New cyclotrimerization of aldehydes to cyclopentenone or tetrahydrofuran induced by dibromotriphenylphosphorane

Article abstract of DOI:10.1002/ejoc.200901105

α-Mono- or α-dialkylated aldehydes undergo cyclotrimerization in the presence of dibromotriphenylphosphorane (PPh₃Br₂) to afford cyclopentenones or tetrasubstituted tetra-hydrofurans in good yields. These transformations proceed by a tandem aldol dimerization/Nazarov reaction or a tandem aldol dimerization/Prins cyclization.

Full text of DOI:10.1002/ejoc.200901105

FULL PAPER
DOI: 10.1002/ejoc.200901105
New Cyclotrimerization of Aldehydes to Cyclopentenone or Tetrahydrofuran
Induced by Dibromotriphenylphosphorane
Marie-Pierre Heck,*[a] Christophe Matt,[b][‡] Alain Wagner,[b] Loïc Toupet,[c] and
Charles Mioskowski[a,b][‡‡]
Keywords: Aldehydes / Aldol reactions / Cyclotrimerization / Phosphorus
α-Mono- or α-dialkylated aldehydes undergo cyclotrimeri-
zation in the presence of dibromotriphenylphosphorane
(PPh3Br2) to afford cyclopentenones or tetrasubstituted tetra-
hydrofurans in good yields. These transformations proceed
by a tandem aldol dimerization/Nazarov reaction or a tan-
dem aldol dimerization/Prins cyclization.
Introduction
One of the oldest methods allowing the formation of se-
lective carbon–carbon and carbon–oxygen bonds makes use
of aldehydes as starting materials. Whereas the aldolization
of two aldehyde units is fully reported to yield unsaturated
aldehydes,[1] the self-reaction of three aldehyde units is
documented to generate different families of compounds
(Figure 1): the condensation of aldehydes mediated by bases
or Lewis acids[2] or recently by -proline[3] is reported to
give unsaturated aldehydes and triketides [Equation (1)].
The cyclotrimerization of aldehydes catalyzed by bromine,[4]
acetonyltriphenylphosphonium bromide,[5] and protic or
Lewis acids[6] is well known to afford 1,3,5-trioxanes [Equa-
tion (2)]. 2-Deoxyribose-5-phosphate aldolase[7] (DERA,
EC 4.1.2.4) as well as -proline[3b] are reported to catalyze
the tandem aldol condensation of aldehydes to trideoxy-
hexoses [Equation (3)]. The self-condensation of propion-
aldehyde with an ammonium salt is known to lead to cyclo-
pentenone as a byproduct [Equation (4)].[8] More recently,
the first asymmetric self-aldol reaction of acetaldehyde cat-
alyzed by diarylprolinol yielded its trimer acetal [Equa-
tion (5)].[9] Enolizable aldehydes underwent trimerization by
the aldol-Tishchenko reaction to produce 1,3-diol mono-
esters [Equation (6)].[10,11]
Figure 1. The products of the usual trimerization reactions of alde-
hydes.
Note, whereas the self-cyclization of aldehydes is well
documented, to the best of our knowledge the difference of
reactivity of α-mono- and α-dialkylated aldehydes has never
been examined. In this paper we report the trimerization of
these two types of aldehydes, which yields cyclopentenones
or tetrahydrofurans, respectively.
Results and Discussion
[a] CEA-iBiTecS, Service de Chimie Bioorganique et de Marquage,
Bât. 547, 91191 Gif-sur-Yvette, France
During the course of our study on dibromotri-
phenylphosphorane (PPh3Br2), a reagent well known to
promote bromination reactions[12] and the deprotection of
acetal groups under mild conditions,[13] we discovered that
PPh3Br2 gives rise to a new cyclotrimerization of aldehydes.
Although aldehyde polymerizations are known to be ini-
tiated by tertiary phosphanes,[14] their condensation has not
been studied with dibromotriphenylphosphorane. We re-
port herein our results of a variety of aldehydes submitted
to treatment with PPh3Br2.
Fax: +33-1-69087991
marie-pierre.heck@cea.fr
[b] Université de Strasbourg, Laboratoire des Systèmes Chimiques
Fonctionnels, Faculté de Pharmacie,
74 route du Rhin, BP60024, 67401 Illkirch, France
[c] Université de Rennes 1, Institut de Physique UMR 6251,
35042 Rennes, France
[‡] Present address: Idealp-pharma, 66 boulevard Niels Bohr,
69603 Villeurbanne cedex, France
[‡‡]Deceased June 2, 2007
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901105.
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Cyclotrimerization of Aldehydes
First, the reactions of α-substituted aldehydes (R1
=
pentenone 2 bearing the double bond with the highest de-
alkyl) 1 in the presence of PPh3Br2 in CH2Cl2 was studied. gree of substitution. This type of cycloisomerization of pen-
The results are summarized in Table 1. The reaction of pro- tadienal 8 to cyclopentenone 2 through a Nazarov mecha-
panal (1a) with PPh3Br2 afforded a single product identified nism appears to be largely unknown.[22]
as 2-ethyl-3,5-dimethylcyclopenten-2-one (2a; entry 1, 68%
yield).[8a] The self-condensation of butanal (1b) under iden-
tical reaction conditions furnished 3,5-diethyl-2-propylcy-
clopenten-2-one (2b; entry 2, 64% yield).
Table 1. Trimerization of monosubstituted aldehydes 1.[a]
Entry
Aldehyde
Product
Yield [%][b]
1
2
1a (R1 = CH3)
2a
2b
68
64
1b (R1 = CH3CH2)
[a] Reaction conditions: 1 equiv. aldehyde 1, 1 equiv. PPh3Br2 in
CH2Cl2 (1 ) at room temperature, 3 h. [b] Isolated yields.
This self-condensation of aldehydes 1 provides a new
one-pot strategy for the preparation of substituted cyclo-
pentenones 2, the essential moiety of prostaglandin deriva-
tives that have various biological activities[15] and that are
a structural feature found in numerous natural products.[16]
Generally, the preparation of cyclopentenones requires a
multistep synthesis, the key step being a Pauson–Khand re-
action,[17] or an intermolecular Horner–Wadsworth–Em-
mons reaction of diketophosphonate,[18] or other types of
cycloaddition reactions.[19] To the best of our knowledge,
the only example of a cross-condensation reaction between
an acyclic ketone and an aldehyde catalyzed by zirconium
chloride at 200 °C was reported to afford polysubstituted
cyclopentenones.[20]
Scheme 1. Proposed reaction mechanism for the trimerization of 1.
This one-step self-condensation of aldehyde 1, proceed-
ing by a tandem aldol dimerization/Nazarov reaction to
give cyclopentenone 2, has no precedent in the literature.
To validate our proposed mechanism and especially the in-
volvement of the α,β-unsaturated aldehyde (intermediate 6,
Scheme 1), we next carried out the reactions of aldehydes
13 and alkyl aldehydes 1 with PPh3Br2 (Table 2).
Table 2. Cross-coupling reactions of aldehydes 1 and 13.[a]
To make sure that the cyclotrimerization of aldehyde 1
into cyclopentenone 2 was mediated by PPh3Br2, 1 was al-
lowed to self-react in CH2Cl2 in the absence of PPh3Br2. In
this case the reaction did not proceed and aldehyde 1 was
totally recovered. The reaction did not occur either when
aldehyde 1 was treated with anhydrous HBr in CH2Cl2.
These investigations allowed us to confirm that the reaction
was mediated by PPh3Br2 and we propose the mechanism
depicted in Scheme 1. We speculate that the reaction first
proceeds by activation of aldehyde 1 with PPh3Br2 to afford
oxonium intermediate 3. This Lewis acid–aldehyde conju-
gate evolves to phosphorane enolate 4, which undergoes al-
dol condensation with aldehyde 1 to give the aldolization
product 5. The release of triphenylphosphane oxide and hy-
drogen bromide affords the corresponding α,β-unsaturated
aldehyde 6. Aldehyde 6 then reacts with 4 to give 7, which
Entry Aldehyde 1 Aldehyde 13
Product
Yield [%][b]
R1
R2
R3
1
2
3
4
5
CH3CH2
(CH3)2CH
CH3
CH3CH2
CH3CH2
CH3
CH3
CH3
CH3
H
CH3
CH3
C5H11
H
14a
14b
14c
14d
–
52
25
20
66
0
H
[a] Reaction conditions: 1 equiv. aldehyde 1, 1 equiv. aldehyde 13,
1 equiv. PPh3Br2 in CH2Cl2 (1 ) at room temperature, 3 h. [b] Iso-
lated yields.
As we predicted, the cross-reactions of aldehydes 1 and
yields α,β- and δ,γ-unsaturated aldehyde 8. Activation of 8 13 gave rise to the corresponding 2,3,5-trisubstituted cyclo-
with PPh3Br2 leads to oxonium 9, which evolves to pen- pentenones 14. The condensation of trans-2,3-dimethylacro-
tadienylic cation 10, which undergoes a Nazarov-like lein (13) and butanal with PPh3Br2 afforded cyclopentenone
mechanism involving conrotatory ring-closure to give cyclic 14a in 52% yield (entry 1, Table 2). When 3-methylbutyral-
carbocation 11.[21] Carbocation 11 is subjected to deproton- dehyde and trans-2,3-dimethylacrolein were treated with
ation and rearrangement to afford cyclopentenone 12, PPh3Br2, the cyclopentenone 14b was obtained in 25% yield
which isomerizes to the corresponding substituted cyclo- (entry 2). The reaction of propionaldehyde and 2-meth-
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967

M.-P. Heck, C. Matt, A. Wagner, L. Toupet, C. Mioskowski
FULL PAPER
yloct-2-enal yielded cyclopentenone 14c in 20% yield (en-
try 3). Thus, the presence of a bulkier substituent either at
the R1 position of aldehyde 1 or at the R3 position of 13
(entries 2 and 3, Table 2) resulted in a substantially reduced
yield (25% cyclopentenone 14b and 20% of 14c, respec-
tively). Conversely, methacrolein (13; R2 = CH3, R3 = H,
entry 4, Table 2) reacted with propanal (1) to give 14d in
the highest yield obtained (66%, entry 4). In accordance
with our proposed mechanism, acrolein failed to react with
propanal (entry 5, Table 2). The intermediate carbocation
11 may not be sufficiently stabilized for this substrate.
Next, to extend the scope of our method, we studied the
reactions of α-disubstituted (R1,R2 = alkyl) aldehydes 15
with PPh3Br2. Surprisingly, aldehydes 15, submitted to our
typical reaction conditions, gave new trimerization products
identified as tetrasubstituted tetrahydrofurans 16.[23] The
results are summarized in Table 3.
Figure 2. ORTEP drawing of the X-ray structure of tetra-
hydrofuran 16ab.
Table 3. Trimerization of disubstituted aldehydes 15.[a]
Entry
Aldehyde 15
Product Yield [%][b]
R1
R2
1
2
3
4
5
CH3
CH3CH2
CH3CH2
CH3
CH3
CH3CH2
16a[c]
16b
16c
16d
16e
70
55
58
60
43
–CH2(CH2)3CH2–
–CH2(CH2)2CH2–
[a] Reaction conditions: 1 equiv. aldehyde, 1 equiv. PPh3Br2 in
CH2Cl2 (1 ) at room temperature, 3 h. [b] Isolated yields. [c] In
the case of product 16a, two isomers were separated: minor isomer
16aa (10% yield), major isomer 16ab (60% yield).
The self-reaction of isobutyraldehyde with PPh3Br2 in
CH2Cl2 afforded the polysubstituted tetrahydrofuran 16a in
70% yield (entry 1, Table 3). The same self-condensation re-
action was realized with 2-methylbutyraldehyde and 2-eth-
Scheme 2. Possible mechanism for the formation of substituted
tetrahydrofurans 16.
ylbutyraldehyde to yield compounds 16b and 16c (entries 2 furnish aldolization product 19. The substituents R1 and R2
and 3, 55 and 58% yields, respectively). Aldehydes α-substi- in the α position of aldehyde 19 prevent the transformation
tuted by a five- or six-membered carbocycle afforded the into the corresponding α,β-unsaturated aldehyde (similar to
corresponding polysubstituted tetrahydrofurans 16d and aldol 5 yielding 6 in Scheme 1). The release of PPh3Br2
16e (entries 4 and 5, 60 and 43% yield, respectively).
from 19 furnishes 20, which reacts with activated aldehyde
The X-ray structure of 16ab[24] was determined and the 17 to afford 21. Compound 21 evolves to enol ether 22 with
resulting ORTEP plot is shown in Figure 2. It confirms the the release of triphenylphosphane oxide. Subsequent acti-
expected oxygen-containing five-membered ring product.
vation of the carbonyl moiety affords 23, which yields
The trimerization reactions of α-disubstituted aldehydes through a Prins[26] reaction type mechanism intermediate
allow a new and easy one-pot access to tetrahydrofurans, 24, which finally leads to tetrahydrofuran 16.
important heterocycle constituents in many bioactive natu-
This proposed mechanism involves the formation of the
ral products.[25] We propose a possible reaction mechanism enol ether 22. To gain information about the possible in-
to explain the formation of tetrahydrofuran 16 starting volvement of 22, we treated the synthesized tetrahydrofuran
from aldehyde 15 (Scheme 2).
16a with potassium carbonate (1 equiv.) in methanol. This
First, the reaction follows the same path as that proposed reaction afforded compound 22 in 75% yield (Scheme 3).
in Scheme 1: Activation of aldehyde 15 with PPh3Br2 af- Compound 22 was then subjected to PPh3Br2 under our
fords oxonium 17 which evolves to phosphorane enolate 18 standard trimerization conditions and, as expected, com-
and then undergoes aldol condensation with aldehyde 15 to pound 16a was quantitatively obtained (Scheme 3). This re-
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Eur. J. Org. Chem. 2010, 966–971

Cyclotrimerization of Aldehydes
phenylphosphane oxide, which was removed by filtration. The mix-
ture was concentrated under vacuum to afford the crude product
which was purified by silica gel column chromatography or by kug-
elrohr distillation to yield the corresponding trimerization product
2 or 16 from the starting aldehyde 1 or 15, respectively.
sult highlights the probability of 22 being an intermediate
of the trimerization reaction, which is in agreement with
our proposed mechanism depicted in Scheme 2.
General Procedure B. Cross-Coupling Reaction of α-Monosubsti-
tuted Aldehyde 1 and α,β-Unsaturated Aldehyde 13: The α,β-unsatu-
rated aldehyde 13 (5.5 mmol, 1 equiv.) followed by the α-monosub-
stituted aldehyde 1 (5.5 mmol, 1 equiv.) were successively added to
a stirred solution of dibromotriphenylphosphorane (5.5 mmol,
1 equiv.) in CH2Cl2 (3.5 mL). The resulting mixture was stirred for
4 h at room temperature and then concentrated under vacuum.
Then Et2O (3 mL) was added to precipitate triphenylphosphane
oxide, which was removed by filtration. The solvent was evaporated
under vacuum and the residue was purified by flash chromatog-
raphy to afford the trimerization product 14.
Scheme 3. Formation and reactivity of aldehyde 22.
Finally, to confirm that the cyclotrimerization of alde-
hyde 15 was not an acid-catalyzed reaction, we partially hy-
drolyzed PPh3Br2 prior to the reaction (to generate HBr in
situ). This process led to a dramatic decrease in the yield of
tetrahydrofuran 16a (5% yield after 48 h of reaction). These
investigations have allowed us to propose that the trimeri-
2-Ethyl-3,5-dimethylcyclopent-2-enone (2a): From propionaldehyde
zation of α-disubstituted aldehydes 15 to tetrahydrofurans (0.37 mL, 5.2 mmol) and dibromotriphenylphosphorane (2.18 g,
5.2 mmol) in CH2Cl2 (2.5 mL), the crude cyclopentenone 2a was
obtained following the general procedure A. Kugelrohr distillation
under vacuum (15 Torr) at 80 °C or purification by flash
chromatography (hexane/Et2O, 9:1) afforded 2a (162 mg, 68%
yield) as a colorless oil. 1H NMR (200 MHz, CDCl3): δ = 2.72 (dd,
2J = 18.3, 3J = 6.7 Hz, 1 H, CHHЈ), 2.33 (t, J = 7.3 Hz, 1 H,
CHHЈ), 2.15 (m, 3 H, CH3-CH, CH3-CH2), 2.02 (s, 3 H, =CCH3),
1.15 (d, 3J = 7.4 Hz, 3 H, CH-CH3), 0.89 (t, 3J = 7.5 Hz, 3 H,
CH2-CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 211.8, 167.7,
16 is mediated by PPh3Br2 and that the enol ether 22 is an
intermediate of the reaction.
Conclusions
We have reported in this paper an original one-pot self-
cyclotrimerization reaction of aldehydes induced by dibro-
motriphenylphosphorane. The transformation of α-mono-
substituted aldehydes into polysubstituted cyclopentenones
appears to proceed by a tandem aldol dimerization/Naza-
rov reaction. The self-condensation of α-disubstituted alde-
hydes with dibromotriphenylphosphorane follows a tandem
aldol dimerization/Prins process to furnish substituted
tetrahydrofuran derivatives, important structures found in
natural products. Further studies aimed at probing the ge-
neral use of this three-component cyclotrimerization reac-
tion are ongoing.
140.4, 40.4, 39.4, 16.7, 16.3, 16.0, 12.8 ppm. IR (neat): ν = 2966,
˜
2930, 2873, 1695, 1646, 1456, 1438, 1385, 1348 cm–1. MS (DCI/
NH3): m/z = 139 [MH]+, 156 [MNH4]+. C9H14O (138.21): calcd. C
78.21, H 10.21; found C 78.41, H 9.98.
3,5-Diethyl-2-propylcyclopent-2-enone (2b): From butyraldehyde
(0.45 mL, 5 mmol) and dibromotriphenylphosphorane (2.10 g,
5 mmol) in CH2Cl2 (3 mL), the crude cyclopentenone 2b was ob-
tained following the general procedure A. Purification by flash
chromatography (hexane/Et2O, 9:1) afforded 2b (192 mg, 64%
1
yield) as a yellow oil. H NMR (200 MHz, CDCl3): δ = 2.68 (dd,
3
2J = 18, J = 6.5 Hz, 1 H, CHCHHЈC=) 2.44 (q, J = 7.6 Hz, 1 H,
CH-CHHЈ-C=), 2.29–2.10 (m, 3 H, CH3CH2-CH, CH3-CH2-C=),
1.89–1.76 (m, 2 H, CH3CH2-CH2), 1.43–1.27 (m, 4 H, CH3CH2-
CH2, CH3CH2-CH), 1.14 (t, J = 7.6 Hz, 3 H, CH3-CH2-C=), 0.92
(t, J = 7.4 Hz, 3 H, CH3CH2-CH2), 0.88 (t, J = 7.3 Hz, 3 H,
CH3CH2-CH) ppm. 13C NMR (50 MHz, CDCl3): δ = 211.9, 173.8,
139.1, 46.2, 34.9, 24.9, 24.6, 24.1, 21.8, 14.0, 12.1, 11.3 ppm. IR
Experimental Section
General: All reactions were performed in dried glassware under ar-
gon. All reagents were purchased from commercial sources, alde-
hydes were freshly distilled prior to use, and other reactants were
used without further purification. Methylene chloride was freshly
distilled from CaH2 prior to use. TLC and flash chromatography
were, respectively, performed on precoated silica gel 60 F 254 plates
and on silica gel 60 (230–400 mesh). 1H and 13C NMR spectra were
recorded at the indicated field strength in CDCl3; chemical shifts
were measured relative to internal TMS. High-resolution mass
spectra were recorded with a MALDI-TOF spectrometer (matrix:
dihydroxybenzoic acid). Mass spectra were obtained with a Finni-
gan-4600 quadrupole spectrometer using either a chemical (CI,
NH3) or electronic (EI, 70 eV) ionization mode. IR spectra were
recorded on NaCl plates as thin films.
(neat): ν = 2961, 2360, 1697, 1462, 1287, 1175, 839, 709, 588,
˜
503 cm–1. HRMS: calcd. for C12H20O 180.1514; found 180.1511.
5-Ethyl-2,3-dimethylcyclopent-2-enone (14a): From trans-2-methyl-
2-butenal (0.5 mL, 5.2 mmol), butyraldehyde (0.46 mL, 5.2 mmol),
and dibromotriphenylphosphorane (2.18 g, 5.2 mmol) in CH2Cl2
(3.5 mL), the crude cyclopentenone 14a was obtained following the
general procedure B. Purification by flash chromatography (hex-
ane/Et2O, 8:2) afforded 14a (372 mg, 52% yield) as a colorless oil.
2
3
1H NMR (200 MHz, CDCl3): δ = 2.65 (dd, J = 18.3, J = 5.8 Hz,
1 H, CHHЈ), 2.17 (m, 1 H, CHHЈ), 2.03 [s, 3 H, =C(CH3)-C=O],
1.83 (m, 1 H, CH3CH2-CH), 1.68 [s, 3 H, CHHЈ=C(CH3)], 1.35
General Procedure A. The Cyclotrimerization Reaction of α-Mono-
substituted Aldehyde 1 and of α-Disubstituted Aldehyde 15: The al-
dehyde 1 or 15 (4 mmol, 1 equiv.) was added dropwise to a stirred
solution of dibromotriphenylphosphorane (4 mmol, 1 equiv.) in
CH2Cl2 (2.5 mL). The yellowish solution, which gradually turned
black, was stirred for 4 h at room temperature and then was con-
centrated under vacuum. Et2O (3 mL) was added to precipitate tri-
3
(m, 2 H, CH3CH2), 0.93 (t, J = 7.1 Hz, 3 H, CH3CH2) ppm. 13C
NMR (50 MHz, CDCl3): δ = 211.7, 168.5, 135.6, 46.3, 38.0, 24.5,
17.0, 11.4, 7.9 ppm. IR (neat): ν = 2963, 2922, 1698, 1655, 1438,
˜
1387, 1328, 1042, 916, 805, 733 cm–1. MS (DCI/NH3): m/z = 139
[MH]+. C9H14O (138.21): calcd. C 78.21, H 10.21; found C 78.09,
H 10.05.
Eur. J. Org. Chem. 2010, 966–971
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969

M.-P. Heck, C. Matt, A. Wagner, L. Toupet, C. Mioskowski
2970, 2873, 1466, 1387, 1369, 1223, 1117, 1065, 1041, 980,
FULL PAPER
5-Isopropyl-2,3-dimethylcyclopent-2-enone (14b): From trans-2-
methyl-2-butenal (0.46 mL, 4.8 mmol), 3-methylbutyraldehyde 759 cm–1. MS (EI): m/z = 278, 235, 199, 198, 165, 163, 157, 127,
(0.51 mL, 4.8 mmol), and dibromotriphenylphosphorane (2 g,
4.8 mmol) in CH2Cl2 (3.2 mL), the crude cyclopentenone 14b was
obtained following the general procedure B. Purification by column
chromatography (hexane/Et2O, 8:2) afforded 14b (183 mg, 25%
yield) as a colorless oil. 1H NMR (200 MHz, CDCl3): δ = 2.52–
2.18 [m, 4 H, (CH3)2CH-CH, (CH3)2CH-CH, CHHЈ], 2.05 [s, 3 H,
=C(CH3)-C=O], 1.69 [s, 3 H, CHHЈ=C(CH3)], 0.94 [d, J = 7.8 Hz,
3 H, (CH3)(CH3)CH], 0.68 [d, J = 6.6 Hz, 3 H, (CH3)(CH3)
CH] ppm. 13C NMR (50 MHz, CDCl3): δ = 211.4, 168.8, 136.5,
97, 85, 72, 43. C12H23BrO2 (279.21): calcd. C 51.62, H 8.30; found
C 51.49, H 8.39.
1
Major diastereoisomer 16ab: M.p. 58 °C[24]. H NMR (400 MHz,
3
CDCl3): δ = 3.88 [d, J = 7.2 Hz, 1 H, (CH3)2C-CH-OH], 3.49 [d,
3J = 7.6 Hz, 1 H, -O-CH-C(CH3)2Br], 3.15 [d, 3J = 7.2 Hz, 1 H,
(CH3)2CH-CH-O-], 1.90–1.85 (br. s, 1 H, OH), 1.81 [s, 3 H,
CBr(CH3)(CH3)], 1.79–1.77 [br. s, 1 H, (CH3)2CH], 1.78 [s, 3 H,
CBr(CH3)(CH3)], 1.11 [s, 3 H, C(CH3)(CH3)], 1.00 [d, 3J = 6.4 Hz,
3 H, (CH3)(CH3)CH], 0.96 [s, 3 H, C(CH3)(CH3)], 0.88 [d, 3J =
6.8 Hz, 3 H, (CH3)(CH3)CH] ppm. 13C NMR (50 MHz, CDCl3): δ
= 90.9, 86.2, 81.7, 69.2, 44.3, 31.6, 29.8, 29.2, 23.9, 21.0, 18.5,
50.6, 46.7, 33.8, 28.5, 20.7, 16.9, 7.7 ppm. IR (neat): ν = 2957, 1698,
˜
1650, 1465, 1387, 1328, 1185, 1065 cm–1. MS (DCI/NH3): m/z =
153 [MH]+, 170 [MNH4]+. C10H16O (152.23): calcd. C 78.90, H
10.59; found C 78.75, H 10.55.
14.1 ppm. IR (neat): ν = 2970, 2873, 1466, 1387, 1369, 1223, 1117,
˜
1065, 1041, 980, 759 cm–1. MS (EI): m/z = 278, 235, 199, 198, 165,
163, 157, 127, 97, 85, 72, 43. C12H23BrO2 (279.21): calcd. C 51.62,
H 8.30; found C 51.46, H 8.33.
3,5-Dimethyl-2-pentylcyclopent-2-enone (14c): From 2-methyloct-2-
enal (84 mg, 0.6 mmol), propionaldehyde (43 µL, 0.6 mmol), and
dibromotriphenylphosphorane (253 mg, 0.6 mmol) in CH2Cl2
(1.2 mL), the crude cyclopentenone 14c was obtained following the
general procedure B. Silica gel chromatography (hexane/Et2O, 8:2)
afforded 14c (22 mg, 20% yield) as a colorless oil. 1H NMR
(200 MHz, CDCl3): δ = 2.73 (dd, 2J = 18.2, 3J = 7.2 Hz, 1 H,
CHHЈ), 2.32 (q, J = 7.2 Hz, 1 H, CHHЈ), 2.14 (m, 3 H, CH3-CH,
CH3-CH2-C=), 2.02 (s, 3 H, =C-CH3), 1.29 [m, 6 H, CH3(CH2)3-
CCDC-735049 (for 16ab) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2-(1-Bromo-1-methylpropyl)-5-sec-butyl-4-ethyl-4-methyltetrahydro-
furan-3-ol (16b): From 2-methylbutyraldehyde (0.43 mL, 4 mmol)
and dibromotriphenylphosphorane (1.69 g, 4 mmol) in CH2Cl2
(3 mL), the crude 16b was obtained following the general procedure
A. Purification by silica gel chromatography (hexane/EtOAc,
8.5:1.5) afforded a mixture of inseparable diastereoisomers 16b
(236 mg, 55 % yield) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 3.82 [d, 3J = 5.4 Hz, 1 H, (CH3)(C2H5)C-CH-OH],
3.61 [d, 3J = 6.2, 1 H, -O-CH-CBr(CH3)(C2H5)], 3.32 [d, 3J =
6.0 Hz, 1 H, (CH3)(C2H5)CH-CH-O-], 3.27–3.20 (m, 1 H, OH),
1.98–1.90 [m, 2 H, CBr(CH3 )(CH3 CH2 )], 1.69 [s, 3 H,
CBr(CH3)(CH3CH2)], 1.68–1.62 [br. s, 1 H, (CH3)(C2H5)CH-],
1.54–1.47 [m, 2 H, (CH3)(CH3CH2)CH-], 1.15–1.05 [m, 2 H,
(CH3)C(CH2CH3)], 1.09 [t, 3J = 7.1 Hz, 3 H, CBr(CH3)(CH3CH2)],
1.05–0.90 [m, 9 H, (CH3)(C2H5)CH-, (CH3)C(CH2CH3), (CH3)-
C(CH2CH3)], 0.88 [t, 3J = 7.0 Hz, 3 H, (CH3)(CH3CH2)CH-] ppm.
13C NMR (100 MHz, CDCl3): δ = 91.4, 90.9, 86.9, 86.5, 79.0, 73.1,
3
3
CH2], 1.14 (d, J = 7.4 Hz, 3 H, CH-CH3), 0.86 [t, J = 6.7 Hz, 3
H, CH3(CH2)3-CH2] ppm. 13C NMR (50 MHz, CDCl3): δ = 212.1,
168.1, 139.4, 40.6, 39.5, 31.7, 28.0, 22.9, 22.4, 17.0, 16.6, 14.0 ppm.
IR (neat): ν = 2959, 2929, 2857, 1699, 1648, 1457, 1385, 1233, 1096,
˜
978, 806, 667, 533 cm–1. MS (DCI/NH3): m/z = 181 [MH]+.
C12H20O (180.29): calcd. C 79.94, H 11.18; found C 79.74, H 11.06.
5-Ethyl-3-methylcyclopent-2-enone (14d): From methacrolein
(0.46 mL, 5.55 mmol), butyraldehyde (0.5 mL, 5.55 mmol), and di-
bromotriphenylphosphorane (2.34 g, 5.55 mmol) in CH2Cl2
(3.7 mL), the crude cyclopentenone 14d was obtained following the
general procedure B. Silica gel chromatography (hexane/Et2O, 8:2)
afforded 14d (456 mg, 66% yield) as a colorless oil. 1H NMR
(200 MHz, CDCl3): δ = 5.86 (d, J = 1.4 Hz, 1 H, =CH-C=O), 2.70
(dd, 2J = 18.3, 3J = 6.2 Hz, 1 H, CHHЈ), 2.26 (m, 1 H, CHHЈ),
2.09 (s, 3 H, =C-CH3), 1.77 (m, 1 H, CH3CH2-CH), 1.33 (m, 2
H, CH3CH2), 0.89 (t, J = 7.3 Hz, 3 H, CH3CH2) ppm. 13C NMR
(50 MHz, CDCl3): δ = 211.2, 177.4, 129.7, 47.6, 38.9, 23.9, 19.1,
47.2, 35.9, 34.1, 30.1, 27.6, 25.2, 16.3, 15.8, 10.9 ppm. IR (neat): ν
˜
= 3461, 2968, 2937, 2878, 1458, 1381, 1064, 1004, 787 cm–1. MS
(DCI/NH3): m/z = 241, 258, 338 [M(79Br) + NH4]+, 340 [M(81Br)
+ NH4]+. C15H29BrO2 (321.29): calcd. C 56.07, H 9.10; found C
56.29, H 9.03.
11.0 ppm. IR (neat): ν = 3433, 2962, 2933, 2874, 1696, 1624, 1461,
˜
1431, 1379, 1324, 1287, 1174, 1102, 1051, 966, 838 cm–1. MS (DCI/
NH3): m/z = 125 [MH]+, 142 [MNH4]+.
2-(1-Bromo-1-ethylpropyl)-4,4-diethyl-5-(1-ethylpropyl)tetrahydro-
furan-3-ol (16c): From 2-ethylbutyraldehyde (0.62 mL, 5 mmol) and
dibromotriphenylphosphorane (2.11 g, 5 mmol) in CH2Cl2 (5 mL),
the crude 16c was obtained following the general procedure A. Pu-
rification by silica gel chromatography (hexane/Et2O, 8:2) afforded
a mixture of inseparable diastereoisomers 16c (351 mg, 58% yield)
2-(1-Bromo-1-methylethyl)-5-isopropyl-4,4-dimethyltetrahydrofuran-
3-ol (16aa and 16ab): From 2-methylpropionaldehyde (0.44 mL,
4.82 mmol) and dibromotriphenylphosphorane (2.05 g, 4.82 mmol)
in CH2Cl2 (3.3 mL), the crude 16a was obtained following the gene-
ral procedure A. Purification by silica gel chromatography (hexane/
Et2O, 8.5:1.5) afforded two major separable diastereoisomers 16aa
and 16ab: minor diastereoisomer 16aa (50 mg, 10% yield) as a col-
orless oil and major diastereoisomer 16ab (266 mg, 60% yield) as
a white solid.
1
3
as an orange oil. H NMR (200 MHz, CDCl3): δ = 3.96 [d, J =
6.3 Hz, 1 H, (C2H5)2C-CH-OH], 3.61 [d, 3J = 4.3 Hz, 1 H, -O-CH-
CBr(C2H5)2], 3.51 [d, J = 6.3 Hz, 1 H, (C2H5)2CH-CH-O-], 2.11–
3
1.92 [m, 4 H, OH, (C2H5)2CH-, CBr(C2H5)(CH3CH2)], 1.61–1.29
[m, 10 H, 5(CH3)(CH2)], 1.07–0.81 [m, 18 H, 6(CH3)(CH2)] ppm.
13C NMR (50 MHz, CDCl3): δ = 87.0, 86.3, 80.2, 49.4, 40.5, 40.1,
31.6, 31.7, 30.7, 24.6, 24.2, 23.5, 23.0, 20.8, 11.4, 10.9, 9.5 ppm. IR
Minor diastereoisomer 16aa: 1H NMR (400 MHz, CDCl3): δ =
3
3
3.67 [d, J = 5.2 Hz, 1 H, (CH3)2C-CH-OH], 3.39 [d, J = 5.6 Hz,
1 H, -O-CH-C(CH3)2Br], 3.10 [d, 3J = 9.2 Hz, 1 H, (CH3)2CH-CH-
O-], 1.82 [s, 3 H, CBr(CH3)(CH3)], 1.79 [s, 3 H, CBr(CH3)(CH3)],
1.81–1.78 [br. s, 1 H, (CH3)2CH], 1.63–1.55 (br. s, 1 H, OH), 1.07
(neat): ν = 3515, 2965, 2878, 1460, 1381, 1109, 1070, 839, 557 cm–1.
˜
MS (DCI/NH3): m/z = 380 [M(79Br)NH4]+, 382 [M(81Br)NH4]+.
C18H35BrO2 (363.37): calcd. C 59.50, H 9.71; found C 59.40, H
9.61.
3
[s, 3 H, C(CH3)(CH3)], 1.01 [d, J = 7.1 Hz, 3 H, (CH3)(CH3)CH],
0.99 [s, 3 H, C(CH3)(CH3)], 0.92 [d, J = 6.8 Hz, 3 H, (CH3)(CH3)
CH] ppm. 13C NMR (50 MHz, CDCl3): δ = 91.7, 91.5, 82.9, 66.0,
3-(1-Bromocyclohexyl)-1-cyclohexyl-2-oxaspiro[4.5]decan-4-ol (16d):
43.9, 31.9, 29.5, 28.8, 22.16, 21.2, 21.15, 19.3 ppm. IR (neat): ν =
From cyclohexanecarbaldehyde (0.6 mL, 5 mmol) and dibromotri-
˜
970
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 966–971

Cyclotrimerization of Aldehydes
[2] a) R. Kuhn, M. Hoffer, Ber. Dtsch. Chem. Ges. 1930, 63, 2164–
2174; b) S. Seisel, M. Neuwirth, Justus Liebigs Ann. Chem.
phenylphosphorane (2.11 g, 5 mmol) in CH2Cl2 (5 mL), the crude
16d was obtained following the general procedure A. Purification
by silica gel chromatography (hexane/Et2O, 8.5:1.5) afforded a mix-
ture of diastereoisomers 16d (400 mg, 60% yield) as a colorless oil.
1923, 433, 121–138; see ref.[1]
.
[3] a) A. Cordova, W. Notz, C. F. Barbas III, J. Org. Chem. 2002,
67, 301–303; b) N. S. Chowdari, D. B. Ramachary, A. Cordova,
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Rao, K. V. Reddy, Tetrahedron 1997, 53, 14997–15004; b) R.
Camarena, A. C. Cano, F. Delgado, N. Zuniga, C. Alvarez,
Tetrahedron Lett. 1993, 34, 6857–6858.
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8422–8423; H. J. M. Gijsen, C.-H. Wong, J. Am. Chem. Soc.
1995, 117, 7585–7591.
[8] a) J. I. Grayson, R. Dinkel, Helv. Chim. Acta 1984, 67, 2100–
2110; b) E. M. Campi, W. R. Jackson, Aust. J. Chem. 1989, 42,
471–478.
Major diastereoisomer 16d: 1H NMR (200 MHz, CDCl3): δ = 4.08
3
(m, 1 H, -CH-OH), 3.55 [d, J = 4.8 Hz, 1 H, -O-CH-CBr-(CH2)5-
], 3.10 [d, 3J = 7.3 Hz, 1 H, -(CH2)5-CH-CH-O-], 1.97–0.89 [m,
32 H, OH, -(CH2)5-CH-, 15-(CH2)5-] ppm. 13C NMR (50 MHz,
CDCl3): δ = 93.3, 90.1, 47.5, 38.3, 37.9, 35.0, 30.7, 30.6, 29.0, 28.4,
26.4, 26.2, 26.0, 25.2, 24.1, 22.5, 22.1 ppm. IR (neat): ν = 3468,
˜
2930, 2852, 1447, 1247, 1116, 1048, 904, 735 cm–1. MS (DCI/NH3):
m/z = 416 [M(79Br)NH4]+, 418 [M(81Br)NH4]+. C21H35BrO2
(399.41): calcd. C 63.15, H 8.83; found C 63.05, H 8.90.
3-(1-Bromocyclopentyl)-1-cyclopentyl-2-oxaspiro[4.4]nonan-4-ol
(16e): From cyclopentanecarbaldehyde (0.6 mL, 5.6 mmol) and di-
bromotriphenylphosphorane (2.37 g, 5.6 mmol) in CH2Cl2
(5.5 mL), the crude 16e was obtained following the general pro-
cedure A. Purification by silica gel chromatography (pentane/Et2O,
9:1) afforded a mixture of diastereoisomers 16e (285 mg, 43% yield)
as a colorless oil.
[9] Y. Hayashi, S. Samanta, T. Itoh, H. Ishikawa, Org. Lett. 2008,
10, 5581–5583.
[10] a) A. Miyano, D. Tashiro, Y. Kawasaki, S. Sakaguchi, Y. Ishii,
Tetrahedron Lett. 1998, 39, 6901–6902; b) R. Mahrwald, Curr.
Org. Chem. 2003, 7, 1713–1723; c) C. M. Mascarenhas, M. O.
Duffey, S.-Y. Liu, J. P. Morken, Org. Lett. 1999, 1, 1427–1429.
[11] For a catalytic version of the aldol-Tishchenko reaction, see:
C. M. Mascarenhas, S. P. Miller, P. S. White, J. P. Morken, An-
gew. Chem. Int. Ed. 2001, 40, 601–603.
[12] a) G. A. Wiley, B. M. Rein, R. L. Hershkowitz, Tetrahedron
Lett. 1964, 5, 2509–2513; b) A. N. Thakore, P. Pope, A. C.
Oehlschlager, Tetrahedron 1971, 27, 2617–2626; c) G. Palumbo,
C. Ferreri, R. Caputo, Tetrahedron Lett. 1983, 24, 1307–1310;
d) R. T. Hrubiec, M. B. Smith, J. Org. Chem. 1984, 49, 431–
435.
Major diastereoisomer 16e: 1H NMR (400 MHz, CDCl3): δ = 5.69
3
(br. s, 3J = 1.6 Hz, 1 H, OH), 4.15 (d, J = 7.2 Hz, 1 H, -CH-OH),
3.84 [d, 3J = 7.2 Hz, 1 H, -O-CH-CBr-(CH2)4-], 3.56 [d, 3J =
9.2 Hz, 1 H, -(CH2)4-CH-CH-O-], 2.36–2.30 [m, 4 H, CBr-(CH2)2-
(CH2)2], 2.06–1.95 [m, 1 H, -(CH2)4-CH-], 1.92–1.84 (m, 4 H, 2-
CH2-), 1.81–1.35 (m, 16 H, 8-CH2-) ppm. 13C NMR (100 MHz,
CDCl3): δ = 89.1, 84.8, 82.9, 82.1, 55.7, 40.9, 40.5, 38.5, 33.9, 31.2,
29.2, 26.8, 26.0, 25.8, 25.5, 25.4, 24.3, 23.0 ppm. IR (neat): ν =
˜
[13] A. Wagner, M.-P. Heitz, C. Mioskowski, J. Chem. Soc., Chem.
Commun. 1989, 1619–1620.
3470, 2930, 2852, 1447, 1247, 1116, 1048, 730 cm–1. C18H29BrO2
(357.33): calcd. C 60.50, H 8.18; found C 60.40, H 8.25.
[14] a) J. N. Koral, B. W. Song, J. Polym. Sci. 1961, 54, S34–S35; b)
O. Vogl, Pure Appl. Chem. 1992, A29, 1085–1113.
[15] a) A. Rossi, G. Elia, M. G. Santoro, J. Biol. Chem. 1996, 271,
32192–32196; b) S. M. Roberts, M. G. Santoro, E. S. Sickle, J.
Chem. Soc. Perkin Trans. 1 2002, 1735–1742.
2,2,4-Trimethyl-3-(2-methylpropenyloxy)pentanal (22): Compound
16a (1 g, 4 mmol) was added to a solution of ground potassium
carbonate (0.52 g, 4 mmol) in methanol (20 mL) at 0 °C. The mix-
ture was stirred for 3 h at room temperature and then was hy-
drolyzed with water (20 mL). Et2O was added (20 mL) and the or-
ganic layer was separated, dried with magnesium sulfate, and the
solvent removed under vacuum at 0 °C. Purification by silica gel
chromatography (hexane/Et2O, 8:1) afforded aldehyde 22 (595 mg,
75% yield). NMR (200 MHz, CDCl3): δ = 9.71 (s, 1 H, H-C=O),
[16] G. A. Howe, Proc. Natl. Acad. Sci. USA 2001, 98, 12317–
12319.
[17] P. L. Pauson, Tetrahedron 1985, 41, 5855–5860.
[18] B. Yan, C. D. Spilling, J. Org. Chem. 2008, 73, 5385–5396.
[19] a) X. Qi, J. M. Ready, Angew. Chem. Int. Ed. 2008, 47, 1–4,
and references cited therein.
[20] T. Yuki, M. Hashimoto, Y. Nishiyama, Y. Ishii, J. Org. Chem.
1993, 58, 4497–4499.
[21] a) A. J. Frontier, C. Collison, Tetrahedron 2005, 61, 7575–7606;
b) H. Pellissier, Tetrahedron 2005, 61, 6479–6517.
[22] a) A. K. Miller, M. R. Banghart, C. M. Beaudry, J. M. Suh, D.
Trauner, Tetrahedron 2003, 59, 8919–8930; b) C. Kuroda, S.
Honda, Y. Nagura, H. Koshio, T. Shibue, T. Takeshita, Tetra-
hedron 2004, 60, 319–331.
[23] Tetrahydrofurans 16 were obtained as a mixture of isomers. In
the case of product 16a, two isomers 16aa and 16ab were sepa-
rated. The conformation of the major isomer 16ab is shown in
Figure 2.
3
5.81 [br. s, 1 H, HC=C(CH3)2], 3.42 [d, J = 3.7 Hz, 1 H, -O-HC-
CH(CH3)2], 1.97–1.78 [m,
1 H, CH(CH3)2], 1.61 [s, 3 H,
(CH3)(CH3)C=], 1.53 [s, 3 H, (CH3)(CH3)C=], 1.11 [s, 3 H,
3
C(CH3)(CH3)], 1.08 [s, 3 H, C(CH3)(CH3)] 0.91 [t, J = 7.0 Hz, 6
H, CH(CH3)2] ppm. 13C NMR (50 MHz, CDCl3): δ = 205.5, 142.9,
107.8, 91.7, 90.7, 51.1, 30.2, 21.9, 20.0, 18.8, 17.4, 14.9 ppm. IR
(neat): ν = 2964, 2927, 2876, 1724, 1689, 1470, 1390, 1337, 1182,
˜
1160, 1047, 989, 886, 821 cm–1. MS (DCI/NH3): m/z = 199
[MH]+.
Supporting Information (see also the footnote on the first page of
this article): General experimental procedures and characterization
data for compounds 2a,b, 14a–d, 16aa,ab, 16b–e, and 22, and the
crystallographic data of compound 16ab in CIF format.
[24] The recrystallization of 16ab in cold pentane (5 °C) produced
colorless needles within 12 h.
[25] M. C. Elliott, J. Chem. Soc. Perkin Trans. 1 2002, 2301–2323.
For a review, see: T. L. B. Boivin, Tetrahedron 1987, 43, 3309–
3362.
[26] a) I. M. Pastor, M. Yus, Curr. Org. Chem. 2007, 11, 925–957;
b) S. N. Chavre, H. Choo, J. H. Cha, A. N. Pae, K. Choi II,
Y. S. C h o, Org. Lett. 2006, 8, 3617–3619.
[1] a) C. H. Heathcock, in: Comprehensive Organic Synthesis (Eds.:
B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991, vol.
2. pp. 133–180, and references cited therein; b) H. Yamamoto,
S. Saito, Chem. Eur. J. 1999, 5, 1959–1962.
Received: September 28, 2009
Published Online: January 4, 2010
Eur. J. Org. Chem. 2010, 966–971
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
971