=9.0,
7.6 Hz, 1H), 3.61 (dd, J=9.0, 7.6 Hz, 1H), 3.27 (dd, J=13.3, 3.6 Hz, 1H),
2.79 (dd, J=13.3, 9.2 Hz, 1H), 2.50 (ddt, J=18.1, 6.2, 1.6 Hz, 1H), 2.32
1,2,3,6,7-Hexahydro-9,10-dimethoxy-4H-benzo[a]quinolizin-4-one (23):[35]
Compound 23 was prepared by following the general procedure B as de-
Chem. Eur. J. 2008, 14, 10938 – 10948
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10945

A. Mann et al.
scribed above from 5 (100 mg, 0.40 mmol) in THF. The residue was puri-
fied by flash chromatography (98:2 EtOAc/MeOH) to give 23 as a yellow
(6S,12bS)-Methyl 1,2,3,4,6,7,12,12b-octahydro-4-oxoindolo
zine-6-carboxylate (27’): The residue was purified by flash chromatogra-
phy (25:75 to 0:100 pentane/EtOAc) to give 27’ as a yellow solid. [a]D20
À40.2 (c=1 in CHCl3); m.p. 1978C; IR (neat): n˜ =3269, 2919, 2852, 1742,
1615, 1467 cmÀ1 1H NMR (CDCl3, 200 MHz): d=8.51 (brs, 1H), 7.54–
7.50 (m, 1H), 7.37–7.31 (m, 1H), 7.23–7.12 (m, 2H), 4.98–4.92 (m, 1H),
4.43 (dd, J=8.4, 4.9 Hz, 1H), 3.72 (s, 3H), 3.45 (ddd, J=15.7, 8.4, 1.9 Hz,
1H), 3.05 (ddd, J=15.7, 4.9, 1.9 Hz, 1H), 2.53–2.35 (m, 3H), 2.23–2.15
(m, 1H), 2.00–1.74 ppm (m, 2H); 13C NMR (CDCl3, 50 MHz): d=172.2
(C), 170.8 (C), 136.4 (C), 133.2 (C), 126.9 (C), 122.4 (CH), 120.0 (CH),
118.4 (CH), 111.3 (CH), 108.9 (C), 56.8 (CH), 54.9 (CH), 52.4 (CH3),
32.5 (CH2), 27.2 (CH2), 22.7 (CH2), 18.4 ppm (CH2); HRMS-ESI: m/z:
calcd: 299.1390 [M+H]+; found: 299.1392 (D=0.5 ppm).
ACHTUNGTREN[NGNU 2,3-a]quinoli-
oil (92 mg, 88%). IR (neat): n˜ =2935, 2835, 1609, 1511, 1463, 1255 cmÀ1
;
=
1H NMR (CDCl3, 300 MHz): d=6.68 (s, 1H), 6.63 (s, 1H), 4.91–4.85 (m,
1H), 4.62 (dd, J=10.6, 4.4 Hz, 1H), 3.87 (s, 6H), 2.33–2.90 (m, 6H),
1.65–2.00 ppm (m, 3H); 13C NMR (CDCl3, 50 MHz): d=169.5 (C), 147.9
(C), 147.8 (C), 129.2 (C), 127.4 (C), 111.6 (CH), 108.3 (CH), 56.8 (CH),
56.2 (CH3), 56.0 (CH3), 39.8 (CH2), 32.3 (CH2), 31.0 (CH2), 28.6 (CH2),
19.7 ppm (CH2); HRMS-ESI: m/z: calcd: 262.1438 [M+H]+; found:
262.1431 (D=2.5 ppm).
;
A
2,3,4,6,7,11b-hexahydro-9,10-dimethoxy-4-oxo-1H-
ACHTUNGTRENNUNG
by following the general procedure B as described above from 6 (150 mg,
0.49 mmol) in THF. The residue was purified by flash chromatography
(EtOAc) to give 24 (131 mg, 84%) as a white solid. [a]2D0 =+123.2 (c=
1.0 in CHCl3); m.p. 149–1508C; IR (neat): n˜ =2931, 2855, 1735, 1640,
5-Bromopent-2-enyl)trimethylsilane (28): Grubbs II catalyst (44 mg,
0.052 mmol) was added to
a solution of 1-bromo-3-butene (700 mg,
5.19 mmol) and allyltrimethylsilane (3.30 mL, 20.74 mmol). The suspen-
sion was heated under microwaves for 1 min at 608C. After cooling, the
excess of the reactive compounds were evaporated under reduced pres-
sure and the residue was purified by flash chromatography (heptane
purum) to give 28 as a colorless oil (769 mg, E/Z 63:37, 67%). IR (neat):
1621, 1514 cmÀ1 1H NMR (CDCl3, 300 MHz): d=6.62 (brs, 2H), 5.75
;
(dd, J=5.9, 3.5 Hz, 1H), 4.79 (dd, J=11.0, 4.2 Hz, 1H), 3.87 (s, 3H), 3.86
(s, 3H), 3.65 (s, 3H), 3.17 (dd, J=15.8, 3.5 Hz, 1H), 3.06 (dd, J=15.8,
6.6 Hz, 1H), 2.66 (dtd, J=17.7, 4.7, 1.3 Hz, 1H), 2.51–2.40 (m, 2H), 2.05–
1.94 (m, 2H), 1.75–1.64 ppm (m, 1H); 13C NMR (CDCl3, 50 MHz): d=
171.5 (C), 170.5 (C), 148.2 (C), 148.1 (C), 128.0 (C), 124.2 (C), 111.4
(CH), 108.4 (CH), 56.1 (CH3), 56.0 (CH3), 54.8 (CH), 52.4 (CH3), 50.5
(CH), 31.9 (CH2), 31.6 (CH2), 30.2 (CH2), 19.6 ppm (CH2); HRMS-ESI:
m/z: calcd: 320.1492 [M+H]+; found: 320.1483 (D=2.8 ppm).
n˜ =2954, 1246, 837 cmÀ1 1H NMR (CDCl3, 300 MHz): d=5.61–5.48 (m,
;
1H), 5.31–5.17 (m, 1H), 3.36–3.35 (m, 2H), 2.59–2.51 (m, 2H), 1.51–1.43
(m, 2H), 0.02 (s, 3.3H), 0.01 ppm (s, 5.7H); 13C NMR (CDCl3, 50 MHz):
minor Z isomer: d=128.9 (CH), 123.6 (CH), 32.6 (CH2), 30.9 (CH2), 19.0
(CH2), À1.7 ppm (CH3); 13C NMR (CDCl3, 50 MHz): major E isomer:
d=130.2 (CH), 124.9 (CH), 36.4 (CH2), 33.4 (CH2), 23.0 (CH2),
À1.9 ppm (CH3); GCMS m/z: 222 [M]+, 139, 73.
1,2,3,6,7,12b-HexahydroindoloACTHNUGRTENNUG[2,3-a]quinolizin-4ACHTUNGTERN(NUGN 12H)one (25): Com-
pound 25 was prepared by following the general procedure B as de-
scribed above from 7 (200 mg, 0.88 mmol) in THF. The residue was puri-
fied by flash chromatography (99:1 EtOAc/MeOH) to give 25 (180 mg,
85%) as a white solid. M.p. 240–2418C; IR (neat): n˜ =3200, 2921, 2851,
3,4-Dihydro-1-[5-(trimethylsilyl)pent-3-enyl]pyridine-2(1H)one
(29):
Compound 29 was prepared by following the general procedure B as de-
scribed above from 10 (100 mg, 0.44 mmol) in THF. The residue was pu-
rified by flash chromatography (85:15 pentane/EtOAc) to give 29 a color-
less oil (82 mg, 78%). IR (neat): n˜ =2951, 1668, 1406, 1384, 1246,
1607, 1437 cmÀ1 1H NMR (CDCl3 +CD3OD, 300 MHz): d=7.49 (brd,
;
J=7.5 Hz, 1H), 7.33 (brd, J=7.9 Hz, 1H), 7.16 (td, J=7.5, 1.4 Hz, 1H),
7.10 (td, J=7.5, 1.5 Hz, 1H), 5.17–5.07 (m, 1H), 4.78 (brdd, J=9.8,
4.8 Hz, 1H), 2.89–2.74 (m, 3H), 2.63–2.55 (m, 1H), 2.50–2.34 (m, 2H),
1.98–1.91 (m, 1H), 1.87–1.72 ppm (m, 2H); 13C NMR (CDCl3 +CD3OD,
50 MHz): d=170.2 (C), 136.4 (C), 133.4 (C), 126.6 (C), 121.8 (CH), 119.4
(CH), 118.2 (CH), 111.1 (CH), 108.6 (C), 54.7 (CH), 40.5 (CH2), 32.2
(CH2), 28.7 (CH2), 21.0 (CH2), 19.2 ppm (CH2); HRMS-ESI: m/z: calcd:
241.1335 [M+H]+; found: 241.1342 (D=2.6 ppm).
837 cmÀ1 1H NMR (CDCl3, 200 MHz): d=6.02–5.96 (m, 1H), 5.52–5.36
;
(m, 1H), 5.24–5.04 (m, 2H), 3.43 (brt, J=7.3 Hz, 2H), 2.52–2.43 (m,
2H), 2.32–2.20 (m, 4H), 1.46 (dd, J=8.5, 1.0 Hz, 0.6H), 1.39 (dd, J=7.8,
1.0 Hz, 1.4H), À0.01 (s, 2.3H), À0.04 ppm (s, 5.6H); 13C NMR (CDCl3,
75 MHz): major E isomer: d=169.2 (C), 130.2 (CH), 129.2 (CH), 124.6
(CH), 105.7 (CH), 46.6 (CH2), 32.2 (CH2), 31.6 (CH2), 22.9 (CH2), 20.4
(CH2), À1.9 ppm (CH3); 13C NMR (CDCl3, 75 MHz): minor Z isomer:
d=169.3 (C), 130.1 (CH), 128.3 (CH), 123.0 (CH), 105.8 (CH), 46.2
(CH2), 33.7 (CH2), 31.6 (CH2), 26.5 (CH2), 18.7 (CH2), À1.7 ppm (CH3);
HRMS-ESI: m/z: calcd: 238.1622 [M+H]+; found: 238.1629 (D=
3.2 ppm).
Hexahydro-1-vinylindolizin-5(1H)one (30):[33b] In a stainless steel auto-
clave under an inert atmosphere, a solution of dicarbonylacetylacetonato
rhodium (1.7 mg, 0.007 mmol) and biphephos (10.5 mg, 0.013 mmol) in
anhydrous degassed CH2Cl2 (3 mL), prepared in a Schlenk glassware
under an inert atmosphere, was added to a solution of 10 (150 mg,
0.665 mmol) in anhydrous degassed CH2Cl2 to reach a final concentration
of 0.04m. The autoclave was flushed with H2/CO 1:1 three times. Then,
the autoclave was filled with 5 atm of H2/CO 1:1 and was heated at 608C
with stirring for 4 h. Then, the autoclave was cooled to room temperature
and the gases were slowly and carefully released. TFA (49 mL,
0.665 mmol) was added and the solution was stirred at room temperature
for 12 h. The reaction mixture was then concentrated under reduced
pressure to give an oil. The residue was purified by flash chromatography
(98:2 CH2Cl2/MeOH) to give 30 as a pale-yellow oil (90 mg, 82%) as a
mixture of isomers (cis/trans 90:10). IR (neat): n˜ =2946, 2878, 1613, 1467,
1412, 1331 cmÀ1
9-Bromo-1,2,3,6,7,12b-hexahydroindoloACTHUNRTGENNUG[2,3-a]quinolizin-4ACHTUNGTREN(NGUN 12H)one (26):
Compound 26 was prepared by following the general procedure B as de-
scribed above from 8 (100 mg, 0.33 mmol) in THF. The residue was puri-
fied by flash chromatography (EtOAc purum) to give 26 (76 mg, 73%)
as a white solid. M.p. 272–2748C; IR (neat): n˜ =3165, 2934, 1609, 1437,
1311 cmÀ1 1H NMR (CDCl3 +CD3OD, 300 MHz): d=7.59 (d, J=1.6 Hz,
;
1H), 7.24–7.17 (m, 2H), 5.15–5.05 (m, 1H), 4.75 (brdd, J=9.6, 4.5 Hz,
1H), 2.87–2.67 (m, 3H), 2.63–2.54 (m, 1H), 2.50–2.32 (m, 2H), 1.96–
1.71 ppm (m, 3H); 13C NMR (CDCl3 +CD3OD, 75 MHz): d=170.2 (C),
135.1 (C), 134.8 (C), 128.3 (C), 124.4 (CH), 120.7 (CH), 112.5 (CH),
112.4 (C), 108.2 (C), 54.6 (CH), 40.4 (CH2), 32.2 (CH2), 28.5 (CH2), 20.8
(CH2), 19.1 ppm (CH2); HRMS-ESI: m/z: calcd: 319.0441 [M+H]+,
321.0421; found: 319.0446, 321.0429 (D=1.7 ppm).
ACHTUNGTRENNUNG(6S,12bR)-Methyl 1,2,3,4,6,7,12,12b-octahydro-4-oxoindoloACHUTNGTREN[NUNG 2,3-a]quinoli-
zine-6-carboxylate (27): Compound 27 was prepared by following the
general procedure B as described above from 9 (150 mg, 0.52 mmol) in
THF. The residue was purified by flash chromatography (25:75 pentane/
EtOAc) to give 27 (139 mg, 89%) as a pale-yellow solid. M.p. 165–
1678C; IR (neat): n˜ =3273, 2952, 2850, 1737, 1610, 1429 cmÀ1 1H NMR
;
(CDCl3, 300 MHz): d=8.07 (brs, 1H), 7.53 (dd, J=6.6, 2.0 Hz, 1H),
7.35–7.30 (m, 1H), 7.24–7.09 (m, 2H), 6.12 (dd, J=6.4, 1.4 Hz, 1H),
5.11–5.03 (m, 1H), 3.63 (s, 3H), 3.46 (dt, J=15.7, 1.6 Hz, 1H), 3.07 (ddd,
J=15.7, 6.4, 2.4 Hz, 1H), 2.78–2.64 (m, 1H), 2.54–2.40 (m, 2H), 2.07–1.97
(m, 2H), 1.83–1.75 ppm (m, 1H); 13C NMR (CDCl3, 50 MHz): d=171.6
(C), 170.5 (C), 136.6 (C), 132.5 (C), 126.8 (C), 122.4 (CH), 119.9 (CH),
118.5 (CH), 111.1 (CH), 106.6 (C), 52.6 (CH3), 52.2 (CH), 50.1 (CH),
32.2 (CH2), 29.8 (CH2), 22.9 (CH2), 19.7 ppm (CH2); [a]2D0 =+129.2 (c=1
in CHCl3); HRMS-ESI: m/z: calcd: 299.1390 [M+H]+; found: 299.1385
(D=1.9 ppm).
Major isomer (cis 30): 1H NMR (CDCl3, 200 MHz): d=5.60 (ddd, J=
17.8, 9.5, 9.5 Hz, 1H), 5.08 (dd, J=11.5, 1.5 Hz, 2H), 3.72–3.41 (m, 3H),
2.79 (dt, J=9.3, 5.5 Hz, 1H), 2.48–2.23 (m, 2H), 2.03–1.61 (m, 5H), 1.40–
1.25 ppm (m, 1H); 13C NMR (CDCl3, 75 MHz): d=169.8 (C), 135.8
(CH), 116.7 (CH2), 61.8 (CH), 46.6 (CH), 43.5 (CH2), 31.0 (CH2), 28.6
(CH2), 25.5 (CH2), 20.9 ppm (CH2).
Minor isomer (trans 30’, diagnostic peak only): 1H NMR (CDCl3,
200 MHz): d=3.06 (td, J=10.5, 3.2 Hz, 1H); HRMS-ESI: m/z: calcd:
166.1226 [M+H]+; found: 166.1228 (D=0.8 ppm).
10946
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10938 – 10948

A General Approach to Aza-Heterocycles
FULL PAPER
3-(Octahydro-5-oxoindolizin-1-yl)propanal (31): Compound 31 was pre-
pared by following the general procedure B as described above from 10
(100 mg, 0.44 mmol) in THF. The residue was purified by flash chroma-
tography (96:4 CH2Cl2/MeOH) to give 31 as a colorless oil (60 mg, 69%)
and as a mixture of isomers (cis/trans 90:10). IR (neat): n˜ =2944, 2873,
1716, 1601, 1470, 1412 cmÀ1
Major isomer (cis 31): 1H NMR (CDCl3, 300 MHz): d=9.78 (brt, J=
1.0 Hz, 1H), 3.61–3.39 (m, 3H), 2.57–2.37 (m, 3H), 2.30–2.09 (m, 3H),
2.00–1.66 (m, 5H), 1.47–1.21 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz):
d=201.6 (CH), 169.5 (C), 61.9 (CH), 43.0 (CH2), 41.9 (CH2), 40.7 (CH),
31.1 (CH2), 26.5 (CH2), 24.9 (CH2), 21.1 (CH2), 19.5 ppm (CH2).
30 mL), dried over Na2SO4, filtered, and evaporated to give 35 as a
slightly yellow oil (1.325 g, E/Z 63:37, 92%), which was used without fur-
ther purifications. IR (neat): n˜ =2954, 2089, 1247, 838 cmÀ1 1H NMR
;
(CDCl3, 200 MHz): d=5.64–5.46 (m, 1H), 5.33–5.14 (m, 1H), 3.31–3.21
(m, 2H), 2.36–2.24 (m, 2H), 1.54–1.43 (m, 2H), 0.02 (s, 3.3H), 0.00 ppm
(s, 5.7H); 13C NMR (CDCl3, 50 MHz): minor Z isomer: d=128.9 (CH),
122.3 (CH), 51.2 (CH2), 26.9 (CH2), 18.8 (CH2), À1.8 ppm (CH3);
13C NMR (CDCl3, 50 MHz) major E isomer: d=129.9 (CH), 123.8 (CH),
51.5 (CH2), 32.4 (CH2), 22.9 (CH2), À2.0 ppm (CH3); GCMS: m/z: 183
[M]+, 101, 86, 73.
5-(Trimethylsilyl)pent-3-en-1-amine (36): Lithium aluminum hydride
(0.311 g, 8.20 mmol) was added portionwise to a solution of 35 (1.253 g,
6.83 mmol) in Et2O (30 mL) at 08C. The suspension was stirred overnight
at room temperature. After this time, in an ice bath, H2O (0.31 mL) then
NaOH 15% (0.31 mL) and H2O (0.93 mL) were added and the suspen-
sion was stirred for 2 h. The suspension was filtered off, and the organic
layer was dried over Na2SO4, filtered, and evaporated to give 36 as a
slightly yellow oil (1.05 g, E/Z 63:37, 98%), which was used without fur-
Minor isomer (trans 31’, diagnostic peak only): 1H NMR (CDCl3,
300 MHz): d=2.99 (td, J=10.4, 4.0 Hz, 1H); HRMS-ESI: m/z: calcd:
196.1332 [M+H]+; found: 196.1327 (D=2.6 ppm).
(1R)-2-Methoxy-1-phenylethanamine (32): (R)-(À)-2-Amino-2-phenyle-
thanol (2.00 g, 14.58 mmol) in THF (20 mL) was added dropwise to a sus-
pension of sodium hydride 60% in mineral oil (1.224 g, 30.62 mmol) in
THF (10 mL), and the suspension was stirred for 2 h at room tempera-
ture. Iodomethane (0.95 mL, 15.31 mmol) was added and the solution
was stirred for 1 h, then heated to reflux for a further 3 h. The reaction
mixture was cooled, diluted with cold brine, extracted with diethyl ether,
dried (Na2SO4), and evaporated. The residue was purified by flash chro-
matography (95:5 CH2Cl2/MeOH) to give 32 as a colorless oil (1.894 g,
86%). [a]2D0 =À47.4 (c=0.67 in CHCl3); IR (neat): n˜ =2885, 1452, 1111,
ther purifications. IR (neat): n˜ =2952, 1246, 837 cmÀ1 1H NMR (CDCl3,
;
200 MHz): d=5.59–5.38 (m, 1H), 5.31–5.11 (m, 1H), 2.75–2.65 (m, 2H),
2.20–2.06 (m, 2H), 1.52–1.40 (m, 2H), 1.34 (brs, 2H), 0.01 (s, 3.3H),
À0.01 ppm (s, 5.7H); 13C NMR (CDCl3, 50 MHz): minor Z isomer: d=
127.8 (CH), 124.3 (CH), 31.2 (CH2), 29.7 (CH2), 18.7 (CH2), À1.8 ppm
(CH3); 13C NMR (CDCl3, 50 MHz): major E isomer: d=128.8 (CH),
125.7 (CH), 42.0 (CH2), 36.9 (CH2), 22.9 (CH2), À1.9 ppm (CH3);
HRMS-ESI: m/z: calcd: 158.1360 [M+H]+; found: 158.1361 (D=
0.8 ppm).
699 cmÀ1 1H NMR (CDCl3, 200 MHz): d=7.33–7.18 (m, 5H), 4.12 (dd,
;
J=8.8, 3.8 Hz, 1H), 3.44 (dd, J=9.2, 3.8 Hz, 1H), 3.31 (s, 3H), 3.29 (dd,
J=9.3, 8.8 Hz, 1H), 1.71 ppm (brs, 2H); 13C NMR (CDCl3, 50 MHz): d=
142.5 (C), 128.4 (CH), 127.4 (CH), 126.8 (CH), 79.0 (CH2), 58.9 (CH3),
55.4 ppm (CH); LRMS-ESI: m/z: 152 [M+1], 135 [MÀ16].
(S)-Methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate (33): Acetyl
chloride (0.66 mL, 9.32 mmol) was added dropwise to MeOH (5 mL) at
08C under an argon atmosphere. After 5 min, 3-(3,4-dimethoxyphenyl)-l-
alanine (700 mg, 3.11 mmol) was added and the solution was stirred at
reflux for 2 h. After cooling, the solvent was evaporated and the residue
was dissolved in water. Saturated aqueous NaHCO3 solution was added
(30 mL) and the aqueous layer was extracted with CH2Cl2 (3ꢄ30 mL).
The organic layer was dried over Na2SO4, filtered, and concentrated to
give 33 as a yellow solid (687 mg, 92%), which was used without further
purification. [a]2D0 =+4.5 (c=1.0 in CHCl3); m.p. 55–568C; IR (neat): n˜ =
Acknowledgements
This work was supported by the Ministꢅre dꢁlꢁguꢁ ꢂ l’Enseignement Su-
pꢁrieur et ꢂ la Recherche (EA, TS). The authors thank P. Wehrung and
P. Buisine (IFR85) for HRMS analyses.
[1] L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137–170; Angew.
Chem. Int. Ed. Engl. 1993, 32, 131–163.
[2] a) L. F. Tietze, Chem. Rev. 1996, 96, 115–136; b) L. F. Tietze, G.
Brasche, K. M. Gericke in Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, 2006.
[3] T.-L. Ho in Tandem Organic reactions, Wiley, NY, 1992.
[4] P. J. Parsons, A. J. Shell, Chem. Rev. 1996, 96, 195–206.
[5] D. Enders, C. Grondal, M. R. M. Hꢃttl, Angew. Chem. 2007, 119,
1590–1601; Angew. Chem. Int. Ed. 2007, 46, 1570–1581.
[6] A. Padwa, K. S. Bur, Tetrahedron 2007, 63, 5341–5378.
[7] L. E. Overman, L. D. Pennington, J. Org. Chem. 2003, 68, 7143–
7157.
[8] R. W. Hoffmann, D. Brꢃckner, New J. Chem. 2001, 25, 369–373.
[9] B. Breit, W. Seiche, Synthesis 2001, 1–36.
[10] I. Ojima, C.-Y. Tsai, M. Tzamarioudaki, D. Bonnafoux, “The Hydro-
formylation Reaction” in Organic Reactions, Vol. 56, Wiley, New
York, 2000, p. 1 .
[11] W.-H. Chiou, S.-Y. Lee, I. Ojima, Can. J. Chem. 2005, 83, 681–692.
[12] P. W. N. M. van Leeuwen in Rhodium-Catalyzed Hydroformylation,
Kluwer, Dordrecht, 2000.
[13] a) P. Eilbracht, L. Bꢆrfacker, C. Buss, C. Hollmann, B. E. Kitsos-
Rzychon, C. L. Kranemann, T. Rische, R. Roggenbuck, A. Schmidt,
Chem. Rev. 1999, 99, 3329–3365; b) P. Eilbracht, A. M. Schmidt,
Top. Organomet. Chem. 2006, 18, 65–95.
1
3375, 2962, 2936, 2835, 1729, 1514 cmÀ1; H NMR (CDCl3, 300 MHz): d=
6.78 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 6.69 (s, 1H), 3.84 (s,
3H), 3.83 (s, 3H), 3.70 (s, 3H), 3.69 (m, 1H), 3.01 (dd, J=13.6, 5.2 Hz,
1H), 2.80 (dd, J=13.6, 7.7 Hz, 1H), 1.54 ppm (brs, 2H); 13C NMR
(CDCl3, 75 MHz): d=175.5 (C), 149.0 (C), 148.0 (C), 129.6 (C), 121.4
(CH), 112.4 (CH), 111.3 (CH), 55.90 (2CH3), 55.86 (CH), 52.0 (CH3),
40.6 ppm (CH2); LRMS-ESI: m/z: 240.1 [M+H]+, 223.0 [MÀNH2]+.
(S)-Methyl 2-amino-3-(1H-indol-3-yl)propanoate (34): Acetyl chloride
(2.09 mL, 29.4 mmol) was added dropwise to MeOH (13 mL) at 08C
under an argon atmosphere. After 5 min, l-tryptophane (2.00 g,
9.8 mmol) was added and the solution was stirred at reflux for 2 h. After
cooling, the solvent was evaporated and the residue was dissolved in
water. Saturated aqueous NaHCO3 solution was added (50 mL) and the
aqueous layer was extracted with CH2Cl2 (3ꢄ30 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated to give 34 as a pale-
yellow solid (1.68 g, 79%), which was used without further purification.
[a]2D0 =+16.9 (c=1.0 in CHCl3); m.p. 91–928C; IR (neat): n˜ =3259, 3295,
1727, 1567, 1450, 1224 cmÀ1 1H NMR (CDCl3, 300 MHz): d=8.23 (brs,
;
1H), 7.63 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.23–7.11 (m, 2H),
7.06 (d, J=1.5 Hz, 1H), 3.85 (m, 1H), 3.73 (s, 3H), 3.30 (dd, J=14.2,
4.7 Hz, 1H), 3.07 (dd, J=14.2, 7.9 Hz, 1H), 1.63 ppm (brs, 2H);
13C NMR (CDCl3, 75 MHz): d=175.8 (C), 136.4 (C), 127.5 (C), 123.1
(CH), 122.2 (CH), 119.6 (CH), 118.8 (CH), 111.3 (CH), 111.1 (C), 55.1
(CH), 52.1 (CH3), 30.8 ppm (CH2); LRMS-ESI: m/z: 219.0 [M+H]+,
202.0 [MÀNH2]+.
[14] a) W.-H. Chiou, N. Mizutani, I. Ojima, J. Org. Chem. 2007, 72,
1871–1882; b) I. Ojima, M. Tzamarioudaki, M. Eguchi, J. Org.
Chem. 1995, 60, 7078–7079; c) A. Padwa, S. C. Bur, Tetrahedron
2007, 63, 5341–5378.
[15] R. W. Hoffmann, D. Brꢃckner, V. J. Gerusz, Heterocycles 2000, 52,
121–124.
5-Azidopent-2-enyltrimethylsilane
(35):
Sodium
azide
(1.538 g,
23.67 mmol) was added to a solution of 28 (1.745 g, 7.89 mmol) in DMF
(8 mL). The suspension was stirred overnight at 708C. After cooling,
Et2O (50 mL) was added and the organic layer was washed by H2O (3ꢄ
Chem. Eur. J. 2008, 14, 10938 – 10948
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10947

A. Mann et al.
[16] D. J. Bergmann, E. M. Campi, W. R. Jackson, A. F. Patti, Chem.
Commun. 1999, 1279–1280.
[17] E. Teoh, E. M. Campi, W. R. Jackson, A. J. Robinson, Chem.
Commun. 2002, 978–979.
[18] W.-H. Chiou, A. Schoenfelder, L. Sun, A. Mann, I. Ojima, J. Org.
Chem. 2007, 72, 9418–9425.
[19] E. Petricci, A. Mann, A. Schoenfelder, A. Rota, M. Taddei, Org.
Lett. 2006, 8, 3725–3728.
[20] M. D. Mihovilovic, P. Stanetty, Angew. Chem. 2007, 119, 3684–3688;
Angew. Chem. Int. Ed. 2007, 46, 3612–3615.
[21] N. W. Speckamp, J. M. Molenaar, Tetrahedron 2000, 56, 3817–3856.
[22] B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. Turchi, C. A. Maryan-
off, Chem. Rev. 2004, 104, 1431–1628.
[29] For a Pictet–Spengler reaction driven by hydroformylation on solid
support, see: G. Dessole, M. Marchetti, M. Taddei, J. Comb. Chem.
2003, 5, 198–200.
[30] CCDC-696805 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
[31] a) At present, we have no explanation for that result. Similar obser-
vations have been made, see S. M. Allin, S. L. James, M. R. J. Else-
good, W. P. Martin, J. Org. Chem. 2002, 67, 9464–9467; b) S.-H.
Yamada, K. Murato, T. Shioiri, Tetrahedron Lett. 1976, 1605–1608.
[32] A. Michaut, T. Boddaert, Y. Coquerel, J. Rodriguez, Synthesis 2007,
2867–2871.
[23] B. Breit, W. Seiche, J. Am. Chem. Soc. 2003, 125, 6608–6609.
[24] D. G. Cuny, S. L. Buchwald, J. Am. Chem. Soc. 1993, 115, 2066–
2068.
[33] a) S. M. Amorde, A. S. Judd, S. F. Martin, Org. Lett. 2005, 7, 2031–
2033; b) W. R. Judd, S. Ban, J. Aubꢁ, J. Am. Chem. Soc. 2006, 128,
13736–13741.
[25] E. Billig, A. G. Abatjoglou, D. R. Bryant, US 4668651, 1988.
[26] Stability of biphephos was observed by 31P NMR spectroscopy after
heating in solvent for 12 h in presence of acid additives. See the Sup-
porting Information for details.
[34] L. Micouin, J.-C. Quirion, H.-P. Husson, Synth. Commun. 1996, 26,
1605–1611.
[35] Z. Zhang, D. C. Leitch, M. Lu, B. O. Patrick, L. L. Schafer, Chem.
Eur. J. 2007, 13, 2012–2022.
[27] J. Royer, H.-P. Husson, Heterocycles 1993, 36, 1493–1496.
[28] M. Amat, J. Bosch, J. Hidalgo, M. Canto, M. Perez, N. Llor, E.
Molins, C. Miravitlles, M. Orozco, J. Luque, J. Org. Chem. 2000, 65,
3074–3084.
Received: September 1, 2008
Published online: November 13, 2008
10948
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10938 – 10948