Microwave-assisted domino hydroformylation without syngas

Article abstract of DOI:10.1055/s-0030-1259281

Hydroformylation is a powerful reaction that has suffered for some negative prejudices related to the use of gaseous H₂ and CO. Now it is possible to carry out hydroformylation and different cyclohydrocarbonylations, even on complex substrates, using aqueous formalin as H₂ and CO surrogate in few minutes under microwave irradiation. The catalytic system developed by Morimoto (Rh/BINAP for decomposition of formaldehyde and Rh/Xantphos for hydroformylation) is compatible with microwave dielectric heating and with complex substrates containing ligand atoms allowing rapid domino hydroformylation cyclization reactions without using the external supply of gaseous H₂ and CO (gas cylinder) and without any particular safety limitation or device. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259281

LETTER
199
Microwave-Assisted Domino Hydroformylation without Syngas
M
icrowave-Ass
l
iste
d
D
e
omino Hyd
n
roformylatio
a
n
Cini,a Etienne Airiau,b Nicolas Girard,b André Mann,b Jessica Salvadori,a Maurizio Taddei*a
a
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
Fax +39(0577)234333; E-mail: taddei.m@unisi.it
Laboratoire d’Innovation Thérapeutique, UMR 7200 CNRS-Université de Strasbourg, Faculté de Pharmacie,
74 route du Rhin, 67401 Illkirch, France
b
Received 15 October 2010
perature and atmospheric syngas pressure6 or the applica-
tion of microwave dielectric heating to reduce the reaction
time.7 However, in any case, the use of syngas is required
still limiting the friendliness of the process. Recently,
Abstract: Hydroformylation is a powerful reaction that has suf-
fered for some negative prejudices related to the use of gaseous H2
and CO. Now it is possible to carry out hydroformylation and dif-
ferent cyclohydrocarbonylations, even on complex substrates, using
aqueous formalin as H2 and CO surrogate in few minutes under mi- Morimoto and co-workers reported the results of a highly
crowave irradiation. The catalytic system developed by Morimoto
selective hydroformylation of terminal alkenes using
formaldehyde as a substitute of syngas.8 While Rh(I)
(Rh/BINAP for decomposition of formaldehyde and Rh/Xantphos
for hydroformylation) is compatible with microwave dielectric
BINAP catalyzes the decomposition of formaldehyde into
heating and with complex substrates containing ligand atoms allow-
CO and H2, Rh(I)Xantphos catalyzes the further hydro-
ing rapid domino hydroformylation cyclization reactions without
formylation. The reaction was described on some simple
linear alkenes giving, after 20 hours at 90 °C, the corre-
sponding aldehydes in good yields. This procedure at-
tracted immediately our attention by its simplicity.9,10 By
the way, if these conditions would be widely applicable,
hydroformylation could be usable by everybody without
practical limitations. As it was not obvious that the cata-
lytic system Rh(I)/BINAP/Xantphos could be applied to
substrates that contains coordinative functional groups,
we decided to investigate the application of the procedure
to domino cyclohydrocarbonylation using also micro-
wave dielectric heating to speed up the process and let it
even more affordable. At first, we wanted to verify if the
system formaldehyde/Rh(I) complex could be used as a
syngas substituted under microwave dielectric heating.
using the external supply of gaseous H2 and CO (gas cylinder) and
without any particular safety limitation or device.
Key words: microwaves, hydroformylation, homogeneous cataly-
sis, domino reactions
Hydroformylation of alkenes is a perfect example of effi-
cient C–C bond formation in an atom economical fash-
ion.1 This reaction, via an hydrometallation, introduces an
aldehyde onto a double bond, providing a new functional
group suitable for additional transformations. Tons of al-
dehydes are produced every year by hydroformylation
making it the largest applied process in homogeneous ca-
talysis.2 Recently, the design of ligands with improved
chemo- and regioselectivity has given a new glance to the
hydoformylation of olefins. Not only the linear/branched
ratio is now under control but even the presence of func-
tional groups on the alkene substrate is well tolerated.
Consequently, the application of hydroformylation in
domino processes has been exploited as a strategy to pre-
pare many heterocycles.3,4 Despite the above-mentioned
improvements, the potential of the hydroformylation reac-
tion is still under-utilized by the community of organic
chemists in the design of synthetic sequences. The use of
gaseous H2 and CO (the so called syngas) at high pressure
(5–80 bar) and temperature (60–120 °C) for long reaction
times (12–36 h) requires special devices such as stainless-
steel autoclaves. Moreover, a dedicated safety laboratory
is mandatory for the management of high-pressure gas.5
These facilities, not always available especially in aca-
demia, are the main obstacles to the diffusion of hydro-
formylation into organic and medicinal chemistry
Table 1 Microwave-Assisted Formalin-Based Hydroformylation of
Terminal Alkenes
HCHOaq [RhCl(cod)]2, BINAP, Xantphos
toluene, MW, 90 °C, 30 min
CHO
R
R
1–3
4–6
Entry Alkenea
Aldehyde
Yield (%)b
(l/b ratio)c
1
2
3
1 R = C6H13
4 R = C6H13
5 R = Bn
90 (98:2)
87 (95:5)
92 (98:2)
2 R = Bn
3 R = PMBO(CH2)2
6 R = PMBO(CH2)2
a Reaction conditions: alkene (1 mmol), formalin (0.5 mL),
[RhCl(cod)]2 (0.01 mmol), BINAP (0.02 mmol), Xantphos (0.02
mmol), toluene (5 mL) sealed vial, MW, 150 W (value previously set-
tled on the microwave oven), max internal pressure recorded 1.06·106
research laboratories. Recent improvements have been the Pa, 90 °C, 30 min.
b Yield of isolated and fully characterized products.
development of efficient catalysts to work at room tem-
c Linear/branched aldehyde ratio determined by integration of the al-
dehyde peaks in the 1H NMR spectra of the crude reaction mixture.
SYNLETT 2011, No. 2, pp 0199–0202
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x.
x
x.
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Advanced online publication: 23.12.2010
DOI: 10.1055/s-0030-1259281; Art ID: G31110ST
© Georg Thieme Verlag Stuttgart · New York

200
E. Cini et al.
LETTER
Thus 1-octene 1 was submitted to reaction with formalin as the combination of Biphephos and syngas
(37% aq fomaldehyde) in toluene with [RhCl(cod)]2 in the demonstrated a real benefit for the formation of 8 (entry
presence of the two ligands BINAP and Xantphos (entry 4). Unfortunately, the hydroformylation of 7 with forma-
1, Table 1). After heating at 90 °C for 30 minutes, we ob- lin did not proceed with Biphephos and BINAP as part-
served a conversion of 95% and nonanal 4 was isolated in ners (entry 5). These preliminary experiments
90% yield. The analysis of the crude showed the presence demonstrate that the reaction conditions have to be care-
of less than 2% of the branched aldehyde. The same con- fully controlled in order to favor the hydroformylation
ditions were applied to other linear alkenes with good re- over the side reactions. Changing the solvent for EtOH
sults (entries 2 and 3, Table 1).
(entry 7) or THF (entry 8) did not afford better results.
When Biphep (for formalin decomposition) and Nixant-
phos (for hydroformylation) were associated to Rh(I), the
conversion to 8 in terms of selectivity and yield was im-
proved (entries 9 and 10).8 Lowering the temperature and
increasing the reaction time is beneficial for the produc-
tion of cyclocondensed 8. The time saving by using mi-
crowaves instead of traditional heating is demonstrated
comparing entries 10 and 11. An attempt to use paraform-
aldehyde as syngas source,8 was unsuccessful giving a
complex mixture of byproducts (entry 12). Our results
demonstrate that the association of Rh(I), Biphep, Nixant-
phos, and formalin (Morimoto’s conditions) could be a
suitable substitute for syngas in domino hydroformylation
assisted by microwave heating. It is worth noting that, in
this case, only trans-8 was isolated (entries 9–11), where-
as under the previous settled conditions (entry 4),11 a 4:1
Encouraged by these results, we decided to apply the for-
malin-based hydroformylation to compound 7, a substrate
known to undergo domino hydroformylation–cyclization
reaction.11 b,g-Unsaturated amides are known to be prone
to double-bound isomerization and conjugation with the
carbonyl. Results of the investigation are reported in
Table 2. Applied to substrate 7, the standard conditions
[BINAP, Xantphos, and Rh(I)] gave an excellent conver-
sion (entry 1). Three compounds were formed, the major
adduct was the expected cyclized product 8 together with
the acrylamide 9 resulting from the double-bound isomer-
ization and the reduced compound 10. Increasing the re-
action time (entry 2) produced few changes in the product
distribution. These results are comparable to the tradition-
al conditions using syngas and Xantphos (entry 3), where-
Table 2 Optimization of MW-Assisted Domino Formalin-Based Hydroformylation
O
O
N
NH
O
O
NH
NH
O
+
+
OH
OH
OH
7
8
9
10
Entry
Catalyst, ligands/Source of CO/H2
Reaction conditions
Products (%)a
1
2
[RhCl(cod)]2, BINAP, Xantphos/formalin
[RhCl(cod)]2, BINAP, Xantphos/formalin
[RhCl(cod)]2, Xantphos/syngas
toluene, MW, 90 °C, 30 min
toluene, MW, 90 °C, 90 min
toluene, MW, 90 °C, 90 min
toluene, MW, 90 °C, PTSA, 90 min
toluene, MW, 90 °C, PTSA. 90 min
toluene, MW, 130 °C, 30 min
EtOH, MW, 130 °C, 30 min
THF, MW, 130 °C, 30 min
8 (55); 9 (28); 10 (17)
8 (60); 9 (27); 10 (13)
8 (45); 9 (30); 10 (10)b
8 (91);c 9 (5); 10 (4)
8 (<2); 9 (48); 10 (35)b
8 (67); 9 (15); 10 (18)
8 (41); 9 (3); 10 (46)b
8 (58); 9 (30); 10 (12)
8 (76); 9 (14); 10 (10)
8 (89);d 9 (7); 10 (4)
3
4
Rh(CO)2acac, Biphephos/syngas
5
Rh(CO)2acac, BINAP, Biphephos/formalin
[RhCl(cod)]2, BINAP, Xantphos/formalin
[RhCl(cod)]2, BINAP, Xantphos/formalin
[RhCl(cod)]2, BINAP, Xantphos/formalin
6
7
8
9
[RhCl(cod)]2, BIPHEP, Nixantphos/formalin
[RhCl(cod)]2, BIPHEP, Nixantphos/formalin
[RhCl(cod)]2, BIPHEP, Nixantphos/formalin
toluene, MW, 130 °C, 30 min
toluene, MW, 90 °C, 30 min
toluene, oil bath, 90 °C, 20 h
10
11
12
8 (84);e 9 (9); 10 (2) + sm
f
[RhCl(cod)]2, BIPHEP, Nixantphos/paraformaldhyde toluene, MW, 90 °C, 90 min
a Ratio determined by 1H NMR analysis of the crude reaction mixture.
b Additional byproducts isolated.
c Compound 8 was isolated in 83% yield after column chromatography as a 4:1 mixture of trans/cis isomers.
d Compound 8 isolated in 80% yield after column chromatography as a single trans isomer.
e Compound 8 isolated in 78% yield after column chromatography as a single trans isomer.
f Complex mixture of byproducts.
Synlett 2011, No. 2, 199–202 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Domino Hydroformylation
201
mixture of trans/cis diastereomers was formed. In order to
demonstrate the scope of the process, various terminal
olefins 11–19 were submitted to the above-optimized
reaction conditions, {RhCl(cod)]2, BIPHEP, Nixantphos,
toluene, MW, 90 °C, 30 min} and the results are collected
in Table 3.12,13
Table 3 Scope of the MW-Assisted Domino Formalin-Based
Hydroformylation Cyclization Reaction
Entry Starting material
Producta
Yield (%)b
O
N
1
2
O
NH
79c
O
The domino hydroformylation occurred always with good
to acceptable yields demonstrating the wide scope of the
process. In entries 1–3 of Table 3, the chiral amides 11–13
gave the corresponding oxazolidinones 20–22 in good to
moderate yields via transient acyliminium. It is worth not-
ing that compound 13 derived from methionine, gave low
yield of 22 (entry 3 in Table 3) due to persistance of unre-
acted starting material. As in the case of PTSA, (entry 5 in
Table 1) the pH variation decreases the efficiency of the
process (probably due to formaldehyde decomposition).
Interestingly, olefin 14 afforded bicyclic adehyde 23 after
an intramolecular Mannich reaction (entry 4). As expect-
ed, the allyl or homoallylic alcohols 15–18 gave the cor-
responding lactols 24–27 (entries 5–7) in good yields. In
the last case, only one of the two possible cyclizations oc-
curred, even increasing the reaction time. However, an
analogous result was obtained using syngas under micro-
wave dielectric heating.
OH
Ph
Ph
11
20
64c
O
N
O
NH
O
OH
MeOOC
MeOOC
12
21
O
N
O
O
O
NH
3
4
35c
OH
O
MeS
MeS
13
22
CHO
56e
O
NH
O
N
O
Finally, homoallylamine 19 gave internal enamide 28 in
moderate yield (entry 8).7a
Ph
Ph
14
R
23
In conclusion we have demonstrated that the system of
formalin/Rh(I)/BIPHEP/Nixantphos (or BINAP/Xant-
phos), assisted by microwave heating can be successfully
applied for hydroformylation of complex substrates de-
signed for domino processes. In our opinion, most of the
negative prejudices attached to the hydroformylation
reaction are relieved by the use of formalin in place of
syngas, and the community of organic and medicinal
chemists may now consider the implementation of the hy-
droformylation reaction in a synthetic plan as easy as the
Suzuki, Heck, or metathesis reactions.
24 85d
25 76d
R
OH
5
6
OH
24 R = Bu
25 R = Ph
15 R = Bu
16 R = Ph
OH
OH
76
OH
O
17
18
26
OH
O
7
8
78e
OHC
Acknowledgment
3
OH
OH
The authors thank Sigma-tau Pharmaceuticals Inc. (Pomezia,
Rome, Italy) for financial support.
27
65
Ph
N
Reference and Notes
Ph
NHCbz
Cbz
19
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11, 820. (b) Breit, B. Topics Curr. Chem. 2007, 279, 139.
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28
a Reaction conditions: alkene (1 mmol), formalin (0.5 mL),
[RhCl(cod]2] (0.01 mmol), BIPHEP (0.02 mmol), Nixantphos (0.02
mmol), toluene (5 mL) sealed vial, MW, 150 W (value previously set-
tled on the microwave oven), max internal pressure recorded 1.06·106
Pa, 90 °C, 30 min.
b Yield of isolated and fully characterized products.
c Diasteromeric ratio (dr) > 98:2.
d dr = 50:50.
e dr = 75:25 (relative configuration not defined).
Synlett 2011, No. 2, 199–202 © Thieme Stuttgart · New York

202
E. Cini et al.
LETTER
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Chemin, C.; Girard, N.; Lonzi, G.; Mann, A.; Petricci, E.;
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(11) Airiau, E.; Girard, N.; Mann, A.; Salvadori, J.; Taddei, M.
Org. Lett. 2009, 11, 5314.
(12) Domino hydroformylation of compounds 11–13 was
described in: Airiau, E.; Spangenberg, T.; Girard, N.;
Schoenfelder, A.; Salvadori, J.; Taddei, M.; Mann, A. Chem.
Eur. J. 2008, 14, 10938.
(13) (3S,8aR)-3-Phenylhexahydro-5H-[1,3]oxazolo[3,2-a]-
pyridin-5-one (20) – General Procedure
A MW vessel was charged with [RhCl(cod)]2 (2.5 mg, 0.005
mmol), BIPHEP (5.2 mg, 0.01 mmol), and Nixantphos (5.5
mg, 0.01 mmol) under nitrogen (the reaction was carried out
without degassing the solution, an experiment done on a
degassed solution, gave comparable results). After adding
toluene (3 mL), alkene 11 (103 mg, 0.5 mmol), and formalin
(37%, 205 mL, 2.5 mmol), the mixture was heated for 30
min at 90 °C by microwave irradiation at 250 W (value
previously settled on the microwave oven, model Discover
from CEM). The solvent was removed in vacuo and the
product purified by column cromatography (eluent hexane–
EtOAc, 4:1) and isolated as a waxy material (85 mg, 79%
yield, dr > 98:2). Characterization as in ref. 12. Compounds
24–26 were described in ref. 7d and compound 28 in ref. 5.
New compounds isolated in this work:
(8) Makado, G.; Morimoto, T.; Sugimoto, Y.; Tsutsumi, K.;
Kagawa, N.; Kakiuchia, K. Adv. Synth. Catal. 2010, 352,
299.
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hydroformylation: (a) Smejkal, T.; Han, H.; Breit, B.;
Krische, M. J. J. Am. Chem. Soc. 2009, 131, 10366.
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55, 1286.
1-Oxaspiro[4.5]decan-2-ol (26)
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 = 100.7, 89.9, 38.7, 35.5, 34.4, 32.2,
25.8, 23.7). ESI-LRMS: m/z = 179 [M + Na]+, 157 [M + H]+.
5-Hydroxy-5-(6-hydroxytetrahydro-2H-pyran-2-yl)-
pentanal (27)
1H NMR (400 MHz, CDCl3): d = 9.77 (s, 1 Ha), 9.74 (t, J =
1.6 Hz, 1 Hb), 5.48 (s, 1 Ha, 1 Hb), 4.07–4.02 (m, 2 Ha, 2 Hb),
2.54–2.50 (m, 2 Ha), 2.48–2.44 (m, 2 Hb), 1.88–1.45 (m, 10
Ha, 10 Hb). 13C NMR (100 MHz, CDCl3): d = 201.9, 102.1,
101.4, 78.8, 78.1, 43.2, 34.3, 30.5, 29.8, 28.0, 27.3, 23.9,
19.2, 17.7. ESI-LRMS: m/z = 257 [M + MeOH + Na]+.
(10) Degradation of formaldehyde in carbonylation reactions:
(a) Morimoto, T.; Yamasaki, K.; Hirano, A.; Tsutsumi, K.;
Kagawa, N.; Kakiuchi, K.; Harada, Y.; Fukumoto, Y.;
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