Microwave-assisted domino hydroformylation/cyclization reactions: Scope and limitations

Article abstract of DOI:10.1055/s-0030-1258207

Hydroformylation of alkenes can be carried out in short time and with low syngas pressure under microwave (MW) dielectric heating. Alkenes, carrying O-, N-, or C-nucleophilic fragments, can be designed for domino reactions, mainly cyclocondensations. Ally

Full text of DOI:10.1055/s-0030-1258207

SPECIAL TOPIC
2901
Microwave-Assisted Domino Hydroformylation/Cyclization Reactions:
Scope and Limitations
Microwaves or
titional
e
H
eating for
n
D
ominoHy
n
droformylati
e
on
R
eaction? Airiau,a Claire Chemin,a Nicolas Girard,a Giacomo Lonzi,b André Mann,*a Elena Petricci,b
Jessica Salvadori,b Maurizio Taddei*b
a
Laboratoire d’Innovation Thérapeutique, UMR 7200 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin,
67401 Illkirch, France
E-mail: andre.mann@pharma.u-strasbg.fr
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
b
Fax +39(0577)234280; E-mail: taddei.m@unisi.it
Received 13 April 2010
To the memory of Charles Mioskowski
tions (including patents). As most of the reactors for MWs
have been designed to resist the pressure internally gener-
ated by the solvent, they can be considered as small auto-
claves adjustable to run reactions with gaseous reagents.
Abstract: Hydroformylation of alkenes can be carried out in short
time and with low syngas pressure under microwave (MW) dielec-
tric heating. Alkenes, carrying O-, N-, or C-nucleophilic fragments,
can be designed for domino reactions, mainly cyclocondensations.
Allyl and homoallyl alcohols are excellent substrates for cyclizative
hydroformylation to lactols under MW heating. In the presence of
NaOAc as an additional nucleophile, a domino reaction occurs giv-
ing 2-acetoxytetrahydrofurans, suitable to introduce a C-nucleo-
phile on tetrahydrofuran rings through an oxocarbenium ion. The
synthesis of the furanopiperidine substructure of cyclopamine is de-
scribed as an application. With alkene amides, the domino process
collapsed to a transient acyliminium ion that further cyclized with
an additional C-nucleophile. To perform domino hydroformylation
Pictet–Spengler or aza-Sakurai reactions, an autoclave under con-
ventional heating is essential. Syntheses of ( )-epilupinine and of a
homoberberine alkaloid are reported to illustrate each sequence. Al-
though apparently more versatile, hydroformylation of alkenes us-
Since its discovery in 1938, hydroformylation of olefins
has evolved as one of the industrially most important pro-
cesses, which relies on homogeneous catalysis.4 Recently
we reported a general procedure for the MW-assisted hy-
droformylation of terminal olefins in adapting the 80 mL
vial of a MW oven.5 This glass vial, tested for resisting up
to 1700 kPa, is connected to an external pressure control-
ling system equipped with a valve that allows to control
the inlet and outlet of the gas during the pressurization or
depressurization steps. From this experience, CEM has
designed a kit for gas addition adapted to its Discover syn-
ing MW heating is sensitive to the nature of the nucleophiles present thesis apparatus.6 Moreover, other suppliers of MW de-
in the substrates, evidencing that the conventional heating process
cannot be completely replaced by MW irradiation.
vices provide PTFE vials that can be filled with
pressurized gas and safely submitted to MW dielectric
heating.7
Key words: domino reaction, heterocycles, nucleophilic addition,
cyclization, hemiacetals, Pictet–Spengler reaction
The combination of hydroformylation MW heating re-
vealed several advantages over the classical autoclave
process: the reaction time and temperature were consider-
The use of microwaves (MWs) to heat organic reactions
ably reduced, and improvements in the selectivity were
has attracted considerable attention during the last 20
observed in some cases.8 Moreover, as the hydroformyla-
years.1 This technique allows to reduce markedly the time
tion can be run in small flasks, the amount of H2 and CO
required for a chemical process, the formation of by-prod-
wasted at the end of the reaction can be reduced to a min-
ucts, and by the way improves yields and purity. Although
imum, a real atom-economic hydroformylation is at
MW irradiation is an alternative to conventional heating,
hand.9 Another advantage of MWs is the possibility to
the use of this technology has launched a new concept in
promote the integration of the hydroformylation products
synthetic technologies, as transmission and absorption of
in domino reactions. Recently, several applications of
energy are different compared to conventional thermal
domino processes initiated by the hydroformylation of
heating. As MWs generate temperature profiles different
alkenyl substrates have been reported.10
from traditional heating, in some cases kinetic control can
In order to investigate the potential of MW dielectric heat-
ing in domino hydroformylation/cyclization processes,
we report here on the transformation of terminal olefins
by using extensively MW-assisted hydroformylation and
comparing it with the traditional autoclave pressurized
process. The unsaturated substrates were designed to con-
tain various O, N, or C nucleophiles. Therefore, once the
aldehydes are formed, domino sequences can take place
towards the production of heterocycles of interest. Al-
though MW heating was more versatile, the nature of the
be achieved.2 Moreover, several reactions have been re-
ported in which the chemo-, regio- and stereoselectivity
changed under MW conditions in comparison to conven-
tional heating.3 Over the years the importance taken by
MW-assisted reactions in organic synthesis can be easily
measured by the increasing number of scientific publica-
SYNTHESIS 2010, No. 17, pp 2901–2914
x
x.
x
x
.
2
0
1
0
Advanced online publication: 13.08.2010
DOI: 10.1055/s-0030-1258207; Art ID: C03410SS
© Georg Thieme Verlag Stuttgart · New York

2902
E. Airiau et al.
SPECIAL TOPIC
nucleophile subordinated the choice of the best heating
technology, demonstrating that the conventional heating
can be sometimes preferred to MWs.
26
21
HN
H
18
13
25
Br
22
23
20
17
24
11
19
12
1
H
2
O
9
OAc
O
16
10
5
3
14
HO
8
15
Oxygen as the Nucleophile
4
7
I
6
cyclopamine
Decades ago hydroformylation of allyl and homoallyl al-
cohols has been investigated as a rapid method to generate
five- and six-membered hemiacetals originating from
spontaneous cyclization of the transient linear hydroxy al-
dehyde.10h Moreover, the versatile reactivity of cyclic
hemiacetals points them out as useful intermediates in the
synthesis of many valuable compounds.11
OH
O
O
OH
IV
III
II
Scheme 1 Retrosynthetic proposal for the alkaloid substructure of
In contrast to extensive efforts devoted to study the influ-
ence of achiral or chiral catalysts on this reaction,12 rela-
tively few substrates have been investigated. We came
across the possibility to use the allyl alcohol hydroformy-
lation to prepare substituted tetrahydrofurans within a
project directed to the synthesis of the furanopiperidine
substructure of cyclopamine, the most important compo-
nent of the veratrum alkaloid family.13
cyclopamine
CHO
a
OR
+
OH
OH
O
O
+
1
2
3 R = H
4 R = Et
5
Scheme 2 Reagents and conditions: (a) H2/CO (1:1), Rh (cat), li-
Our retrosynthetic sequence was based on a disconnection
at the level of C22 and C23 giving a spiro-tetrahydrofuran
derivative with two leaving groups (structure I in
Scheme 1). Dihydrofuran II and the cyclic hemiacetal III
are the corresponding precursors that are accessible by hy-
droformylation of unsaturated alcohol IV. To establish the
feasibility of this strategy, compound 1 was subjected to
cyclizative hydroformylation, under different reaction
conditions (Scheme 2). Although making the linear alde-
hyde 2 is crucial, the direct preparation of adducts 5 or 3
was our first goal. Different parameters were studied in
order to maximize their yields (see Table 1 for the data).
The reactions were performed inside a sealed pressurized
vial using the gas kit, an available accessory of the Discovery
microwave synthesis instrument.6 (PPh)3Rh(CO)H and
Rh(CO)2acac were used as precatalyst in the presence of
various ligands such as Ph3P, xantphos, or biphephos.
Toluene, THF, and EtOH were the solvents of choice. The
influence of temperature and additives such as ionic liq-
uids was also investigated. The solvent had an influence
in the products distribution. In toluene (in the presence of
small amounts of [bmim][BF4] in order to raise the tem-
perature to 110 °C) the starting alcohol 1 was recovered
after two hours of reaction (Table 1, entry 1). With THF,
the hemiacetal 3 (as a 1:1 diastereomeric mixture) was
formed in low yields (35%) together with the linear alde-
hyde 2 (Table 1, entry 2). The use of EtOH as the solvent
increased the conversion of 1, but acetal 4 (diastereomeric
mixture) was the only isolated product (Table 1, entry 3).
A temperature above 90 °C and a period of 3 hours were
required to obtain a complete conversion.
gand (see Table 1).
No remarkable effect was observed changing the Rh(I)
source (Table 1, cf. entries 7 and 8), while, as expected,
xantphos promoted the formation of the tetrahydrofuran
derived from the linear aldehyde 2, and biphephos gave
poor results due to the high temperature required for the
reaction (Table 1, entry 9). In the presence of Ph3P, the
only detectable product was the reduced 1-isopropylcy-
clohexanol (Table 1, entry 10). Exploring different reac-
tion conditions in THF, we observed that the presence of
a small amount of water increased the yields of 3 up to
92% after two cycles of 30 and 45 minutes, respectively
(Table 1, entry 11). As previously observed, two irradia-
tion cycles gave better results in terms of yields in respect
to a single reaction cycle of overall 75 minutes. To induce
the in situ conversion of 3 into 5, the hydroformylation
was repeated in the presence of acid additives, but no ef-
fect was observed (Table 1, entries 12 and 13). Analo-
gously, elimination of EtOH from 4 under several acidic
conditions gave unsatisfactory results.
One approach to 5 was the transformation of 3 into the ac-
etate 6 or mesylate 7 followed by pyridine mediated elim-
ination (Scheme 3). Then, the possibility to transform
directly alcohol 1 into the acetate 6 during the process of
tandem hydroformylation/cyclization was explored.
When running the reaction on 1 in THF under MW dielec-
tric heating in the presence of (PPh3)3Rh(CO)H/xantphos
as catalyst and a mixture of NaOAc/AcOH (1:1) as addi-
tive; the acetate 6 was obtained in good yields (Table 1,
entry 14). This result was remarkable as 2-acetoxytetrahy-
drofurans are employed to generate five-membered ring
oxocarbenium ions,14 the ideal intermediates for the ste-
reoselective introduction of nucleophiles in position 2 of
a tetrahydrofuran ring.15 The formation of these adducts
At a lower temperature, the conversion of 1 required a
longer time and the formation of many by-products was
observed (Table 1, entry 6). At 110 °C in THF, the con-
version of 1 was almost quantitative after 60 minutes, but
lactol 3 was isolated only in 65% yield (Table 1, entry 7).
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

SPECIAL TOPIC
Microwaves or Conventional Heating for Domino Hydroformylation Reaction?
2903
Table 1 Optimization of the Reaction Conditions for the Hydroformylation of 1
Entry
1
Reaction conditionsa
Products (yield, %)b
staring material
2 (10) + 3 (35)
4 (67)
MW, toluene, [bmim][BF4], 110 °C, 2 h, A
MW, THF, [bmim][BF4], 110 °C, 2 h, A
MW, EtOH, 110 °C, 90 min, A
MW, EtOH, PTSA, 110 °C, A
2
3
4
dec.
5
MW, THF, 90 °C, 3 h, A
3 (55)
6
MW, THF, 60 °C, 5 h, A
3 (40) + dec.
3 (65)
7
MW, THF, 110 °C, 1 h, A
8
MW, THF, 110 °C, 1 h, B
3 (62)
9
MW, THF 110 °C, 1 h, C
dec.
c
10
11
12
13
14
15
16
17
MW, THF, 110 °C, 1 h, D
–
MW, THF–H2O, 110 °C, 30 + 45 min, A
MW, THF, PTSA, 110 °C, 1 h, A
MW, THF–H2O–HCl, 110 °C, 1 h, A
MW, THF–H2O, NaOAc, AcOH, 110 °C, 1 h, A
autoclave, THF–H2O, 110 °C, 12 h, A
autoclave, THF–H2O, 110 °C, 24 h, E
autoclave, THF–H2O, NaOAc, AcOH, 110 °C, 12 h, A
3 (92)
dec.
dec.
6 (88)
3 (48)
3 (70)
dec.
a A: (PPh3)3Rh(CO)H (0.01 equiv)/xantphos (0.04 equiv), H2/CO 827 kPa; B: Rh(CO)2acac (0.01 equiv)/xantphos (0.04 equiv), H2/CO 827 kPa;
C: (PPh3)3Rh(CO)H (0.01 equiv)/biphephos (0.04 equiv), H2/CO 827 kPa; D: Rh(CO)2acac (0.02 equiv)/Ph3P (0.1 equiv), H2/CO 827 kPa; E:
Rh(CO)2acac (0.01 equiv)/biphephos (0.04 equiv), H2/CO 1240 kPa.
b dec. = decomposition products.
c Reduction of the double bond to form 1-isopropylcyclohexanol was observed.
directly during hydroformylation of allylic alcohols in- Rh(CO)2acac/biphephos at 60 °C for 24 hours, the yield of
creases the synthetic value of the transformation.
3 could be increased to 70% (Table 1, entries 15,16). At-
tempts to transform 1 into 6 with a mixture of NaOAc/
AcOH in THF in an autoclave gave mainly decomposition
products (Table 1, entry 17).
OH
OR
a
b
O
O
O
The MW-assisted hydroformylation in THF was applied
to different allyl alcohols. Varying the additive from H2O
to EtOH or NaOAc/AcOH it was possible to obtain hemi-
acetals, ethyl acetals, or the corresponding acetates in
good to acceptable yields (Table 2).
3
6 R = Ac
7 R = Ms
5
b
OAc
c
OH
O
The reaction gave the expected products with aliphatic
and aromatic alcohols (Table 2, entries 1–3) and also with
homoallylic alcohols. With alcohol 11, the 2-hydroxytet-
rahydropyran 23a was isolated together with small
amounts of the tetrahydrofuran 23b originating from the
formation of the branched aldehyde during hydroformyla-
tion (Table 2, entry 4). In our hands, it was the only case
where a branched aldehyde (or its cyclized derivative)
was observed so far; a chelating effect of the OH toward
the Rh catalyst could be the explanation: the homoallyl al-
cohol accommodates the large Rh atom, promoting the
Markownikoff-type hydrometalation. When the reaction
was repeated in the presence of EtOH or NaOAc/AcOH,
6
1
Scheme 3 Reagents and conditions: (a) Ac2O, Et3N, CH2Cl2, r.t.,
80% or MsCl, Et3N, CH2Cl2, 20 °C, 10 h, 60%; (b) pyridine, 80 °C, 6
h, 80%; (c) (PPh3)3Rh(CO)H (0.01 equiv)/xantphos (0.04 equiv), H2/
CO 827 kPa, THF, NaOAc/AcOH (1.5 equiv), MW, 110 °C, 60 min,
88%.
Conversely when compound 1 was submitted to hydro-
formylation in an autoclave under conditions comparable
to the MW heating, the transformation into 3 was accom-
plished after 12 hours, but the product was isolated only
in moderate yield (48%). However, working with
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

2904
E. Airiau et al.
SPECIAL TOPIC
Table 2 Tandem Hydroformylation/Cyclization of Unsaturated Alcohols 8–13
Entry
1
Alcohol
Reaction conditionsa
Products
Yield (%)
MW, THF–H2O, 110 °C, 60 min, A
MW, THF NaOAc/AcOH, 110 °C, 30 + 45 min, A
MW, EtOH, 90 °C, 60 min, A
14 (67)
15 (70)
16 (77)
OR
O
OH
R = H: 14, R = Ac: 15, R = Et: 16
8
MW, THF–H2O, 110 °C, 60 min, A
MW, THF, NaOAc/AcOH, 110 °C, 30 + 45 min, A
MW, EtOH, 90 °C, 60 min, A
17 (76)
18 (72)
19 (79)
OR
O
2
3
OH
9
R = H: 17, R = Ac: 18, R = Et: 19
Ph
MW, THF–H2O, 110 °C, 60 min, A
MW, THF, NaOAc/AcOH, 110 °C, 60 min, A
MW, EtOH, 90 °C, 60 min, A
20 (60)
21 (70)
22 (70)
Ph
R = H: 20, R = Ac: 21, R = Et: 22
OR
O
OH
10
23a (62)
24a (70)
Ph
O
OR
Ph
R = H: 23a, R = Ac: 24a
MW, THF–H2O, 130 °C, 40 min, A
4
5
MW, THF, NaOAc/AcOH, 110 °C, 30 + 45 min, A
OH
11
23b (9)
24b (11)
Ph
OR
O
R = H: 23b, R = Ac: 24b
MW, THF–H2O, 110 °C, 60 min, A
MW, THF, NaOAc/AcOH, 110 °C, 30 + 45 min, A
25 (72)
26 (89)
OR
O
OH
R = H: 25 R = Ac: 26
12
TBDMSO
13
OAc
6
7
MW, THF, NaOAc/AcOH, 110 °C, 30 + 45 min, A
27 (67)
O
OH
TBDMSO
27
autoclave, THF–H2O, 110 °C, 12 h, A
autoclave, THF, NaOAc/AcOH, 110 °C, A
autoclave, EtOH, 80 °C, 4 h, A
14 (37)
15 (0)
16 (50)
8
autoclave, THF–H2O, 110 °C, 12 h, A
autoclave, THF–H2O, 60 °C, 24 h, E
autoclave, THF, NaOAc/AcOH, 80 °C, A
autoclave, EtOH, 80 °C, 4 h, A
17 (35)
17 (55)
18 (0)
8
9
9
19 (60)
autoclave, THF–H2O, 110 °C, 12 h, A
autoclave, EtOH, 80 °C, 4 h, A
20 (0)
22 (70)
10
a A: (PPh3)3Rh(CO)H (0.01 equiv)/xantphos (0.04 equiv), H2/CO 827 kPa; E: Rh(CO)2acac (0.01 equiv)/biphephos (0.04 equiv), H2/CO 1241
kPa.
the corresponding derivatives were formed in good yields. ing at lower temperature and for longer periods increased
For example, reaction on chiral alcohol 13 in the presence the yields and the purity of the products formed in auto-
of NaOAc/AcOH gave acetoxytetrahydrofuran 27 clave. When the alcohols 8–10 were submitted to hydro-
(Table 2, entry 6), a key intermediate for a concise synthe- formylation in the presence of NaOAc and AcOH under
sis of (+)-muscarine.16 When the alcohols 8–10 were sub- conventional heating, the corresponding 2-acetoxy deriv-
mitted to hydroformylation in autoclave under atives 15, 18, and 21 were never isolated. However, in the
conventional heating (external oil bath), the observed re- presence of EtOH, 2-ethoxy derivatives 16, 19, and 22
sults were highly substrate dependent (Table 2, entries 7– were obtained in acceptable yields. The exclusive possi-
9). Alcohol 8 cyclized towards the same products ob- bility to introduce an acetoxy group directly at C-2 in-
served under MW heating, although after longer time and creased the synthetic potential of the corresponding
in lower yields. Alcohol 9 gave a mixture of the cyclic and adducts. Indeed these products can be easy functionalized
open chain products, while aromatic alcohol 10 formed as demonstrated by the stereoselective reaction of 15 or 18
the expected heterocycles in poor yields. However, work- with allyltrimethylsilane in the presence of BF3·OEt2
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

SPECIAL TOPIC
Microwaves or Conventional Heating for Domino Hydroformylation Reaction?
2905
(Scheme 4). Compounds 28 or 29 were obtained in good ino hydroformylation/cyclization of an ally alcohol al-
yields (>90% overall from the corresponding allyl alco- lowed a general and rather short access to new bicyclic
hols 8 and 9). Moreover, Et3N-mediated elimination of furopyridine scaffolds.
acetic acid from 15 and 18 assisted by MWs, afforded di-
hydrofurans 30 and 31, versatile intermediates suitable for
different transformations.
Nitrogen (and Carbon) Nucleophiles
The hydroformylation of an alkene in combination with a
nitrogen nucleophile has been largely explored for the
synthesis of aza-heterocycles.19 The structures of the
products depend on the nature of nucleophiles present in
the olefinic substrate. With primary amines, imines are
formed, whereas the presence of secondary amines leads
to iminium ions (or enamines). With a secondary amide,
the lower electron density of the nitrogen affords a more
electrophilic acyliminium ion. If a carbon nucleophile is
present in the substrate, an additional reaction takes place
in a domino multicomponent process. The reactivity of
the second C-nucleophile is decisive for the outcome of
the domino sequence: with aromatic nucleophiles, the cy-
clization is often followed by rearomatization; with a p-
nucleophile (as an allysilane) the ring closure generates a
carbocation that evolves by elimination.20
OAc
O
O
O
28
b
a
15
or
O
30
or
or
OAc
O
O
18
29
trans/cis = 7:3
31
Scheme 4
Reagents and conditions: (a) CH2=CHCH2TMS,
CH2Cl2, BF3·OEt2, –78 °C, 28 (95%); 29 (95%); (b) Et3N, THF, MW,
60 °C, 10 min, 30 (65%); 31 (71%).
As a model reaction for the preparation of the heterocyclic
part of cyclopamine, spirodihydrofuran 5 was treated with
NBS in water–THF followed by acetylation of the lactol
with Ac2O in pyridine to give compound 32 as a single di-
astereomer (Scheme 5). Further reaction17 with 2-(chlo-
romethyl)allyltrimethylsilane in the presence of BF3·OEt2
gave compound 33 in good yield and high stereoselectivi-
ty, featuring that the reaction passed through an oxocarbe-
nium ion. Careful NOE experiments suggested that the
relative stereochemistries of the substituents around the
tetrahydrofuran were 2,3-trans and 3,4-cis. Then, the sec-
ondary bromide and the primary chloride in 33 were sub-
stituted with benzylamine under MW heating, producing
a piperidine by ring closure. Further treatment with H2 in
the presence of Pd(OH)2/C gave the furanopiperidine 34
in good yields, as a mixture of diastereomers in 8:1 ratio.
Electron-rich aromatics are excellent partners for Pictet–
Spengler cyclizations on acyliminium ions generated by
hydroformylation.21 As the Pictet–Spengler reaction has
been reported to occur under MW dielectric heating,22 we
started to explore this process looking at the transforma-
tion recently described under conventional heating.23 Un-
der comparable conditions (Table 3, entry 1), amide 35
was recovered after two hours of MW dielectric heating.
The temperature was increased up to 110 °C (changing
the ligand to xantphos), but decomposition was observed.
Changes in the temperature, solvent, time, and amount of
ligands did not result in the expected cyclization product
36 (Table 3, entries 2–7), but only the isomerized product
37 was isolated (Scheme 6). However, conventional heat-
ing of 35 with PTSA in an autoclave at 80 °C produced
65% of 36 (Table 3, entry 9).
Cl
Br
Br
To better understand the level at which the domino pro-
cess is hampered, an intermolecular version of the reac-
tion was attempted. Thus, a mixture of the tryptophan
methyl ester 38 and oct-1-ene 39 were mixed together and
submitted to hydroformylation under different reaction
conditions. After 30 minutes of MW dielectric heating in
THF, imine 40 was isolated in 56% yields (Scheme 7).
b
a
O
OAc
O
O
5
32
33
HN
c
O
34
Scheme 5 Reagents and conditions: (a) NBS, H2O–THF (1:1), r.t.,
Ac2O, pyridine, r.t., 59%; (b) ClCH2(C=CH2)CH2TMS, BF3·OEt2,
CHCl3, –60 °C, 98%; (c) BnNH2, Cs2CO3, MeOH, MW, 2 × 3 min,
H2, Pd(OH)2/C, EtOAc, r.t., 52%.
COOMe
O
COOMe
O
HN
N
see Table 3
N
H
N
COOMe
O
H
Unfortunately, if compared with cyclopamine,18 3¢,6¢-
dimethylhexahydro-3¢H-spiro(cyclohexane-1,2¢-fu-
ro[3,2-b]pyridine) (34) has the wrong stereochemistry at
C3a¢, as a result of an inversion of configuration that oc-
curs during the nucleophilic substitution of the secondary
bromide. However, the above procedure based on a dom-
36
35
HN
N
H
37
Scheme 6
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

2906
E. Airiau et al.
SPECIAL TOPIC
Table 3 Domino Hydroformylation Pictet–Spengler Cyclization
Entry
Reaction conditionsa
Products (yield, %)
1
2
3
4
5
6
7
8
9
MW, THF, 80 °C, PTSA (1 equiv), 2 h, A
MW, THF, 110 °C, PTSA (1 equiv), 1 h, B
MW, toluene, [bmim][BF4], PTSA (0.1 equiv), 110 °C, 2 h, B
MW, EtOH, PTSA, 110 °C, 30 min, B
MW, THF, 70 °C, 5 h, A
starting material
dec.
dec.
dec.
starting material + 37 (20)
MW, THF, 70 °C, PTSA (1 equiv), 5 h, A
MW, THF, 70 °C, TFA, (0.5 equiv), 5 h, A
MW, THF, 70 °C, 5 h, C
dec.
dec.
37 (20)
36 (65)
autoclave, THF, 80 °C, PTSA (1 equiv), 12 h, A
a A: Rh(CO)2acac (0.01 equiv)/biphephos 0.04 equiv), H2/CO 827 kPa; B: (PPh3)3Rh(CO)H (0.01 equiv)/xantphos (0.04 equiv), H2/CO 827
kPa; C: Rh(CO)2acac (0.02 equiv)/biphephos (0.08 equiv), H2/CO 827 kPa.
COOH
COOH
Attempts to cyclize 40 under MW irradiation in the pres-
ence of different acid additives were unsuccessful. On the
other hand, refluxing 40 in toluene for 12 hours in the
presence of PTSA gave the cyclization product 41 in 50%
yield. This result suggests that the domino process de-
pends on the success of the second reaction. Although
there are several reports describing that MW accelerates
the Pictet–Spengler reaction, conditions compatible with
the MW-assisted hydroformylation process were not
found. The influence of the Pictet–Spengler reaction is re-
vealed in the preparation of the 13-methylprotoberberine
(48) (Scheme 8).24
OMe
Br
OMe
a
b
OMe
OMe
43
42
MeO
MeO
MeO
d
c
HN
O
HN
O
MeO
OMe
Br
OMe
OMe
45
44
OMe
MeO
MeO
MeO
The strategy was based on the hydroformylation (in auto-
clave) of a suitably decorated styryl 45, designed to give
a branched aldehyde 46 further amenable to the acylimin-
ium ion 47, the substrate for the Pictet–Spengler cycliza-
tion (Scheme 8). Commercially available 2,3-
dimethoxybenzoic acid (42) was converted by bromina-
tion to the bromo acid 43, then a Schotten–Baumann con-
densation with homoveratrylamine afforded the amide 44.
The vinyl function was introduced by a Stille coupling un-
der optimized conditions and the vinyl adduct 45 (77%)
was obtained, ready for the hydroformylation reaction. At
this stage, it has to be emphasized that for styrene like
HN
O
N+
O
OHC
MeO
OMe
OMe
OMe
OMe
47
46
MeO
MeO
MeO
O
N
O
N
MeO
OMe
OMe
OMe
OMe
49
48
COOMe
COOMe
+
Scheme 8 Reagents and conditions: (a) dimethyldibromohydan-
toin, 0.1 M aq NaOH, 12 h, r.t., 95%; (b) SOCl2, CH2Cl2, followed by
homoveratrylamine, Et3N, CH2Cl2, r.t., 84%; (c) Pd(PPh3)4 (0.04
equiv), CH2=CHSnBu3 (3 equiv), toluene, 100 °C, 12 h, then
Pd(PPh3)4 (0.02 equiv), 24 h, 100 °C, 90%; (d) Rh(CO)2acac (0.01
equiv), biphephos (0.02 equiv), H2/CO (700 kPa, 1:1), THF, 80 °C,
BF3·OEt2 (2 equiv), 12 h, 45%.
a
C6H13
N
NH2
N
N
H
C8H17
40
H
38
39
COOMe
NH
C8H17
b
compounds the hydroformylation delivers mainly the
branched aldehyde. However, when the reaction was car-
ried out in autoclave [Rh(CO)2acac, biphephos, THF,
80 °C, 12 h, BF3·OEt2], the azepine derivative 49 was ob-
tained in 45% yield.
N
H
41
Scheme 7 Reagents and conditions: (a) PPh3)3Rh(CO)H (0.01
equiv)/xantphos (0.04 equiv), H2/CO 827 kPa, THF, MW, 110 °C, 1
h, 56%; (b) toluene, reflux, PTSA (1 equiv), 12 h, 50%.
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

SPECIAL TOPIC
Microwaves or Conventional Heating for Domino Hydroformylation Reaction?
2907
Optimization of the reaction conditions revealed the si- In this case, the intermediate aldehyde 53a cyclized to the
multaneous formation of compound 50 and 51, the latter bicyclic alkene 53b, a substrate for a further hydroformy-
originated from abnormal linear hydroformylation of the lation towards linear aldehyde 54. With the idea of synthe-
styryl type double bond. Interestingly, the compound 50 sizing the quinolizidine alkaloid ( )-epilupinine, the
coming from the branched aldehyde was by far the major allylsilane 59 was prepared as described in Scheme 11.
adduct. However, when submitted separately to Pictet– Starting from 5-bromopent-1-ene (55), the allylsilane part
Spengler cyclization, the amide 50 did not cyclize, where- was introduced by a metathetic process giving the bromo
as azepinone 51 gave product 49 in good yield allylsilane 56. Then, bromide displacement by sodium
(Scheme 9).
azide followed by LiAlH4 reduction delivered the amine
58. Finally coupling with vinylacetic acid yielded the ami-
doallylsilane 59. Hydroformylation of 59 was carried out
under MW dielectric heating under different conditions.
As in the previous case, the expected overall domino pro-
cess did not go to completion and enamine 60 was the
main product isolated together with about 20% of 61 com-
ing from protodesilylation. Attempts to optimize the reac-
tion were not successful. However, allylsilane 60 cyclized
in the presence of TFA to give the quinolizidine 62. Con-
versely, when submitted to cyclizative hydroformylation
in an autoclave in the presence of an acid additive, allylsi-
lane 59 afforded the quinolizinyl aldehyde 63 with good
diastereoselectivity.
MeO
MeO
N
O
MeO
MeO
OMe
OMe
a
b
HN
O
50
OMe
OMe
MeO
45
O
N
MeO
OMe
MeO
MeO
c
OMe
51
O
N
a
TMS
TMS
b
OMe
Br
N3
Br
49
55
56
57
OMe
TMS
Scheme 9 Reagents and conditions: (a) Rh(CO)2acac (0.01 equiv),
Ph3P (0.02 equiv), H2/CO (2000 kPa, 1:1), THF, PTSA, 65 °C, 12 h,
76%; (b) Rh(CO)2acac (0.01 equiv), biphephos (0.02 equiv), H2/CO
(700 kPa, 1:1), THF, PTSA, 85 °C, 24 h, 56%; (c) CH2Cl2, reflux
BF3·OEt2, 76%.
c
TMS
d
O
NH
NH2
58
59
TMS
e
f
Probably the formation of the acyliminium ion 47 is dis-
favored with respect to 50 because of a strong conjugation
with the aromatic ring. Thus, the fate of the Pictet–
Spengler reaction influences the overall domino process
proceeding exclusively towards the (unexpected) ho-
moberberine 49.25
O
N
O
N
60
62
O
N
61
The allylsilane is another potential nucleophile that can
react with an (acyl)iminium ion. Recently our group re-
ported a domino hydroformylation aza-Sakurai cycliza-
tion with the formation of indolizidine 54 (Scheme 10).26
Scheme 11 Reagents and conditions: (a) CH2=CHCH2SiMe3 (4
equiv), Grubbs II (0.01 equiv), CH2Cl2, reflux, 12 h, 81%; (b) NaN3
(3 equiv), DMF, 70 °C, 12 h, 78%; (c) LiAlH4 (2 equiv), THF, 3 h,
r.t., 90%; (d) vinylacetic acid (1 equiv), EDC·HCl (1 equiv), HOBt
(0.2 equiv), CH2Cl2, 12 h, 93%; (e) Rh(CO)2acac (0.02 equiv), biphe-
phos (0.08 equiv), CO/H2 827 kPa, PPTS (0.1 equiv), THF, MW,
60 °C, 2 h, 49%; (f) TFA, r.t., 12 h, 62%.
TMS
hydroformylation
aza-Sakurai
CHO
O
NH
52
O
N
54
cis/trans = 90:10
If the same reaction was performed sequentially omitting
the Lewis acid during the hydroformylation step, the final
linear hydroformylation did not proceed; instead quinoliz-
idine 62 was isolated in good yield. A direct application of
this sequence to the synthesis of epilupinine progressed
with the ozonolysis of the exo double bound to give the al-
dehyde 64, which was reduced to ( )-epilupinine, ob-
tained in 22% overall yield over seven steps from
bromopentene 55 (Scheme 12).
TMS
CHO
O
NH
O
N
53a
53b
Scheme 10 Domino hydroformylation by aza-Sakurai cyclization
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

2908
E. Airiau et al.
SPECIAL TOPIC
der pressure (CEM Corporation) was employed. A 50 ML stainless
lab autoclave was employed for other processes.
TMS
O
N
O
b
NH
O
N
a
4-Methyl-1-oxaspiro[4.5]decan-2-ol (3); Typical Procedure
In an 80 mL microwave tube (PPh3)3Rh(CO)H (131 mg, 0.14
mmol) and xantphos (330 mg, 0.57 mmol) were added to a solution
of compound 1 (1.00 g, 7.14 mmol) in a mixture of THF–H2O (10:1,
10 mL). The solution was pressurized with syngas at 827 kPa and
heated to 110 °C (3 × 30 min) by microwave irradiation at 150 W.
The flask was cooled and the internal gas released. The residue was
dried (Na2SO4), and after filtration and evaporation, the crude was
purified by flash chromatography (PE–EtOAc, 6:1) to give 3 (1.12
g, 90%) as a yellow oil consisting of a mixture of two diastereo-
mers; diastereomeric ratio: 60:40.
O
63 trans/cis = 9:1
62
59
c
d
O
N
N
OH
O
64
65 ( )-epilupinine
1H NMR (400 MHz, CDCl3): d = 5.47–5.40 (m, 1 H), 3.02 (d,
J = 23.0 Hz, 1 H), 2.39–2.31 (m, 1 H), 2.28–2.10 (m, 1 H), 2.03–
1.98 (m, 1 H), 1.75–1.10 (m, 10 H), 0.98–0.88 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 97.7, 88.20, 39.5, 38.8, 37.1,
31.3, 25.6, 22.9, 16.0.
Scheme 12 Reagents and conditions: (a) Rh(CO)2(acac) (0.01
equiv), biphephos (0.02 equiv), CSA (1 equiv), MS 4Å, 500 kPa H2/
CO (1:1), MeCN, 70 °C, 10 h, 78%; (b) Rh(CO)2(acac) (0.01 equiv),
biphephos (0.03 equiv), MS 4 Å, 500 kPa H2/CO (1:1), MeCN, 65 °C,
65%; (c) O3, CH2Cl2, –78 °C to r.t., then, Ph3P (1 equiv) 76%; (d)
LiAlH4 (5 equiv), THF, 5 h, r.t., 70%.
ESI-MS: m/z (%) = 193 (100, [M + Na]+), 171 (35, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C10H18O2 + Na: 193.2385;
found: 193.2380.
Although useful to simplify and speed up the traditionally
time consuming process of hydroformylation, MW-assist-
ed domino hydroformylation processes are limited by the
sensitivity to the nucleophiles. With allyl alcohols MW
gave results superior to the standard autoclave process, al-
lowing a rapid access to lactols or 2-acetoxytetrahydro-
furans. The reaction was reproducible and also the
formation of classical by-products was minimized. On the
other hand, MW dielectric heating seems not compatible
for instance with the reactivity of acyliminium ions: a par-
tial degradative pathway is operating owing to the hot
spots generated by microwave irradiation. From our
present experience, both devices MW irradiation and au-
toclave heating are complementary for performing hydro-
formylations. But it remains that the MW process has to
be tried at first, as it gives faster reaction rate and in case
of failure the traditional autoclave can be a valuable re-
sort. Finally regardless of the apparatus, hydroformyla-
tion is a powerful reaction not only for introducing an
aldehyde function but even better if the olefin substrate is
properly designed, it becomes a powerful tool for per-
forming domino reactions. A few of them have been pre-
sented here; we believe that they will stimulate the
organic chemists to add many more examples in near fu-
ture.
2-Ethoxy-4-methyl-1-oxaspiro[4.5]decane (4); Typical Proce-
dure
In a 10 mL microwave vessel (PPh3)3Rh(CO)H (104 mg, 0.11
mmol) and xantphos (264 mg, 0.45 mmol) were added to a solution
of compound 1 (800 mg, 5.71 mmol) in EtOH (2 mL). The solution
was pressurized with syngas at 827 kPa and heated to 110 °C
(3 × 30 min) by microwave irradiation at 150 W. The flask was
cooled and the internal gas released. The residue was dried
(Na2SO4) and after filtration and evaporation, the crude was purified
by flash chromatography (PE–EtOAc, 8:1) to give 4 (748 mg, 67%)
as a yellow oil consisting of a mixture of two diastereomers; dia-
stereomeric ratio: 60:40.
1H NMR (400 MHz, CDCl3): d = 5.09–4.97 (m, 1 H), 3.88–3.67 (m,
1 H), 3.52–3.31 (m, 1 H), 2.43–2.32 (m, 1 H), 2.31–1.92 (m, 1 H),
1.83–1.33 (m, 10 H), 1.29–1.02 (m, 3 H), 1.01–0.88 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 98.4, 87.91, 60.0, 40.7, 38.8,
37.1, 32.1, 25.9, 22.9, 16.04, 15.2.
ESI-MS: m/z (%) = 221 (100, [M + Na]+), 198 (26, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C12H22O2 + Na: 221.2916;
found: 221.2910.
4-Methyl-1-oxaspiro[4.5]dec-2-yl Acetate (6); Typical Proce-
dure
In a 10 mL microwave tube a solution of (PPh3)3Rh(CO)H (14 mg,
0.015 mmol) and xantphos (35 mg, 0.060 mmol) in THF–H2O
(10:1, 2 mL) was added to a solution of 1 (100 mL, 0.75 mmol),
AcOH (43 mL, 0.75 mmol) and NaOAc (61 mg, 0.75 mmol) in
THF–H2O (10:1, 2 mL) under an inert atmosphere. The solution
was submitted to pressurized syngas at 827 kPa and heated for 60
min at 110 °C by microwave irradiation at 150 W (value previously
settled on the microwave oven). The flask was cooled and the inter-
nal gas released. Sat. aq Na2CO3 (4 mL) was added and the aqueous
layer was extracted with Et2O (3 × 10 mL). The combined organic
layers were dried (Na2SO4). After filtration and concentration in
vacuo, the crude mixture was purified by flash chromatography
(PE–EtOAc, 6:1) to give 6 as a pale yellow oil (109 mg, 88%) con-
sisting of a mixture of two diastereomers; diastereomeric ratio:
60:40.
The reactions were carried out in oven dried or flamed vessels and
performed under argon. Solvents were dried and purified by con-
ventional methods prior use. Petroleum ether (PE) used refers to the
fraction boiling in the range 40–60 °C. Flash column chromatogra-
phy was performed with Merck silica gel 60, 0.040–0.063 mm
(230–400 mesh). Merck aluminum backed plates precoated with sil-
ica gel 60 (UV254) were used for TLC and were visualized by stain-
ing with KMnO4. 1H NMR and 13C NMR spectra were recorded on
a Bruker AC 400 MHz instrument at 400 and at 200 MHz, respec-
tively. Low-resolution mass spectra were obtained on an Agilent
1100 LC/MS instrument in positive or negative mode. GC/MS anal-
ysis was performed on a Varian-GC using a CP 8944 column (30
m × 0.250 mm × 0.39 mm. For MW reaction a CEM Discover mi-
crowave oven equipped with an 80 or 10 mL tube for reactions un-
1H NMR (400 MHz, CDCl3): d = 6.03 (s-like, 1 H), 2.24 (m, 3 H),
2.10 (s, 3 H), 1.70–1.40 (m, 12 H), 1.04 (d, J = 7 Hz, 3 H).
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

SPECIAL TOPIC
Microwaves or Conventional Heating for Domino Hydroformylation Reaction?
2909
13C NMR (100 MHz, CDCl3): d = 163.3, 96.0, 89.1, 38.9, 37.9,
ESI-MS: m/z (%) = 195 (100, [M + Na]+), 173 (30, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C10H20O2 + Na: 195.2544;
37.5, 31.1, 22.9, 21.2, 16.0.
ESI-MS: m/z (%) = 235 (100, [M + Na]+), 213 (50, [M + H]+).
found: 195.2540.
ESI-HMRS: m/z [M + Na]+ calcd for C12H20O3 + Na: 235.2752;
found: 235.2751.
5-Phenyltetrahydrofuran-2-ol (20)
1H NMR (400 MHz, CDCl3): d = 7.32 (m, 5 H), 5.57 (s-like, 1 H),
5.14 (s-like, 1 H), 3.93 (br s, 1 H), 2.24–1.96 (m, 4 H).
1-Oxaspiro[4.5]decan-2-ol (14)
1H NMR (400 MHz, CDCl3): d = 5.41 (s-like, 1 H), 3.85 (br s, 1 H),
2.11–1.90 (m, 4 H), 1.58–1.40 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 141.1, 127.8, 127.9, 127.0, 100.3,
80.2, 33.6, 31.0.
13C NMR (100 MHz, CDCl3): d = 100.7, 89.9, 38.7, 35.5, 34.4,
ESI-MS: m/z (%) = 187 (100, [M + Na]+), 165 (50, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C10H12O2 + Na: 187.1908;
32.2, 25.8, 23.7.
ESI-MS: m/z (%) = 179 (100, [M + Na]+), 157 (26, [M + H]+).
found: 187.1901.
ESI-HMRS: m/z [M + Na]+ calcd for C9H16O2 + Na: 179.2119;
found: 179.2120.
5-Phenyltetrahydrofuran-2-yl Acetate (21)
1H NMR (400 MHz, CDCl3): d = 7.36 (m, 5 H), 5.21 (s-like, 1 H),
5.04 (s-like, 1 H), 2.27–1.90 (m, 4 H), 1.95 (s, 3 H).
1-Oxaspiro[4.5]dec-2-yl Acetate (15)
1H NMR (400 MHz, CDCl3): d = 5.96 (s-like, 1 H), 2.15–1.50 (m,
14 H), 2.10 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 171.2, 141.8, 128.2, 128.9, 127.0,
98.9, 80.2, 34.4, 31.1, 21.1.
13C NMR (100 MHz, CDCl3): d = 165.4, 97.6, 87.7, 38.6, 35.5,
ESI-MS: m/z (%) = 229 (100, [M + Na]+), 207 (60, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C12H14O3 + Na: 229.2275;
34.2, 30.8, 23.7, 21.2.
ESI-MS: m/z (%) = 221 (100, [M + Na]+), 199 (48, [M + H]+).
found: 229.2270.
ESI-HMRS: m/z [M + Na]+ calcd for C11H18O3 + Na: 221.2486;
found: 221.2482.
2-Ethoxy-5-phenyltetrahydrofuran (22)
1H NMR (400 MHz, CDCl3): d = 7.34 (m, 5 H), 5.10 (s-like, 2 H),
3.67 and 3.53 (m, 2 H), 2.26–1.90 (m, 4 H) 1.18 (t, J = 6 Hz, 3 H).
2-Ethoxy-1-oxaspiro[4.5]decane (16)
1H NMR (400 MHz, CDCl3): d = 5.07 (s-like, 1 H), 3.67–3.53 (m,
2 H), 2.14–1.90 (m, 4 H), 1.58–1.40 (m, 10 H), 1.18 (t, J = 7 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 140.6, 128.1, 128.0, 127.3, 105.6,
81.7, 61.8, 33.9, 31.4, 15.7.
ESI-MS: m/z (%) = 215 (100, [M + Na]+), 193 (50, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C12H16O2 + Na: 214.2440;
13C NMR (100 MHz, CDCl3): d = 100.3, 86.7, 62.0, 39.5, 36.3,
34.9, 30.4, 25.8, 23.8, 15.8.
ESI-MS: m/z (%) = 207 (100, [M + Na]+), 185 (70, [M + H]+).
found: 2145.24436.
6-Phenyltetrahydro-2H-pyran-2-yl Acetate (24a)
ESI-HMRS: m/z [M + Na]+ calcd for C11H20O2 + Na: 207.2651;
found: 207.2645.
1H NMR (400 MHz, CDCl3): d = 7.40–7.24 (m, 5 H), 5.69 (s-like,
1 H), 4.79 (dd, J = 8, 2 Hz, 1 H), 2.10 (s, 3 H), 1.9–1.36 (m, 6 H).
5-Butyltetrahydrofuran-2-ol (17)
13C NMR (100 MHz, CDCl3): d = 169.9, 143.6, 128.8, 127.9, 127.4,
1H NMR (400 MHz, CDCl3): d = 5.43 (s-like, 1 H), 4.07–3.99 (m,
2 H), 1.89 (m, 2 H), 1.65 (m, 3 H), 1.40 (m, 5 H), 0.90 (m, 3 H).
94.1, 76.3, 31.5, 29.7, 21.3, 19.9.
ESI-MS: m/z (%) = 243 (100, [M + Na]+), 221 (56, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C13H16O3 + Na: 243.2541;
13C NMR (100 MHz, CDCl3): d = 99.8, 79.9, 33.1, 32.8, 31.6, 27.9,
22.8, 14.6.
ESI-MS: m/z (%) = 167 (100, [M + Na]+), 144 (40, [M + H]+).
found: 243.2540.
4-Methyl-5-phenyltetrahydrofuran-2-yl Acetate (24b)
ESI-HMRS: m/z [M + Na]+ calcd for C8H16O2 + Na: 167.2012;
found: 167.2009.
1H NMR (400 MHz, CDCl3): d = 7.42 (m, 2 H), 7.27 (m, 1 H), 7.02
(m, 2 H), 6.04 (s-like, 1 H), 4.70 (d, J = 8 Hz, 1 H), 2.58 (m, 1 H),
2.28 (m, 1 H), 2.10 (s, 3 H), 1.66 (m, 1 H), 1.06 (d, J = 7 Hz, 3 H).
5-Butyltetrahydrofuran-2-yl Acetate (18)
1H NMR (400 MHz, CDCl3): d = 4.89 (s-like, 1 H), 4.14 (m, 1 H),
1.95 (s, 3 H), 1.85–1.40 (m, 10 H), 0.88 (s-like, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.4, 137.7, 18.5, 128.0, 127.1,
97.3, 86.1, 40.4, 37.0, 21.3, 16.5.
13C NMR (100 MHz, CDCl3): d = 170.1, 98.2, l 80.3, 33.4, 32.9,
ESI-MS: m/z (%) = 243 (100, [M + Na]+), 221 (13, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C13H16O3 + Na: 243.2541;
31.7, 27.3, 22.7, 21.2, 14.2.
ESI-MS: m/z (%) = 209 (100, [M + Na]+), 187 (56, [M + H]+).
found: 243.2538.
ESI-HMRS: m/z [M + Na]+ calcd for C10H18O3 + Na: 209.2379;
found: 209.2375.
4-Methyltetrahydrofuran-2-ol (25)
1H NMR (400 MHz, CDCl3): d = 5.36 (s-like, 1 H), 3.90 (m, 2 H),
3.52 (m, 1 H), 2.62 (m, 1 H), 1.73 (m, 1 H), 1.39 (m, 1 H), 0.96 (d,
J = 7 Hz, 3 H).
2-Butyl-5-ethoxytetrahydrofuran (19)
1H NMR (400 MHz, CDCl3): d = 4.91 (s-like, 1 H), 4.00 (m, 1 H),
3.67 and 3.55 (m, 2 H), 1.75–1.62 (m, 4 H), 1.40 (m, 4 H), 1.18 (t,
J = 6 Hz, 3 H), 0.86 (s-like, 3 H).
13C NMR (100 MHz, CDCl3): d = 99.0, 74.7, 42.4, 31.9, 16.1.
ESI-MS: m/z (%) = 125 (100, [M + Na]+), 103 (25, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C5H10O2 + Na: 125.1215;
13C NMR (100 MHz, CDCl3): d = 105.2, 80.8, 61.8, 33.9, 33.0,
31.9, 23.3, 22.3, 14.3, 14.0.
found: 125.1212.
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

2910
E. Airiau et al.
SPECIAL TOPIC
4-Methyltetrahydrofuran-2-yl Acetate (26)
ESI-HMRS: m/z [M + Na]+ calcd for C9H14O + Na: 161.1966;
found: 161.1963.
1H NMR (400 MHz, CDCl3): d = 5.83 (s-like, 1 H), 3.95 (m, 1 H),
3.59 (m, 1 H), 2.68 (m, 1 H), 2.10 (m, 1 H), 2.08 (s, 3 H), 1.49 (m,
1 H), 0.98 (d, J = 8 Hz, 3 H).
2-Butyl-2,3-dihydrofuran (31)
1H NMR (400 MHz, CDCl3): d = 6.45 (s-like, 1 H), 4.87 (s-like, 1
H), 4.39 (m, 1 H), 2.50 (s, 1 H), 2.18 (s, 1 H), 1.74 (m, 1 H), 1.37
(m, 4 H), 0.89 (t, J = 6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.2, 96.5, 78.3, 40.9, 31.2,
21.1, 16.1.
ESI-MS: m/z (%) = 167 (100, [M + Na]+), 145 (20, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C7H12O3 + Na: 167.1581;
13C NMR (100 MHz, CDCl3): d = 145.4, 101.1, 80.3, 41.9, 30.6,
27.9, 22.9, 13.5.
ESI-MS: m/z (%) = 149 (100, [M + Na]+), 127 (30, [M + H]+).
found: 167.1578.
5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-2-yl
Acetate (27)
ESI-HMRS: m/z [M + Na]+ calcd for C8H14O + Na: 149.1859;
found: 149.1854.
1H NMR (400 MHz, CDCl3): d = 4.97 (s-like, 1 H), 4.09 (m, 1 H),
3.55 (m, 2 H), 1.92–1.75 (m, 4 H), 1.91 (s, 3 H), 0.91 (s, 9 H), 0.04
(s, 6 H).
3-Bromo-4-methyl-1-oxaspiro[4.5]dec-2-yl Acetate (32)
To a solution of 5 (200 mg, 1.32 mmol) in anhyd THF (5 mL) were
added N-bromosuccinimmide (258 mg, 1.45 mmol) and H2O (0.5
mL) portionwise and the reaction mixture stirred at r.t. for 10 min.
The residue was dried (Na2SO4) and after filtration and evaporation,
the crude was dissolved in CHCl3 (5 mL). Ac2O (37 mL, 0.39 mmol)
and pyridine (114 mL, 1.41 mmol) were added under N2. The mix-
ture was stirred at r.t. for 12 h. The residue was treated with aq
NaHCO3 (5 mL) and extracted with CHCl3 (3 × 10 mL) and the
combined organic layers were dried (Na2SO4). After filtration and
evaporation, the crude was purified by flash chromatography (PE–
Et2O, 2:1) to give 32 (41 mg, 59%) as a white solid.
1H NMR (400 MHz, CDCl3): d = 6.35 (s, 1 H), 4.34 (d, J = 5.6 Hz,
1 H), 2.29–2.26 (m, 1 H), 2.29–2.25 (m, 2 H), 2.00 (s, 3 H), 1.64–
1.45 (m, 8 H), 1.10 (d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.7, 100.4, 89.8, 53.2, 47.6,
39.1, 32.1, 25.4, 22.1, 20.1, 12.4
13C NMR (100 MHz, CDCl3): d = 169.8, 97.2, 82.6, 62.1, 33.0,
25.3, 25.1, 21.1, 18.3, –5.4.
ESI-MS: m/z (%) = 275 (100, [M + H]+).
ESI-HMRS: m/z [M + H]+ calcd for C13H27O4Si: 275.4366; found:
275.4362.
2-Allyl-1-oxaspiro[4.5]decane (28); Typical Procedure
To a solution of 15 (100 mL, 0.75 mmol) in EtOH-free CHCl3 (10
mL) was added BF3·OEt2 (120 mL, 0.97 mmol) at –60 °C and the re-
action mixture was stirred for 15 min. Allyltrimethylsilane (87 mL,
0.75 mmol) was added dropwise and the mixture was stirred at r.t.
for 12 h. The residue was treated with aq NaHCO3 (5 mL) and ex-
tracted with Et2O (2 × 5 mL). The combined organic layers were
dried (Na2SO4), filtered, and evaporated to afford 135 mg (95%) of
28, which was not purified further.
ESI-MS: m/z (%) = 315/312 (100, [M + Na]+), 292/290 [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C12H19BrO3 + Na: 314.1712;
1H NMR (400 MHz, CDCl3): d = 5.81–5.74 (m, 1 H), 5.05–4.97 (m,
2 H), 3.96–3.93 (m, 1 H), 2.34–2.29 (m, 1 H), 2.19–2.14 (m, 1 H),
1.91–1.88 (m, 1 H), 1.69–1.28 (m, 15 H).
found: 314.1708.
13C NMR (100 MHz, CDCl3): d = 135.2, 116.4, 79.7, 78.3, 38.6,
3-Bromo-2-[2-(chloromethyl)prop-2-en-1-yl]-4-methyl-1-oxa-
spiro[4.5]decane (33)
37.6, 37.1, 36.1, 30.9, 23.1.
ESI-MS: m/z (%) = 203 (100, [M + Na]+), 181 (45, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C12H20O + Na: 203.2764;
To a solution of 32 (90 mg, 0.30 mmol) in EtOH-free CHCl3 (10
mL) was added BF3·OEt2 (59 mL, 0.46 mmol) at –60 °C and the re-
action mixture was stirred for 15 min. 2-(Chloromethyl)allyltri-
methylsilane (83 mL, 0.46 mmol) was added dropwise and the
mixture was stirred at r.t. for 12 h. The residue was treated with aq
NaHCO3 (5 mL) and extracted with Et2O (2 × 5 mL). The combined
organic layers were dried (Na2SO4), filtered, and evaporated to give
33 (96 mg, 98%), which was used in the next reaction without fur-
ther purification.
1H NMR (400 MHz, CDCl3): d = 5.23 (s, 1 H), 5.10 (s, 1 H), 4.29–
4.24 (m, 1 H), 4.22–4.19 (m, 1 H), 4.14 (d, J = 10.4 Hz, 2 H), 2.53
(dd, J = 4.4, 12.1 Hz, 1 H), 2.38 (dd, J = 7.2, 20.2 Hz, 1 H), 2.01–
1.97 (m, 1 H), 1.65–1.41 (m, 8 H), 1.26–1.14 (m, 2 H), 1.06 (d,
J = 7.2 Hz, 3 H).
found: 203.2760.
2-Allyl-5-butyltetrahydrofuran (29)
1H NMR (400 MHz, CDCl3): d = 5.87–5.80 (m, 1 H), 5.11–5.06 (m,
2 H), 4.00 (m, 1 H), 3.91 (m, 1 H), 2.34–2.29 (m, 2 H), 1.83 (m, 1
H), 1.60 (m, 6 H), 1.40 (m, 2 H), 0.93 (t, J = 6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 134.9, 116.1, 80.6, 79.8, 38.5,
36.4, 33.9, 33.0, 27.4, 22.4, 14.1.
ESI-MS: m/z (%) = 191 (100, [M + Na]+), 168 (45, [M + H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C11H20O + Na: 191.2657;
found: 191.2651.
13C NMR (100 MHz, CDCl3): d = 142.23, 116.96, 84.38, 83.20,
1-Oxaspiro[4.5]dec-2-ene (30); Typical Procedure
A solution of 15 (99 mg, 0.5 mmol) in THF (1 mL) was mixed with
Et3N (100 mg, 1 mmol) inside a microwave vial. The vial was heat-
ed to 60 °C under microwave irradiation (max internal pressure 827
kPa, 150 W) for 10 min. The solvent was evaporated and the crude
purified by column chromatography (pentane–Et2O, 10:1); yield:
44 mg (65%).
58.27, 48.62, 45.44, 38.25, 38.00, 30.55, 25.68, 23.10, 22.07, 13.43.
ESI-MS: m/z (%) = 345/343 (100, [M + Na]+), 323/321 (54, [M +
H]+).
ESI-HMRS: m/z [M + Na]+ calcd for C14H22BrClO + Na: 344.6703;
found: 344.6700.
1H NMR (400 MHz, CDCl3): d = 6.41 (s-like, 1 H), 4.82 (s-like, 1
H), 2.49 (s, 2 H), 1.58–1.43 (m, 10 H).
3¢,6¢-Dimethylhexahydro-3¢H-spiro[cyclohexane-1,2¢-furo[3,2-
b]pyridine] (34)
To a solution of 33 (30 mg, 0.09 mmol) in MeOH (2 mL) in a 10 mL
microwave tube was added benzylamine (3 mL, 0.28 mmol) fol-
lowed by Cs2CO3 (32 mg, 0.1 mmol) and the reaction mixture was
irradiated 2 times by microwaves at 100 °C for 3 min (power max
13C NMR (100 MHz, CDCl3): d = 142.3, 100.2, 81.5, 45.2, 32.1,
25.8, 23.0.
ESI-MS: m/z (%) = 161 (100, [M + Na]+), 139 (40, [M + H]+).
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

SPECIAL TOPIC
Microwaves or Conventional Heating for Domino Hydroformylation Reaction?
2911
150 W). The residue was evaporated and the crude was dissolved in
EtOAc (5 mL) and Pd(OH)2/C (10 mg) was added. The mixture was
stirred under H2 (100 kPa) for 12 h at r.t. After filtration, the solvent
was evaporated and the residue was purified by flash chromatogra-
phy (PE–Et2O, 1:1) to give 34 (14 mg, 52%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 3.27 (m, 1 H), 2.98 (m, 1 H), 2.19
(m, 2 H), 1.83–1.23 (m, 14 H), 1.10 (d, J = 5 Hz, 3 H), 0.92 (d, J = 8
Hz, 3 H).
H), 5.90 (br t, J = 6.2 Hz, 1 H), 5.57 (dd, J = 17.5, 1.0 Hz, 1 H), 5.16
(dd, J = 10.9, 1.0 Hz, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.83 (s, 3 H),
3.80 (s, 3 H), 3.71 (q, J = 6.5 Hz, 2 H), 2.86 (t, J = 6.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 166.0, 152.1, 149.1, 147.7, 145.5,
133.3, 131.5, 131.4, 128.6, 121.5, 120.8, 114.5, 113.2, 112.1, 111.5,
61.8, 56.0, 55.9, 41.0, 35.4.
ESI-MS: m/z = 372 [M + H]+.
13C NMR (100 MHz, CDCl3): d = 89.6, 75.4, 65.8, 52.3, 44.2, 39.6,
39.0, 32.0, 31.2, 25.9, 22.5, 18.3, 8.4.
2-(3,4-Dimethoxyphenethyl)-7,8-dimethoxy-4-methylisoquino-
lin-1(2H)-one (50)
In a stainless steel autoclave under an inert atmosphere, a solution
of Rh(CO)2acac (1.5 mg, 0.006 mmol) and Ph3P (7.1 mg, 0.023
mmol) in anhyd degassed THF (3 mL) (prepared in a Schlenk glass-
ware under an inert atmosphere) was added to a solution of 45 (106
mg, 0.285 mmol) and PTSA (5.4 mg, 0.029 mmol) in anhyd de-
gassed THF to reach a final concentration of 0.04 M. The autoclave
was flushed three times with H2/CO (1:1). Then, the autoclave was
filled with 2000 kPa of H2/CO (1:1) and was heated at 65 °C with
stirring for 12 h. The autoclave was cooled to r.t. and the gases were
slowly and carefully released. After cooling, the reaction mixture
was concentrated under reduced pressure to give an oil. The residue
was purified by flash chromatography (pentane–EtOAc, 20:80) to
give 50 (83 mg, 76%) as a white solid.
1H NMR (400 MHz, CDCl3): d = 7.38–7.28 (m, 2 H), 6.79 (br s, 2
H), 6.74 (s, 1 H), 6.60 (s, 1 H), 4.10 (dd, J = 9.4, 7.3 Hz, 2 H), 4.00
(s, 3 H), 3.96 (s, 3 H), 3.86 (s, 3 H), 3.79 (s, 3 H), 3.02 (dd, J = 8.4,
6.7 Hz, 2 H), 2.16 (d, J = 0.9 Hz, 3 H).
ESI-HMRS: m/z [M + H]+ calcd for C22H25NO5: 384.1811; found:
384.1806
ESI-MS: m/z (%) = 224 (100, [M + H]+).
ESI-HMRS: m/z [M + H]+ calcd for C14H26NO: 224.3624; found:
224.3620.
6-Bromo-2,3-dimethoxybenzoic Acid (43)
In an ice bath, 2,3-dimethoxybenzoic acid (42; 1 g, 5.49 mmol) and
1,3-dibromo-5,5-dimethylhydantoin (863 mg, 3.02 mmol) were
added to 0.7 M aq NaOH (8.6 mL). The reaction mixture was stirred
at r.t. for 2 h, then 1 M aq HCl (15 mL) was added and the aqueous
layer was extracted with EtOAc ( 3 × 20 mL). The combined organ-
ic layers were dried (Na2SO4), filtered, and concentrated to give 43
as a solid (1.433 g, 98%), which was used without further purifica-
tion; mp 110–112 °C.
1H NMR (400 MHz, CDCl3): d = 9.92 (br s, 1 H), 7.27 (d, J = 8.7
Hz, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.2, 152.2, 147.1, 130.7, 128.2,
114.9, 108.7, 62.0, 56.2.
ESI-HMRS: m/z [M + H]+ calcd for C9H9BrO4: 260.9762; found:
260.9755.
2-(3,4-Dimethoxyphenethyl)-8,9-dimethoxy-2,5-dihydro-1H-
benzo[c]azepin-1-one (51)
6-Bromo-N-(3,4-dimethoxyphenethyl)-2,3-dimethoxybenz-
amide (44)
In a stainless steel autoclave under an inert atmosphere, a solution
of Rh(CO)2acac (1.4 mg, 0.005 mmol) and biphephos (8.5 mg,
0.011 mmol) in anhyd degassed THF (3 mL) (prepared in a Schlenk
glassware under an inert atmosphere) was added to a solution of 45
(100 mg, 0.269 mmol) and PTSA (5.1 mg, 0.027 mmol) in anhyd
degassed THF to reach a final concentration of 0.04 M. The auto-
clave was flushed three times with H2/CO (1:1). Then, the autoclave
was filled with 700 kPa of H2/CO (1:1) and was heated at 85 °C with
stirring for 12 h. The autoclave was cooled to r.t. and the gases were
slowly and carefully released. The reaction mixture was then con-
centrated under reduced pressure to give an oil. The residue was pu-
rified by flash chromatography (pentane–EtOAc, 30:70) to give 51
(58 mg, 56%) as a yellow waxy solid.
1H NMR (400 MHz, CDCl3): d = 6.87–6.78 (m, 4 H), 6.72 (d,
J = 8.1 Hz, 1 H), 5.72 (d, J = 7.3 Hz, 1 H), 5.64 (td, J = 7.5, 6.6 Hz,
1 H), 4.30 (br s, 1 H), 3.987 (s, 3 H), 3.85 (br s, 9 H), 3.50 (br s, 1
H), 3.19 (br d, J = 9.1 Hz, 1 H), 3.04 (br d, J = 6.7 Hz, 1 H), 2.91–
2.81 (m, 2 H).
SOCl2 (0.80 mL, 10.98 mmol) was added to a solution of 43 (1.433
g, 5.49 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred
at reflux for 2 h, cooled to r.t. and concentrated. In an ice bath, the
residue was dissolved in CH2Cl2 (10 mL), then Et3N (1.53 mL,
10.98 mmol) and 3,4-dimethoxyphenethylamine (1.39 mL, 8.23
mmol) were added. The mixture was stirred at r.t. for 12 h. Then, 1
M aq HCl (10 mL) was added and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. The residue was purified by
flash chromatography (pentane–EtOAc, 50:50) to give 44 as a yel-
low solid (1.951 g, 84%); mp 100–102 °C.
1H NMR (400 MHz, CDCl3): d = 7.22 (d, J = 8.7 Hz, 1 H), 6.81–
6.77 (m, 4 H), 5.76 (br t, J = 6.0 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 3
H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.72 (q, J = 6.5 Hz, 2 H), 2.89 (t,
J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 165.7, 152.4, 149.2, 147.8, 147.0,
134.2, 131.4, 128.2, 120.9, 114.3, 112.3, 111.6, 109.8, 62.2, 56.2,
56.1, 56.6, 41.2, 35.4.
13C NMR (100 MHz, CDCl3): d = 167.1, 152.0, 149.2, 149.0, 147.7,
138.1, 131.6, 129.6, 128.9, 121.4, 121.0, 120.7, 114.1, 112.4, 111.4,
62.0, 56.2, 56.0, 56.0, 49.9, 34.3, 30.7.
ESI-MS: m/z = 424 [M + H]+.
ESI-HMRS: m/z [M + H]+ calcd for C22H25NO5: 384.1811; found:
384.1816.
N-(3,4-Dimethoxyphenethyl)-2,3-dimethoxy-6-vinylbenzamide
(45)
Vinyltributylstannane (0.98 mL, 3.35 mmol) and Pd(PPh3)4 (52 mg,
0.04 mmol) were added to a solution of 44 in toluene (7 mL). The
reaction mixture was stirred under argon at 100 °C for 12 h. After
cooling, additional Pd(PPh3)4 (26 mg, 0.02 mmol) was added and
the mixture was stirred at 100 °C for 24 h. After cooling and con-
centration, the residue was purified by flash chromatography (pen-
tane–EtOAc, 50:50) to give 45 (375 mg, 90%); mp 117–119 °C.
2,3,9,10-Tetramethoxy-5,6,14,14a-tetrahydrobenzo-[5,6]azepi-
no[2,1-a]isoquinolin-8(13H)-one (49)
To a solution of compound 51 (58 mg, 0.15 mmol) in anhyd CH2Cl2
(4 mL) was added dropwise BF3·OEt2 (33 mL, 0.30 mmol) and the
reaction mixture was stirred at reflux for 12 h. After cooling, sat. aq
Na2CO3 (20 mL) was added and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. The residue was purified by
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 8.5 Hz, 1 H), 6.87 (d,
J = 8.5 Hz, 1 H), 6.83–6.73 (m, 3 H), 6.66 (dd, J = 17.4, 11.1 Hz, 1
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

2912
E. Airiau et al.
SPECIAL TOPIC
flash chromatography (pentane–EtOAc, 40:60) to give 49 (49 mg,
76%) as a white solid.
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated. The residue was
purified by flash chromatography (pentane–EtOAc, 30:70) to give
59 (538 mg, 93%, 70:30 E/Z) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 5.93 (ddt, J = 17.0, 10.3, 7.1 Hz,
1 H), 5.64 (br s, 1 H), 5.49–5.32 (m, 1 H), 5.29–5.12 (m, 3 H), 3.32–
3.17 (m, 2 H), 2.98 (dt, J = 7.2, 1.6 Hz, 2 H), 2.28–1.95 (m, 2 H),
1.60–1.43 (m, 2 H), 1.42–1.23 (m, 2 H), 0.03 to –0.05 (m, 9 H).
1H NMR (400 MHz, CDCl3): d = 6.94 (d, J = 8.2 Hz, 1 H), 6.89 (d,
J = 8.2 Hz, 1 H), 6.67 (s, 1 H), 6.45 (s, 1 H), 4.50 (dd, J = 9.5, 7.9
Hz, 1 H), 4.32 (ddd, J = 13.0, 6.3, 5.0 Hz, 1 H), 3.96 (s, 3 H), 3.88
(s, 3 H), 3.86 (s, 3 H), 3.77 (s, 3 H), 3.61 (ddd, J = 13.0, 8.3, 4.6 Hz,
1 H), 2.98–2.77 (m, 3 H), 2.71–2.65 (m, 1 H), 2.13–2.07 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 167.1, 152.4, 148.0, 147.8, 147.6,
130.4, 129.5, 127.7, 127.0, 123.2, 113.9, 111.5, 109.3, 62.0, 56.1,
56.0, 54.6, 38.1, 37.7, 30.0, 28.6.
13C NMR (100 MHz, CDCl3): d = 170.5, 131.7, 127.5, 127.2, 119.5,
41.7, 39.2, 30.2, 29.8, 22.7, –1.9.
ESI-HMRS: m/z [M + H]+ calcd for C22H26NO4: 384.4376; found:
ESI-HMRS: m/z [M + H]+ calcd for C13H25NOSi: 240.1784; found:
384.4372.
240.1782.
6-(Bromohex-2-enyl)trimethylsilane (56)
3-(6-Oxooctahydro-2H-quinolizin-1-yl)propanal (63)
To a solution of 5-bromopent-1-ene (55; 400 mg, 2.68 mmol) and
allyltrimethylsilane (2.14 mL, 13.42 mmol) in anhyd degassed
CH2Cl2 (14 mL) was added 2nd generation Grubbs catalyst (23 mg,
0.027 mmol). The reaction mixture was stirred at reflux for 12 h,
cooled to r.t., and concentrated. The residue was purified by flash
chromatography (pentane) to give 56 (509 mg, 81%, 70:30 E/Z) as
a colorless liquid; bp 97–99 °C/760 Torr.
1H NMR (400 MHz, CDCl3): d = 5.45–5.42 (m, 1 H), 5.31–5.14 (m,
1 H), 3.46–3.39 (m, 2 H), 2.26–2.11 (m, 2 H), 1.99–1.87 (m, 2 H)
1.24–1.30 (m, 2 H), 0.07–0.00 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 128.2, 126.5, 124.5, 123.3, 33.3,
33.0, 31.9, 31.2, 22.9, 22.8, 18.7, 18.0, –1.8, –1.5.
ESI-HMRS: m/z [M + H]+ calcd for C9H19BrSi: 235.0518; found:
235.0522.
In a stainless steel autoclave under an inert atmosphere, a solution
of Rh(CO)2acac (1.3 mg, 0.005 mmol) and biphephos (7.6 mg,
0.010 mmol) in anhyd degassed MeCN (3 mL) (prepared in a
Schlenk glassware under an inert atmosphere) was added to a solu-
tion of 59 (58 mg, 0.242 mmol), camphorsulfonic acid (56 mg,
0.242 mmol) and few 4 Å molecular sieves in anhyd degassed
MeCN (3 mL). The autoclave was flushed three times with H2/CO
(1:1). Then, the autoclave was filled with 500 kPa of H2/CO (1:1)
and was heated at 70 °C with stirring for 12 h. The autoclave was
cooled to r.t. and the gases were slowly and carefully released. The
reaction mixture was then concentrated under reduced pressure to
give an oil. The residue was purified by flash chromatography
(EtOAc–MeOH, 90:10) to give 63 (36 mg, 78%) as a colorless oil.
trans-Isomer
1H NMR (400 MHz, CDCl3): d = 9.78 (t, J = 1.4 Hz, 1 H), 4.81 (ddt,
J = 13.1, 4.2, 2.1 Hz, 1 H), 2.98 (ddd, J = 9.4, 8.0, 5.8 Hz, 1 H),
2.55–2.33 (m, 3 H), 2.30–2.21 (m, 2 H), 2.15–2.08 (m, 1 H), 1.95–
1.73 (m, 3 H), 1.72–1.66 (m, 1 H), 1.60 (m, 2 H), 1.44–1.26 (m, 3
H), 1.16–1.02 (m, 1 H).
6-(Azidohex-2-enyl)trimethysilane (57)
To a solution of 56 (187 mg, 0.80 mmol) in anhyd DMF (10 mL)
was added NaN3 (155 mg, 2.39 mmol). The mixture was stirred 5 h
at 70 °C, then diluted with H2O (20 mL). The aqueous layer was ex-
tracted with Et2O (3 × 20 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated to give 57 as a colorless
oil (122 mg, 78%, 70:30 E/Z), which was used without further puri-
fication.
13C NMR (100 MHz, CDCl3): d = 201.8, 169.4, 61.3, 42.7, 42.1,
40.8, 32.9, 30.2, 27.6, 25.0, 24.0, 19.0.
ESI-HMRS: m/z [M + H]+ calcd for C12H19NO2: 210.1794; found:
210.1789.
IR (neat): 2954, 2094, 1246, 854 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.62–5.42 (m, 1 H), 5.30–5.18 (m,
1 H), 3.26 (q, J = 6.9 Hz, 2 H), 2.35–2.26 (m, 1.5 H), 2.12–2.05 (m,
0.5 H), 1.70–1.41 (m, 4 H), 0.06 to –0.02 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 127.9, 127.0, 124.5, 123.3, 51.2,
50.9, 29.9, 29.2, 22.9, 22.8, 18.6, 17.9, –1.8, –1.6.
9-Vinyloctahydro-4H-quinolizin-4-one (62)
In a stainless steel autoclave under an inert atmosphere, a solution
of Rh(CO)2acac (1.2 mg, 0.004 mmol) and biphephos (10.5 mg,
0.013 mmol) in anhyd degassed MeCN (7 mL) (prepared in a
Schlenk glassware under an inert atmosphere) was added to a solu-
tion of 59 (107 mg, 0.446 mmol) in anhyd degassed MeCN (7 mL).
The autoclave was flushed three times with H2/CO (1:1). Then, the
autoclave was filled with 500 kPa of H2/CO (1:1) and heated at
65 °C with stirring for 6 h. The autoclave was cooled to r.t. and the
gases were slowly and carefully released. After degassing with ar-
gon, camphorsulfonic acid (56 mg, 0.242 mmol) was added and the
reaction mixture was stirred at 65 °C for 4 h. After cooling, the mix-
ture was then concentrated under reduced pressure to give an oil.
The residue was purified by flash chromatography (EtOAc–MeOH,
95:5) to give 62 (52 mg, 65%) as a colorless oil.
6-(Trimethylsilyl)hex-4-en-1-amine (58)
To a solution of 57 (321 mg, 1.63 mmol) in anhyd Et2O (10 mL) was
added LiAlH4 (123 mg, 3.25 mmol) under argon at 0 °C. The solu-
tion was allowed to warm to r.t. and stirred for 3 h, then quenched
by the addition of H2O (120 mL), 15% aq NaOH (120 mL), and then
H2O (370 mL). The suspension was stirred for 1 h, then filtered over
a Celite pad and concentrated to give 58 as a colorless oil (251 mg,
90%, 70:30 E/Z), which was used without further purification.
1H NMR (400 MHz, CDCl3): d = 5.57–5.33 (m, 1 H), 5.31–5.13 (m,
1 H), 2.79–2.63 (m, 2 H), 2.22–2.08 (m, 1 H), 1.58–1.33 (m, 2 H),
0.07 to –0.02 (m, 9 H).
trans-Isomer
1H NMR (400 MHz, CDCl3): d = 5.51 (ddd, J = 17.1, 10.2, 8.9 Hz,
1 H), 5.04–4.95 (m, 2 H), 4.77–4.70 (dm, J = 13.0 Hz, 1 H), 2.96
(dddd, J = 10.3, 7.4, 5.8 Hz, 1 H), 2.37–2.17 (m, 3 H), 1.95–1.84
(m, 2 H), 1.75–1.60 (m, 3 H), 1.56–1.26 (m, 4 H).
N-[6-(Trimethylsilyl)hex-4-enyl]but-3-enamide (59)
But-3-enoic acid (0.27 mL, 3.15 mmol) was added to a solution of
58 (415 mg, 2.42 mmol) in anhyd CH2Cl2 (10 mL) in an ice bath.
Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (604 mg, 3.15 mmol) and 1-hydroxybenzotriazole hydrate (65
mg, 0.48 mmol) were added and the solution was stirred at r.t. for
12 h. Sat. aq NaHCO3 (20 mL) was added and the aqueous layer was
13C NMR (100 MHz, CDCl3): d = 139.7, 116.3, 60.3, 48.7, 42.7,
33.1, 32.1, 29.8, 28.1, 24.9, 18.8.
ESI-HMRS: m/z [M + H]+ calcd for C11H17NO: 180.1388; found:
180.1388.
Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York

SPECIAL TOPIC
Microwaves or Conventional Heating for Domino Hydroformylation Reaction?
2913
trans-6-Oxooctahydro-2H-quinolizine-1-carbaldehyde (64)
To a solution of 62 (82 mg, 0.46 mmol) in anhyd CH2Cl2 (5 mL) and
anhyd MeOH (2 mL) under argon at –78 °C was bubbled a stream
of ozone until a light blue color was observed (saturation of O3).
The solution was flushed successively with O2 and argon. Ph3P (132
mg, 0.50 mmol) was added and the reaction mixture was allowed to
reach r.t. and stirred for 4 h. The solvents were removed under re-
duced pressure and the residue was purified by column chromatog-
raphy (EtOAc–MeOH, 98:2) to yield 64 (83 mg, 76%) as a colorless
oil.
1H NMR (400 MHz, CDCl3): d = 9.60 (d, J = 2.8 Hz, 1 H), 4.82–
4.77 (m, 1 H), 3.50 (ddd, J = 10.4, 8.0, 5.5 Hz, 1 H), 2.42–2.24 (m,
4 H), 2.13–2.06 (m, 1 H), 2.03–1.98 (m, 1 H), 1.80–1.73 (m, 2 H),
1.68–1.57 (m, 1 H), 1.53–1.39 (m, 3 H).
(6) http://www.cem.com/page163.html.
(7) http://www.anton-paar.com/001/en/60/262.
(8) Petricci, E.; Mann, A.; Salvadori, J.; Taddei, M. Tetrahedron
Lett. 2007, 48, 8501.
(9) In a 10 mL vial, the gas present under the reaction conditions
is roughly 3 mmol for 1 mmol of substrate.
(10) (a) Dübon, P.; Farwick, A.; Helmchen, G. Synlett 2009,
1413. (b) Kemme, S. T.; Smejkal, T.; Breit, B. Adv. Synth.
Catal. 2008, 350, 989. (c) Chiou, W.-H.; Mizutani, N.;
Ojima, I. J. Org. Chem. 2007, 72, 1871. (d) Padwa, A.; Bur,
S. C. Tetrahedron 2007, 63, 5341. (e) Teoh, E.; Campi, E.
M.; Jackson, W. R.; Robinson, A. J. Chem. Commun. 2002,
978. (f) Hoffmann, R. W.; Brückner, D.; Gerusz, V. J.
Heterocycles 2000, 52, 121. (g) Bergmann, D. J.; Campi, E.
M.; Jackson, W. R.; Patti, A. F. Chem. Commun. 1999,
1279. (h) Eilbracht, P.; Rzychon, L. B.; Kranemann, C. L.;
Rische, T.; Roggenbuck, R.; Schmidt, A. Chem. Rev. 1999,
99, 3329. (i) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J.
Org. Chem. 1995, 60, 7078.
13C NMR (100 MHz, CDCl3): d = 201.7, 169.7, 55.9, 55.4, 41.9,
32.8, 28.2, 25.5, 23.9, 18.7.
ESI-HMRS: m/z [M + H]+ calcd for C10H15NO2: 182.1181; found:
182.1183
(11) (a) Schmidt, B.; Biernat, A. Synlett 2007, 2375.
(b) Morinaka, B. I.; Skepper, C. K.; Molinski, T. F. Org.
Lett. 2007, 9, 1975.
((1R*,9aS*)-Octahydro-1H-quinolizin-1-yl)methanol [( )-Epi-
lupinine, 65]
(12) (a) da Silva, J. G.; Barros, H. J. V.; dos Santos, E. N.;
Gusevskaya, E. V. Appl. Catal., A 2006, 309, 169.
(b) Nozaki, K.; Li, W.-G.; Horiuchi, T.; Takaya, H.
Tetrahedron Lett. 1997, 38, 4611. (c) For stereoselective
hydroformylation of allylic alcohol derivatives, see: Breit,
B. Acc. Chem. Res. 2003, 36, 264.
(13) Heretsch, P.; Rabe, S.; Giannis, A. Org. Lett. 2009, 11, 5410.
(14) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A.
J. Am. Chem. Soc. 1999, 121, 12208.
To a solution of 64 (63 mg, 0.35 mmol) in anhyd THF (6 mL) under
argon at 0 °C was added LiAlH4 (66 mg, 1.74 mmol). The solution
was stirred at reflux for 5 h, then quenched by the addition of H2O
(65 mL), aq 15% NaOH (65 mL), and then H2O (130 mL). The sus-
pension was stirred for 1 h, then filtered over a Celite pad and con-
centrated. The residue was purified by flash chromatography [Et2O
(saturated with NH3)–MeOH, 70:30] to give 65 (41 mg, 70%) as a
white solid; mp 78–80 °C.
1H NMR (400 MHz, CDCl3): d = 3.63 (d, J = 10.9, 3.7 Hz, 1 H),
3.51 (dd, J = 10.9, 5.9 Hz, 1 H), 2.48 (br s, 1 H), 2.83–2.73 (m, 2
H), 2.04–1.96 (m, 2 H), 1.90–1.80 (m, 2 H), 1.77–1.73 (m, 1 H),
1.70–1.63 (m, 3 H), 1.61–1.55 (m, 2 H), 1.42–1.35 (m, 1 H), 1.25–
1.14 (m, 3 H).
(15) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54,
9913.
(16) Boukouvalas, J.; Radu, I.-I. Tetrahedron Lett. 2007, 48,
2971.
(17) (a) D’Aniello, F.; Taddei, M. J. Org. Chem. 1992, 57, 5247.
(b) D’Aniello, F.; Mattii, D.; Taddei, M. Synlett 1993, 119.
(18) Giannis, A.; Heretsch, P.; Sarli, V.; Stößel, A. Angew. Chem.
Int. Ed. 2009, 48, 7911.
13C NMR (100 MHz, CDCl3): d = 64.50, 64.49, 57.0, 56.7, 44.0,
29.8, 28.4, 25.6, 25.1, 24.6.
ESI-HMRS: m/z [M + H]+ calcd for C10H19NO: 170.1545; found:
(19) For some recent literature, see: (a) Airiau, E.; Spangenberg,
T.; Girard, N.; Breit, B.; Mann, A. Org. Lett. 2010, 12, 528.
(b) Spangenberg, T.; Breit, B.; Mann, A. Org. Lett. 2009, 11,
261. (c) Spangenberg, T.; Airiau, E.; BuiTheThuong, M.;
Donnard, M.; Billet, M.; Mann, A. Synlett 2008, 2859.
(d) Vieira, T. O.; Alper, H. Chem. Commun. 2007, 2710.
(e) Wittmann, K.; Wisniewski, W.; Mynott, R.; Leitner, W.;
Kranemann, C. L.; Rische, T.; Eilbracht, P.; Sander, S.;
Ernsting, J. M. Chem. Eur. J. 2001, 7, 4584.
170.1548.
Acknowledgment
This work was supported by the Ministère délégué à l’Enseigne-
ment Supérieur et à la Recherche (EA). Financial support from
CEM Italy (Bergamo) is also acknowledged.
(20) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104,
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Synthesis 2010, No. 17, 2901–2914 © Thieme Stuttgart · New York