Diastereoselective synthesis of hexahydropyrrolo [2, 1-b]oxazoles by a rhodium-catalyzed hydroformylation/silica-promoted deformylation sequence

Article abstract of DOI:10.1002/anie.200802550

Fleetingly formyl: A new rhodium-catalyzed hydroformylation reaction of N-allyl oxazolidines, carried out under a CO/H2 atmosphere, followed by a diastereoselective deformylative cyclization affords hexahydropyrrolo[2,1-b] oxazoles in good yields. The rea

Full text of DOI:10.1002/anie.200802550

Angewandte
Chemie
DOI: 10.1002/anie.200802550
Asymmetric Synthesis
Diastereoselective Synthesis of Hexahydropyrrolo[2,1-b]oxazoles by a
Rhodium-Catalyzed Hydroformylation/Silica-Promoted
Deformylation Sequence**
Maxym Vasylyev and Howard Alper*
Iminium cations are intermediates in many synthetically
important reactions, such as the Mannich,[1] Leuckart-Wal-
lach,[2] Strecker,[3] and Vilsmeier–Haack[4] reactions to name
just a few, which lead to formation of carbon–carbon bonds.
Moreover, the ability of iminium cations to be generated at
mild “physiological” conditions is widely employed in nature
for the biosynthesis of a range of nitrogen-containing
secondary metabolites (alkaloids).[5] Although the iminium
cations are usually formed from a secondary amine and an
aldehyde, an oxazolidine heterocycle can be considered a
masked equivalent of an iminium cation. This property of
oxazolidines has been successfully utilized for the synthesis of
a variety of naturally occurring and synthetic pyrrolidine and
piperidine derivatives.[6]
Herein, we report the novel synthesis of hexa-
hydropyrrolo[2,1-b]oxazoles 2a–h. This reaction proceeds
diastereoselectively through a unique hydroformylation–
deformylation pathway, involving the formation of a 1,3-
oxazetidinium intermediate by addition of a carbonyl group
nate) and 2 mol% xantphos ligand (xantphos = 9,9-dimethyl-
4,5-bis(diphenylphosphino)xanthene) as the catalyst system,
in toluene at 808C under 25 atm carbon monoxide and 5 atm
hydrogen gas, gave the reaction product in only 21% yield.
The product, according to the spectral data, appeared to
be (3R,7aS)-3-phenylhexahydropyrrolo[2,1-b]oxazole[8] 2a
(Table 1, entry 1). Surprisingly, no carbonyl group was
incorporated into the product molecule, and the reaction
resembled hydroalkylation of the allylic double bond.
Table 1: Reaction of 1a under carbonylative conditions.
À
À
to the iminium cation originated from the {N CH2 O}
fragment of the oxazolidine heterocycle.
We recently demonstrated that N-(ethoxycarboxymeth-
yl)oxazolidines, when subjected to carbonylation, undergo
intramolecular reductive ring expansion, presumably by
nucleophilic attack of the oxygen atom of the oxazolidine
ring at the carbon atom of the ester functional group.[7] The
initial aim of our research was to investigate whether we could
utilize the nucleophilicity of the oxazolidine oxygen atom in
reactions with electrophiles other than a carboxylic group. We
prepared a range of substituted chiral N-allyl oxazolidines
1a–h [Eq. (1)]. We envisioned that, upon introduction of the
electrophilic functional group (formyl) by modification of the
allylic fragment, the reaction intermediate would be subject
to intramolecular attack by the oxygen atom of the oxazoli-
dine ring.
Entry Catalyst, [mol%] Ligand L,
[mol%]
CO
[atm]
H2
t
Yield
[atm] [8C] [%][a]
1
[Rh(CO)2(acac)], xantphos, 2 25
5
–
80 21
0.5
[b]
2
[Rh(CO)2(acac)], xantphos, 2 25
80
–
0.5
3
[Rh(CO)2(acac)], xantphos, 8 25
10
10
10
10
10
70 43
70 71
70 87
2
4
[Rh(CO)2(acac)], xantphos, 20 25
5
5[c]
6
[Rh(CO)2(acac)], xantphos, 20 25
5
[b]
[Rh(CO)2(acac)], dppm, 20
5
25
70
–
7
[{Rh(CO)2Cl}2], xantphos, 20 25
5
70 39
Applying hydroformylation conditions to model substrate
1a with 0.5 mol% of [Rh(CO)2(acac)] (acac = acetylaceto-
[a] Yield of isolated product after purification by column chromatography
on SiO2. [b] No reaction occurred; starting material was recovered.
[c] THF was used as the solvent. acac=acetylacetonate; xantphos=9,9-
[*] Dr. M. Vasylyev, Prof. Dr. H. Alper
Centre for Catalysis Research and Innovation
Department of Chemistry, University of Ottawa
10 Marie Curie, Ottawa, Ontario, K1N 6N5 (Canada)
Fax: (+1)613-562-5871
dimethyl-4,5-bis(diphenylphosphino)xanthene;
phosphino)methane.
dppm=bis(diphenyl-
To optimize the reaction conditions, we increased the
amount of [Rh(CO)2(acac)] to 5 mol% and the amount of the
xantphos ligand up to 20 mol%; at the same time, we
decreased the temperature of the reaction from 80 to 708C
and changed the carbon monoxide/hydrogen gas ratio. As a
E-mail: howard.alper@uottawa.ca
[**] We are grateful to the Natural Sciences and Engineering Research
Council of Canada for support of the research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802550.
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result, the performance of the reaction was improved
reaction is slower than the hydroformylation step. An attempt
to isolate resulted in the formation of (3R,7aS)-3-
(Table 1, entries 3 and 4). Switching the solvent to THF
improved the reactivity even further, providing 2a in 87%
yield (Table 1, entry 5).
5
phenylhexahydropyrrolo[2,1-b]oxazole 2a solely, suggesting
that cyclization was induced by contact with silica used for the
chromatographic separation.[10] Therefore, although hydro-
formylation did take place, the subsequent cyclization reac-
tion was accompanied by decarbonylation.
Even though the reaction does not seem to involve a
hydroformylation process, our attempts to apply Ir and Pd
complexes as the catalysts, as well as the use of bis(diphenyl-
phosphino)methane (dppm) as a ligand (Table 1, entry 6)
resulted in quantitative recovery of the starting material 1a.
The use of [{Rh(CO)2Cl}2] as a source of the rhodium metal
proved to be less efficient than [Rh(CO)2(acac)] and led to a
lower yield of 2a (Table 1, entry 7).
With the optimized conditions in hand, we examined the
scope of the cyclization reaction of N-allyl oxazolidines 1a–h.
The cyclization reaction gave hexahydropyrrolo[2,1-b]oxa-
zoles 2a–h in good yields with a variety of substituents at the
3-position of the hexahydropyrrolo[2,1-b]oxazole (Table 2).
However, replacement of an aromatic functional group (R =
Ph or Bn) by an aliphatic iBu or iPr substituent resulted in
somewhat lower yields of 2 (Table 2, entries 3, 4, 7, and 8).
To gain more insight into the mechanism of the reaction,
we conducted an experiment using deuterium gas instead of
molecular hydrogen [Eq. (3)]. In this case, the isolated
product was 5,7-dideuterated 3-phenylhexahydropyrrolo-
[2,1-b]oxazole 3 (see the Supporting Information, S90–
S92).[11]
Table 2: Reaction of 1a–g under carbonylative conditions.[a]
Entry
Product
R
7-CH[b]
d.r.[c]
Yield [%][d]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
(R)-Ph
(S)-Ph
(R)-iBu
(S)-iBu
(R)-Bn
(S)-Bn
(R)-iPr
(S)-iPr
S
R
S
R
S
R
S
R
25:1
25:1
6:1
6:1
9:1
11:1
11:1
10:1
87
82
63
61
85
75
72
73
2g
2h
On the other hand, when dideuterated oxazolidine 4 was
used for the cyclization reaction [Eq. (4)], all deuterium
labels were lost, providing 2a as the product. This result lends
additional support to the fact that no hydrogen-atom transfer
occurred from the oxazolidine ring to the allyl fragment
during the cyclization process. Furthermore, the presence of
deuterium at the 7-position in 3-phenylhexahydropyrrolo[2,1-
b]oxazole 3 [Eq. (3)] and the loss of both deuterium atoms
[Eq. (4)] clearly demonstrate that the reaction proceeds
[a] Reaction conditions: Substrate (1 mmol), [Rh(CO)2(acac)] (5 mol%),
xantphos (20 mol%), CO (25 atm), H2 (10 atm), THF (10 mL), 708C,
1 day. [b] Configuration of the major diastereoisomer confirmed by
transient 1D NOE experiments. [c] Determined by H NMR spectrosco-
py. [d] Yield of isolated product after purification by column chromatog-
raphy on SiO2.
1
À
On the basis that no carbonyl group was introduced into
the product of the reaction, our initial hypothesis on the
reaction mechanism involved hydroalkylation of the allylic
through a double C H activation of hydrogen atoms within
À
À
the {N CH2 O} fragment.
double bond, with formation of a Rh hydride intermediate
3
À
through initial activation of the sp C H bond. In this case, the
Rh hydride would undergo oxidative addition to the double
bond, eliminating the need for hydrogen gas for the reaction.
However, in the absence of hydrogen gas no reaction
occurred (Table 1, entry 2), indicating that initial formation
of the Rh hydride by the reaction of the catalyst with
dihydrogen is a prerequisite for the transformation.
Valuable information on how the cyclization reaction
occurs was obtained during our attempts to shorten the
reaction time. After a reaction time of 7 h, the main product,
according to NMR spectroscopic data,[9] was the aldehyde 5
[Eq. (2)]. This result demonstrates that the cyclization
On the basis of these results, we surmised that the
mechanism of the cyclization reaction of the initially formed
aldehyde 5 may have involved generation of a heteroatom-
stabilized carbene (Fischer carbene)[12] upon activation of a
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Chemie
À
À
À
C H bond of the {N CH2 O} fragment, followed by reduc-
tive elimination of dihydrogen.[13] The following decarbon-
ylation of the aldehyde and subsequent hydride transfer
would then explain the origin of a deuterium atom at the 7-
position in 3-phenylhexahydropyrrolo[2,1-b]oxazole
3
[Eq. (3)].
To validate this hypothesis by providing evidence for
decarbonylation of the aldehyde 5, we conducted an addi-
tional isotope labeling experiment using 13CO/H2 gas mixture
and (4R)-N-allyl-4-isopropyloxazolidine 1g as a substrate.[14]
However, as is clearly shown by the 13C NMR spectra of the
aldehyde (Figure 1a) and the cyclic product 2g (Figure 1b),
cyclization proceeded with retention of the 13C-labeled
carbon atom of the carbonyl group, thus refuting the
carbene-based mechanism.
Scheme 1. Proposed mechanism for the deformylative cyclization of
4-(oxazolidin-3-yl)butanals upon contact with silica gel.
An unusual, yet possible[15] interaction of the carbonyl
group with the generated iminium cation, bringing about the
formation of a 1,3-oxazetidinium intermediate, seemed to
occur favorably in an intramolecular fashion, as opposed to an
intermolecular process, which, as mentioned above, would
give no reaction product. Moreover, the cyclization of
aldehyde 5 under an atmosphere of H2/CO was relatively
slow in toluene or benzene, and even slower in THF.
However, addition of silica gel immediately prompted the
cyclization process. Although the formation of the five-
membered heterocyclic system in the presence of silica gel
occurred relatively fast, the possible restrictions imposed by
the length of the carbonyl-terminated aliphatic chain are yet
to be determined.
In summary, we have developed a new rhodium-catalyzed
reaction of N-allyl oxazolidines to provide hexahydropyrrolo-
[2,1-b]oxazoles in good yields by hydroformylation and
subsequent SiO2-initiated diastereoselective cyclization. The
reaction may proceed by a unique hydroformylation–defor-
mylation sequence in which the formyl functional group
À
virtually substitutes for the {CH2 O} fragment of the oxazo-
lidine heterocycle.
Figure 1. 13C NMR spectra of the 13C-labeled aldehyde (A) and cyclic
product 2g (B).
Received: June 1, 2008
Revised: November 21, 2008
Published online: January 12, 2009
Keywords: carbonylation · diastereoselectivity · heterocycles ·
hydroformylation · rhodium
An alternative mechanism, which would involve hydro-
lytic cleavage of the oxazolidine ring and reaction of the
generated amine with the carbonyl group, was repudiated on
the basis of an experiment carried out with (4S,5R)-3,4-
dimethyl-5-phenyloxazolidine and 3-phenylpropanal in THF
in the presence of silica gel. The experiment did not produce
any of the expected (4S,5R)-3,4-dimethyl-2-phenethyl-5-
phenyloxazolidine.
Taking into account all of the aforementioned results, we
propose a mechanism for the cyclization reaction of the
aldehyde 5, (Scheme 1). Addition of the Lewis and Brønsted
acidic silica gel to the reaction mixture generates the iminium
ion 6, which then undergoes an addition to the carbonyl group
to form the 1,3-oxazetidinium ion 7. Subsequent fragmenta-
tion of the highly unstable 1,3-oxazetidinium intermediate
results in the formation of cyclic iminium ion 8 and
formaldehyde. Finally, nucleophilic attack of the oxygen
.
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Angew. Chem. Int. Ed. 2009, 48, 1287 –1290
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À
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[9] NMR spectroscopy was carried out on a sample taken from the
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Information, S76–S81). At the same time, reaction of 1a for
7 h in C6D6 gave an approximately 1.5:1 mixture of 5 and 2a (see
the Supporting Information, S93–S94).
[10] The smooth conversion of 5 into 2a upon treatment of the
reaction mixture with silica gel was confirmed by GC and GCMS
analysis (see the Supporting Information, S82–S86).
[11] Owing to the nonstereoselective nature of the hydroformylation
reaction, 5,7-dideuterated 3-phenylhexahydro-pyrrolo[2,1-
b]oxazole 3 was isolated as a mixture of diastereoisomers.
Indeed, the 13C NMR spectrum of the deuterated compound 3
reveals two distinctive signals for the 3-position and two
overlapping triplets for the 5-position (see the Supporting
Information, S91).
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