Crucial role of β-elimination in determining regio- and chemoselectivity of the rhodium-catalyzed hydroformylation of N -allylpyrroles: A new approach to 5,6-dihydroindolizines

Article abstract of DOI:10.1055/s-0030-1257860

Rhodium-catalyzed hydroformylation of the chiral (S)-3-alkyl-3-pyrrol-1- ylprop-1-enes at 100 atmospheres total pressure and 25C led to the preferential formation of the branched 3-alkyl-2-methyl-3-pyrrol-1-ylpropanals. At 30 atmospheres and 125°C, the linear 4-alkyl-4-pyrrol-1-ylbutanals were obtained: these aldehydes are not the final products, but evolve into more stable 5,6-dihydroindolizines, with the same optical purity as the starting olefins, via a domino cyclization-dehydration process. According to the generally accepted mechanism for rhodium-catalyzed hydroformylation, the regioselectivity, and then the final chemoselectivity, can be rationalized by taking into account that while at room temperature no -elimination occurs, at high temperature the -elimination involves the branched rhodium-alkyl intermediate only.

Full text of DOI:10.1055/s-0030-1257860

SPECIAL TOPIC
2915
Crucial Role of b-Elimination in Determining Regio- and Chemoselectivity of
the Rhodium-Catalyzed Hydroformylation of N-Allylpyrroles: A New
Approach to 5,6-Dihydroindolizines
New
A
pproac
h
to
o
5,6-Dihydro
b
indolizines erta Settambolo*
ICCOM-CNR, UOS di Pisa, Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
E-mail: settambolo@dcci.unipi.it
Received 7 May 2010
Both electronic and steric effects determine the regiose-
Abstract: Rhodium-catalyzed hydroformylation of the chiral (S)-3-
lectivity of the formation of rhodium–alkyl complexes
alkyl-3-pyrrol-1-ylprop-1-enes at 100 atmospheres total pressure
(Figure 1). Indeed, the hydroformylation under mild con-
and 25 °C led to the preferential formation of the branched 3-alkyl-
ditions of vinylaromatic substrates such as styrene,3 vinyl-
2-methyl-3-pyrrol-1-ylpropanals. At 30 atmospheres and 125 °C,
the linear 4-alkyl-4-pyrrol-1-ylbutanals were obtained: these alde- furans,4
hydes are not the final products, but evolve into more stable 5,6-di-
vinylthiophenes,5
vinylpyrroles,6
and
vinylpyridines7 always provides a large predominance of
the branched isomer over the linear one (B/L = 95:5 for
styrene). As far as oxygen-containing substrates are con-
cerned, vinyl ethers provide a regioisomeric ratio B/L of
≥ 80:20.8 Under the same conditions, alkenes with a-hy-
drogens (i.e., linear alk-1-enes) give the two regioisomers
in an almost 1:1 molar ratio.9 An oxygen in the b-position
to the vinyl group favors the formation of the branched
isomers, as observed for allyl ethyl ether (B/L = 70:30)
and similar substrates.8 The linear isomers largely
predominate over the branched ones in the hydroformyla-
tion of 3-alkyl-substituted alk-1-enes (e.g., 3-methylbut-
1-ene).10
hydroindolizines, with the same optical purity as the starting
olefins, via a domino cyclization–dehydration process. According
to the generally accepted mechanism for rhodium-catalyzed hydro-
formylation, the regioselectivity, and then the final chemoselectivi-
ty, can be rationalized by taking into account that while at room
temperature no b-elimination occurs, at high temperature the b-
elimination involves the branched rhodium–alkyl intermediate
only.
Key words: b-elimination, hydroformylations, rhodium–alkyl
complexes, N-allylated pyrroles, indolizines
According to the generally accepted mechanism for the
rhodium-catalyzed hydroformylation of olefins,1 metal
hydride addition to the double bond to give an isomeric
metal–alkyl intermediates is a key step. This step can be
reversible or nonreversible, depending on the substrate
nature and the reaction conditions. Under mild conditions,
i.e. at room temperature, the insertion is a nonreversible
step; this is very important, because the regioselectivity
for the formation of the branched b and the linear l rhodi-
um–alkyl intermediates determines the regioselectivity
for the formation of the final aldehydes B and L, respec-
tively (Scheme 1). In contrast, if the alkyl formation is re-
versible, the selectivity-determining step will occur later,
i.e. at the stage of the addition of carbon monoxide to the
tricarbonyl species to give the tetracarbonyl species, as
demonstrated by theoretical calculations in the case of hy-
droformylation of 1,1-diphenylethene at 100 °C.2
Z
δ−
δ−
>>
δ+
Rh
Z
δ+
Rh
Z = Ar, OR
Z
δ−
≤
δ−
Rh
δ+
Rh
Z
δ+
Z = alkyl
Figure 1
At higher reaction temperature (>90 °C) and reduced car-
bon monoxide and hydrogen partial pressure, the amount
of linear aldehyde generally increases. Under these condi-
OHC
Z
H
branched
Rh
H
Z
*
B
L
[Rh-H]
b
l
[Rh-H]
Z
Z
linear
H
Z
CHO
H
Z
Rh
* reversible only at high temperature
Scheme 1
SYNTHESIS 2010, No. 17, pp 2915–2921
x
x.
x
x
.
2
0
1
0
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1257860; Art ID: C03610SS
© Georg Thieme Verlag Stuttgart · New York

2916
R. Settambolo
SPECIAL TOPIC
tions, the step resulting in the formation of the isomeric
alkyl–rhodium intermediates becomes reversible via a b-
elimination process involving mainly the branched spe-
cies. Thus the whole process brings about a partial isomer-
ization of the branched alkyl isomer into the linear one
and hence determines an increase in the linear aldehyde
content (Scheme 1). In the case of styrene, for instance, a
strong increase in the linear aldehydic isomer (B/L = 98:2
at 20 °C to 64:36 at 130 °C) is observed.11 For ethyl vinyl
ether the above increase is lower, with the percentage of
linear aldehyde ranging from 12% at 29 °C to 24% to
100 °C.8 In the case of vinylidenic alkenes, the linear al-
dehyde isomer is obtained with complete selectivity at any
temperature (80–130 °C).12
N
R
O
5a–c + 5a'–c'
CO/H2 (1:1)
N
Rh4(CO)12
toluene
R
4a–c
N
N
a R = Me
b R = i-Pr
c R = n-Pr
O
R
R
6a–c
7a–c
100 atm, 25 °C: 5 >> 6
30 atm, 125 °C: 6 >> 5
Scheme 2
Direct experimental evidence for the formation of alkyl–
rhodium intermediates is unavailable, because these spe-
cies are present in a very low concentration in the reaction
mixtures and very reactive under typical hydroformyla-
tion conditions. In the last decades deuterioformylation
experiments were shown to be the best possible experi-
mental probe to investigate the nature and fate of the in-
termediates involved in the reaction.13 2H NMR
investigations of crude deuterioformylation mixtures al-
lowed the reversibility or nonreversibility of the alkyl–
metal intermediate formation to be established via identi-
fication of the position of the incorporated deuterium at-
oms into unconverted substrates. In this way, the behavior
of vinyl and allyl ethers,8 vinyl- and vinylidenic olefins,14
as well as styrene15 and pyridines7a under rhodium-cata-
lyzed hydroformylation conditions has been rationalized
by our research group. In the last years, theoretical inves-
tigations have also contributed significantly to the clarifi-
cation of the aforementioned aspects.16–21 In particular,
the regioselectivities and diastereoselectivities of a vari-
ety of unsaturated substrates in nonreversible rhodium-
catalyzed hydroformylation have been elucidated by com-
putational methods by examination of the stability of the
relevant alkyl–rhodium transition states (TS).19a The theo-
retical results turned out to be in good agreement with the
experimental results obtained under mild reaction condi-
tions, i.e. the regioselectivities and diastereoselectivities
determined for the final aldehyde products.
ate only. In particular, the dihydroindolizines 7a–c have
the same optical purity as the starting material, thus indi-
cating that the b-elimination process occurs without in-
volving the methinic hydrogen a to the nitrogen atom.
1-Allylpyrroles 4a–c were prepared in 92% ee by a highly
stereospecific multistep reaction sequence (Scheme 3)
that uses L-a-amino acids as the source of chirality.24 L-a-
Amino acid methyl ester hydrochlorides 1a¢–c¢ were cho-
sen to introduce both the stereogenic center and the useful
ester functionality. L-Alanine and L-valine methyl ester
hydrochlorides (1a¢ and 1b¢) were commercially avail-
able. L-Norvaline methyl ester hydrochloride (1c¢) was
prepared from the corresponding L-amino acid 1c by treat-
ment with gaseous hydrogen chloride in methanol (98%
yield). Condensation of 1a¢–c¢ with 2,5-dimethoxytet-
rahydrofuran, according to a well-known procedure,24
gave the corresponding 1H-pyrrole derivatives 2a–c in
good yield (70–92%) and excellent enantiomeric excess
(99%). Esters 2a–c were chemoselectively transformed
into aldehydes 3a–c by treatment with one molar diisobu-
tylaluminum hydride in hexane (1.8 equiv) at –78 °C; the
excess of the reducing agent was destroyed with metha-
nol, and the resulting solution was hydrolyzed with Roch-
elle salt, at the same temperature. Under the adopted
experimental conditions the substrate conversion was
complete and neither overreduction to the respective alco-
hols nor significant racemization of the produced alde-
hydes was observed. The thus produced (2S)-2-pyrrol-1-
ylpropanal (3a), (2S)-3-methyl-2-pyrrol-1-ylbutanal (3b),
and (2S)-2-pyrrol-1-ylpentanal (3c) were obtained in high
yield (>78%) and with almost complete retention of chiral
integrity (>92% ee). The Wittig reaction was carried out
with the Schlosser–Schaub instant ylide reagent at –30 °C
in tetrahydrofuran. The olefins (3S)-3-pyrrol-1-ylbut-1-
ene (4a), (3S)-4-methyl-3-pyrrol-1-ylpent-1-ene (4b), and
(3S)-3-pyrrol-1-ylhex-1-ene (4c) were obtained in good
yield (65–75%) and high ee (>92–98%). Under the exper-
imental conditions described here, enolization of the alde-
hydes did not occur and the corresponding olefins were
obtained with retention of optical integrity.
Within the framework of our investigations on rhodium-
catalyzed hydroformylation of aromatic and heteroaro-
matic olefins, N-allylpyrroles proved to be special sub-
strates. When the reaction was carried out on the chiral
(S)-3-alkyl-3-pyrrol-1-ylprop-1-enes 4a–c under high
pressure and at low temperature, the branched aldehydes
5 formed preferentially (Scheme 2).22
In contrast, at low pressure and high temperature an al-
most completely linear regioselectivity was observed
(Scheme 2). Interestingly, the substituted pyrrolylbuta-
nals 6 produced are not the final products, but evolve into
the more stable 5,6-dihydroindolizines 7 via a domino cy-
clization/dehydration process.23 These results can be ra-
tionalized by taking into account that while at room
temperature no b-elimination occurs, at high temperature
the b-elimination involves the branched alkyl intermedi-
The hydroformylation reaction was carried out in toluene,
in the presence of dodecacarbonyltetrarhodium as the cat-
Synthesis 2010, No. 17, 2915–2921 © Thieme Stuttgart · New York

SPECIAL TOPIC
New Approach to 5,6-Dihydroindolizines
2917
NH3⋅Cl
OMe
NH2
ii
N
iv
N
N
i
iii
OH
R
R
OMe
R
R
R
O
O
O
O
1a–c
1'a–c
2a–c
3a–c
4a–c
Scheme 3 Reagents and conditions: (i) R = n-Pr: HCl(g), MeOH, reflux, 60 min, 98%; (ii) 2,5-dimethoxytetrahydrofuran, AcOH, NaOAc,
80 °C, 30–120 min; (iii) 1 M DIBAL-H in hexane (1.8 equiv), –78 °C, 15–40 min; (iv) Ph3PMeBr, NaNH2, THF, –30 °C, 30 min.
alyst precursor, at 25 °C and under a total pressure of 100 the reaction mixture both at partial and complete substrate
atmospheres (CO/H2 = 1:1).22 The crude reaction mix- conversion, the cyclization reaction being faster than hy-
tures were analyzed by GLC and GLC-MS by using n-de- droformylation. Under the same hydroformylation condi-
cane as internal standard. In all cases (4a–c) the reaction tions 4b gave 5-isopropyl-5,6-dihydroindolizine (7b); the
afforded 2-methyl-3-pyrrol-1-ylalkanals 5 (diastereomer- regiosiomeric ratio 7b/(5b + 5b¢) was 87:13. In a similar
ic mixture) as main products (see Scheme 2). Compound manner, 5-n-propyl-5,6-dihydroindolizine (7c) was ob-
4a gave 2-methyl-3-pyrrol-1-ylbutanals 5a and 5a¢ in a tained from 4c [7c/(5c + 5c¢) = 84:16]. No traces of the
77:23 regioisomeric ratio. A similar amount of the linear aldehydes 6b and 6c, the precursors to 7b and 7c,
branched aldehyde 5c and 5c¢ was obtained by the hydro- were observed in the reaction mixture, both at partial and
formylation of 4c. When a branched alkyl group was complete substrate conversion. Only by the use of a lower
linked to the carbon atom a to the double bond (in the case rhodium/substrate ratio (1:1000), at 10% conversion, a
of 4b), the regioisomeric ratio 5b/5b¢ slightly decreased to small amount of aldehyde 6a could be detected in the re-
71:29 (Scheme 2). Traces of the alcohols coming from the action mixture, the indolizine formation still being a fast
branched aldehydes were also observed at complete sub- process compared to the oxo one.
strate conversion. In particular, alcohols 8b and 8b¢ were
Interestingly, 4a showed, at all conversions, practically
the same ee, that is, the starting ee value (98%). The same
applied for dihydroindolizine 7a, its ee value remaining
the same as the corresponding olefin 4a (98%) at all reac-
obtained as almost exclusive products from 4b under hy-
droformylation conditions at 80 °C, over long reaction
times (24 h) (Scheme 4).
tion times (Table 1).
The regioselectivity values obtained at room temperature
N
are very similar to the values obtained for styrene and de-
i
4b
rivatives.11 The high a-regioselectivity of the reaction
must be related to the regioselectivity of formation of the
HO
rhodium–alkyl intermediates (Scheme 1): the polarizable
pyrrole ring directly bonded to the partially negative car-
8b + 8b'
bon atom favors the branched isomer b over the linear
alkyl l (Figure 1), thus explaining the predominance of the
branched aldehyde. The p-excessive nature of the pyrrole
ring could account for the lower a-regioselectivity.
Scheme 4 Reagents and conditions: (i) Rh4(CO)12, CO/H2 (1:1),
80 °C, toluene, 24 h; then alumina (hexane–EtOAc, 95:5).
When the reaction was carried out at high temperature and
low pressure, an inversion of regioselectivity was ob-
served.23 In the case of 4a, the conversion was 25% after
0.2 hours and the reaction mixture contained 5-methyl-
5,6-dihydroindolizine (7a) and branched aldehydes 5a
and 5a¢ in a 57:43 [7a/(5a + 5a¢)] molar ratio (Scheme 2).
This value remained unchanged at total conversion (after
1.5 h, 59:41 regioisomeric ratio). The linear aldehyde 6a,
the precursor of 7a, was present only in trace amounts in
In contrast, at high temperature and low pressure, an inter-
conversion of the alkyl intermediates takes place via a b-
hydride elimination, generating the starting olefin again
and hence promoting a successive increase of the linear
aldehyde. Taking into account the generally accepted
mechanism of hydroformylation,25 we can affirm that, un-
der the above conditions, the branched alkyl–rhodium in-
termediate b undergoes a b-hydride elimination process
Table 1 Hydroformylation of (3S)-3-Pyrrol-1-ylalk-1-enes 4a–c in the Presence of Dodecacarbonyltetrarhodiuma
4
R
eeb (%) of 4
Conversion (%)
Ratio 7/5 (%)
85:15
Yieldc (%) of 7
eeb (%) of 7
4a
4b
4c
Me
i-Pr
n-Pr
98
92
92
97
99
99
73
70
75
98
92
92
87:13
84:16
a Reaction conditions: 4, Rh4(CO)12, toluene, <CO/H2 (1:1), 125 °C, 30 atm, 0.5 h.
b Determined by GC [chiral capillary column CHIRALDEX G-TA (g-cyclodextrin trifluoroacetyl, 50 m × 0.25 mm)].
c Yield of isolated pure product.
Synthesis 2010, No. 17, 2915–2921 © Thieme Stuttgart · New York

2918
R. Settambolo
SPECIAL TOPIC
β-elimination
O
β-elimination
N
Rh
N
N
N
N
Rh
R
R
R
R
R
4
l
6
4'
b
N
R
O
5
Scheme 5
not involving the stereogenic center, generating the olefin room temperature and high pressure can be considered to
4 again and not 4¢ (Scheme 5). In fact, no traces of the in- be a new access to optically active amino aldehydes,
ternal olefin 4¢ were observed in the crude reaction mix- building blocks in biosynthesis and total synthesis of dif-
ture at both partial or total conversion. Due to the ferent alkaloids.28 When the oxo process is applied at high
influence of the electron-withdrawing heteroaromatic ef- temperature and low pressure, racemization is avoided
fect, the methinic hydrogen bonded to the carbon vicinal and the regioselectivity is enhanced; this leads to a regio-
to the annular nitrogen in b probably does not have suffi- selective and stereospecific synthetic approach to optical-
cient hydride character for b-hydride elimination ly active 5-alkyl-5,6-dihydroindolizine derivatives.29 The
(Scheme 5). This behavior of N-allylpyrroles is unusual unusual behavior of the N-allylpyrroles depicted here
compared to that of other aromatic or aliphatic allyl- shows that the nature of the substrate is a crucial parame-
olefins.9b,26
ter for determining the selectivity of the rhodium-cata-
lyzed hydroformylation reaction.
The six-membered nature of the newly formed ring, to-
gether with the observation that the sum of the linear alde-
hyde and the indolizine product gives a constant value
with respect to the branched aldehyde suggest that the in-
dolizine structure comes from the pyrrolylbutanal, possi-
bly via an intramolecular nucleophilic attack of the
pyrrole C2 carbon atom on the carbonyl group of the lin-
ear aldehyde. Then a bicyclic alcohol should form; it then
undergoes water elimination very easily to give a double
bond conjugated with the pyrrole ring (Scheme 6).
Reactions requiring an inert atmosphere were conducted under an-
hyd N2, and the glassware was oven-dried (120 °C). Anhyd solvents
were purified prior to use as follows: toluene was dried over molec-
ular sieves and distilled under N2 and THF was distilled from Na un-
der N2. All reagents were purchased in the highest quality available
and were used without further purification. Schlosser–Schaub ‘in-
stant ylide’ reagent (methyltriphenylphosphonium bromide + sodi-
um amide) was purchased from Fluka. Rh4(CO)12 was from Strem
Products. TLC analyses were performed on aluminum oxide 60 F254
neutral or silica gel 60 F254 plates from Merck. For preparative chro-
matography, Merck aluminum oxide 90 active neutral (70–230
mesh) or silica gel 60 (70–230 mesh) was used. Optical rotations
were measured with a JASCO DIP-370 digital polarimeter at the
given temperature. Microanalyses were performed at the Laborato-
rio di Microanalisi, Istituto di Chimica Organica, Facoltà di Farma-
cia, Università di Pisa. 1H NMR spectra were recorded at 200 MHz,
13C NMR spectra at 50 MHz on a Varian Gemini 200 spectrometer.
Chemical shifts are given in d (ppm) relative to CDCl3. GC/MS
analyses were performed on a Perkin-Elmer Q-Mass 910, equipped
with an EI source, interfaced with a Perkin-Elmer 8500 chromato-
graph equipped with a 30 m × 0.25 mm apolar DB1 capillary col-
umn, using helium as a carrier.
OH
O
N
N
N
– H2O
R
R
R
6a–c
7a–c
Scheme 6
The very high ee values obtained for 7 indicate that the hy-
droformylation conditions are perfectly compatible with
the optically active pyrrolylolefins employed, allowing a
complete configurational stability also under potentially
isomerizing conditions (high temperature and low pres-
sure).
(–)-(S)-Methyl 2-Pyrrol-1-ylpentanoate (2c); Typical Procedure
2,5-Dimethoxytetrahydrofuran (5.5 mL, 43 mmol) was added to a
suspension of methyl (–)-(S)-2-aminopentanoate hydrochloride
In the light of these findings, it is clear that b-elimination (1c¢; 7.16 g, 43 mmol), AcOH (290 mL), and NaOAc (36.0 g), heat-
ed to 80 °C. After 30 min the reaction mixture was cooled to r.t. and
plays a crucial role in the rhodium-catalyzed hydroformy-
hydrolyzed with 40% aq NaOH (40 mL). The two phases were sep-
arated, the aqueous layers were extracted with CH2Cl2 (3 × 150
mL), and the combined organic layers were washed with H2O until
the aqueous phase was neutralized. The organic layers were dried
(Na2SO4), concentrated in vacuo, and purified by vacuum distilla-
tion (bp 80 °C/0.1 mmHg); this afforded 2c as a colorless liquid.
lation of N-allylpyrroles. Indeed, different products, dihy-
droindolizines and/or pyrrolylpropanals, were obtained
when the temperature and pressure values of the reaction
were changed. As the pyrrole ring is known to be a useful
protecting group for primary amines,27 the process at
Synthesis 2010, No. 17, 2915–2921 © Thieme Stuttgart · New York

SPECIAL TOPIC
New Approach to 5,6-Dihydroindolizines
2919
26
Yield: 5.0 g (27.6 mmol, 65%, 99% ee); [a]D –4.02 (c 2.3,
MeOH); chiral GC (120 °C × 60 min): tR (R) = 21.91 min, tR
(S) = 25.94 min.
Yield: 0.21 g (1.6 mmol, 63%, 92% ee); bp 50 °C/0.02 mm Hg;
[a]D +58.5 (c 1.1, MeOH); chiral GC (100 °C × 60 min): tR
(S) = 16.09 min, tR (R) = 16.55 min.
26
1H NMR (200 MHz, CDCl3): d = 6.74 (t, J = 2.2 Hz, 2 H), 6.17 (t,
J = 2.2 Hz, 2 H), 4.57 (dd, J = 6.4; 9.1 Hz, 1 H), 3.71 (s, 3 H), 2.04
(m, 2 H), 1.25 (m, 2 H), 0.92 (t, J = 9.0 Hz, 3 H).
1H NMR (200 MHz, CDCl3): d = 6.69 (t, J = 2.1 Hz, 2 H), 6.16 (t,
J = 2.1 Hz, 2 H), 5.97 (m, 1 H), 5.09 (m, 2 H), 4.43 (m, 1 H), 1.82
(m, 2 H), 1.26 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H).
MS: m/z (%) = 181 [M+] (58), 139 (32), 122 (100), 107 (40), 94 (10),
MS: m/z (%) = 149 [M+] (60), 120 (8), 106 (100), 81 (24), 67 (52),
80 (75), 68 (13).
55 (20).
(–)-(S)-2-Pyrrol-1-ylpentanal (3c); Typical Procedure
(+)-(S)-3-Pyrrol-1-ylbut-1-ene (4a)24
According to the procedure described above, the aldehyde 3a (2.2
g, 18.0 mmol) reacted with the Schlosser–Schaub reagent (14 g,
28.8 mmol), affording 4a as a colorless liquid.
A 1 M soln of DIBAL-H (36 mL, 36 mmol) in hexane was added
to a soln of 2c (3.0 g, 17.0 mmol) in THF–hexane (1:7) cooled at
–78 °C and stirring was continued at that temperature for 20 min.
The reaction mixture was then quenched with MeOH (5 mL) at
–78 °C and sat. aq mixed sodium–potassium tartrate (60 mL) was
added, still at –78 °C. After warming to r.t., the two phases were
separated, the aqueous phase was extracted with Et2O (3 × 100 mL),
and the combined organic layers were washed with H2O (4 × 150
mL). The organic layers were dried (Na2SO4), concentrated in vac-
uo, and purified by vacuum distillation (bp 65 °C/0.02 mmHg); this
gave 3c as a colorless liquid.
Yield: 2.21 g (15.0 mmol, 88%, 95% ee); [a]D26 –44.4 (c 1.05, ben-
zene); chiral GC (100 °C × 60 min): tR (S) = 30.10 min, tR (R) =
35.80 min.
1H NMR (200 MHz, CDCl3): d = 9.63 (d, J = 1.0 Hz, 1 H), 6.67 (t,
J = 2.1 Hz, 2 H), 6.26 (t, J = 2.1 Hz, 2 H), 4.42 (dd, J = 4.8, 9.5 Hz,
1 H), 1.96 (m, 2 H), 1.28 (m, 2 H), 0.95 (t, J = 7.0 Hz, 3 H).
Yield: 1.8 g (15 mmol, 85%, 98% ee); bp 70–74 °C/20 mmHg;
26
[a]D +62.5 (c 0.52, MeOH); chiral GC (80 °C × 60 min): tR
(R) = 14.97 min, tR (S) = 16.35 min.
(+)-(S)-4-Methyl-3-pyrrol-1-ylpent-1-ene (4b)
According to the procedure described above, the aldehyde 3b (0.4
g, 2.6 mmol) reacted with the Schlosser–Schaub reagent (2.0 g, 4.8
mmol), affording 4b as a colorless liquid.
26
Yield: 0.2 g (1.3 mmol, 51%, 92% ee); bp 80 °C/0.05 mmHg; [a]D
+88.9 (c 1.5, MeOH); chiral GC (80 °C × 60 min): tR (R) = 47.19
min, tR (S) = 48.20 min.
1H NMR (200 MHz, CDCl3): d = 6.67 (t, J = 2.2 Hz, 2 H), 6.15 (t,
J = 2.2 Hz, 2 H), 6.04 (m, 1 H), 5.16 (m, 2 H), 3.99 (t, J = 8.2 Hz, 1
H), 2.08 (m, 1 H), 0.97 (d, J = 6.6 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3
H).
MS: m/z (%) = 151 [M+] (36), 122 (78), 84 (20), 80 (100), 68 (20).
MS: m/z (%) = 149 [M+] (37), 106 (100), 79 (27), 67 (21), 55 (10).
(–)-(S)-2-Pyrrol-1-ylpropanal (3a)24
According to the procedure described above, (–)-(S)-methyl 2-pyr-
rol-1-ylpropanoate (2a; 4.9 g, 32.0 mmol) reacted with a 1 M hex-
ane soln of DIBAL-H (64 mL, 64 mmol), affording 3a as a colorless
liquid.
Hydroformylation of 1-Allylpyrroles 4; Typical Procedure
A soln of the olefinic substrate 4 (5–6 mL) in toluene (5 mL) and
Rh4(CO)12 (substrate/Rh = 100:1) was introduced by suction into an
evacuated 25-mL stainless-steel autoclave. The autoclave was filled
with CO up to the required pressure and heated to the required tem-
perature. After 15 min, H2 was introduced, giving the required final
pressure (CO/H2, 1:1). The autoclave was then rocked until com-
plete conversion (GC monitoring) and allowed to cool to r.t. The re-
sidual reaction gases were evacuated and the crude reaction mixture
was directly removed from the open autoclave for further manipu-
lation.
Yield: 2.79 g (22.7 mmol, 80%, 98% ee); bp 78–81 °C/5 mmHg;
[a]D26 –70.8 (c 0.99, benzene).
(+)-(S)-3-Methyl-2-pyrrol-1-ylbutanal (3b)
According to the procedure described above, (–)-(S)-methyl 3-
methyl-2-pyrrol-1-ylbutanoate (2b; 2.5 g, 14.0 mmol) reacted with
a 1 M hexane soln of DIBAL-H (34 mL, 34 mmol), affording 3b as
a colorless liquid.
(+)-(S)-5-Methyl-5,6-dihydroindolizine (7a)
From the reaction mixture obtained by the hydroformylation carried
out at 30 atm total pressure and 125 °C, 7a was obtained as an or-
ange oil after column chromatography (silica gel, CH2Cl2–hexane,
1:7).
Yield: 1.62 g (11 mmol, 78%, 92% ee); bp 60 °C/0.01 mmHg;
[a]D +59.4 (c 1.1, benzene); chiral GC (120 °C × 60 min): tR
(S) = 12.24 min, tR (R) = 13.51 min.
1H NMR (200 MHz, CDCl3): d = 9.75 (d, J = 1.8 Hz, 1 H), 6.70 (t,
J = 2.2 Hz, 2 H), 6.27 (t, J = 2.2 Hz, 2 H), 4.13 (dd, J = 2.2, 8.8 Hz,
1 H), 2.46 (m, 1 H), 1.08 (d, J = 7.0 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3
H).
MS: m/z (%) = 151 [M+] (49), 122 (100), 108 (32), 94 (18), 80 (70),
68 (32), 55 (50).
26
26
Yield: 0.33 g (2.5 mmol, 73%, 92% ee); [a]D +107.5 (CH2Cl2,
c = 1.18); chiral GC (in. temp: 100 °C; in. hold: 60 min): tR
(R) = 26.8 min, tR (S) = 35.0 min.
1H NMR (200 MHz, CDCl3): d = 6.70 (m, 1 H, H3), 6.42 (d, J = 9.8
Hz, 1 H, H8), 6.14 (m, 1 H, H2), 6.03 (m, 1 H, H1), 5.65 (m, 1 H,
H7), 4.10 (m, 1 H, H5), 2.53 (m, 1 H, H6), 2.20 (m, 1 H, H6¢), 1.43
(d, J = 6.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.2, 32.2, 49.6, 106.2, 108.0,
117.9, 118.4, 120.1, 128.5.
(+)-(S)-3-Pyrrol-1-ylhex-1-ene (4c); Typical Procedure
Schlosser–Schaub reagent (2 g, 4.8 mmol) in anhyd THF (14 mL)
was stirred at r.t. for 1 h. A soln of 3c (0.39 g, 2.6 mmol) in anhyd
THF (6 mL) was added to the yellow suspension cooled at –30 °C.
After 30 min the temperature was increased to r.t. and the mixture
was hydrolyzed with 40% aq NaOH (12 mL). The aqueous phase
was extracted with hexane (3 × 30 mL) and the combined organic
layers were washed until neutrality. After drying (Na2SO4), the hex-
ane soln was concentrated in vacuo, affording, after vacuum distil-
lation, 4c as a colorless liquid.
MS: m/z (%) = 133 [M+] (63), 132 (19), 118 (100), 117(44), 91 (23).
(+)-(S)-5-Isopropyl-5,6-dihydroindolizine (7b)
From the hydroformylation reaction mixture, 7b was obtained as an
orange oil after column chromatography (silica gel, CH2Cl2–hex-
ane, 1:7).
Synthesis 2010, No. 17, 2915–2921 © Thieme Stuttgart · New York

2920
R. Settambolo
SPECIAL TOPIC
26
Yield: 0.30 g (1.9 mmol, 70%, 92% ee); [a]D +60.8 (c 1.08,
13C NMR (50 MHz, CDCl3): d = 11.0 (CH3), 13.7 (CH3), 13.8
(CH3), 19.5 (CH2), 19.6 (CH2), 35.0 (CH2), 36.6 (CH2), 52.0 (CH*),
52.9 (CH*), 59.9 (CH*), 108.3 (pyr), 108.6 (pyr), 119.6 (pyr) 119.7
(pyr), 140.7 (CHO).
MS: m/z (5c) (%) = 179 [M+] (9), 151 (37), 122 (32), 108 (26), 95
(12), 80 (27), 68 (100), 55 (18), 41 (15), 29(5).
CH2Cl2).
1H NMR (200 MHz, CDCl3): d = 6.66 (t, J = 2.2 Hz, 1 H), 6.41 (dd,
J = 2.3, 9.6 Hz, 1 H), 6.12 (dd, J = 2.8, 3.4 Hz, 1 H), 6.03 (dd,
J = 1.5, 3.7 Hz, 1 H), 5.64 (m, 1 H), 3.84 (m, 1 H), 2.65 (m, 1 H),
2.44 (m, 1 H), 2.22 (m, 1 H), 0.99 (d, J = 6.6 Hz, 3 H), 0.86 (d,
J = 7.0 Hz, 3 H).
MS: m/z (5c¢) (%) = 179 [M+] (8), 151 (38), 122 (41), 108 (33),
95(15), 80 (36), 68 (100), 55 (20), 41 (18), 29(7).
13C NMR (50 MHz, CDCl3): d = 18.51, 19.4, 25.8, 31.4, 60.0, 105.5,
106.8, 117.9, 119.8, 121.0, 128.9.
Compounds 5b and 5b¢
MS: m/z (%) = 161 [M+] (80), 146 (3), 132 (2), 118 (100), 91 (22),
Compounds 5b and 5b¢ were characterized after being obtained
from the 5b + 5b¢ + 7b mixtures resulting from hydroformylation
under analogous reaction conditions.
63 (5), 39 (10).
(+)-(S)-5-Propyl-5,6-dihydroindolizine (7c)
From the hydroformylation reaction mixture, 7c was obtained as an
orange oil after column chromatography (silica gel, CH2Cl2–hex-
ane, 1:7).
1H NMR (200 MHz, CDCl3): d = 0.87 (d, J = 6.4 Hz, 6 H, CH3-
5b+5b¢), 0.99 (d, J = 6.6 Hz, 3 H, CH3-5b¢), 1.00 (d, J = 6.6 Hz, 3 H,
CH3-5b), 1.06 (d, J = 7.2 Hz, 3 H, CH3-5b¢), 1.15 (d, J = 7.0 Hz, 3 H,
CH3-5b), 2.14 (sept, J = 6.6 Hz, 1 H, CHiPr-5b¢), 2.28 (sept, J = 7.0 Hz,
1 H, CHiPr-5b), 2.95 (split q, J = 7.2, 2.2 Hz, 2 H, CH*5b+5b¢), 3.81
(dd, J = 7.8, 7.2 Hz, 1 H, CH*5b), 4.06 (dd, J = 7.6, 7.4 Hz, 1 H,
CH*5b¢), 6.16 (t, J = 2.2 Hz, 2 H, pyr-5b¢), 6.17 (t, J = 2.2 Hz, 2 H,
pyr-5b), 6.63 (t, J = 2.2 Hz, 2 H, pyr-5b¢), 6.64 (t, J = 2.2 Hz, 2 H,
pyr-5b), 9.58 (d, J = 2.2 Hz, 1 H, CHO5b), 9.65 (d, J = 1.8 Hz, 1 H,
CHO5b¢).
13C NMR (50 MHz, CDCl3): d = 10.2 (CH3), 12.1 (CH3), 18.3
(CH3), 20.4 (CH3), 30.3 (CH), 31.3 (CH), 48.3 (CH*), 49.2 (CH*),
65.7 (CH*), 67.6 (CH*), 107.9 (pyr), 108.1 (pyr), 120.7 (pyr), 203.2
(CHO).
26
Yield: 0.405 g (2.5 mmol, 75%, 92% ee); [a]D +43.5 (CH2Cl2,
c = 0.86); chiral GC (in. temp: 120 °C; in. hold: 60 min): tR
(R) = 25.32 min, tR (S) = 37.74 min.
1H NMR (200 MHz, CDCl3): d = 6.68 (t, J = 1.8 Hz, 1 H), 6.42 (d,
J = 9.8 Hz, 1 H), 6.13 (t, J = 3.1 Hz, 1 H), 6.03 (br s, 1 H), 5.63 (m,
1 H), 4.04 (q, J = 6.5 Hz, 1 H), 2.68 (m, 1 H), 2.28 (m, 1 H), 1.85–
1.25 (m, 4 H), 0.95 (t, J = 7.5 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 13.6, 18.9, 28.9, 36.2, 53.8, 105.6,
107.1, 117.2, 119.3, 119.6, 127.9.
MS: m/z (%) = 161 [M+] (40), 132 (6), 118 (100), 91 (8).
MS: m/z (5b) (%) = 179 [M+] (10), 151 (40), 122 (13), 108 (67), 95
(27), 80 (18), 68 (100), 55 (13), 41 (19), 29 (5).
Compounds 5a and 5a¢
Compounds 5a and 5a¢ were characterized after being obtained
from the 5a + 5a¢ + 7a mixtures resulting from hydroformylation re-
action carried out at 100 atm total pressure and 25 °C, after remov-
ing the solvent at reduced pressure and separation from the catalyst
by pentane extraction.
1H NMR (200 MHz, CDCl3): d = 0.95 (d, J = 7.4 Hz, 3 H, CH3-5a),
1.17 (d, J = 7.4 Hz, 3 H, CH3-5a¢), 1.55 (d, J = 7 Hz, 3 H, CH3-5a¢),
1.57 (d, J = 6.6 Hz, 3 H, CH3-5a), 2.85 (m, 2 H, CH*5a+5a¢), 4.20 (m,
1 H, CH*5a¢), 4.40 (m, 1 H, CH*5a), 6.20 (t, J = 2.2 Hz, 2 H,
pyr5a+5a¢), 6.66 (t, J = 1.8 Hz, 2 H, pyr5a+5a¢), 6.72 (t, J = 2.2 Hz, 2 H,
pyr5a+5a¢), 6.75 (t, J = 1.8 Hz, 2 H, pyr5a+5a¢), 9.49 (d, J = 1.8 Hz, 1
H, CHO5a¢), 9.71 (d, J = 1.8 Hz, 1 H, CHO5a).
13C NMR (50 MHz, CDCl3): d = 10.8 (CH3), 18.5 (CH3), 20.1
(CH3), 47.6 (CH*), 52.8 (CH*), 53.8 (CH*), 55.1 (CH*), 107.5–
108.7 (pyr), 119.2 (pyr), 135.5 (CHO).
MS: m/z (5a) (%) = 151 [M+] (3), 133 (63), 123 (100), 108 (16), 94
(72), 78 (22), 68 (68), 50 (18), 39 (33).
MS: m/z (5a¢) (%) = 151 [M+] (6), 123 (100), 108 (13), 94 (68), 78
(18), 68 (87), 41 (30).
MS: m/z (5b¢) (%) = 179 [M+] (10), 151 (43), 122 (25), 108 (94), 95
(31), 80 (24), 68 (100), 55 (17), 41 (24), 29 (6).
Compounds 8b and 8b¢
Colorless liquid mixture (column chromatography, alumina, hex-
ane–EtOAc, 95:5); yield: 30%.
1H NMR (200 MHz, CDCl3): d = 0.85 (d, J = 6.4 Hz, 6 H, CH3-8b+8b¢),
0.98 (d, J = 6.6 Hz, 3 H, CH3-8b¢), 1.02 (d, J = 6.6 Hz, 3 H, CH3-8b),
1.06 (d, J = 7.2 Hz, 3 H, CH3-8b¢), 1.08 (d, J = 7.0 Hz, 3 H, CH3-8b),
2.11 (sept, J = 6.6 Hz, 1 H, CHiPr-8b¢), 2.22 (m, 2 H, CH*8b+8b¢) 2.28
(sept, J = 7.0 Hz, 1 H, CHiPr-8b),, 3.70 (dd, J = 7.8, 7.2 Hz, 1 H,
CH*8b), 3.98 (d, J = 7.0 Hz, 2 H, CH2-8b+8b¢), 4.03 (dd, J = 7.6, 7.4
Hz, 1 H, CH*8b¢), 6.16 (t, J = 2.2 Hz, 2 H, pyr-8b¢), 6.17 (t, J = 2.2
Hz, 2 H, pyr-8b), 6.63 (t, J = 2.2 Hz, 2 H, pyr-8b¢), 6.64 (t, J = 2.2 Hz,
2 H, pyr-8b).
MS: m/z (8b) (%) = 181 [M+] (7), 179 (59), 161 (33), 146 (19), 136
(100), 118 (95), 94 (20), 41 (14).
MS: m/z (8b¢) (%) = 181 [M+] (7), 179 (57), 161 (33), 146 (16), 136
(90), 118 (100), 94 (24), 41 (16).
Compounds 5c and 5c¢
Compounds 5c and 5c¢ were characterized after being obtained from
the 5c + 5c¢ + 7c mixtures resulting from hydroformylation under
analogous reaction conditions.
Acknowledgment
Thanks go to Professor Raffaello Lazzaroni, Pisa University (Italy),
for stimulating and fruitful discussions.
1H NMR (200 MHz, CDCl3): d = 0.87 (t, J = 7.5 Hz, 3 H, CH3-5c),
0.89 (t, J = 7.5 Hz, 3 H, CH3-5c¢), 0.90 (d, J = 7.2 Hz, 3 H, CH3-5c),
1.15 (d, J = 6.9 Hz, 3 H, CH3-5c¢), 1.19 (m, 4 H, CH2-5c+5c¢), 1.75 (m,
4 H, CH2-5c+5¢c), 2.72 (split q, J = 7.2, 2.4 Hz, 1 H, CH*5c¢), 2.73
(split q, J = 7.2, 2.1 Hz, 1 H, CH*5c), 4.09 (split t, J = 6.3, 4.2 Hz, 1
H, CH*5c¢), 4.11 (split t, J = 10.5, 4.2 Hz, 1 H, CH*5c), 6.15 (t,
J = 2.1 Hz, 4 H, pyr5c+5c¢), 6.63 (t, J = 1.8 Hz, 2 H, pyr5c), 6.66 (t,
J = 1.8 Hz, 2 H, pyr5c¢), 9.43 (d, J = 2.1 Hz, 1 H, CHO5c¢), 9.68 (d,
J = 2.1 Hz, 1 H, CHO5c).
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New Approach to 5,6-Dihydroindolizines
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Synthesis 2010, No. 17, 2915–2921 © Thieme Stuttgart · New York