In situ generation of 2,3-allenolates in the coupling of secondary homopropargylic alcohols and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.11.032

A study on a novel oxonia [3,3]-sigmatropic rearrangement as competitive alternative pathway to the acetylenic Prins cyclization on the addition of secondary homopropargylic alcohols to aldehydes catalyzed by iron(III) is described. 'Ab initio' theoretica

Full text of DOI:10.1016/j.tetlet.2005.11.032

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 283–286
In situ generation of 2,3-allenolates in the coupling of secondary
homopropargylic alcohols and aldehydes
Pedro O. Miranda, Miguel A. Ram ´ı rez, Juan I. Padr o´ n and V ´ı ctor S. Mart ´ı n*
*
Instituto Universitario de Bio-Org a´ nica ꢀAntonio Gonz a´ lezꢁ, Universidad de La Laguna C/Astrof ı´ sico Francisco S a´ nchez, 2,
3
8206 La Laguna, Tenerife, Spain
Received 11 October 2005; revised 28 October 2005; accepted 4 November 2005
Available online 22 November 2005
Abstract—A study on a novel oxonia [3,3]-sigmatropic rearrangement as competitive alternative pathway to the acetylenic Prins
cyclization on the addition of secondary homopropargylic alcohols to aldehydes catalyzed by iron(III) is described. ꢀAb initioꢁ theo-
retical calculations of the species involved on the rearrangement supports the in situ formation of 2,3-allenolates. The domino pro-
cess involves three consecutive chemical events in one-pot format reaction (ꢀ70% average).
Ó 2005 Elsevier Ltd. All rights reserved.
In continuation of our research program directed to-
ward the synthesis of marine natural compounds con-
OH
O
O
3
+
1
H
taining six-membered oxacycles, we addressed our
FeCl3
+
2
,3
attention toward the Prins cyclization promoted by
the inexpensive, environmentally friendly, and stable
iron(III) halides, as a way to obtain 2-alkyl-4-halo-5,6-
CH Cl , rt
OH
O
2
2
1
2
4
dihydro-2H-pyrans (Scheme 1).
4
Scheme 2. Coupling of secondary homopropargylic alcohols and
aldehydes catalyzed by iron(III) halides.
Extending our previous work, we explored such meth-
odology for the synthesis of 2,6-disubtituted dihydro-
pyrans using secondary homopropargylic alcohols.
Surprisingly the treatment of pent-4-yn-2-ol (1,
1
4
2
R = R = H, R = Me) and 3-methylbutanal (2,
Precedents for the synthesis of these type of compounds
making use of allenol as starting material have been
3
R = i-Bu) in the presence of FeCl led to unsaturated
3
5
6
(
4
E)-b-hydroxyketone 3 and (E)-a,b-unsaturated ketone
in 2.5:1 ratio and 65% yield, without any trace of
reported from the laboratories of Trost and Yu using
vanadium and indium as catalysts, respectively.
the expected Prins-type cyclic product (Scheme 2).
Herein, we report a study on a novel oxonia [3,3]-sigma-
tropic rearrangement as competitive alternative pathway
to the alkyne Prins cyclization resulting on the addition
of secondary homopropargylic alcohols to aldehydes
catalyzed by iron(III). Ab initio theoretical calculations
of the species involved in the rearrangement as well as
experimental evidence support the in situ formation of
X
O
FeX3
+
R
H
CH X , rt, 5 min
2 2
O
R
OH
7
key allenolates (Scheme 3).
Scheme 1. Synthesis of 2-alkyl-4-halo-5,6-dihydro-2H-pyrans.
Firstly to test the scope of FeX in this coupling reac-
3
tion, we carried out the reaction between pent-4-yn-
Keywords: [3,3]-Sigmatropic rearrangement; Prins cyclization;
Iron(III) halides.
1
4
2
2
-ol (1, R = R = H, R = Me) and several aldehydes
8
*
Corresponding authors. Tel.: +34 922318579; fax: +34 922318571
V.S.M.); e-mail: vmartin@ull.es
using FeCl and FeBr as promoters. Table 1 summa-
3 3
9
(
rizes the results obtained in this study.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.032

2
84
P. O. Miranda et al. / Tetrahedron Letters 47 (2006) 283–286
Table 2. Structure–reactivity relationship study of the addition of
R2
R4
R4
R4
secondary homopropargylic alcohols and 3-methylbutanal using
iron(III) chloride as promoter
HO
R3
R3
.
R1
FeX
3
1
2
4
R1
Entry
R
R
R
3:4
Yield (%)
O
O
1
+
R1
oxonia-
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Ph
Ph
H
Me
n-C H
2 5
c-C
Ph
4-BrPh
4-MePh
H
Ph
Me
H
H
H
H
H
H
H
H
7:3
7:3
7:3
0:10
0:10
0:10
—
—
—
—
9:1
65
66
61
87
25
30
—
—
—
—
40
R2
[3,3]-sigmatropic
rearrangement
R2
3
R CHO
6
H
11
2
Scheme 3. Oxonia-[3,3]-sigmatropic rearrangement during the coup-
ling of secondary homopropargylic alcohols and aldehydes.
TIPS
Me
H
Table 1. Addition of secondary homopropargylic alcohols and alde-
hydes using FeX
10
11
H
Me
Me
Me
3
as promoter
R1
R3
R3
X
From this study, we have observed that the process
4
R1
R2
1
, R = H
3
1
3
4
OH
O
depends basically on the nature of R , R , and R . We
therefore decided to use commercially available pent-4-
yn-2-ol and the suitable aldehyde as a possible 2,3-alleno-
late source. It should be pointed out that the nature of
the aldehyde is a factor to consider, inasmuchas it can
favor Prins reaction or the corresponding domino pro-
cess (Table 1, entry 5).
FeX3
CH Cl
+
+
2
2
R3
3
R3
O
R CHO
R1
5
2
O
4
1
2
3
Entry
R
R
R
X
3:4
Yield (%)
1
2
3
4
5
6
7
8
9
0
H
H
H
H
H
Me
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-C
6
H
13
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
7:3
7:3
10:0
10:0
3:2:5
70
65
40
12
60
40
44
47
50
—
i-Bu
t-Bu
Ph
The next step was the treatment of pent-4-yn-2-ol, in the
presence of 3-methylbutanal, with various Lewis acids to
evaluate the influence of the catalyst. The results are
shown in Table 3.
a
c-C
i-Bu
6
H
11
b
9:1
n-C
6
H
13
10:0
10:0
7:3
i-Bu
c-C H
6 11
Ph
When we use other Lewis acids such as AlCl and InCl ,
3
3
similar results to FeCl were obtained but the reactions
3
1
—
were slower and the obtained yields lower. The methyl
a
3
0% corresponds to the isolated Prins product 5.
anti/syn ratio (3:7).
ketone 4 was the major product, when we use BF ÆOEt
3
2
b
and iron(III) chloride combined with carboxylic or sul-
4
b
fonic acids (entries 7 and 8).
Using the optimized conditions, we pondered the possi-
bility of running the reaction with two different alde-
hydes, taking advantage of different reactivities and
attempting to obtain cross-over products. The results
of this study are summarized in Table 4.
The process produced in moderate to good yield the
unsaturated b-hydroxyketone 3, with a range of alde-
hydes except when benzaldehyde was used (entries 4
and 10). Using 3-methylpent-4-yn-2-ol a syn/anti (3:7)
unsaturated b-hydroxyketone, was obtained (entry 6).
When cyclohexanal was used (entry 5), the Prins-tetra-
hydropyran 5 was the major product. The reaction is
more selective with ferric bromide to the products 3
and 4 (entries 7 and 8), although with lower yields.
Any attempt to control the final balance of the obtained
products (3:4) under experimental conditions (tempera-
ture, addition order, solvent, etc.) proved to be fruitless.
11
In this experiment, a mixture of cross-over 7, b-hydroxy-
ketone 3 and a,b-unsaturated ketone 4 was obtained
using iron(III) chloride as promoter (Table 4), product
7
being the major one (entries 1 and 2), except when
an aromatic aldehyde with an electron-donating group
was used (entry 3). When iron(III) bromide was used
In order to evaluate the factors in this domino process,
1
Table 3. Addition of pent-4-yn-2-ol and 3-methylbutanal promoted by
Lewis acids
we decided to study the influence of the substituents (R ,
2
3
4
R , R , and R ) in the progress of the reaction (Table 2).
It should be pointed out that although the propargylic
Entry
Acids
AlCl
InCl
ZnCl2
BF ÆOEt
TiCl
CeCl
Yield (%)
Ratio (3:4)
2
10
portion (including the R substituent) is lost during
the whole process it may influence the course of the reac-
1
2
3
4
5
6
7
8
3
47
54
—
75
—
—
65
63
6:4
7:3
—
0:10
—
—
2:8
2:8
3
2
tion. Thus, we also evaluated the nature of the group R
and R . As indicated in Table 2, an aromatic substituent
in both R and R are deleterious for the process, in R
yielding the a,b-unsaturated ketone, and R impeding
4
3
2
1
2
2
4
1
3
FeCl
FeCl
3
/HOAc
3
/CSA
the reaction. Moreover when the alkyne is disubstituted
4
(
R = Me, TIPS) the reaction is inhibited.

P. O. Miranda et al. / Tetrahedron Letters 47 (2006) 283–286
285
Table 4. Cross-over domino reaction of secondary homopropargylic
alcohols and aldehydes using FeX as catalyst
reaction with the suitable aldehyde or protonation con-
ducts to compound 7 or 4, respectively.
3
R1
R5
R3
The relative stability of the species involved on the oxo-
nia [3,3]-sigmatropic rearrangement should address to
an unsaturated b-hydroxyketone 7 or Prins-tetrahydro-
pyran 5. To evaluate the stability of these species ꢀab ini-
tioꢁ theoretical calculations at B3LYP/6-31G(d) level
were performed (Table 5). A slight exothermic process
was found for the studied models (entries 1–3). The
3
R CHO
R1
+
OH O
5
R CHO
R3
OH
Me
+
7
R1
+
R
FeX3
1
O
R3
R3
6
4
OH
O
3
bulkiness increment of R (methyl to cyclohexyl) is con-
3
comitant with an increase in the activation energy of a
transition state as shown in Figure 1. This fact is in
agreement with the experimental data (Table 1, entry
1
3
5
Entry
X
R
R
R
7:3:4
Yield (%)
1
2
3
4
5
Cl
Cl
Cl
Br
Br
H
H
H
H
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
t-Bu
C H
6 5
4-MePh
C
5:3:2
5:3:2
2:1:7
10:0:0
10:0:0
47
45
62
25
5), where a Prins-tetrahydropyran was obtained as the
major product.
6
H
5
a
To support 2,3-allenol12 (11) as intermediate of this
reaction, we performed a couple of runs using this sub-
stance as starting material and iron(III) chloride as cat-
alyst (Scheme 5). We found the cross-over aldol (12) as
the sole product when the reaction was run in the pres-
ence of the suitable aldehyde and the (E)-a,b-unsatu-
rated ketone (13) in absence of the last one.
Me
t-Bu
33
a
anti/syn ratio (1:1).
the process became completely chemoselective, the
cross-over 7 being obtained as a single product, albeit
with limited yield (entries 4–5). It must be emphasized
that in this case aromatic aldehydes are valid substrates
in the reaction.
In conclusion, we report a novel oxonia [3,3]-sigma-
tropic rearrangement as competitive alternative pathway
to the Prins cyclization, that leads to an allenol, further
A plausible mechanism for this new domino process is
outlined in Scheme 4. The addition of homopropargylic
alcohol and aldehyde promoted by ferric halide gener-
ates the oxonium ion 8 that undergoes an oxonium-
3,3]-sigmatropic rearrangement to give the allenolate
. Further intramolecular 1,3-oxygen transposition gen-
1,3-O-transposition and enolate coupling. The address
of the reaction (rearrangement or Prins type cyclization)
depends directly on the stability of the species involved
in the rearrangement, as shown by the ꢀab initioꢁ calcu-
lations, being favored this sigmatropic rearrangement.
In this domino process, three consecutive chemical
[
9
5
b
erates unsaturated enolate 10. Subsequent coupling
Table 5. Ab initio calculations of the species involves on the 2-oxonia
[
3,3]-sigmatropic rearrangement
R2
R3
R3
1
2
3
X
Entry
R
R
R
DH* (kcal/mol) DH (kcal/mol)
HO
FeX3
O
O
1
2
3
H
H
H
Me Me
Me i-Pr
Me c-C
6.61
8.13
À3.24
À0.69
À0.45
R1
1
R1
R1
Prins
cyclization
R2
8
R2
6
H
11 10.02
+
5
3
Oxonia-
R CHO
[
3,3]-sigmatropic
rearrangement
R3
.
O
R1
R2
Figure 1. Transition state corresponding to entry 1 (Table 5).
R3
R3
.
R1
OFeCl2
R1
1,3-O-transposition 10
OFeCl2
9
CHO
n
-C H
n-C H
6 13
6
13
.
5
R CHO
FeCl3
CH Cl , rt
2
OH
11
O
12
(60%)
OH
H
2
R1
R3
R5
R3
R1
n-C H
6 13
FeCl3
O
7
OH
O
4
O
CH Cl , rt
13
(75%)
2
2
Scheme 4. Proposed mechanism for the addition of secondary
Scheme 5. Coupling of 2,3-allenols and aldehydes catalyzed by
propargylic alcohols and aldehydes.
iron(III) halides.

286
P. O. Miranda et al. / Tetrahedron Letters 47 (2006) 283–286
events take place in one-pot reaction (70–80% average).
A noteworthy aspect of the reaction is that the carbon–
carbon formation is very rapid and it is usually com-
pleted within 1 min. The reaction has been scaled up
to 2 g with no difficulty.
3. For recent advances in the Prins reaction, see: (a) Jasti, R.;
Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc.
2
005, 127, 9939–9945; (b) Rychnovsky, S. D.; Dalgard, J.
E. J. Am. Chem. Soc. 2004, 126, 15662–15663, and
references cited therein; (c) Dobbs, A. P.; Guesn e´ , J. J.;
Martinovic, S.; Coles, S. J.; Hursthouse, M. B. J. Org.
Chem. 2003, 68, 7880–7883; (d) Yadav, V. K.; Kumar, N.
V. J. Am. Chem. Soc. 2004, 126, 8652–8653; (e) Overman,
L. E.; Velthuisen, E. J. Org. Lett. 2004, 6, 3853–3856; (f)
Yu, C.-M.; Yoon, S. K.; Hong, Y. T.; Kim, J. Chem.
Commun. 2004, 1840–1841.
Acknowledgements
This research was supported by the Ministerio de Cien-
cia y Tecnolog ´ı a (PPQ2002-04361-C04-02) and the Can-
ary Islands Government. P.O.M. thanks the Spanish
M.E.C., for a FPI fellowship. J.I.P. thanks the Spanish
MCYT-F.S.E., for a Ram o´ n y Cajal contract.
4
. (a) Miranda, P. O.; Diaz, D. D.; Padr o´ n, J. I.; Bermejo, J.;
Mart ´ı n, V. S. Org. Lett. 2003, 11, 1979–1982; (b) Miranda,
P. O.; Diaz, D. D.; Padr o´ n, J. I.; Ram ´ı rez, M. A.; Mart ´ı n,
V. S. J. Org. Chem. 2005, 70, 57–62.
5
. (a) Trost, B. M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230–
1
231; (b) Trost, B. M.; Jonasson, C.; Wucher, M. J. Am.
Chem. Soc. 2001, 123, 12736–12737.
6. Yu, C.-M.; Kim, Y.-M.; Kim, J.-M. Synlett 2003, 10,
518–1520.
Supplementary data
1
7
. For a study describing the relatives rates of oxonia-Cope
rearrangement versus Prins cyclization in the coupling of
allylic alcohols and aldehydes, see Ref. 3a.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2005.11.032.
8
9
. FeCl
3 3
and FeBr were purchased form the Aldrich
Chemical Co.
. To the best of our knowledge, this is the first report on the
use of Fe(III) halides promoting this kind of reaction.
References and notes
1
0. We do not have any experimental evidence of the
incorporation of this fragment in the course of the
reaction.
1
. (a) Betancort, J. M.; Mart ´ı n, V. S.; Padr o´ n, J. M.;
Palaz o´ n, J. M.; Ram ´ı rez, M. A.; Soler, M. A. J. Org.
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J. M.; Palaz o´ n, J. M.; Mart ´ı n, V. S. J. Org. Chem. 1997,
11. Typical experimental procedure for a ferric halide promoted
domino reaction: To a solution of homopropargylic
alcohol (1 equiv) and aldehyde(s) (1 equiv of each) in dry
6
2, 4584–4590; (c) Betancort, J. M.; Mart ´ı n, T.; Palaz o´ n,
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. (a) Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 661–
2 2 3
CH Cl was added anhydrous FeX (1 equiv) in one
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2
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