Control of skeletal connectivity in indium promoted reactions: 1,2-Additions and cope rearrangements en route to lactol formation

Article abstract of DOI:10.1021/jo070020k

(Chemical Equation Presented) Indium promoted coupling reactions between propargyl aldehydes (3) and allyl halides under aqueous and organic conditions are reported. Coupling reactions under aqueous conditions occur via 1,2-addition with excellent yields

Full text of DOI:10.1021/jo070020k

Control of Skeletal Connectivity in Indium Promoted Reactions:
1,2-Additions and Cope Rearrangements En Route to
Lactol Formation
Thomas Mitzel,* Joe Wzorek, Annie Troutman, and Kristen Allegue
Department of Chemistry, Trinity College, 300 Summit Street, Hartford, Connecticut 06106
thomas.mitzel@trincoll.edu
ReceiVed January 4, 2007
Indium promoted coupling reactions between propargyl aldehydes (3) and allyl halides under aqueous
and organic conditions are reported. Coupling reactions under aqueous conditions occur via 1,2-addition
with excellent yields to afford 4-hydroxy-1-ene-5-ynes (8). Coupling reactions under organic conditions
also add in a 1,2-fashion, but the initial products can be induced to undergo oxy-Cope rearrangements
giving 2,5-hexadienals (9). Oxy-Cope rearrangement of 8 followed by a secondary addition step under
highly basic conditions leads to lactol formation (10) in good to excellent yields. This paper reveals the
versatility and control of product formation which may be attained when working with propargyl aldehyde
(3) and allyl halide systems under indium promoted coupling conditions.
Introduction
find wide use as synthetic templates in natural product syntheses
2
(eq 1). A natural extension of this chemistry was to utilize a
Previous work in our laboratory has focused on stereocon-
trolled coupling reactions between R-chloropropargyl phenyl
1
sulfide (1) and aldehyde partners. This work culminated in
stereocontrolled formation of epoxyalkyne structures (2) which
(1) (a) Engstrom, G.; Morelli, M.; Palomo, C.; Mitzel, T. Tetrahedron
Lett. 1999, 40, 5967. (b) Palomo, C.; Jendza, K.; Mitzel, T. M. J. Org.
Chem. 2002, 67, 136.
(
2) (a) Odedra, A.; Wu, C.-J.; Madhushaw, R. J.; Wang, S.-L.; Liu,
R.-S. J. Am. Chem. Soc. 2003, 125, 9610. (b) Lo, C.-Y.; Guo, H.; Lian,
J.-J.; Shen, F.-M.; Liu, R.-S. J. Org. Chem. 2002, 67, 3930. (c) Kanger, T.;
Piret, J.; M u¨ u¨ risep, A. M.; Pek, T.; Lopp, M. Tetrahedron: Asymmetry
1
998, 9, 2499. (d) Bernard, N.; Chemla, F.; Normant, J. F. Tetrahedron
3a
propargyl aldehyde (3) as the electrophilic component, forming
a â-hydroxy phenyl sulfide structure (4), which could then be
converted to either an enediyne (5) or an epoxydiyne (6) (eq
Lett. 1998, 39, 6715. (e) Aurrecoechea, J. M.; Alonso, E.; Solay, M.
Tetrahedron 1998, 54, 3833. (f) Piotti, M. E.; Alper, H. J. Org. Chem.
1
1
997, 62, 8484. (g) Wu, S. H.; Huang, B. Z.; Gao, X. Synth. Commun.
990, 20, 1279. (h) Bohlmann, F.; Burkhardt, T.; Zdero, C. Naturally
2
). Both enediyne and epoxydiyne functional groups are present
Occurring Acetylenes; Academic Press: New York, 1973.
3) Examples of formation of propargyl aldehydes: (a) Journet, M.; Cai,
4
in natural products shown to have anticarcinogenic properties.
This system was intriguing due to the short synthetic route, good
stereocontrol of the coupling step with indium organometallics
to aldehydes as shown in previous studies, and benign
conditions under which indium promoted C-C bond forming
reactions of this type are conducted.
(
D.; DiMichele, L. M.; Larsen, R. D. Tetrahedron Lett. 1998, 39, 6427. (b)
Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J. Org. Chem.
2
002, 67, 5032. (c) Dixon, D. J.; Ley, S. V.; Tate, E. W. Synlett 1998,
1
1
093. (d) Trost, B. M.; Schmidt, T. J. Am. Chem. Soc. 1988, 110, 2301. (e)
Molander, G. A.; McWilliams, J. C.; Noll, B. C. J. Am. Chem. Soc. 1997,
19, 1265. (f) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
1
10.1021/jo070020k CCC: $37.00 © 2007 American Chemical Society
3
042
J. Org. Chem. 2007, 72, 3042-3052
Published on Web 03/10/2007

1
,2-Additions and Cope Rearrangements
Study of the above system, as will be discussed, led to
TABLE 1. Ratio of 1,2-Addition Product (4) vs Plausible Product
of Side Reaction (7)
detection of an interesting side product that appeared to be
formed by either a Michael addition or a 1,2-addition followed
by a Cope rearrangement. Formation of this side product was
found to be solvent dependent, raising interesting theoretical
and regiocontrol questions pertaining to indium promoted
couplings involving systems containing both conjugated elec-
5
trophilic and nucleophilic species. Recent work by Loh et al.,
6
7
Li et al., and Chan et al., which has focused on coupling of
conjugated indium species with carbonyl moieties and the effects
of solvent conditions upon regiocontrol, has revealed an exciting
area of chemistry in which good work has been accomplished,
but many questions still remain. This paper focuses on the study
of the addition of allylic indium organometallic species to
propargyl aldehyde partners and the effects of solvent and
reaction conditions on final product formation, with emphasis
on construction of six-membered ring lactols in good yields.
DMF
(ratio of 4/7)
entry
R
H2O
3:1 H2O/DMF
1
2
3
4
TMS
only 1,2-
only 1,2-
only 1,2-
only 1,2-
only 1,2-
only 1,2-
only 1,2-
only 1,2-
3:1
1.5:1
1:4
n-butyl
phenyl
TBSO(CH2)3
2:1
TABLE 2. Coupling of 3 and Allyl Bromide under Aqueous and
Organic Conditions
entry
R
solvent
ratio: 8/9
recovery (%)
1
2
3
4
5
6
7
8
9
10
TMS
H2O
DMF
THF
H2O
DMF
THF
H2O
DMF
THF
H2O
DMF
THF
only 1,2
7:1
1:3
only 1,2
5:1
1:3
only 1,2
6:1
1:4
only 1,2
10:1
1:2
55
57
8
87
85
7
90
87
7
53
55
9
n-butyl
phenyl
Results and Discussion
TBSO(CH2)3
11
Early Studies. Studies in this area began with an examination
of indium coupling reactions of propargyl aldehydes (3) with
R-chloropropargyl sulfide (1). Product formation was shown to
be solvent dependent, with clean 1,2-addition observed under
aqueous conditions but mixtures of isomeric products formed
under organic conditions (Table 1). The percent recovery of
product mixture, while excellent in water, was quite low in
organic solvents, rendering isolation and full characterization
of the side product within this particular system difficult. A
plausible structure for the isomeric byproduct is 7. The
difference witnessed in regioselectivity, which appeared to be
linked to solvent conditions, was intriguing and warranted
further investigation. First, however, it was necessary to
determine beginning conditions that could maximize yields of
product in nonaqueous systems.
12
the nucleophilic species. Conditions mentioned in Table 1 were
replicated with the new system, yielding results shown in
Table 2.
Use of organic solvent conditions resulted in a mixture of 8
and 9 as shown. The percent recovery of products was good in
DMF but very low in THF. Indium promoted coupling reactions
have historically been shown to proceed more quickly and in
higher percent yields in more polar solvents, so this finding
was not too surprising. Using water as a solvent, only 8 was
formed. On the basis of this outcome, it was theorized that 9
formed via an oxy-Cope rearrangement, following the pathway
proposed in Scheme 1. The first step along this mechanistic
pathway is a 1,2-addition, forming an oxy-intermediate chelated
to the indium complex. Under aqueous conditions, this
1
,8
9
Model System/Mechanistic Hypothesis. As a result of
difficulties noted with isolation and characterization of mixtures
reported in Table 1, the system was simplified, replacing 1 with
a structurally more simplistic allyl bromide as the source of
9
c
(
8) For reviews and examples: (a) Li, C.-J. Chem. ReV. 2005, 105, 3095.
(
b) Araki, S.; Hirashita, T. In Main Group Metals in Organic Synthesis;
Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 1, pp 323-386. (c) Paquette, L. A. In Green Chemistry: Frontiers in
Benign Chemical Synthesis and Processing; Anastas, P., Williamson, T.,
Eds.; Oxford University Press: New York, 1998. (d) Li, C. J.; Chan, T. H.
Organic Reactions in Aqueous Media; John Wiley & Sons: New York,
1997. (e) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149. (f) Paquette,
L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996, 118, 1931.
(9) For reviews and examples: (a) Clayden, J.; Greeves, N.; Warren,
S.; Wothers, P. Organic Chemistry; Oxford University Press: New York,
2001; pp 947-951. (b) Gagosz, F. Org. Lett. 2005, 7, 4129. (c) White,
B. H.; Snapper, M. L. J. Am. Chem. Soc. 2003, 135, 14901-14904. (d)
Santora, V. J.; Moore, H. W. J. Org. Chem. 1996, 61, 7976. (e) Viola, A.;
MacMillan, J. H. J. Am. Chem. Soc. 1970, 92, 2404.
(
4) (a) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J. S.;
Shen, B. Chem. ReV. 2005, 105, 739. (b) Basak, A.; Mandal, S.; Bag, S. S.
Chem. ReV. 2003, 103, 4077. (c) Konig, B.; Pitsch, W.; Klein, M.; Vasold,
R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2001, 66, 1742. (d) Shair,
M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am.
Chem. Soc. 1996, 118, 9509. (e) Bergman, R. G. Acc. Chem. Res. 1973,
6
, 25.
(5) Lin, M. J.; Loh, T. P. J. Am. Chem. Soc. 2003, 125, 13042.
6) Yi, X. H.; Meng, Y.; Hua, X. G.; Li, C. J. J. Org. Chem. 1998, 63,
(
7
472.
7) (a) Isaac, M. B.; Chan, T. H. Chem. Commun. 1995, 1003. (b) Chan,
T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228.
(
J. Org. Chem, Vol. 72, No. 8, 2007 3043

Mitzel et al.
SCHEME 1. Hypothesized Oxy-Cope Rearrangement
TABLE 4. Lactol Formation Using 3 Containing Varying R
Groups
entry
R
recovery (%)
1
2
3
4
H3C(H2C)4-
H3C(H2C)3-
Ph
93
89
23
25
TMSa
a
When R ) TMS in the starting alcohol, R ) H in the final product.
case did rearrangement occur, and starting material was isolated
1
0a
pure. Use of potassium bis(TMS) amide resulted in decom-
position of the starting material at room temperature. At
TABLE 3. Conditions To Induce Cope Rearrangement
-
78 °C, no reaction occurred with this reagent. Mixing 8 with
n-BuLi gave a small amount of 9 at both -78 °C and room
temperature; however, much decomposition was noted under
both conditions. Sodium hydride resulted in no rearrangement
10b
1
0c
at any temperature. Potassium hydride proved to be best for
inducing oxy-Cope rearrangement of 8, with rearrangement
occurring at approximately -40 °C in a THF mixture of 8 and
KH in the presence of 18-crown-6. TLC and MS data revealed
disappearance of all starting material and formation of a single
product. To our surprise, the data did not match a structure
product mixture
recovery %)
(
entry
base
conditions
8
9
10
1
2
3
4
5
6
7
8
9
Amberlite resin stirring
Amberlite resin column
100
100
100
0
0
0
0
0
0
11,12
consistent with 9 but rather matched that of 10, a lactol.
Lactols create much interest in carbohydrate chemistry and
KN(TMS)2
KN(TMS)2
n-BuLi
n-BuLi
NaH
KH
KH
KH
-78 °C, THF
11
a
-78 °C to rt, THF
-78 °C, THF
decomposition
85
35
100
100
1
2
15
65
0
0
0
0
0
as organic templates, so we were quite motivated to elucidate
the mechanism of formation for the lactol product and how it
related to an oxy-Cope rearrangement. To determine the
efficiency of this transformation, a series of propargyl homoal-
lylic alcohols (8) was exposed to KH in the presence of 18-
crown-6. In each case, the starting material, dissolved in THF,
was cooled to-78 °C at which time KH and 18-crown-6 were
added. After stirring at -78 °C for 30 min, the reaction mixture
was raised to -40 °C where it was kept until TLC revealed the
disappearance of the starting alcohol and appearance of product.
The reactions were very clean and are summarized in Table 4.
Use of 18-crown-6 was necessary to promote the reaction.
Mixing of 8 with KH in the absence of 18-crown-6 led to
decomposition of the starting material with no discernible
product formed.
Although results from Table 4 do not present a product arising
from a straightforward Cope rearrangement, closer scrutiny of
the system reveals this is indeed what occurs. Previous work13
with anionic oxy-Cope rearrangements has noted a fairly
common side reaction involving fragmentation of unsaturated
groups at the â-position to an alcohol moiety. For our system,
-78 °C to rt, THF
-78 °C to rt, THF
-78 °C, THF
-78 °C to rt, THF
-78 °C to 40 °C, THF
0
a
decomposition
1
0
0
0
100
a
Entries 4 and 9 resulted mostly in decomposition of starting material.
intermediate quickly picks up a proton to give 8. Under organic
conditions, where no proton source is present, the oxy-indium
intermediate is long-lived, and the unprotonated oxygen is much
more likely to promote an oxy-Cope rearrangement to form an
allenol intermediate. The formation of an allenol intermediate
was shown to occur with hexen-1-yn-3-ol thermolytically in
1
970, and it seems reasonable that this intermediate is forming
9c
under our conditions as well. After rearrangement occurs, the
ensuing allenyl intermediate is protonated and tautomerizes upon
workup to give 9 as the final structure. From Table 2, it is seen
that the Cope rearrangement, if this is indeed the pathway
followed, does not occur efficiently, so it was necessary to
determine conditions that would maximize the potential of
rearrangement, increasing the percent formation of 9.
Cope Rearrangement and Lactol Formation. Since it was
possible to form 8 in high yield under aqueous conditions, it
was initially decided to isolate this product and promote the
oxy-Cope rearrangement in a second, separate step. Several
reagents were tested for this purpose as shown in Table 3.
Amberlite IRA-900 ion-exchange resin with a benzyltrialkyl-
ammonium functionality was utilized to determine if conversion
could occur under mild conditions. Alcohol (8) was both stirred
with Amberlite resin and “washed” down the resin in column
chromatography fashion using hexanes as the eluent. In neither
(10) Representative examples: (a) Tsui, H.-C.; Paquette, L. A. J. Org.
Chem. 1998, 63, 9968. (b) Evans, D. A.; Baillargeon, D. J.; Nelson, J. V.
J. Am. Chem. Soc. 1978, 100, 2242. (c) Wei, S.-Y. Tomooka, K.; Nakai,
T. J. Org. Chem. 1991, 56, 5973.
(11) (a) Cuerrier, D.; Moldoveanu, T.; Inoue, J.; Davies, P. L.; Campbell,
R. L. Biochemistry 2006, 45, 7446. (b) Yu, X.-M.; Han, H.; Blagg, B. S.
J. J. Org. Chem. 2005, 70, 5599. (c) Bates, R. B.; Haber, W. A.; Setzer,
W. N.; Stessman, C. C. J. Nat. Prod. 1999, 62, 340.
(12) (a) Vu, C. C.; Peterson, L. A. Chem. Res. Toxicol. 2005, 18, 1012.
(
b) Pansare, S. V.; Jain, R. P. Org. Lett. 2000, 2, 175. (c) Buckley, N.;
Oppenheimer, N. J. J. Org. Chem. 1996, 61, 8048.
13) (a) Wilson, S. Org. React. 1993, 43, 93. (b) Lutz, R. P. Chem. ReV.
1984, 84, 205.
(
3044 J. Org. Chem., Vol. 72, No. 8, 2007

1
,2-Additions and Cope Rearrangements
SCHEME 2. Fragmentation Pathway for Anionic Oxy-Cope
SCHEME 3. Lactol Formation by Reaction Cope Dianion
with 12
the fragments shown in Scheme 2 could arise from this type of
cleavage. This step is reversible, and re-formation of the two
fragments is possible, especially under strongly basic conditions.
When R ) phenyl, the product mixture contains a large amount
of 12, indicating that bond cleavage occurs quickly with little
recombination of the fragments and that rearrangement is slower
than cleavage. We have not seen evidence for 11 or products
that could arise from the alkynyl anion in our product mixtures.
MS data associated with 12 are detected in all systems. When
R ) alkyl, 12 is not witnessed in our final product mixture,
and product recoveries are as high as 93% (Table 4, entry 1).
It is surmised that 12 is integrated into the final lactol structure
by reaction with the anion of 9 as shown in Scheme 3. Initial
oxy-Cope rearrangement gives an anion intermediate (A). Under
the highly basic conditions, KH may remove a proton from the
acidic doubly allylic proton position in structure A of
Scheme 3.
A dianionic species such as one that would form from A is
feasible and has literature precedence.14 The dianion formed
by deprotonation of A reacts with 12, giving allenic anion (B).
At this stage, reduction of the sp-hybridized atom in the allene
occurs by interaction with KH. Although this step is a bit
to act as reducing agents.16 The dianionic intermediate proposed
in Kowalski’s work reveals the viability of forming these
multicharged species under highly basic conditions.1 Finally,
quenching of the anionic intermediate (C) leads to 10 as shown
in Scheme 3. Formation of this anionic species would argue
toward highly basic conditions being necessary to drive this
reaction in THF, and indeed an increase in the amount of KH
15
unconventional, Kowalski et al. have shown a similar reduction
5a,b
15b
of sp-centers with an alkali metal hydride (eq 3 ), and other
1
7
(up to 4 equiv) accelerates the reaction and raises the yield of
lactol product. To provide further evidence for this pathway,
substituted allylic systems (13, 14) were used in the addition/
rearrangement reaction. Crotyl bromide was used to form 13
while 3-chloro-1-butene was used to form 14. As shown in
Scheme 4, each of these systems forms a lactol structure which
would be predicted following the mechanistic pathway in
Scheme 3. The yield for 15 is low, which is believed to be due
to the second allylic position present in the intermediate shown
in Figure 1. Deprotonation may occur from the second allylic
site, giving rise to other products and lowering the overall
(16) (a) Pi, R.; Friedl, T.; Schleyer, P. v. R.; Klusener, P.; Brandsma, L.
J. Org. Chem. 1987, 52, 4299. (b) Zippi, E. M. Synth. Commun. 1994, 24,
2515. (c) Ohkuma, T.; Shohei, H.; Noyori, R. J. Org. Chem. 1994, 59,
work has shown the propensity for KH and other metal hydrides
217. (d) Zhang, W.; Liao, S.; Xu, Y. Zhang, Y. Synth. Commun. 1997, 27,
977.
3
(
(
14) Dimmel, D. R.; Charpure, S. B. J. Am. Chem. Soc. 1971, 93, 3991.
15) (a) Kowalski, C. J.; Haque, S. J. Am. Chem. Soc. 1986, 108, 1325.
(17) For an NMR comparison of a lactol containing similar structural
qualities: Barlow, A. J.; Compton, B. J.; Weavers, R. T. J. Org. Chem.
2005, 70, 2470.
(
b) Kowalski, C. J.; Lal, G. S. J. Am. Chem. Soc. 1986, 108, 5356.
J. Org. Chem, Vol. 72, No. 8, 2007 3045

Mitzel et al.
SCHEME 5. Formation of Ester Product
FIGURE 1. Allylic sites available for deprotonation under anionic
rearrangement conditions for 13.
SCHEME 4. Use of Substituted Allylic Systems
SCHEME 6. Formation of Cope Product via Cascade
Conditions
product yield. When 13 was exposed to KH/18-crown-6 in THF
as the sole solvent, the solution quickly turned black, and no
product was isolated from the mixture. Use of Et2O as a
cosolvent (30%), however, gave rise to the formation of lactol,
albeit in a low yield (9.5%). Use of 14 also required Et2O as a
cosolvent during the reaction and resulted in formation of 16
in 40% yield. In each case, the mechanistic pathway proposed
in Scheme 3 is confirmed, giving strong evidence for the oxy-
Cope rearrangement. Entry 4 from Table 4 is interesting in that
the final product is lacking the TMS groups originally present
in the starting material. These groups appear to be cleaved during
workup of the product mixture. The highly basic conditions
present during this reaction system promote formation of
hydroxy anions during quenching and workup, creating condi-
tions conducive to cleavage of the TMS groups.18
One-Pot Coupling/Cope Rearrangement. With the mech-
anism of product formation clarified and control of the lactol
products discovered, the final goal was to promote both a
coupling reaction and Cope rearrangement in a one-pot se-
quence. As Table 2 shows, some Cope product was formed in
reactions conducted in DMF and THF. It is assumed the oxy-
organometallic complex formed in the coupling step may
rearrange if oxygen remains unprotonated. Yields of conversion
in DMF and THF at room temperature were low, so conditions
that may help raise overall yields and conversion rates were
sought. Reactions outlined in Table 1 were repeated in DMF
and THF with heating. In both cases, yields were not raised
and decomposition of the mixture actually increased in DMF
around 50 °C.
We next turned to a seldom used solvent, N-methylformamide
NMF). The choice of NMF was determined by our need for
19
(
a very polar, organic solvent. NMF has a dielectric constant of
19a
19b
1
86.9, significantly greater than that of water at 78.37. It
was our hope that NMF would be polar enough to allow the
oxy-indium complexed intermediate to be sufficiently long-lived
to promote Cope rearrangement. As before, the coupling reaction
of 3 and allyl bromide was conducted at room temperature with
stirring. Although 8 was formed in good yield (80-95%), no
Cope product was produced under these conditions. Heating
caused an increase in the reaction rate en route to 8 but, again,
no Cope product. Cooling the NMF system to 0 °C provided
interesting results, as some of the systems revealed an increased
rate of coupling at this temperature compared to room temper-
ature, but again, no Cope product was isolated. It is possible
the oxy-anion intermediate is hydrogen bonding with the amide
proton of NMF, raising the energy for an oxy-Cope reaction to
occur. Upon workup of this reaction with water, 8 was isolated
as the product.
The system was sonicated next. It was hoped that the extra
energy offered by sonication would promote Cope rearrange-
ment. There was indeed a minor, secondary reaction, resulting
from 8; however, it was determined that the oxy-indium complex
was reacting with NMF to form ester 17 as shown in Scheme
5
. Various Lewis acids were then tested, with the thought that
a Lewis acid may chelate with the oxygen atom, reducing
interaction of the oxygen with NMF, but 17 was formed under
Lewis acid conditions as well. Dimethylsulfoxide (DMSO) was
introduced as a cosolvent (DMSO/NMF (1:1)) in the presence
of a Lewis acid, and this change solved our problem to an extent
see Scheme 6). Under cosolvent conditions, 9 was isolated in
yields up to 35%. Overall recovery of the product mixture was
approximately 45% with 17 and 8 making up the additional
0%. To determine whether the initial step of this reaction was
a Michael addition or a 1,2-addition followed by a Cope
rearrangement, aliquot workups were performed during the
course of the study. After approximately 30 min, formation of
the 1,2-addition product was witnessed in all systems. After
approximately 2-4 h, 8 was the sole species in the reaction
Sonication of the reaction mixtures was next attempted.
Percent formation of 9 increased slightly in DMF but never
above 11%. Initial coupling to form 7 increased significantly
in THF with sonication, with yields over 80% realized; however,
an increase of Cope product was not witnessed under these
conditions.
(
1
(
18) Abad, A.; Agullo, C.; Cunat, A. C.; Perni, R. H. J. Org. Chem.
999, 64, 1741.
19) (a) Rohdewald, P.; Moldner, M. J. Phys. Chem. 1973, 77, 373.
b) Vidulich, G. A.; Kay, R. L. J. Phys. Chem. 1962, 66, 383.
1
(
(
3046 J. Org. Chem., Vol. 72, No. 8, 2007

1
,2-Additions and Cope Rearrangements
mixture, signifying 1,2-addition of the organometallic to the
aldehyde. After 24 h of reaction, traces of 17 and 9 began to
build in the mixture until it reached a peak after 72-84 h at
which time the reaction was stopped. At no time were
fragmentation products (Scheme 2) isolated in the mixtures
which signifies coupling initially occurs by 1,2-addition which
is then followed by a Cope rearrangement to give 9. Although
yields of the Cope product are modest, this is a nice cascade,
one-pot reaction sequence which can be controlled with only
slight solvent modifications. DMSO as the sole solvent was not
effective in promoting formation of 9. Use of DMSO as the
sole solvent yielded mainly 8 with only traces of 9 as witnessed
by GC-MS. In the absence of sonication, only 8 is isolated in
excellent yields. If the reaction mixture is sonicated, 9 is formed
in modest yields beginning from uncoupled aldehyde 3 and an
allyl halide.
of this reaction proceeded as described in part I.a. Separation was
accomplished using radial chromatography on silica gel (35:1
hexanes-ethyl acetate) to give a mixture of diastereomeric hydroxy
1
sulfides. Yield ) 418 mg (1.54 mmol) ) 70%; H NMR (300 MHz,
CDCl
3
) δ 0.24 (s, 9H), 1.79 (d, J ) 1.7 Hz, 0.25H), 1.84 (d, J )
1
1
.6 Hz, 0.75H), 4.15 (dd, J ) 1.7, 7.8 Hz, 0.25H), 4.23 (dd, J )
.6, 5.3 Hz, 0.75H), 4.69 (d, J ) 7.8 Hz, 0.25H), 4.80 (d, J ) 5.3
Hz, 0.75H), 7.1-7.4 (m, 5H), the OH proton was not detected;
13
C NMR (75 MHz, CDCl
3
) δ 0.28 (44.1, 44.4), (66.5, 68.1), (67.5,
67.9), (74.1, 75.0), (83.2, 84.3), (86.4, 86.9), 125.0, 125.3, 126.5
+
(2), 127.3, 136.1; MS m/z (M ) calcd 274.0848, obsd 274.0819.
Anal. Calcd for C15
H, 6.55.
H18OSSi: C, 65.64; H, 6.61. Found: C, 65.17;
Conclusion
Indium promoted coupling of propargyl aldehydes (3) with
allyl halides results in the formation of propargyl alcohols (8)
under aqueous and organic conditions in good to excellent
yields. Use of the NMF/DMSO solvent mixture under sonication
affords a Cope rearrangement product (9) in modest yields,
revealing good regiocontrol in bond formation of these systems.
Exposure of 8 to KH-18-crown-6 in THF or THF-Et2O
solutions at low temperatures results in formation of lactol
compounds (10) in modest to excellent yields affording entry
to synthetic templates for use in natural product syntheses. These
three sets of reaction conditions offer nice versatility in bond-
forming reactions leading to controlled formation of very
different products beginning from an identical starting system
by altering reaction conditions slightly in each case.
4 9
I.a.2. Use of 2-Heptynal (R ) n-C H ) with r-Chloroprop-
argyl Phenyl Sulfide (1). Processing and analysis of this reaction
proceeded as described in part I.a. Separation was accomplished
using radial chromatography on silica gel (40:1 hexanes-ethyl
acetate) to give a mixture of diastereomeric hydroxy sulfides.
1
Yield ) 471 mg (1.76 mmol) ) 83%; H NMR (300 MHz, CDCl
3
)
δ 0.9-1.5 (m, 7H), 1.82 (d, J ) 1.7 Hz, 0.2H), 1.87 (d, J ) 1.6
Hz, 0.8H), 2.13 (t, J ) 6.5 Hz, 2H), 4.09 (m, 1H), 4.86 (m, 1H),
3
7
.1-7.3 (m, 5H), the OH proton was not detected; 1 C NMR (75
MHz, CDCl
3
) δ 15.5, 18.2, 21.3, 34.2, (41.5, 42.9), (65.0, 66.1),
7
1.3, 78.5, 80.2, 84.7, 125.4, 126.1, 126.3, 127.6, 128.0, 136.4;
+
MS m/z (M ) calcd 258.1078, obsd 258.0998. Anal. Calcd for
18OS: C, 74.38; H, 7.02. Found: C, 74.61; H, 6.99.
I.a.3. Use of 3-Phenylpropynal (R ) Phenyl) with r-Chlo-
16
C H
ropropargyl Phenyl Sulfide (1). Processing and analysis of this
reaction proceeded as described in part I.a. Separation was
accomplished using radial chromatography on silica gel (35:1
hexanes-ethyl acetate) to give a mixture of diastereomeric hydroxy
Experimental Section
General Experimental Procedures. Tetrahydrofuran was puri-
fied by distillation under an argon atmosphere over sodium and
1
sulfides. Yield ) 489 mg (1.78 mmol) ) 80%; H NMR (300 MHz,
benzophenone prior to use. Dimethylformamide and CCl
purified by distillation over CaH prior to use. All other solvents
were used as purchased. 18-Crown-6 was purified before use. All
other reagents were used as purchased. Radial chromatography was
performed using a Chromatotron.
4
were
3
CDCl ) δ 1.83 (d, J ) 1.8 Hz, 0.2H), 1.94 (d, J ) 1.8 Hz, 0.8H),
3.95 (dd, J ) 1.8, 8.1 Hz, 0.2H), 4.10 (dd, J ) 1,8, 4.7 Hz, 0.8H),
4.95 (d, J ) 8.1 Hz, 0.2H), 5.11 (d, J ) 4.7 Hz, 0.8H), 7.2-7.7
(m, 10H), the OH proton was not detected; 13C NMR (75 MHz,
2
CDCl
3
) δ (43.8, 44.1), (65.8, 66.0), 68.0, 81.3, 87.2, 93.6, 121.7,
1
25.8 (2), 127.3 (3), 128.1, 128.3(2), 129.3, 129.5, 136.1; MS m/z
I. Coupling Procedures for Propargyl Aldehyde (3) with
r-Chloropropargyl Phenyl Sulfide (1). I.a. General Procedure
Using Water as Solvent. A magnetically stirred solution of
aldehyde (3) (2.2 mmol) in deionized water (22 mL) was treated
with R-chloropropargyl phenyl sulfide (702 mg, 3.0 mmol) and
indium powder (252 mg, 2.2 mmol). The solution was allowed to
proceed at room temperature until no 3 was seen (TLC analysis).
Dichloromethane was added, and stirring was maintained for 30
min. The layers were separated, and the aqueous phase was
extracted with dichloromethane (2 × 10 mL). The combined organic
+
(
M ) calcd 278.0765, obsd 277.9986. Anal. Calcd for C18
C, 77.66; H, 5.07. Found: C, 77.28; H, 5.18.
I.a.4. Use of 6-(tert-Butyldimethylsiloxy)-2-hexynal (R )
CH -OTBS) with r-Chloropropargyl Phenyl Sulfide (1).
H14OS:
(
2 3
)
Processing and analysis of this reaction proceeded as described in
part I.a. Separation was accomplished using radial chromatography
on silica gel (35:1 hexanes-ethyl acetate) to give a mixture of
diastereomeric hydroxy sulfides. Yield ) 633 mg (1.69 mmol) )
1
7
1
1
7%; H NMR (300 MHz, CDCl
3
) δ 0.25 (s, 6H), 0.97 (s, 9H),
.25 (m, 2H), 1.80-2.00 (m, 3H), 3.83 (t, J ) 6.5, 2H), 4.11 (m,
4
layers were dried over MgSO and evaporated to leave a dark yellow
H), 4.99 (m, 1H), 7.1-7.4 (m, 5H), the OH proton was not
to brown oil. Purification was accomplished by flash chromatog-
13
3
detected; C NMR (75 MHz, CDCl ) δ 0.28 (2), 14.5, 15.1, 21.8
raphy or radial chromatography on silica gel (hexanes-ethyl
acetate) to give a mixture of hydroxy sulfides20 as a light yellow
(2), 21.9 33.4, 47.0, 64.6, 65.1, 67.9, 75.2, 81.9, 87.3, 125.4, 126.6
+
(
3
2), 127.1, 128.4, 135.9; MS m/z (M ) calcd 374.1736, obsd
65.1633 (loss of H O). Anal. Calcd for C21 SSi: C, 67.33;
H, 8.07. Found: C, 67.81; H, 7.95.
oil. No Cope product was witnessed under aqueous conditions.
I.a.1. Use of 3-Trimethylsilypropynal (R ) TMS) with
r-Chloropropargyl Phenyl Sulfide (1). Processing and analysis
2
30 2
H O
I.b. General Procedure Using Water/DMF (3:1 Mixture) as
Solvent. A magnetically stirred solution of aldehyde (3) (2.2 mmol)
in a solution of deionized water (16.5 mL) and DMF (5.5 mL) was
treated with R-chloropropargyl phenyl sulfide (702 mg, 3.0 mmol)
and indium powder (252 mg, 2.2 mmol). The solution was allowed
to proceed at room temperature until no 3 was seen (TLC analysis).
(20) (a) Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.;
Schomer, W. M. J. Org. Chem. 1997, 62, 4293. (b) Sato, T.; Otera, J.;
Nozaki, H. J. Org. Chem. 1990, 55, 6116. (c) Shimagaki, M.; Maeda, T.;
Matsuzaki, Y.; Hori, I.; Nakata, T.; Oishi, T. Tetrahedron Lett. 1984, 25,
4
775.
J. Org. Chem, Vol. 72, No. 8, 2007 3047

Mitzel et al.
Dichloromethane was added, and stirring was maintained for 30
min. The layers were separated, and the aqueous phase was
extracted with dichloromethane (2 × 10 mL). The combined organic
layers were washed with 1 N HCl until DMF was no longer present
II.a.2. Use of Hept-2-ynal (R ) n-Butyl) with Allyl Bromide.22
Processing and analysis of this reaction proceeded as described in
part I.a. Separation was accomplished using radial chromatography
on silica gel (35:1 hexanes-ethyl acetate) to give the alcohol.
1
(
generally about 3 × 20 mL washing). The organic layer was dried
Yield ) 290 mg (1.91 mmol) ) 87%; H NMR (300 MHz, CDCl
3
)
over MgSO and evaporated to leave a dark yellow to brown oil.
4
δ 0.91-1.51 (m, 7H), 1.93 (t, J ) 6.4 Hz, 2H), 2.28 (m, 2H), 4.45
Purification was accomplished by flash chromatography or radial
chromatography on silica gel (hexanes-ethyl acetate) to give a
mixture of hydroxy sulfides20 as a light yellow oil. No Cope product
was witnessed under these conditions. The products were analyzed
as shown in part I.a of the Experimental Section.
(m, 1H), 5.12 (m, 2H), 5.75 (m, 1H), the OH proton was not
detected; 13C NMR (75 MHz, CDCl
) δ 12.5, 16.4, 21.9, 32.0, 41.3,
3
+
65.8, 75.1, 79.6, 116.0, 136.9; MS m/z (M ) calcd 152.1201, obsd
152.1201.
II.a.3. Use of 3-Phenylpropynal (R ) Phenyl) with Allyl
Bromide.23 Processing and analysis of this reaction proceeded as
described in part I.a. Separation was accomplished using radial
chromatography on silica gel (35:1 hexanes-ethyl acetate) to give
the alcohol. Yield ) 340 mg (1.98 mmol) ) 90%. Spectra were
compared to that in ref 23.
I.c. General Procedure Using DMF as Solvent. A magnetically
stirred solution of aldehyde (3) (2.2 mmol) in DMF (22 mL) was
treated with R-chloropropargyl phenyl sulfide (702 mg, 3.0 mmol)
and indium powder (252 mg, 2.2 mmol). The solution was allowed
to proceed at room temperature until no 3 was seen (TLC analysis).
Dichloromethane (50 mL) and 1 N HCl (30 mL) were added, and
stirring was maintained for 30 min. The layers were separated, and
the aqueous phase was extracted with dichloromethane (2 × 10
mL). The combined organic layers were washed with 1 N HCl until
DMF was no longer present (generally about 3 × 20 mL washing).
II.a.4. Use of 6-(tert-Butyldimethylsiloxy)-2-hexynal (R )
22
(CH ) -OTBS) with Allyl Bromide. Processing and analysis
2
3
of this reaction proceeded as described in part I.a. Separation was
accomplished using radial chromatography on silica gel (25:1
hexanes-ethyl acetate) to give the alcohol. Yield ) 312 mg (1.17
1
The organic layer was dried over MgSO
4
and evaporated to leave
mmol) ) 53%; H NMR (300 MHz, CDCl ) δ 0.25 (s, 6H), 0.97
3
a brown oil. Separation of the 1,2-product and Cope product was
not possible at this stage due to low yields. Ratios shown in Table
(s, 9H), 1.31 (m, 2H), 2.00 (m, 2H), 2.31 (m, 2H), 3.80 (t, J ) 6.6,
2H), 4.41 (m, 1H), 5.10 (m, 2H), 5.74 (m, 1H), the OH proton was
not detected; 13C NMR (75 MHz, CDCl ) δ 0.25 (2), 14.5, 15.1,
1
are based on a comparison of the NMR peaks in the regions shown
3
below:
21.5 (3), 33.6, 41.3, 64.6, 67.3, 80.1, 92.4, 115.9, 136.9; MS m/z
+
(
M ) calcd 268.1859, obsd 268.1832. Anal. Calcd for C15
H O
28 2
Si:
C, 67.11; H, 10.51. Found: C, 67.21; H, 10.51.
II.b. General Procedure Using DMF as Solvent. A magneti-
cally stirred solution of aldehyde (3) (2.2 mmol) in DMF (22 mL)
was treated with allyl bromide (357 mg, 3.0 mmol) and indium
powder (252 mg, 2.2 mmol). The solution was allowed to proceed
at room temperature until no 3 was seen (TLC analysis). Dichlo-
romethane (50 mL) and 1 N HCl (30 mL) were added, and stirring
was maintained for 30 min. The layers were separated, and the
aqueous phase was extracted with dichloromethane (2 × 10 mL).
The combined organic layers were washed with 1 N HCl until DMF
was no longer present (generally about 3 × 20 mL washing). The
Mixture ratios, in general, between allene and alkyne products were
determined by comparing the allene proton shift, which is ap-
proximately δ 6.0-6.5 ppm, and the terminal proton of the alkyne
moiety, which occurs between δ 1.7-2.6 ppm depending on the
nature of R.
II. Coupling Procedures for Propargyl Aldehyde (3) with
Allyl Bromide. II.a. General Procedure Using Water as Solvent.
A magnetically stirred solution of aldehyde (3) (2.2 mmol) in
deionized water (22 mL) was treated with allyl bromide (357 mg,
4
organic layer was dried over MgSO and evaporated to leave a
brown oil. Separation of the 1,2-product and the Cope product was
not possible at this stage. Ratios shown in Table 2 are based on a
comparison of the NMR peaks in the regions shown below:
3
.0 mmol) and indium powder (252 mg, 2.2 mmol). The solution
was allowed to proceed at room temperature until no 3 was seen
TLC analysis). Dichloromethane (30 mL) was added, and stirring
(
was maintained for 30 min. The layers were separated, and the
aqueous phase was extracted with dichloromethane (2 × 10 mL).
4
The combined organic layers were dried over MgSO and evapo-
II.c. General Procedure Using THF as Solvent. A magnetically
stirred solution of aldehyde (3) (2.2 mmol) in THF (22 mL) was
treated with allyl bromide (357 mg, 3.0 mmol) and indium powder
rated to leave a dark yellow to brown oil. Purification was
accomplished by flash chromatography or radial chromatography
on silica gel (hexanes-ethyl acetate) to give the alcohol as a light
yellow oil. No Cope product was witnessed under aqueous
conditions.
(252 mg, 2.2 mmol). The solution was allowed to proceed at room
temperature until no 3 was seen (TLC analysis). The stirring period
for THF is generally 2-4 days in the absence of sonication.
Dichloromethane (50 mL) and 1 N HCl (30 mL) were added, and
stirring was maintained for 30 min. The layers were separated, and
the aqueous phase was extracted with dichloromethane (2 × 10
mL). The combined organic layers were washed with 1 N HCl until
THF was no longer present (generally 2 × 20 mL washing). The
II.a.1. Use of 3-Trimethylsilypropynal (R ) TMS) with Allyl
Bromide.21 Processing and analysis of this reaction proceeded as
described in part I.a. Separation was accomplished using radial
chromatography on silica gel (25:1 hexanes-ethyl acetate) to give
1
the alcohol. Yield ) 203 mg (1.21 mmol) ) 55%; H NMR (300
MHz, CDCl ) δ 0.17 (s, 9H), 2.48 (m, 2H), 4.42 (t, J ) 6.4 Hz,
3
4
organic layer was dried over MgSO and evaporated to leave a
1
H), 5.20 (m, 2H), 5.89 (m, 1H), the OH proton was not detected;
brown oil. Separation of the 1,2-product and the Cope product was
1
3
3
C NMR (75 MHz, CDCl ) δ 0.2 (3), 42.2, 62.2, 90.0, 106.1, 119.2,
+
1
33.0; MS m/z (M ) calcd 168.0970, obsd 167.0913 (loss of H).
(
22) For comparative synthesis: Hartley, R. C.; Lamothe, S.; Chan,
T. H. Tetrahedron Lett. 1993, 34, 1449.
(23) For spectral comparison: Mamane, V.; Gress, T.; Krause, H.;
Furstner, A. J. Am. Chem. Soc. 2004, 126, 8654.
(
21) For comparative NMR data: Burova, S. A.; McDonald, F. E.
J. Am. Chem. Soc. 2004, 124, 8188.
3048 J. Org. Chem., Vol. 72, No. 8, 2007

1
,2-Additions and Cope Rearrangements
not possible at this stage. Ratios shown in Table 2 are based on a
comparison of the NMR peaks in the regions discussed in part II.b
above.
the eluent to give a mixture of two diastereomers as a light yellow
oil. Yield ) 342 mg (89% recovery, theoretical 100% recovery
given fragmentation would be 385 mg); 1H NMR (300 MHz,
III. Formation of Lactol (10) from Alcohol (3) Using KH (18-
Crown-6). III.a. Formation of 6-(Hept-1-ynyl)-4-pentyl-5-vinyl-
tetrahydro-2H-pyran-2-ol from Undec-1-ene-5-yn-4-ol (R )
n-Pentyl). To a preweighed, flame dried, 250 mL, three-necked
flask equipped with a magnetic stir bar was added a KH-mineral
oil mixture. The mixture was washed with 3 × 5 mL THF to
remove the mineral oil. The flask was placed under high vacuum
3
CDCl ) δ 0.9-1.10 (m, 6H), 1.2-1.50 (m, 11H), 1.7-1.75 (m,
1H), 2.22 (m, 2H), 2.47 (m, 2H), 4.45 (m, 1H), 4.82 (m, 0.4H),
5.10 (m, 0.6H), 5.21 (m, 2H), 5.80 (m, 1H), the OH proton was
not detected; 13C NMR (75 MHz, CDCl
23.5, 23.6, 29.8, 30.5, 32.1, 32.3, (41.3, 41.4), (66.5, 67.6), 77.7,
79.3, (90.4, 92.5), 118.2, 135.0; MS m/z (M ) calcd 264.2089, obsd
) δ 15.0 (2), 19.4, 23.0,
3
+
246.1873 (loss of water). Anal. Calcd for C17
10.67. Found: C, 77.43; H, 10.75.
28 2
H O : C, 77.22; H,
(0.002 mmHg) to remove solvent traces leaving KH as a gray solid,
which was then weighed (720 mg, 18.0 mmol of KH). To this solid
was added 50 mL of THF, and the resulting mixture was cooled to
III.c. Formation of 4-Phenyl-6-(2-phenylethynyl)-5-vinyl-
tetrahydro-2H-pyran-2-ol from 6-Phenyl-hex-1-ene-5-yn-4-ol
(R ) Phenyl). To a preweighed, flame dried, 100 mL, three-necked
flask equipped with a magnetic stir bar was added a KH-mineral
oil mixture. The mixture was washed with 3 × 5 mL of THF to
remove the mineral oil. The flask was placed under high vacuum
(0.002 mmHg) to remove solvent traces leaving KH as a gray solid,
which was then weighed (313 mg, 7.83 mmol of KH). To this solid
was added 30 mL of THF, and the resulting mixture was cooled to
-78 °C under an argon atmosphere. A 10 mL solution of alcohol
(334 mg, 1.94 mmol) and 18-crown-6 (525 mg, 1.99 mmol) in THF
were added to the KH mixture with stirring over a 5-10 min period.
The resulting solution was allowed to warm to -40 °C over a period
of 1.5 h, then allowed to warm to 0 °C over an additional 1 h. The
reaction was quenched by dropwise addition of 20 mL of water
over 30 min. The mixture was extracted with 2 × 20 mL of
dichloromethane. The organic layers were combined and washed
with 3 × 25 mL of 1 N HCl. The organic layers were dried over
-
78 °C under an argon atmosphere. A 20 mL solution of alcohol
762 mg, 4.59 mmol) and 18-crown-6 (1.192 g, 4.51 mmol) in THF
(
were added to the KH mixture with stirring over a 5-10 min period.
The resulting solution was allowed to warm to -40 °C over a period
of 1.5 h, then allowed to warm to 0 °C over an additional 1 h. The
reaction was quenched by dropwise addition of water (30 mL) over
3
0 min. The mixture was extracted with 2 × 25 mL of dichlo-
romethane. The organic layers were combined and washed with 3
40 mL of 1 N HCl. The organic layers were dried over MgSO
×
4
,
and the solvent was removed in vacuo to give the crude product as
a brown oil. The crude product was purified by radial chromatog-
raphy on silica gel using 25:1 hexanes-ethyl acetate as the eluent
to give a mixture of two diastereomers as a light yellow oil.
There are two diastereomers present as seen by NMR. It is
proposed that the alkyl groups are equatorial and the OH group is
either equatorial or axial as shown below. No further spectral
elucidation was conducted at this time. Yield ) 617 mg (93%
MgSO , and the solvent was removed in vacuo to give the crude
4
recovery, theoretical 100% recovery given fragmentation would be
product as a brown oil. The crude product was purified by radial
1
6
1
4
64 mg); H NMR (300 MHz, CDCl
3
) δ 0.9-1.00 (m, 6H), 1.2-
chromatography on silica gel using 25:1 hexanes-ethyl acetate as
the eluent to give a mixture of two diastereomers as a light yellow
oil. Yield ) 53 mg (18% recovery, theoretical 100% recovery given
.50 (m, 15H), 1.7-1.75 (m, 1H), 2.20 (m, 2H), 2.46 (m, 2H),
.40 (m, 1H), 4.78 (m, 0.4H), 5.03 (m, 0.6H), 5.20 (m, 2H), 5.80
m, 1H), the OH proton was not detected; 13C NMR (75 MHz,
1
(
fragmentation would be 385 mg); H NMR (300 MHz, CDCl ) δ
3
CDCl
3
) δ 14.9, 15.0, 19.7, 23.1 (2), 23.6, 29.5, 30.7, 31.5, 32.0,
1.60 (m, 1H), 2.71 (m, 3H), 4.69 (m, 1H), 4.91 (m, 0.4H), 5.15
3
1
2.5, 37.3, (41.3, 41.4), (66.5, 67.5), 77.7, 79.4, (90.4, 92.4), 118.0,
34.9; MS m/z (M ) calcd 292.2402, obsd 274.2315 (loss of water).
(m, 0.6H), 5.20 (m, 2H), 5.95 (m, 1H), 7.2-7.6 (m, 10H), the OH
+
13
proton was not detected; C NMR (75 MHz, CDCl ) δ 25.1, 39.8,
3
Anal. Calcd for C19
H, 11.09.
32 2
H O : C, 78.03; H, 11.03. Found: C, 77.95;
(41.2, 41.3), (66.9, 68.1), 78.4, 88.1, (91.0, 93.1), 118.9, 122.1,
123.6, 127.7, 128.3(2), 129.2, 129.4(2), 132.8(2), 134.4(2), 136.6;
+
MS m/z (M ) calcd 304.1463, obsd 286.1427 (loss of water). Anal.
20 2
Calcd for C21H O : C, 82.86; H, 6.62. Found: C, 82.83; H, 6.58.
III.d. Formation of 6-Ethynyl-5-vinyl-tetrahydropyran-2-ol
from 6-Trimethylsilyl-hexa-1-ene-5-yn-4-ol (R ) TMS, in Start-
ing Material Only, Cleaved during Reaction). To a preweighed,
flame dried, 50 mL, three-necked flask equipped with a magnetic
stir bar was added a KH-mineral oil mixture. The mixture was
washed with 3 × 5 mL of THF to remove the mineral oil. The
flask was placed under high vacuum (0.002 mmHg) to remove
solvent traces leaving KH as a gray solid, which was then weighed
(174 mg, 4.35 mmol of KH). To this solid was added 15 mL of
THF, and the resulting mixture was cooled to -78 °C under an
argon atmosphere. A 5 mL solution of alcohol (168 mg, 1.00 mmol)
and 18-crown-6 (269 mg, 1.00 mmol) in THF were added to the
KH mixture with stirring over a 5-10 min period. The resulting
solution was allowed to warm to -40 °C over a period of 1.5 h,
then allowed to warm to 0 °C over an additional 1 h. The reaction
was quenched by dropwise addition of 15 mL of water over 30
min. The mixture was extracted with 2 × 15 mL of dichlo-
romethane. The organic layers were combined and washed with
III.b. Formation of 6-(Hex-1-ynyl)-4-butyl-5-vinyl-tetrahydro-
H-pyran-2-ol from Dec-1-ene-5-yn-4-ol (R ) n-Butyl). To a
2
preweighed, flame dried, 250 mL, three-necked flask equipped with
a magnetic stir bar was added a KH-mineral oil mixture. The
mixture was washed with 3 × 5 mL of THF to remove the mineral
oil. The flask was placed under high vacuum (0.002 mmHg) to
remove solvent traces leaving KH as a gray solid, which was then
weighed (475 mg, 11.8 mmol of KH). To this solid was added 35
mL of THF, and the resulting mixture was cooled to -78 °C under
an argon atmosphere. A 15 mL solution of alcohol (448 mg, 2.95
mmol) and 18-crown-6 (752 mg, 2.85 mmol) in THF were added
to the KH mixture with stirring over a 5-10 min period. The
resulting solution was allowed to warm to -40 °C over a period
of 1.5 h, then allowed to warm to 0 °C over an additional 1 h. The
reaction was quenched by dropwise addition of 20 mL of water
over 30 min. The mixture was extracted with 2 × 20 mL of
dichloromethane. The organic layers were combined and washed
with 3 × 25 mL of 1 N HCl. The organic layers were dried over
3 × 15 mL of 1 N HCl. It should be noted that the R
f
of the product,
as monitored by TLC, was reduced significantly during the workup
phase, signifying removal of the TMS groups. We were unable to
avoid cleavage of the TMS-group in our workup procedure using
4
several methods. The organic layers were dried over MgSO , and
the solvent was removed in vacuo to give the crude product as a
brown oil. The crude product was purified by radial chromatography
on silica gel using 25:1 hexanes-ethyl acetate as the eluent to give
a mixture of two diastereomers as a light yellow oil. Yield ) 18
4
MgSO , and the solvent was removed in vacuo to give the crude
product as a brown oil. The crude product was purified by radial
chromatography on silica gel using 25:1 hexanes-ethyl acetate as
J. Org. Chem, Vol. 72, No. 8, 2007 3049

Mitzel et al.
10H), the OH proton was not detected; 13C NMR (75 MHz, CDCl
)
3
mg (25% recovery, theoretical 100% recovery given fragmentation
1
would be 75 mg); H NMR (300 MHz, CDCl
.46 (m, 2H), 2.58 (m, 2H), 4.45 (m, 1H), 4.85 (m, 0.3H), 5.11
m, 0.7H), 5.25 (m, 2H), 5.90 (m, 1H), the OH proton was not
3
) δ 1.10 (m, 2H),
δ 19.0, 28.0, 37.5, (40.9, 41.5), (66.2, 67.4), 78.3, 88.1, (90.9, 93.1),
2
122.6, 124.2, 125.8, 128.1, 128.3 (2), 128.5 (2), 128.6, 128.9, 132.1,
+
(
132.2, 133.1, 138.4; MS m/z (M ) calcd 318.1620, obsd 300.1514
13
detected; C NMR (75 MHz, CDCl
66.1, 67.2), 75.1, 83.1, (90.6, 92.9), 119.1, 134.2; MS m/z (M )
calcd 152.0837, obsd 152.0833. Anal. Calcd for C : C, 71.03;
H, 7.95. Found: C, 70.99; H, 8.01.
3
) δ 25.6, 38.1, (40.8, 40.9),
(loss of water). Anal. Calcd for C22
Found: C, 83.20; H, 6.89.
22 2
H O : C, 82.99; H, 6.96.
+
(
H O
9 12 2
V. Formation of Lactol (16) from Alcohol (14) Using KH (18-
Crown-6). V.a. Formation of 6-(Hex-1-ynyl)-4-butyl-5-methyl-
5-vinyl-tetrahydro-2H-pyran-2-ol from Undec-6-yne-2-ene -5-
ol (R ) n-Butyl). To a preweighed, flame dried, 200 mL, three-
necked flask equipped with a magnetic stir bar was added a KH-
mineral oil mixture. The mixture was washed with 3 × 5 mL of
THF to remove the mineral oil. The flask was placed under high
vacuum (0.002 mmHg) to remove solvent traces leaving KH as a
gray solid, which was then weighed (765 mg, 19.1 mmol of KH).
IV. Formation of Lactol (15) from Alcohol (13) Using KH
18-Crown-6). IV.a. Formation of 6-(Hex-1-ynyl)-4-butyl-5-(2-
(
methylvinyl)-tetrahydro-2H-pyran-2-ol from 3-Methyl-dec-5-
yne-1-ene-4-ol (R ) n-Butyl). To a preweighed, flame dried, 200
mL, three-necked flask equipped with a magnetic stir bar was added
a KH-mineral oil mixture. The mixture was washed with 3 × 5
mL of THF to remove the mineral oil. The flask was placed under
high vacuum (0.002 mmHg) to remove solvent traces leaving KH
as a gray solid, which was then weighed (695 mg, 17.3 mmol of
To this solid was added 50 mL of a 30% Et
and the resulting mixture was cooled to -78 °C under an argon
atmosphere. A 20 mL solution (30% Et O in THF) of alcohol (790
2
O solution in THF,
KH). To this solid was added 50 mL of a 30% Et
THF, and the resulting mixture was cooled to -78 °C under an
argon atmosphere. A 20 mL solution (30% Et O in THF) of alcohol
762 mg, 4.59 mmol) and 18-crown-6 (1.192 g, 4.51 mmol) were
2
O solution in
2
mg, 4.78 mmol) and 18-crown-6 (1.261 g, 4.78 mmol) were added
to the KH mixture with stirring over a 5-10 min period. The
resulting solution was allowed to warm to -40 °C over a period
of 1.5 h, then allowed to warm to 0 °C over an additional 1 h. The
reaction was quenched by dropwise addition of 30 mL of water
over 30 min. The mixture was extracted with 2 × 25 mL of
dichloromethane. The organic layers were combined and washed
with 3 × 40 mL of 1 N HCl. The organic layers were dried over
2
(
added to the KH mixture with stirring over a 5-10 min period.
The resulting solution was allowed to warm to -40 °C over a period
of 1.5 h, then allowed to warm to 0 °C over an additional 1 h. The
reaction mixture was quenched by dropwise addition of 30 mL of
water over 30 min. The mixture was extracted with 2 × 25 mL of
dichloromethane. The organic layers were combined and washed
with 3 × 40 mL of 1 N HCl. The organic layers were dried over
4
MgSO , and the solvent was removed in vacuo to give the crude
product as a brown oil. The crude product was purified by radial
chromatography on silica gel using 30:1 hexanes-ethyl acetate as
the eluent to give a light yellow oil. More than one diastereomer
was present by NMR, but they were not separated at this stage.
4
MgSO , and the solvent was removed in vacuo to give the crude
product as a brown oil. The crude product was purified by radial
chromatography on silica gel using 30:1 hexanes-ethyl acetate as
the eluent to give a mixture of two diastereomers as a light yellow
Yield ) 296 mg (45% recovery, theoretical 100% recovery given
1
oil. Yield ) 57 mg (9.5% recovery, theoretical 100% recovery given
fragmentation would be 657 mg); H NMR (300 MHz, CDCl
3
) δ
1
fragmentation would be 598 mg); H NMR (300 MHz, CDCl
0
(
0
3
) δ
0.90-1.10 (m, 6H), 1.15-1.50 (m, 14H), 2.08 (m, 2H), 2.38 (m,
.90-1.00 (m, 6H), 1.20-1.50 (m, 11H), 1.71-1.79 (m, 4H), 2.11
m, 2H), 2.43 (m, 2H), 4.45 (m, 1H), 4.87 (M, 04.H), 5.10 (m,
.6H), 5.55-5.70 (m, 2H), the OH proton was not detected;
) δ 13.6 (2), 17.5, 19.1, 22.4, 22.9, 23.1,
0.5 (2), 31.0, 37.2, (40.9, 41.2), (65.9, 66.2), 76.9, 77.4, (90.4,
2H), 4.39 (m, 1H), 4.95 (m, 0.5H), 5.10 (m, 0.5H), 5.25-5.60 (m,
13
2H), 5.85-5.95 (m, 1H), the OH proton was not detected; C NMR
13
C
3
(75 MHz, CDCl ) δ 13.9, 14.1, (15.1, 15.3), 19.1, 21.6, 22.7, 25.6,
NMR (75 MHz, CDCl
3
30.4, 31.3 (2), 39.5, (40.2, 40.4), (66.2, 67.5), 75.8, 77.2, (91.2,
+
3
9
93.7), 116.2, 137.8; MS m/z (M ) calcd 278.2246, obsd 278.2149.
+
2.1), 124.2, 133.7; MS m/z (M ) calcd 278.2246, obsd 260.2142
: C, 77.65; H, 10.86.
Anal. Calcd for C18
H, 10.74.
30 2
H O : C, 77.65; H, 10.86. Found: C, 78.01;
(
loss of water). Anal. Calcd for C18
H
30
O
2
Found: C, 77.73; H, 10.81.
IV.b. Formation of 4-Phenyl-6-(2-phenylethynyl)-5-(2-meth-
ylvinyl)-tetrahydro-2H-pyran-2-ol from 3-Methyl-6-phenyl-hex-
V.b. Formation of 4-Phenyl-6-(2-phenylethynyl)-5-methyl-5-
vinyl-tetrahydro-2H-pyran-2-ol from 7-Phenyl-hept-6-yne-2-
ene-5-ol (R ) Phenyl). To a preweighed, flame dried, 200 mL,
three-necked flask equipped with a magnetic stir bar was added a
KH-mineral oil mixture. The mixture was washed with 3 × 5 mL
of THF to remove the mineral oil. The flask was placed under high
vacuum (0.002 mmHg) to remove solvent traces leaving KH as a
gray solid, which was then weighed (630 mg, 15.75 mmol of KH).
5-yne-1-ene-4-ol (R ) Phenyl). To a preweighed, flame dried, 100
mL, three-necked flask equipped with a magnetic stir bar was added
a KH-mineral oil mixture. The mixture was washed with 3 × 5
mL of THF to remove the mineral oil. The flask was placed under
high vacuum (0.002 mmHg) to remove solvent traces leaving KH
as a gray solid, which was then weighed (270 mg, 6.75 mmol of
To this solid was added 50 mL of a 30% Et
and the resulting mixture was cooled to -78 °C under an argon
atmosphere. A 20 mL solution (30% Et O in THF) of alcohol (732
2
O solution in THF,
KH). To this solid was added 30 mL of a 30% Et
THF, and the resulting mixture was cooled to -78 °C under an
argon atmosphere. A 10 mL (30% Et O solution in THF) solution
2
O solution in
2
2
mg, 3.94 mmol) and 18-crown-6 (1.040 g, 3.95 mmol) were added
to the KH mixture with stirring over a 5-10 min period. The
resulting solution was allowed to warm to -40 °C over a period
of 1.5 h, then allowed to warm to 0 °C over an additional 1 h. The
reaction was quenched by dropwise addition of 30 mL of water
over 30 min. The mixture was extracted with 2 × 25 mL of
dichloromethane. The organic layers were combined and washed
with 3 × 40 mL of 1 N HCl. The organic layers were dried over
of alcohol (314 mg, 1.69 mmol) and 18-crown-6 (449 g, 1.70 mmol)
were added to the KH mixture with stirring over a 5-10 min period.
The resulting solution was allowed to warm to -40 °C over a period
of 1.5 h, then allowed to warm to 0 °C over an additional 1 h. The
reaction was quenched by dropwise addition of 15 mL of water
over 30 min. The mixture was extracted with 2 × 15 mL of
dichloromethane. The organic layers were combined and washed
with 3 × 20 mL of 1 N HCl. The organic layers were dried over
4
MgSO , and the solvent was removed in vacuo to give the crude
4
MgSO , and the solvent was removed in vacuo to give the crude
product as a brown oil. The crude product was purified by radial
chromatography on silica gel using 30:1 hexanes-ethyl acetate as
the eluent to give a light yellow oil. More than one diastereomer
was present by NMR, but they were not separated at this stage.
product as a brown oil. The crude product was purified by radial
chromatography on silica gel using 20:1 hexanes-ethyl acetate as
the eluent to give a mixture of two diastereomers as a light yellow
oil. Yield ) 24 mg (8.8% recovery, theoretical 100% recovery given
Yield ) 94 mg (15% recovery, theoretical 100% recovery given
1
1
fragmentation would be 270 mg); H NMR (300 MHz, CDCl
3
) δ
fragmentation would be 626 mg); H NMR (300 MHz, CDCl
3
) δ
1.65 (m, 1H), 1.74 (m, 3H), 2.70-2.75 (m, 3H), 4.68 (m, 1H),
4.95 (m, 0.4H), 5.16 (m, 0.6H), 5.50-5.80 (m, 2H), 7.2-7.6 (m,
0.95 (s, 1.5H), 1.07 (s, 1.5H), 2.70-2.75 (m, 3H), 4.58 (m, 1H),
4.91 (m, 0.5H), 5.18 (m, 0.5H), 5.21 (m, 2H), 5.93 (m, 1H), 7.20-
3050 J. Org. Chem., Vol. 72, No. 8, 2007

1,2-Additions and Cope Rearrangements
7
.61 (m ,10H), the OH proton was not detected; 13C NMR (75 MHz,
product was purified using radial chromatography (silica gel, 20:1
CDCl
3
) δ (15.3, 15.5), 34.0, 39.5, (40.2, 40.7), (65.9, 67.1), 77.9,
hexanes-ethyl acetate) to give the formate ester as a light yellow
1
8
1
8.2, (89.9, 90.6), 115.3, 122.1, 125.7, 126.8 (2), 128.4 (2), 128.7,
28.8, 128.9, 130.2 (2), 137.5, 141.0; MS m/z (M ) calcd 318.1620,
oil. Yield ) 317 mg (1.62 mmol) ) 63%; H NMR (300 MHz,
+
CDCl ) δ 0.17 (s, 9H), 2.48 (m, 2H), 5.20 (m, 2H), 5.48 (t, J )
3
obsd 318.1620. Anal. Calcd for C22
Found: C, 82.78; H, 7.05.
H O
22 2
: C, 82.99; H, 6.96.
13
6
3
.3 Hz, 1H), 5.87 (m, 1H), 8.07 (s, 1H); C NMR (75 MHz, CDCl )
+
δ 0.2(3), 41.7, 62.6, 89.3, 106.1, 119.2, 133.8, 160.9; MS m/z (M )
calcd 196.0920, obsd 196.0913. Anal. Calcd for C10 : C,
1.18; H, 8.21. Found: C, 60.99; H, 8.15. It should be noted that
VI. Formation of Formate Ester (17) from Aldehyde (3) in
N-Methylformamide. VI.a. Formation of Undec-5-yn-1-ene-4-
ol, Formate Ester from Octynal. To a 100 mL round-bottomed
flask was added 55 mL of NMF along with octynal (622 mg, 5.02
mmol), allyl bromide (912 mg, 7.54 mmol), and indium powder
16 2
H O
6
there was approximately 15% of the formate formed in which the
TMS group had been removed. This isomer was noted via NMR
and MS of the crude material but was not isolated further.
(634 mg, 5.52 mmol). The flask was capped with a rubber stopper,
VI.d. Formation of Dec-5-yn-1-ene-4-ol, Formate Ester from
Heptynal. To a 100 mL round-bottomed flask was added 60 mL
of NMF along with octynal (605 mg, 5.50 mmol), allyl bromide
(990 mg, 8.25 mmol), and indium powder (694 mg, 6.05 mmol).
The flask was capped with a rubber stopper, and the mixture was
sonicated for 72 h at which time TLC revealed the reaction was no
longer progressing. Sonication was stopped, and 60 mL of dichlo-
rmethane was added to the product mixture with stirring for 30
min. Water (40 mL) was added with stirring for 10 min, and the
layers separated. A 1 N HCl solution (25 mL) was added to the
organic layer with stirring for 10 min at which time the layers were
separated. The organic layer was washed with 2 × 20 mL of 1 N
and the mixture was sonicated for 72 h, at which time TLC revealed
the reaction was no longer progressing. Sonication was stopped,
and 60 mL of dichlormethane was added to the product mixture
with stirring for 30 min. Water (40 mL) was added with stirring
for 10 min, and the layers separated. A 1 N HCl solution (25 mL)
was added to the organic layer with stirring for 10 min at which
time the layers were separated. The organic layer was washed with
2
× 20 mL of a 1 N HCl solution. The organic layer was dried
over MgSO , and the solvent was removed in vacuo to give a yellow
liquid. Purification was performed using radial chromatography
silica gel, 25:1 hexanes-ethyl acetate) to give the formate ester
4
(
1
as a light yellow oil. Yield ) 613 mg (3.16 mmol) ) 63%; H
NMR (300 MHz, CDCl ) δ 0.83 (t, J ) 7.3 Hz, 3H), 1.27 (m,
H), 1.44 (m, 2H), 2.14 (m, 2H), 2.47 (m, 2H), 5.11 (m, 2H), 5.44
t, J ) 5.9 Hz, 1H), 5.76 (m, 1H), 8.01 (s, 1H); 13C NMR (75
MHz, CDCl ) δ 15.0, 19.6, 23.2, 29.1, 32.0, 40.5, 64.6, 77.5, 88.6,
19.6, 133.2, 161.0; MS m/z (M ) calcd 194.1307, obsd 194.1315.
Anal. Calcd for C12 : C, 74.19; H, 9.34. Found: C, 74.83; H,
.99.
VI.b. Formation of 6-Phenyl-hex-5-yn-1-en-4-ol, Formate
3
4
HCl solution. The organic layer was dried over MgSO , and the
4
(
solvent was removed in vacuo to give a yellow liquid. Purification
was performed using radial chromatography (silica gel, 25:1
hexanes-ethyl acetate) to give the formate ester as a light yellow
3
+
1
1
oil. Yield ) 642 mg (3.57 mmol) ) 65%; H NMR (300 MHz,
18 2
H O
CDCl ) δ 0.91 (t, J ) 7.4 Hz, 3H), 1.31 (m, 2H), 1.47 (m, 2H),
3
8
2
1
1
.17 (m, 2H), 2.44 (m, 2H), 5.15 (m, 2H), 5.47 (t, J ) 6.1 Hz,
H), 5.80 (m, 1H), 8.02 (s, 1H); 13C NMR (75 MHz, CDCl
) δ
Ester from 3-Phenylpropynal. To a 100 mL round-bottomed flask
was added 55 mL of NMF along with 3-phenylpropynal (585 mg,
3
5.2, 19.4, 23.5, 32.1, 40.4, 65.2, 77.5, 88.3, 119.4, 133.4, 161.7;
+
MS m/z (M ) calcd 180.1150, obsd 180.1161. Anal. Calcd for
4.50 mmol), allyl bromide (810 mg, 6.75 mmol), and indium
powder (574 mg, 5.00 mmol). The flask was capped with a rubber
stopper, and the mixture was sonicated for 72 h, at which time
TLC revealed the reaction was no longer progressing. Sonication
was stopped, and 50 mL of dichlormethane was added to the product
mixture with stirring for 30 min. Water (35 mL) was added with
stirring for 10 min, and the layers separated. A 1 N HCl solution
C
11
H
16
2
O : C, 73.30; H, 8.95. Found: C, 73.47; H, 8.96.
VII. Formation of Cope Product (9) from Alcohol (3). VII.a.
Formation of 3-Pentyl-hexa-2,5-dienal from 2-Octynal. To a 25
mL round-bottomed flask was added a solution of 5.5 mL of NMF
and 5.5 mL of DMSO. To this solution was added 2-octynal (124
mg, 1 mmol), allyl bromide (180 mg, 1.5 mmol), indium powder
(20 mL) was added to the organic layer with stirring for 10 min at
3
(126 mg, 1.1 mmol), and InCl (219 mg, 1.0 mmol). The mixture
which time the layers were separated. The organic layer was washed
was sonicated for 84 h at which time TLC showed no further
changes in the product mixture. At this stage, sonication was
stopped, and dichloromethane (40 mL) was added with stirring for
with 2 × 20 mL of 1 N HCl solution. The organic layer was dried
4
over MgSO , and the solvent was removed in vacuo to give a yellow
liquid. Purification was performed using radial chromatography
silica gel, 30:1 hexanes-ethyl acetate) to give the formate ester
30 min. To the resulting mixture was added 25 mL of 1 N HCl
(
1
with stirring for 30 min. The layers were separated, and the organic
as a light yellow oil. Yield ) 540 mg (2.70 mmol) ) 60%; H
NMR (300 MHz, CDCl ) δ 2.41 (m, 2H), 5.14 (m, 2H), 5.51 (t,
J ) 5.7 Hz, 1H), 5.92 (m, 1H), 7.2-7.4 (m, 5H), 8.06 (s, 1H);
NMR (75 MHz, CDCl ) δ 40.5, 65.1, 77.3, 90.5, 118.3, 122.7,
1
2
6
layer was washed with 3 × 15 mL of 1 N HCl, then dried over
3
13
MgSO . Purification was performed using radial chromatography
C
4
(silica gel, 25:1 hexanes-ethyl acetate) to give the aldehyde as a
3
+
1
28.1, 128.3, 128.4, 131.0, 132.3, 135.6, 161.3; MS m/z (M ) calcd
mixture of diastereomers. Yield ) 58 mg (0.35 mmol) ) 35%; H
00.0837, obsd 200.0824. Anal. Calcd for C13
.04. Found: C, 78.21; H, 6.15.
H O
12 2
: C, 77.98; H,
3
NMR (300 MHz, CDCl ) δ 0.98 (m, 3H), 1.28 (m, 6H), 1.90 (m,
2H), 2.57 (m, 2H), 5.15 (m, 2H), 5.72 (m, 1H), 5.82 (m, 1H), 9.51
(d, J ) 7.7 Hz, 0.5H), 9.54 (d, J ) 7.7 Hz, 0.5H); 13C NMR (75
VI.c. Formation of 6-Trimethylsilyl-hex-yn-4-1-en-4-ol, For-
mate Ester from 3-Trimethylsilylpropynal. To a 50 mL round-
bottomed flask was added 30 mL of NMF along with 3-trimeth-
ylsilylpropynal (324 mg, 2.57 mmol), allyl bromide (462 mg, 3.85
mmol), and indium powder (324 mg, 2.82 mmol). The flask was
capped with a rubber stopper, and the mixture was sonicated for
MHz, CDCl ) δ 15.0, 22.5, 24.7, 31.7, 32.1, 40.4, 115.1, 126.1,
3
+
134.9, 163.3, (193.1, 193.2); MS m/z (M
66.1339. Anal. Calcd for C11 18O: C, 79.46; H, 10.91. Found:
C, 78.91; H, 10.33.
) calcd 166.1358, obsd
1
H
VII.b. Formation of 3-Butyl-hexa-2,5-dienal from 2-Heptynal.
Processing and analysis of this reaction proceeded as described in
part VI.a. Purification was accomplished using radial chromatog-
raphy on silica gel (25:1 hexanes-ethyl acetate) to give the
84 h at which time TLC revealed the reaction was no longer
progressing. Sonication was stopped, and 30 mL of dichlormethane
was added to the product mixture with stirring for 30 min. Water
(15 mL) was added with stirring for 10 min, and the layers
aldehyde as a mixture of diastereomers. Yield ) 51 mg (0.34
separated. A 1 N HCl solution (10 mL) was added to the organic
layer with stirring for 10 min at which time the layers were
separated. The organic layer was washed with 2 × 10 mL of 1 N
1
mmol) ) 34%; H NMR (300 MHz, CDCl
3
) δ 0.97 (m, 3H), 1.41
(m, 4H), 1.91 (m, 2H), 2.57 (m, 2H), 5.17 (M, 2H), 5.69 (m, 1H),
HCl solution. The organic layer was dried over MgSO
4
, and the
5.85 (m, 1H), 9.51 (d, J ) 7.7 Hz, 0.5 H), 9.53 (d, J ) 7.7 Hz,
solvent was removed in vacuo to give a yellow liquid. The crude
0.5H); 13C NMR (75 MHz, CDCl
3
) δ 14.8, 22.7, 31.2, 31.9, 40.6,
J. Org. Chem, Vol. 72, No. 8, 2007 3051

Mitzel et al.
+
1
1
1
15.9, 125.3, 134.8, 161.1, (191.0, 191.3); MS m/z (M ) calcd
52.1201, obsd 152.1239. Anal. Calcd for C10 16O: C, 78.90; H,
0.59. Found: C, 78.50; H, 10.27. Bp ) 85-87 °C at 12 Torr.
VII.c. Formation of 3-Phenyl-hexa-2,5-dienal from 3-Phenyl-
VII.d. Formation of 3-Trimethylsilyl-hexa-2,5-dienal from
3-Trimethylsilyl-propynal. Processing and analysis of this reaction
proceeded as described in part VI.a. Purification was accomplished
using radial chromatography on silica gel (50:1 hexanes-ethyl
H
24
propynal. Processing and analysis of this reaction proceeded as
described in part VI.a. Purification was accomplished using radial
chromatography on silica gel (30:1 hexanes-ethyl acetate) to give
acetate) to give the aldehyde as a mixture of diastereomers.
1
Yield ) 49 mg (0.29 mmol) ) 29%; H NMR (300 MHz, CDCl
3
)
δ 0.17 (s, 9H), 2.60 (m, 2H), 5.21 (m, 2H), 5.85 (m, 1H), 6.27 (m,
.7H), 6.58 (m, 0.3H), 9.64 (m, 1H); 13C NMR (75 MHz, CDCl
)
3
the aldehyde as a mixture of diastereomers. Yield ) 46 mg (0.27
0
1
mmol) ) 27%; H NMR (300 MHz, CDCl
(
3
Hz, 0.5H); C NMR (75 MHz, CDCl
(
3
) δ 2.63 (m, 2H), 5.15
δ (0.1, 0.3)[3], (35.3, 37.1), 115.0, 133.6, 140.1, (160.1, 160.2),
m, 2H), 5.85 (m, 1H), 5.90 (m, 0.5H), 6.30 (m, 0.5H), 7.19 (m,
+
(
192.9, 193.1); MS m/z (M ) calcd 168.0970, obsd 168.0968. Anal.
H), 7.35 (m, 2H), 9.63 (d, J ) 7.6 Hz, 0.5H), 9.68 (d, J ) 7.7
13
Calcd for C19
9
H16OSi: C, 64.23; H, 9.58. Found: C, 64.51; H,
3
) δ 41.9, 115.1, 123.0, 126.3-
.69.25
2), 127.3, 128.1, 128.4, 134.7, 135.1, (159.6, 159.8), (190.0, 190.2);
+
MS m/z (M ) calcd 172.0888, obsd 171.9998. Anal. Calcd for
C
12
H12O: C, 83.69; H, 7.02. Found: C, 84.01; H, 6.85.
Acknowledgment. Financial support received from the
National Science Foundation-REU granting program, Pfizer
Undergraduate Research Award Grant, the Howard Hughes
Medical Association, and the Trinity College Internal Grant
Foundation is greatly acknowledged.
(
24) Ullrich, F. W.; Rotscheidt, K.; Breitmaier, E. Chem. Ber. 1986, 119,
1
737.
25) For comparitive syntheses: (a) Mandai, T.; Arase, H.; Otera, J.;
(
Kawada, M. Tetrahedron Lett. 1985, 26, 2677. (b) Otera, J.; Mandai, T.;
Shiba, M.; Saito, T.; Shimohata, K.; Takemori, K.; Kawasaki, Y. Organo-
metallics 1983, 2, 332.
JO070020K
3052 J. Org. Chem., Vol. 72, No. 8, 2007