Cobalt-catalyzed 1,4-hydrovinylation of allylsilane and allylboronic esters for the synthesis of hydroxy-functionalized 1,4-dienes

Article abstract of DOI:10.1021/jo100951d

(Figure presented) The cobalt(I)-catalyzed 1,4-hydrovinylation reaction of allyl trimethylsilane and allyl pinacol boronic ester with symmetrical and unsymmetrical 1,3-dienes generates building blocks for the in situ allylboration or the Lewis acid induced allylation reaction utilizing the corresponding allyl silane derivatives. The products of these three-component reactions are hydroxy-functionalized 1,4-dienes which can be used for the synthesis of pyranones. An alternate reaction sequence for the synthesis of the hydroxy-functionalized 1,4-dienes by performing the allylation first followed by the cobalt-catalyzed 1,4-hydrovinylation is also possible. Accordingly, polyfunctionalized complex structures can be generated by both approaches in a convergent fashion.

Full text of DOI:10.1021/jo100951d

pubs.acs.org/joc
Cobalt-Catalyzed 1,4-Hydrovinylation of Allylsilane and Allylboronic
Esters for the Synthesis of Hydroxy-Functionalized 1,4-Dienes
Marion Arndt, Anne Reinhold, and Gerhard Hilt*
€
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Straβe, 35043 Marburg, Germany
hilt@chemie.uni-marburg.de
Received May 14, 2010
The cobalt(I)-catalyzed 1,4-hydrovinylation reaction of allyl trimethylsilane and allyl pinacol
boronic ester with symmetrical and unsymmetrical 1,3-dienes generates building blocks for the in
situ allylboration or the Lewis acid induced allylation reaction utilizing the corresponding allyl silane
derivatives. The products of these three-component reactions are hydroxy-functionalized 1,4-dienes
which can be used for the synthesis of pyranones. An alternate reaction sequence for the synthesis of
the hydroxy-functionalized 1,4-dienes by performing the allylation first followed by the cobalt-
catalyzed 1,4-hydrovinylation is also possible. Accordingly, polyfunctionalized complex structures
can be generated by both approaches in a convergent fashion.
SCHEME 1
Introduction
New synthetic methods must fulfill various aspects to be of
use to the scientific community. Besides fulfilling economic
and ecologic demands the methods should also be very selec-
tive in terms of chemo-, regio-, and stereoselectivity. In addi-
tion, these methods should be highly tolerant toward other
functional groups present in the starting material while avoid-
ing side reactions and the need of protecting groups.1 In this
context the cobalt-catalyzed 1,4-hydrovinylation reaction of
alkenes with 1,3-dienes has attracted considerable interest
for the atom economic synthesis of 1,4-dienes.2 This meth-
odology allows the application of a broad range of tolerated
functional groups permitting the rapid construction of very
interesting functionalized building blocks. Of particular
interest are building blocks with functionalities in vinylic
or allylic position which can be directly used to perform
additional carbon-carbon bond formation reactions. To-
ward this end we identified the cobalt-catalyzed 1,4-hydro-
vinylation of functionalized terminal alkenes in combination
with an allylation reaction of aldehydes utilizing allylboron
derivatives or allyl silanes as an appropriate tool to generate
increasingly complex products in a short one-pot reaction
sequence (Scheme 1).3 These reactions exhibit a high level of
selectivity and very little side reaction is generally observed.
(1) Key reference: Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem.
Soc. Rev. 2009, 38, 3010.
€
(2) (a) Hilt, G.; du Mesnil, F.-X.; Luers, S. Angew. Chem., Int. Ed. 2001,
€
€
40, 387. (b) Hilt, G.; Luers, S. Synthesis 2002, 609. (c) Hilt, G.; Luers, S.;
Schmidt, F. Synthesis 2003, 634. (d) Hilt, G.; Danz, M.; Treutwein, J. Org.
Lett. 2009, 11, 3322. (e) Hilt, G.; Treutwein, J. Chem. Commun. 2009, 1395.
For selected recent applications see: (f) Sharma, R. K.; RajanBabu, T. V.
J. Am. Chem. Soc. 2010, 132, 3295. (g) Saha, B.; Smith, C. R.; RajanBabu,
T. V. J. Am. Chem. Soc. 2008, 130, 9000. (h) Shirakura, M.; Suginome, M.
J. Am. Chem. Soc. 2008, 130, 5410. (i) Saha, B.; RajanBabu, T. V. J. Org.
Chem. 2007, 72, 2357. (j) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc.
2006, 128, 54. (k) Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 1515.
(l) Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 3159. (m) Kumareswaran,
R.; Nandi, M.; RajanBabu, T. V. Org. Lett. 2003, 5, 4345. (n) Moreau, B.;
Wu, J. Y.; Ritter, T. Org. Lett. 2009, 11, 337. (o) Grabulosa, A.; Muller, G.;
Ordinas, J. I.; Mezzetti, A.; Maestro, M. A.; Font-Bardia, M.; Solans, X.
Organometallics 2005, 24, 4961.
(3) For reviews on allylborations see: (a) Pietruszka, J.; Schone, N.; Frey,
W.; Grundl, L. Chem.;Eur. J. 2008, 14, 5178. (b) Kennedy, J. W. J.; Hall,
D. G. J. Org. Chem. 2004, 69, 4412. For recent applications of the Hosomi-
Sakurai reaction see: (c) Reddy, U. C.; Bondalapati, S.; Saikia, K. A. Eur. J.
Org. Chem. 2009, 1625. (d) Sabot, C.; Guerard, K. C.; Canesi, S. Chem.
Commun. 2009, 2941. (e) Kumar, R. S. C.; Reddy, G. V.; Babu, K. S.; Rao,
J. M. Chem. Lett. 2009, 38, 564. (f) Sabot, C.; Commare, B.; Duceppe, M.-A.;
Nahi, S.; Guerard, K. C.; Canesi, S. Synlett 2008, 3226. (g) Spangenberg, T.;
Airiau, E.; Thuong, M. B. T.; Donnard, M.; Billet, M.; Mann, A. Synlett
2008, 2859. (h) Xu, L.-W.; Yang, M.-S.; Qiu, H.-Y.; Lai, G.-Q.; Jiang, J.-X.
Synth. Commun. 2008, 38, 1011. (i) Shizuka, M.; Snapper, M. L. Angew.
Chem., Int. Ed. 2008, 47, 5049.
DOI: 10.1021/jo100951d
r
Published on Web 07/02/2010
J. Org. Chem. 2010, 75, 5203–5210 5203
2010 American Chemical Society

Arndt et al.
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SCHEME 2
Furthermore, the generated products of type 2 are envi-
saged to serve as a platform for various follow-up chemical
transformations. The access to pyranone derivatives upon
ozonolysis and acid-induced cyclization of intermediately
formed 5-hydroxy-1,3-dicarbonyl derivatives was envisaged
as a promising example.4 This three-component reaction
starting from readily available educts inspired us to investi-
gate the further scope of this reaction sequence.
To access the application of unsymmetrical 1,3-dienes as
starting material in the cobalt-catalyzed 1,4-hydrovinylation
commercially available myrcene was used. In this case the
1,4-hydrovinylation can take place either at C1 or at C4 of
the 1,3-diene subunit (Scheme 3). The regioselectivity is reason-
ably high when the cobalt 1,2-bis-diphenylphosphinoethane
complex [CoBr2(dppe)] is applied in the synthesis of inter-
mediate 4 (C1:C4 = 18:82).
The desired product 5 was generated upon reaction with
octanal in 42% yield over two steps. Accordingly, materials
with various differently substituted double bonds can be
envisaged to be generated in a short reaction sequence by this
approach. In addition, it should be noted that commercially
available myrcene consists of a mixture of double bond
isomers of which 90% resemble the desired starting material.
The cobalt catalyst very selectively converts the myrcene
component of the mixture into the intermediate 4 while the
other double bond isomers in the mixture remain un-
touched. In fact, products of type 5 are generated as single
double bond isomers and the mild reaction conditions do
not lead to double bond isomerization or elimination of the
alcohol functionality to generate corresponding polyene
structures.
A flexible route to products of type 2 can also be realized
when the two reactions are exchanged. At the moment this
aspect seems to be trivial but the applicability of the reaction
sequence in both ways in the synthesis of a highly complex
product, such as a natural product, is of additional value.
The procedure was tested for the allylboration of norbor-
nene carbaldehyde, applied as the commercially available
mixture of endo/exo isomers (endo:exo = 1:0.31), to 6 fol-
lowed by the cobalt-catalyzed 1,4-hydrovinylation reaction
(Scheme 4).
Utilizing this methodology, the intermediate 6 was iso-
lated in 83% as a mixture of diastereomers. From this inter-
mediate the desired product was generated under cobalt-
catalysis from 2,3-dimethyl-1,3-butadiene (DMB) with the
[CoBr2(dppe)] complex to afford 2i in 72% yield. The
application of octanal as the aldehyde in the allylboration
reaction led to product 7 in 83% isolated yield. The cobalt-
catalyzed transformation with myrcene as the 1,3-diene was
performed with varying bidentate phosphine ligands. The
product 5 was generated in 37% yield in a ratio of C1:C4 =
29:71 when dppe was applied as the ligand. The same re-
action performed with dppp (1,3-bis-diphenylphosphino-
propane) gave the desired product 5 in 59% and a C1:C4
ratio of 17:83. The best result was obtained when the dppp*
ligand(2,2-dimethyl-1,3-bis-diphenylphosphinopropane) was
utilized. In this case the desired product was obtained in 58%
and a C1:C4 ratio of 8:92 was detected. This strategy gives
similar good results as the previously described one-pot pro-
cedure using the cobalt-catalyzed reaction in the first transfor-
mation. Therefore, applications in the synthesis of more com-
plex molecules by both strategies seem reasonable for the
future.
Results and Discussion
First we investigated the use of allyl pinacol boronic ester
(1, (OR)2=pinacol) in the cobalt-catalyzed 1,4-hydrovinyl-
ation with a simple symmetrical 1,3-diene such as 2,3-dim-
ethyl-1,3-butadiene (DMB) (Scheme 2). The reaction was
performed in dichloromethane at room temperature utilizing
the cobalt 1,2-bis-diphenylphosphinoethane dibromide com-
plex as catalyst precursor.
Over the course of the investigation we realized that the
isolation of the intermediate 3 is not advantageous mainly
because of its instability upon column chromatography on
silica gel. Therefore, the aldehydes were added at low tem-
peratures to the reaction mixture after completion of the cobalt-
catalyzed reaction without any purification of the intermediate 3.
For the isolation of the products of type 2 triethanolamine was
added to cleave the boronates formed in situ (see the Experi-
mental Section). The results of the reaction sequence utilizing
various aldehydes are summarized in Table 1.
The results are consistently satisfying in the respect that all
applied aldehydes were converted in the three-component
one-pot reaction sequence. The steric demand of the aliphatic
aldehydes could be increased up to a tert-butyl substituent,
with virtually no loss of efficiency (entries 1-4), and aromatic
aldehydes were also accepted in the reaction (entries 5-8). It
should be noted that p-bromobenzaldehyde is converted to
product 2g in excellent yields without participation of the
bromoaryl moiety in side reactions, e.g. a coupling reaction
or a protodebromination via aryl zinc intermediates. Four pro-
ducts (2e-h) especially would lead to unsaturated products
with extended π-systems upon elimination of water. Although
zinc iodide is present in the reaction mixture that could act as a
Lewis acid to facilitate the water elimination, such products
were not encountered. When cinnamic aldehyde was used as
the aldehyde in the allylation reaction such an elimination
of water was detected to generate the even more extended
π-system. However, the product consisted of several E/Z-
isomers and could not be isolated in pure form. In view of
the subsequently planned transformations of the products 2,
we were also delighted that further double bonds in the
aldehyde component were tolerated (entries 9 and 11-13).
These additional double bonds can be transformed into car-
bonyl groups by ozonolysis.
(4) (a) Hilt, G.; Arndt, M.; Weske, D. F. Synthesis 2010, 1321. For a
review concerning the synthesis of 1,3-dicarbonyl compounds, see: (b) Hilt,
G.; Weske, D. F. Chem. Soc. Rev. 2009, 38, 3082.
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TABLE 1. Results for the Cobalt-Catalyzed Hydrovinylation-Allylboration Reaction Sequence
aThe compounds 2a and 2k were described previously, see ref 4a. bMixture of diastereomers in a ratio of 1.0:0.93. The assignment of the signals to one
of the two diastereomers by two-dimensional NMR techniques was not successful. cMixture of diastereomers in a ratio of 1.0:0.49. The assignment of the
signals to one of the two diastereomers by two-dimensional NMR techniques was not successful.
An application of the hydroxyl-functionalized 1,4-dienes
of type 2 was realized in the ozonolysis/acid-initiated cycli-
zation protocol leading to pyranone derivatives 8 in a one-
pot procedure (Scheme 5).5 The results of this one-pot pro-
cedure for various substituted derivatives of type 2 are
summarized in Table 2.
The reaction sequence with the ethyl substituent led to 8a,
the natural product hepialone, in excellent yield,6 and the
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SCHEME 3
SCHEME 4
by the cobalt-catalyzed hydrovinylation of allyl boronic
esters do present a potentially serious drawback. These
compounds present a pronounced lability toward silica gel
column chromatography rendering the purification and
isolation difficult, as we have observed. The use of allyl
silanes as a much more stable alternative holds great
promise. The conversion of allyl trimethylsilane (9) with
DMB leads to intermediate 10, which can then be con-
verted under Lewis acid catalysis to the desired products of
type 2i and 2l (Scheme 6).
Intermediate 10 was isolated in 99% yield and the conver-
sion into the hydroxyl-functionalized 1,4-dienes 2i in 88%
yield and 2l in 90% yield is even superior to the previously
described approach utilizing allyl pinacol boronic ester 1.
Thereby, an alternative protocol for the generation of hydroxyl-
functionalized 1,4-dienes has been established.
SCHEME 5
other aliphatic derivatives investigated gave similar good
results for this two-step one-pot procedure. When additional
double bonds are present in the starting material, ozonolysis
leads to the cleavage of this additional double bond as well,
leading to aldehyde 8e in 40% yield. Continuing from there
the synthesis of a lipid component isolated from vanilla beans
can be realized as we were able to demonstrate beforehand.7
Aryl substituents are also accepted as is shown for the phenyl-
substituted derivative 8f and the derivatives 8g and 8h with
electron poor aromatic moieties. These compounds were isola-
ted in moderate to good yields without degradation of the aryl
substituent by ozonolysis. It should be noted that electron-rich
aromatic moieties also react with ozone, leading to the degrad-
ation of these functional groups. Accordingly, when methoxy-
functionalized aryl substituents were present in the starting
material degradation was observed and no desired product
could be isolated.
Summary
The combination of a cobalt-catalyzed 1,4-hydrovinyla-
tion of allyl boron reagents as well as allyl silanes and a sub-
sequent allylation reaction of aldehydes can be used for the
fast assembly of hydroxyl-functionalized 1,4-dienes of type
2. These materials can be used as a platform for the synthesis
of pyranone derivatives of type 8 by an ozonolysis/acid-
induced cyclization reaction. As we could demonstrate, the
sequence is flexible enough to permit the allylation reaction
to be performed first leading to homoallylic alcohols of type
6/7. These can then be used to afford the hydroxyl-function-
alized 1,4-dienes of type 2 with similar good results. Therefore,
the method presented herein shows strong promise of being
applicable toward the synthesis of more complex compounds
in the future.
When viewed from the perspective of target-oriented
multistep synthesis intermediates of type 3 and 4 generated
(5) For selected examples regarding the use of 1,3-diketone dianions see:
(a) Karapetyan, V.; Mkrtchyan, S.; Ghazaryan, G.; Villinger, A.; Fischer, C.;
Langer, P. Tetrahedron 2009, 65, 9271. (b) Ahmad, R.; Khera, R. A.;
Villinger, A.; Langer, P. Tetrahedron Lett. 2009, 50, 3020.
(6) (a) Rao, B. V.; Rao, A. S. Synth. Commun. 1995, 25, 1531. (b) Kubo, I.;
Matsumoto, T.; Wagner, D. L.; Shoolery, J. N. Tetrahedron Lett. 1985, 26,
563.
(7) See ref 4. Ramaroson-Raonizafinimanana, B.; Gaydou, E. M.;
Bombarda, I. J. Agric. Food Chem. 1999, 47, 3202.
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TABLE 2. Results for the Ozonolysis/Acid-Initiated Cyclization Protocol
SCHEME 6
Experimental Section
(1,2-bis-diphenylphosphinoethane) dibromide (5 mol %) were
suspended under an argon atmosphere in 1.0 mL of dichlor-
omethane. Then 2,3-dimethyl-1,3-butadiene (1.2 mmol) and
2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1) (1.0 mmol)
were added and the mixture was stirred at room temperature
until complete conversion of the starting materials was observed
as monitored by GC/MS. The reaction mixture was cooled to
-78 °C and the aldehyde (1.0 mmol) was added. The mixture
was stirred for 1 h at -78 °C and then allowed to warm to room
temperature. Triethanolamine (1.2 mmol) was added and the
General Methods. All reactions were carried out under an
argon atmosphere in heat gun-dried glassware. Dichloromet-
hane was distilled under nitrogen from P4O10 and ZnI2 was dried
in vacuo at 150 °C prior to use. Commercially available mate-
rials were used without further purification.
General Procedure for the Cobalt-Catalyzed 1,4-Hydro-
vinylation-Allylboration Reaction Sequence. Anhydrous zinc
iodide (10 mol %), zinc powder (10 mol %), and cobalt
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reaction mixture was stirred for another hour. Then the mixture
was filtered over a short pad of silica gel (eluent: diethyl ether)
and the solvent was removed under reduced pressure. The
residue was purified by flash column chromatography on silica
gel to obtain the products of type 2.
(Mþ), 302, 287, 259, 233, 197, 181, 169, 138, 109, 91, 77; HRMS
(m/z) calcd for C19H28O4 320.1988, found 320.1987; IR (Nujol)
3475, 3074, 2995, 2936, 1593, 1508, 1462, 1421, 1327, 1234, 1129,
1009, 756.
1-(4-Bromophenyl)-5,6-dimethyl-3-methylenehept-5-en-1-ol (2g):
light yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.47 (d, 2H, J =
8.4 Hz), 7.24 (d, 2H, J = 8.4 Hz), 4.91 (s, 2H), 4.79-4.71 (m,
1H), 2.86 (d, 1H, J = 15.4 Hz), 2.74 (d, 1H, J = 15.4 Hz),
2.41-2.23 (m, 2H), 2.23-2.19 (m, 1H), 1.70 (s, 3H), 1.67 (s, 3H),
1.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.0, 143.1, 131.4,
127.5, 126.7, 124.5, 121.1, 114.0, 71.0, 46.6, 41.1, 20.6, 20.5,
18.3; MS (EI) m/z (%) 292, 277, 238, 196, 185, 169, 159, 121, 109,
93, 77; HRMS (m/z) calcd for C16H21BrO 308.0776, found
308.0754; IR (Nujol) 3412, 3075, 2987, 2915, 2864, 1642, 1590,
1485, 1440, 1398, 1064, 1011, 894, 820.
7,8-Dimethyl-5-methylenenon-7-en-3-ol (2a): colorless oil; 1H
NMR (300 MHz, CDCl3) δ 4.85-4.80 (m, 2H), 3.65-3.56 (m,
1H), 2.79 (d, 1H, J = 15.5 Hz), 2.68 (d, 1H, J = 15.4 Hz), 2.16
(dd, 1H, J = 13.7, 3.4 Hz), 1.98 (dd, 1H, J = 13.7, 9.4 Hz), 1.89
(s, 1H), 1.66 (s, 3H), 1.62 (s, 3H), 1.57 (s, 3H), 1.53-1.43 (m,
2H), 0.94 (t, 3H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ
144.8, 126.3, 124.7, 112.7, 70.2, 43.9, 41.1, 29.8, 20.5, 20.4, 18.2,
9.9; MS (EI) m/z (%) 182 (Mþ), 149, 135, 121, 109, 93; HRMS
(m/z) calcd for C12H22O 182.1671, found 182.1678; IR (Nujol)
3434, 3075, 2962, 2920, 1641, 1440, 1373, 1113, 1020, 972, 894.
2,3-Dimethyl-5-methylenetetradec-2-en-7-ol (2b): colorless
liquid; 1H NMR (300 MHz, CDCl3) δ 4.87-4.81 (m, 2H),
3.74-3.63 (m, 1H), 2.81 (d, 1H, J = 15.5 Hz), 2.70 (d, 1H,
J = 15.5 Hz), 2.18 (dd, 1H, J = 13.7, 3.2 Hz), 2.01 (dd, 1H, J =
13.7, 9.5 Hz), 1.77 (d, 1H, J = 2.0 Hz), 1.69 (s, 3H), 1.64 (s, 3H),
5,6-Dimethyl-3-methylene-1-(3-nitrophenyl)hept-5-en-1-ol (2h):
1
yellow oil; H NMR (300 MHz, CDCl3) δ 8.25 (t, 1H, J =
1.9 Hz), 8.13 (ddd, 1H, J = 8.1, 2.3, 1.0 Hz), 7.70 (d, 1H, J =
7.7 Hz), 7.52 (t, 1H, J = 7.9 Hz), 4.97-4.93 (m, 2H), 4.89 (ddd,
1H, J = 9.6, 3.7, 2.2 Hz), 2.88 (d, 1H, J = 15.5 Hz), 2.77 (d, 1H,
J = 15.4 Hz), 2.43 (dd, 1H, J = 13.8, 3.8 Hz), 2.39-2.36 (m,
1H), 2.31 (dd, 1H, J = 13.8, 9.6 Hz), 1.71 (s, 3H), 1.70-1.67 (m,
3H), 1.63-1.59 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 148.4,
146.2, 143.5, 131.8, 129.3, 127.0, 124.3, 122.4, 120.8, 114.6, 70.5,
46.7, 41.0, 20.6, 20.6, 18.3; MS (EI) m/z (%) 257, 242, 205, 188,
152, 123, 109, 93, 77; HRMS (m/z) calcd for C16H21NO3
275.1521, found 275.1521; IR (Nujol) 3448, 3080, 2988, 2916,
2865, 1530, 1440, 1350, 1057, 900, 738.
1-(Bicyclo[2.2.1]hept-5-en-2-yl)-5,6-dimethyl-3-methylenehept-
5-en-1-ol (2i). Main isomer: colorless liquid; 1H NMR (600
MHz, CDCl3) δ 6.13 (dd, 1H, J = 5.5, 3.1 Hz), 6.04 (dd, 1H,
J = 5.6, 2.9 Hz), 4.85-4.83 (m, 2H), 3.08-3.06 (m, 1H), 3.00 (tt,
1H, J = 15.3, 2.2 Hz), 2.84-2.77 (m, 2H), 2.65 (d, 1H, J = 15.4
Hz), 2.20 (d, 1H, J = 13.7 Hz), 2.03-1.97 (m, 1H), 1.90 (dd, 1H,
J = 13.9, 10.3 Hz), 1.79-1.77 (m, 1H), 1.77-1.73 (m, 1H), 1.66
(s, 3H), 1.61 (s, 3H), 1.56 (s, 3H), 1.44-1.39 (m, 1H), 1.23 (d, 1H,
J = 8.2 Hz), 0.50 (ddd, 1H, J = 11.5, 4.4, 2.6 Hz); 13C NMR
(100 MHz, CDCl3) δ 145.0, 137.2, 132.9, 126.4, 124.7, 113.3,
72.3, 49.2, 45.8, 44.2, 43.3, 42.2, 41.0, 29.2, 20.6, 20.5, 18.1.
Resolved signals for the minor component: 1H NMR (600
MHz, CDCl3) δ 6.18 (dd, 1H, J = 5.6, 3.1 Hz), 5.86 (dd, 1H,
J = 5.7, 2.7 Hz), 4.86-4.83 (m, 2H), 2.34 (d, 1H, J = 13.5 Hz),
2.05 (ddd, 1H, J = 13.1, 8.9, 3.9 Hz), 1.69 (s, 3H), 1.65 (s, 3H),
1.59 (s, 3H), 1.27 (d, 1H, J = 8.1 Hz), 1.03 (ddd, 1H, J = 11.8,
4.3, 2.7 Hz); 13C NMR (100 MHz, CDCl3) δ 144.7, 138.1, 131.6,
126.5, 124.7, 113.2, 73.0, 49.7, 46.3, 44.4, 43.5, 42.4, 40.9, 30.0,
20.5, 18.2; MS (EI) m/z (%) 213, 203, 176, 147, 124, 109, 91, 77,
67; HRMS (m/z) calcd for C17H26O 246.1984, found 246.1971;
IR (KBr) 3459, 3059, 2969, 2936, 2865, 1640, 1446, 1338, 1070,
1024, 897, 721.
1.59 (s, 3H), 1.50-1.22 (m, 12H), 0.88 (t, 3H, J = 6.6 Hz); 13
C
NMR (75 MHz, CDCl3) δ 144.8, 126.5, 124.7, 112.9, 68.8, 44.5,
41.1, 37.1, 31.8, 29.6, 29.3, 25.7, 22.7, 20.6, 20.5, 18.3, 14.1; MS
(EI) m/z (%) 252 (Mþ), 209, 182, 135, 124, 109, 93, 69, 55;
HRMS (m/z) calcd for C17H32O 252.2453, found 252.2439;
IR (Nujol) 3387, 2955, 2927, 2857, 1642, 1457, 1374, 1125, 1054,
966, 895.
2,7,8-Trimethyl-5-methylenenon-7-en-3-ol (2c): colorless liq-
uid; 1H NMR (300 MHz, CDCl3) δ 4.88-4.83 (m, 2H),
3.49-3.40 (m, 1H), 2.83 (d, 1H, J = 15.4 Hz), 2.69 (d, 1H,
J = 15.4 Hz), 2.20 (dd, 1H, J = 13.6, 2.4 Hz), 1.97 (dd, 1H, J =
13.6, 10.3 Hz), 1.75 (s, 1H), 1.73-1.62 (m, 1H), 1.69 (s, 3H), 1.66
(s, 3H), 1.60 (s, 3H), 0.95 (d, 3H, J = 6.8 Hz), 0.92 (d, 3H, J =
6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 145.2, 126.5, 124.7,
113.0, 73.2, 41.1, 40.9, 33.4, 20.6, 20.5, 18.6, 18.3, 17.8; MS (EI)
m/z (%) 196 (Mþ), 163, 135, 126, 109, 93, 67, 55; HRMS (m/z)
calcd for C13H24O 196.1827, found 196.1824; IR (KBr) 3468,
3074, 2959, 2914, 2873, 1641, 1467, 1446, 1372, 1262, 1045, 1002,
896.
2,2,7,8-Tetramethyl-5-methylenenon-7-en-3-ol (2d): colorless
oil; 1H NMR (300 MHz, CDCl3) δ 4.87-4.84 (m, 2H), 3.31 (dd,
1H, J = 10.9, 1.9 Hz), 2.85 (d, 1H, J = 15.4 Hz), 2.69 (d, 1H, J =
15.4 Hz), 2.21 (d, 1H, J = 13.5 Hz), 1.93 (dd, 1H, J = 13.5,
11.0 Hz), 1.75 (s, 1H), 1.69 (s, 3H), 1.65 (s, 3H), 1.60 (s, 3H), 0.92
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 145.7, 126.5, 124.7, 113.2,
75.7, 40.7, 38.7, 34.4, 28.8, 20.6, 20.6, 18.3; MS (EI) m/z (%) 210
(Mþ), 177, 149, 135, 124, 109, 93, 69, 57; HRMS (m/z) calcd for
C14H26O 210.1984, found 210.1971; IR (KBr) 3568, 3072, 2955,
2867, 1639, 1479, 1363, 1072, 1009, 899.
5,6-Dimethyl-3-methylene-1-phenylhept-5-en-1-ol (2e): color-
less liquid; 1H NMR (300 MHz, CDCl3) δ 7.39-7.24 (m, 5H),
4.95-4.92 (m, 1H), 4.91 (dd, 1H, J = 3.1, 1.5 Hz), 4.80 (ddd, 1H,
J = 8.7, 4.7, 2.2 Hz), 2.88 (d, 1H, J = 15.4 Hz), 2.75 (d, 1H, J =
15.4 Hz), 2.45-2.30 (m, 2H), 2.21 (d, 1H, J = 2.2 Hz), 1.70 (s,
3H), 1.69 (s, 3H), 1.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
144.4, 144.1, 128.4, 127.4, 126.6, 125.7, 124.6, 113.7, 71.6, 46.6,
41.1, 20.6, 20.5, 18.3; MS (EI) m/z (%) 212, 197, 160, 145, 107,
91, 79; HRMS (m/z) calcd for C16H22O 230.1671, found
230.1671; IR (KBr) 3404, 3029, 2986, 2914, 2859, 1642, 1493,
1453, 1373, 1049, 896, 757, 700.
5,6-Dimethyl-3-methylene-1-(3,4,5-trimethoxyphenyl)hept-5-
en-1-ol (2f): light yellow oil; 1H NMR (300 MHz, CDCl3) δ 6.59
(s, 2H), 4.96-4.92 (m, 1H), 4.92-4.89 (m, 1H), 4.76-4.68 (m,
1H), 3.87 (s, 6H), 3.83 (s, 3H), 2.87 (d, 1H, J = 15.5 Hz), 2.74
(d, 1H, J = 15.4 Hz), 2.43-2.28 (m, 2H), 2.24-2.19 (m, 1H),
1.70 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 153.2, 144.3, 139.9, 137.2, 126.6, 124.7, 113.6, 102.7,
71.8, 60.8, 56.1, 46.6, 41.1, 20.6, 20.5, 18.3; MS (EI) m/z (%) 320
1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-5,6-dimethyl-3-methyl-
enehept-5-en-1-ol (2j): colorless liquid; 1H NMR (300 MHz,
CDCl3) δ 4.89-4.84 (m, 2H), 4.07-3.92 (m, 3H), 3.84-3.76 (m,
1H), 2.82 (d, 1H, J= 15.5 Hz), 2.73 (d, 1H, J= 15.4Hz), 2.28 (dd,
1H, J = 14.0, 3.8 Hz), 2.09-1.98 (m, 2H), 1.68 (s, 3H), 1.65 (s,
3H), 1.59 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 143.9, 126.7, 124.5, 113.2, 109.1, 78.5, 69.2, 65.6, 41.0,
40.0, 26.5, 25.2, 20.6, 20.5, 18.3; MS (EI) m/z (%) 254 (Mþ), 239,
211, 163, 153, 145, 131, 123, 109, 101, 93, 81; HRMS (m/z) calcd
for C15H26O3 254.1882, found 254.1895; IR (KBr) 3480, 3075,
2987, 2915, 1643, 1455, 1439, 1372, 1252, 1215, 1156, 1066, 857.
2,3-Dimethyl-5-methylenedocosa-2,17-dien-7-ol (2k): color-
1
less liquid; H NMR (300 MHz, CDCl3) δ 5.36-5.32 (m, 2H),
4.86-4.83 (m, 2H), 3.73-3.65 (m, 1H), 2.81 (d, 1H, J = 15.4 Hz),
2.70 (d, 1H, J = 15.4 Hz), 2.18 (dd, 1H, J = 13.7, 3.2 Hz),
2.04-1.97 (m, 5H), 1.77 (d, 1H, J = 2.2 Hz), 1.69 (s, 3H), 1.64 (s,
3H), 1.60 (s, 3H), 1.51-1.24 (m, 20H), 0.93-0.86 (m, 3H); 13C
NMR (75MHz, CDCl3) δ 144.8, 129.9, 129.8, 126.5, 124.7, 112.9,
5208 J. Org. Chem. Vol. 75, No. 15, 2010

Arndt et al.
JOCArticle
68.8, 44.5, 41.1, 37.1, 32.0, 29.8, 29.7, 29.6, 29.6, 29.5, 29.3, 27.2,
26.9, 25.7, 22.3, 20.6, 20.5, 18.3, 14.0; MS (EI) m/z (%) 362 (Mþ),
344, 319, 301, 277, 237, 220, 193, 179, 163, 149, 135, 124, 109, 95;
HRMS (m/z) calcd for C25H46O 362.3549, found 362.3558; IR
(Nujol) 3376, 2925, 2855, 1641, 1463, 894, 721.
1-(Cyclohex-3-enyl)-5,6-dimethyl-3-methylenehept-5-en-1-ol (2l):
colorless liquid; 1H NMR (300 MHz, CDCl3) δ 5.75-5.61 (m,
2H), 4.90-4.84 (m, 2H), 3.63-3.42 (m, 1H), 2.84 (d, 1H, J =
15.4 Hz), 2.70 (d, 1H, J = 15.4 Hz), 2.26 (d, 1H, J = 13.6 Hz),
2.19-1.87 (m, 5H), 1.83 (d, 1H, J = 2.5 Hz), 1.76 (d, 1H, J = 2.3
Hz), 1.69 (s, 3H), 1.65 (s, 3H), 1.60 (s, 3H), 1.46-1.21 (m, 1H).
Main isomer: 13C NMR (75 MHz, CDCl3) δ 145.0, 127.3,
126.5, 126.5, 124.7, 113.2, 72.0, 41.4, 40.9, 39.6, 26.8, 25.3, 24.5,
20.6, 20.5, 18.3.
General Procedure for the Ozonolysis/Acid-Induced Cycliza-
tion Reaction Sequence. A Schlenk tube, fitted with a glass tube
to admit ozone, was charged with the hydroxyl-functionalized
1,4-diene 2 (1.0 mmol) and 10 mL of dichloromethane. The flask
was cooled to -78 °C and ozone in a stream of oxygen was
bubbled through the solution with stirring. When the solution
turned blue, ozone addition was stopped, the excess of ozone
was removed by a stream of oxygen, and dimethyl sulfide (2.0
mmol) and 2,2,2-trifluoroacetic acid (1.0 mmol) were added
successively. The solution was allowed to warm to room tem-
perature. After being stirred for 1 h, saturated sodium bicarbo-
nate solution (5.0 mL) was added. The organic layer was
separated and the aqueous layer was extracted three times with
dichloromethane. The combined organic layers were dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure. The crude products were purified by flash
column chromatography on silica gel to obtain the products of
type 8.
Resolved signals for the minor component: 13C NMR (75 MHz,
CDCl3) δ 126.8, 126.0, 124.6, 113.3, 71.9, 41.3, 40.9, 39.4,
27.9, 25.3, 20.5; ratio of the diastereomers determined by
13C NMR 1:0.93; MS (EI) m/z (%) 234 (Mþ), 191, 135, 124,
109, 81; HRMS (m/z) calcd for C16H26O 234.1984, found
234.1980; IR (Nujol) 3308, 3072, 3020, 2968, 2858, 1640, 1445,
1070, 897, 662.
2-Ethyl-6-methyl-2H-pyran-4(3H)-one, hepialone (8a):6 light
1
yellow oil; H NMR (300 MHz, CDCl3) δ 5.31 (s, 1H), 4.34-
4.24 (m, 1H), 3.73-3.65 (m, 1H), 2.41-2.37 (m, 2H), 2.00 (s,
3H), 1.90-1.72 (m, 2H), 1.01 (t, 3H, J = 7.5 Hz); 13C NMR (75
MHz, CDCl3) δ 192.8, 174.2, 104.7, 80.4, 40.3, 27.5, 21.0, 9.2.
2-Heptyl-6-methyl-2H-pyran-4(3H)-one (8b): light yellow liq-
uid; 1H NMR (300 MHz, CDCl3) δ 5.30 (s, 1H), 4.40-4.28
(m, 1H), 2.42-2.32 (m, 2H), 1.99 (s, 3H), 1.87-1.72 (m, 1H),
1.71-1.57 (m, 1H), 1.53-1.19 (m, 10H), 0.88 (t, 3H, J = 6.6
Hz); 13C NMR (75 MHz, CDCl3) δ 193.0, 174.3, 104.7, 79.3,
40.8, 34.5, 31.7, 29.3, 29.1, 24.8, 22.6, 21.0, 14.0; MS (EI) m/z
(%) 210 (Mþ), 195, 167, 152, 111, 85, 69; HRMS (m/z) calcd for
C13H22O2 210.1620, found 210.1626; IR (KBr) 3470, 2955, 2927,
2857, 1671, 1613, 1399, 1336, 1240, 1033.
1-((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)-5,6-di-
methyl-3-methylenehept-5-en-1-ol (2m): colorless liquid; 1H
NMR (300 MHz, CDCl3) δ 5.51-5.46 (m, 1H), 4.90-4.79 (m,
2H), 4.16-4.08 (m, 1H), 2.89-2.67 (m, 2H), 2.46-1.98 (m, 7H),
1.68 (s, 3H), 1.65 (s, 3H), 1.60 (s, 3H), 1.29 (s, 3H), 1.18 (t, 1H,
J = 8.3 Hz), 0.83 (d, 3H, J = 8.7 Hz).
Main isomer: 13C NMR (75 MHz, CDCl3) δ 149.4, 144.4,
126.4, 124.8, 117.4, 112.9, 71.8, 42.3, 42.2, 41.0, 40.9, 37.8, 31.7,
31.1, 26.2, 21.4, 20.6, 20.5, 18.3.
Resolved signals for the minor component: 13C NMR (75 MHz,
CDCl3) δ 149.8, 126.4, 124.7, 117.6, 113.0, 71.7, 42.2, 42.1, 41.0,
37.7, 26.2; ratio of the diastereomers determined by 13C NMR
1:0.54; MS (EI) m/z (%) 274 (Mþ), 256, 231, 191, 133, 117, 109,
91; HRMS (m/z) calcd for C19H30ONa 297.2194, found
297.2193; IR (Nujol) 3460, 3075, 2985, 2914, 2832, 2724, 1681,
1643, 1620, 1433, 1382, 1366, 1041, 888, 804.
2-Isopropyl-6-methyl-2H-pyran-4(3H)-one (8c):9 light yellow
1
liquid; H NMR (300 MHz, CDCl3) δ 5.29 (s, 1H), 4.09 (ddd,
1H, J = 13.8, 5.9, 3.9 Hz), 2.41 (dd, 1H, J = 16.6, 13.8 Hz), 2.30
(ddd, 1H, J = 16.7, 3.9, 0.7 Hz), 1.99 (s, 3H), 2.04-1.90 (m, 1H),
1.00 (d, 3H, J = 6.8 Hz), 0.97 (d, 3H, J = 6.8 Hz); 13C NMR (75
MHz, CDCl3) δ 193.4, 174.7, 104.6, 83.8, 37.8, 31.7, 20.9, 17.8, 17.7.
2-tert-Butyl-6-methyl-2H-pyran-4(3H)-one (8d):10 light yel-
(E)-13,17-Dimethyl-10-methyleneoctadeca-12,16-dien-8-ol (5):
colorless liquid; 1H NMR (300 MHz, CDCl3) δ 5.17 (tq,
1H, J = 7.3, 1.2 Hz), 5.13-5.05 (m, 1H), 4.92-4.89 (m, 1H),
4.85-4.81 (m, 1H), 3.77-3.65 (m, 1H), 2.73 (d, 2H, J = 7.5 Hz),
2.25 (dd, 1H, J = 13.6, 3,1 Hz), 2.15-1.92 (m, 5H), 1.72 (d,
1H, J = 2.8 Hz), 1.68 (s, 3H), 1.60 (s, 6H), 1.54-1.20 (m, 12H),
0.88 (t, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3) δ 146.1,
137.1, 131.5, 124.2, 121.4, 112.5, 68.8, 44.7, 39.7, 37.2, 34.7, 31.8,
29.6, 29.3, 26.6, 25.7, 25.7, 22.6, 17.7, 15.9, 14.1; MS (EI) m/z
(%) 306 (Mþ), 288, 273, 245, 219, 178, 163, 123, 109, 95,
81; HRMS (m/z) calcd for C21H38O 306.2923, found 306.2919;
IR (Nujol) 3439, 3074, 2957, 2926, 2855, 1643, 1440, 1383, 1054,
894.
General Procedure for the Cobalt-Catalyzed 1,4-Hydrovinyla-
tion/Allylation Reaction Sequence with Allyl Trimethylsilane.
When allyl silane 9 was used the hydrovinylation products were
isolated as described before. The allylation was then performed
following a protocol by Hosomi.8 The aldehyde (1.0 mmol) was
dissolved under an argon atmosphere in 0.5 mL of dichloro-
methane. A solution of TiCl4 (0.5 mmol, c = 1 mol/L) in dichloro-
methane was added dropwise at -78 °C. The mixture was stirred
for 5 min and the silyl-functionalized hydrovinylation product
10 (1.0 mmol) was subsequently added. The reaction mixture
was stirred at -78 °C until complete conversion was detected by
TLC or GC/MS analysis. The reaction was quenched with water
then extracted with dichloromethane and the combined organic
phases were dried over MgSO4. The solvent was removed and
the residue was purified by flash column chromatography on
silica gel.
1
low liquid; H NMR (300 MHz, CDCl3) δ 5.30 (s, 1H), 3.97
(dd, 1H, J = 14.4, 3.8 Hz), 2.42 (dd, 1H, J = 16.5, 14.4 Hz), 2.31
(ddd, 1H, J = 16.6, 3.9, 0.7 Hz), 2.00 (s, 3H), 0.98 (s, 9H); 13
C
NMR (75 MHz, CDCl3) δ 193.7, 174.8, 104.5, 86.6, 36.2, 33.7,
25.4, 20.9.
10-(6-Methyl-4-oxo-3,4-dihydro-2H-pyran-2-yl)decanal (8e):
1
colorless liquid; H NMR (300 MHz, CDCl3) δ 9.75 (t, 1H,
J = 1.8 Hz), 5.31 (s, 1H), 4.33 (tdd, 1H, J = 11.4, 7.2, 5.6 Hz),
2.46-2.35 (m, 4H), 1.99 (s, 3H), 1.88-1.27 (m, 16H); 13C NMR
(75 MHz, CDCl3) δ 202.7, 193.0, 174.3, 104.7, 79.3, 43.9, 40.8,
34.4, 29.4, 29.3, 29.3, 29.1, 24.8, 22.0, 21.0; MS (EI) m/z (%) 265
(Mþ - 1), 237, 223, 180, 139, 125, 111, 85; HRMS (m/z) calcd for
C16H26O3 þ Naþ 289.1780, found 289.1774; IR (Nujol) 3463,
2926, 1703, 1666, 1618, 1454, 1397, 1337, 996, 835, 693.
6-Methyl-2-phenyl-2H-pyran-4(3H)-one (8f):11 yellow oil; 1H
NMR (300 MHz, CDCl3) δ 7.46-7.34 (m, 5H), 5.44 (s, 1H), 5.39
(dd, 1H, J = 14.2, 3.6 Hz), 2.81 (dd, 1H, J = 16.8, 14.2 Hz), 2.59
(ddd, 1H, J = 16.8, 3.6, 0.8 Hz), 2.08 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 192.3, 174.3, 138.2, 128.8, 126.1, 105.2, 80.8,
42.3, 21.1.
2-(4-Bromophenyl)-6-methyl-2H-pyran-4(3H)-one (8g):9 yel-
low oil; 1H NMR (300 MHz, CDCl3) δ 7.58-7.52 (m, 2H),
(9) The analytical data are consistent with the literature: Yang, W.;
Shang, D.; Liu, Y.; Du, Y.; Feng, X. J. Org. Chem. 2005, 70, 8533.
(10) The analytical data are consistent with the literature: Organ, M. G.;
Froese, R. D. J.; Goddard, J. D.; Taylor, N. J.; Lange, G. L. J. Am. Chem.
Soc. 1994, 116, 3312.
(11) The analytical data are consistent with the literature: Reiter, M.;
Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91.
(8) Hosomi, A.; Miura, K. Bull. Chem. Soc. Jpn. 2004, 77, 835.
J. Org. Chem. Vol. 75, No. 15, 2010 5209

Arndt et al.
JOCArticle
7.31-7.26 (m, 2H), 5.43 (s, 1H), 5.35 (dd, 1H, J = 13.9, 3.7 Hz),
2.75 (dd, 1H, J = 16.8, 14.0 Hz), 2.57 (ddd, 1H, J = 16.8, 3.7, 1.0
Hz), 2.07 (d, 3H, J = 0.4 Hz); 13C NMR (75 MHz, CDCl3) δ
191.7, 174.0, 137.3, 132.0, 127.8, 122.8, 105.4, 80.1, 42.3, 21.0.
6-Methyl-2-(3-nitrophenyl)-2H-pyran-4(3H)-one (8h): yellow
111, 103, 91, 85, 77; HRMS (m/z) calcd for C12H11NO4
233.0688, found 233.0678; IR (KBr) 3081, 2886, 1655, 1605,
1528, 1400, 1347, 1330, 1237, 1029, 1009, 825, 737.
Acknowledgment. We thank the German Science Foun-
dation (Deutsche Forschungsgemeinschaft) for financial
support.
1
solid; H NMR (300 MHz, CDCl3) δ 8.35-8.31 (m, 1H), 8.25
(ddd, 1H, J = 8.1, 2.2, 1.1 Hz), 7.75-7.69 (m, 1H), 7.62 (t, 1H,
J = 7.9 Hz), 5.50 (dd, 1H, J = 13.4, 4.1 Hz), 5.49-5.47 (m, 1H),
2.78 (dd, 1H, J = 16.7, 13.7 Hz), 2.66 (ddd, 1H, J = 16.7, 4.0,
0.9 Hz), 2.12 (d, 3H, J = 0.5 Hz); 13C NMR (75 MHz, CDCl3) δ
190.9, 173.7, 140.4, 131.9, 129.9, 123.6, 122.5, 121.2, 105.7, 79.4,
42.3, 21.0; MS (EI) m/z (%) 233 (Mþ), 203, 185, 161, 149, 119,
1
Supporting Information Available: Copies of H and 13C
NMR spectra for unknown compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
5210 J. Org. Chem. Vol. 75, No. 15, 2010