Ti-catalyzed straightforward synthesis of exocyclic allenes

Article abstract of DOI:10.1002/chem.201304033

Exocyclic allenes constitute useful building blocks in organic synthesis and have recently been identified as key intermediates in the synthesis of natural products. Here the first general method for the most straightforward synthesis of exocyclic allenes

Full text of DOI:10.1002/chem.201304033

DOI: 10.1002/chem.201304033
Full Paper
&
Allenes
Ti-Catalyzed Straightforward Synthesis of Exocyclic Allenes
Juan MuÇoz-Bascꢀn,[a] Carmen Hernꢁndez-Cervantes,[b] Natalia M. Padial,[a] Mꢂriam ꢃlvarez-
Corral,[b] Antonio Rosales,*[a] Ignacio Rodrꢂguez-Garcꢂa,*[b] and J. Enrique Oltra*[a]
Abstract: Exocyclic allenes constitute useful building blocks
in organic synthesis and have recently been identified as key
intermediates in the synthesis of natural products. Here the
first general method for the most straightforward synthesis
of exocyclic allenes reported to date is presented. This
method is based on the Barbier-type cyclization of propargyl
halides catalyzed by titanium; a safe, abundant, and eco-
friendly metal. The reaction proceeds under mild conditions
compatible with different functional groups and provides
good yields of five-, six-, and seven-membered carbocycles
and nitrogen-containing heterocycles bearing an exocyclic
allene group. Experimental evidence supporting the pro-
posed reaction mechanism is also provided. Moreover, this
procedure can be carried out in an enantioselective manner
by using chiral titanocene(III) catalysts. The utility of this
method has been proved in the synthesis of the natural al-
kaloid stemoamide.
Introduction
organic synthesis, especially in addition, cyclization, cycloaddi-
tion, and cycloisomerization reactions.[2] Thus, exocyclic allene
3 (Figure 1) has been recently reported as the key intermediate
in the bio-inspired synthesis of the alkaloid stemoamide.[3]
Owing to the growing interest of allenes in pharmacy and
contemporary chemistry, several procedures for allene synthe-
sis have been developed in recent years, including alkyne iso-
merizations, diene rearrangements, electrocyclic ring-openings,
transformations of propargyl alcohols, 1,4-additions to conju-
gated enynes, Zn-promoted condensations between terminal
alkynes and aldehydes, and others.[4] Nevertheless, there is still
a lack of a general procedure to provide exocyclic allenes in
a straightforward manner.[5] Here we describe the Barbier-type
cyclization of propargyl halides catalyzed by [TiClCp2] (Nugent’s
reagent; Cp=cyclopentadienyl).[6] This new CÀC bond-forming
reaction directly gives five-, six-, and seven-membered carbocy-
cles and heterocycles bearing an exocyclic allene group. More-
over, this procedure can be carried out in an enantioselective
manner.
Allenes were considered highly unstable compounds or simple
chemical curiosities for many years. Nowadays, however, more
than 150 natural products containing the allene motif are
known and many of them, such as the grasshopper ketone (1,
Figure 1) or the carotenoid mimulaxanthin (2, Figure 1), have
the allene function in the exocyclic disposition.[1] Furthermore,
allenes have proved themselves to be useful building blocks in
Figure 1. Chemical structure of exocyclic allenes 1–3.
Results and Discussion
TiIII-Catalyzed synthesis of exocyclic allenes
[a] J. MuÇoz-Bascꢀn, N. M. Padial, Dr. A. Rosales, Prof. J. E. Oltra
Dpto. Quꢁmica Orgꢂnica, Facultad de Ciencias
Universidad de Granada, Campus Fuentenueva s/n
18071 Granada (Spain)
Titanium is the seventh most abundant metal on Earth (the
second amongst transition metals) and many titanium com-
pounds are non-toxic and environmentally friendly.[7] We have
recently observed the formation of allenyl alcohols by conden-
sation between aldehydes and internal propargyl halides cata-
lyzed by [TiClCp2].[8] This observation prompted us to conceive
the possibility of developing a sustainable Ti-catalyzed cycliza-
tion to exocyclic allenes, using the titanocene-regenerating
agent 4 to close the catalytic cycle (Scheme 1).[9]
Fax: (+34)958248437
E-mail: a.rosales.martinez@gmail.com
joltra@ugr.es
[b] C. Hernꢂndez-Cervantes, Dr. M. ꢃlvarez-Corral, Dr. I. Rodrꢁguez-Garcꢁa
Quꢁmica Orgꢂnica, ceiA3, Universidad de Almerꢁa
Almerꢁa, E-04120 (Spain)
Fax: (+34)950015008
E-mail: irodrigu@ual.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304033.
Chem. Eur. J. 2014, 20, 801 – 810
801
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 1. [TiClCp2]-catalyzed Barbier-type cyclization of propargyl halides
5–18.
Entry Substrate
Product[a]
Yield
[%]
1
2
3
74
85
78
Scheme 1. Anticipated catalytic cycle for the Ti-catalyzed synthesis of exocy-
clic allenes.
4
5
6
7
87[b]
To check this hypothesis, aldehyde 5 was treated with a sub-
stoichiometric quantity of commercial [TiCl2Cp2] (0.2 equiv), rel-
atively cheap Mn dust, and a combination of Me3SiCl and
2,4,6-collidine to form 4.[10]As expected, an acceptable 74%
yield of exocyclic allene 19 was obtained (Table 1, entry 1).
Subsequent treatment of ketone 6 under the same condi-
tions provided a good 85% yield of allenyl tertiary alcohol 20
(Table 1, entry 2). This was a gratifying but quite unexpected
result because [TiClCp2]-catalyzed intermolecular condensa-
tions between propargyl halides and ketones have always led
to homopropargylic alcohols.[8,11] This intermolecular reaction
presumably proceeds through allenylÀTiIV organometallic com-
plexes, which attack ketones to form linear alkynes.[8] In con-
trast, the intramolecular reaction (cyclization) only provides
exocyclic allenes, probably because the alternative cyclization
to endocyclic alkynes would be strongly disfavored by steric
strain. In fact, Ti-catalyzed cyclization of ketone 7 also gave the
exocyclic allene present in pyrrolidine 21 (Table 1, entry 3).
[TiClCp2]-catalyzed cyclization of indanone 8 provided the
tricyclic vinylidene 22 stereoselectively in an excellent yield of
87% (Table 1, entry 4). Interestingly, only the cis stereoisomer
was formed. Moreover, the newly formed OH group, which oc-
cupies a benzylic, tertiary, and homoallenic position, remained
in the cyclization product 22 and no dehydration products
were detected, underscoring the experimental mildness of this
method. Moreover, the excellent yield obtained confirms the
compatibility of this method with aromatic rings.
77
76
88
8
80
71
81
75
9
10
11
48[c]
24[d]
12
Once we were confident about the ability of [TiClCp2] to cat-
alyze 5-exo-cyclizations to exocyclic allenes, we decided to test
6-exo ones, because these processes might facilitate access to
interesting terpenoids and carotenoids that are scarce in
nature, which possess one or two vinyliden-cyclohexane units
in their molecules.[1] Treatment of aldehyde 9 with a substoi-
chiometric quantity of [TiClCp2] gave the expected vinyliden-
cyclohexanol 23 (Table 1, entry 5).[11] When ketone 10 was
treated under the same conditions, however, bicyclic lactone
24 was obtained (Table 1, entry 6). The lactonization process
leading to 24 might possibly be provoked by the tendency of
the methyl group to occupy an equatorial disposition, thus
13
14
90
74
[a] The alcohol was sometimes accompanied by a minor quantity of the
corresponding trimethylsilyl ether, which was easily transformed into the
alcohol. [b] Only the cis diastereomer is formed. [c] Yield of isolated 30.
[d] Yield of isolated 31.
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
802
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
pushing the tertiary alcohol towards the spatial proximity of
the corresponding cis methyl-ester group.[12] On the other
hand, [TiClCp2]-catalyzed cyclization of phenylsulfone 11 clean-
ly provided an 88% yield of cycloalkanol 25 (Table 1, entry 7).
Additionally, Ti-catalyzed cyclization of tosylamides 12 and 13
afforded 80 and 71% yields of vinyliden-piperidines 26 and 27,
respectively (Table 1, entries 8 and 9). This reaction might pro-
vide a new method for piperidine synthesis.
The capacity for efficiently increasing molecular complexity
is one of the most valuable properties of new methods in or-
ganic synthesis.[13] In this context, [TiClCp2]-catalyzed cycliza-
tion of cyclohexanone 14 gave an 81% yield of bicycloalkanol
28 bearing the expected exocyciclic allene (Table 1, entry 10)
thus confirming the utility of the method to prepare bridged
carbocycles. As can be seen, molecular complexity was consid-
erably increased in only one step, underscoring the synthetic
potential of the method.
Scheme 2. [TiClCp2]-catalyzed reductive dehalogenation of secondary prop-
argyl halides a) 34 and b) 36.
Seven-membered rings are often classified as “common
rings” owing to their relatively low ring-strain.[14] Therefore, it is
not surprising that they are quite widespread in nature, in
which they can be found in the carbon skeleton of different al-
kaloids and terpenoids.[15] Nevertheless, compared with five-
and six-membered rings, methods for the synthesis of seven-
membered ones are still notoriously scarce.[16] In this scenario,
[TiClCp2]-catalyzed cyclization of aldehyde 15 afforded a 75%
yield of cycloheptanol 29 (Table 1, entry 11). Moreover, cycliza-
tion of ketone 16 gave tertiary alcohol 30 accompanied by
a minor amount of bicyclic lactone 31 (72% total yield;
Table 1, entry 12).[17] Thus, it seems that the (pseudo)equatorial
methyl group of 30 has lesser power to promote lactonization
than the equatorial methyl group of the six-membered alcohol
precursor of lactone 24 (see Table 1, entry 6). Once again, re-
placement of ester groups by sulfones in 17 avoided lactoniza-
tion and cycloheptanol 32 was obtained in an excellent 90%
yield (Table 1, entry 13). Moreover, cyclization of tosylamide 18
afforded azepane 33 (Table 1, entry 14), providing a new
method for the synthesis of this kind of heterocycle, which are
present in the structure of numerous pharmacologically active
alkaloids, such as the anti-Alzheimer’s disease drug galanta-
mine,[18] the Stemona alkaloids,[19] and others.[20]
tion, 2) radical coupling with a second [TiClCp2] species to
form a propargyl-TiIV organometallic complex, and 3) nucleo-
philic addition to the carbonyl group to complete the cycliza-
tion process, followed by catalyst regeneration by
(Scheme 3).
4
Scheme 3. Hypothetical mechanism for [TiClCp2]-catalyzed Barbier-type cycli-
zation of propargyl halides.
In the first step, a propargyl radical would be generated by
[TiClCp2] and/or the dinuclear species [TiClCp2]2.[21] It is well-
known that free radicals are reduced by H-atom transfer (HAT)
from water through the aqua-complex [Ti(OH2)ClCp2],[22] a phe-
nomenon that can be exploited to study free-radicals by using
the aqua-complex [Ti(OD2)ClCp2] as a deuterium labeling
agent.[8] To trap propargyl radicals presumably formed in the
first step, propargyl halides 12, 34, and 36 were treated with
blue [Ti(OD2)ClCp2] generated in situ by adding D2O to green
[TiClCp2] (Scheme 4). In all products obtained, deuterium incor-
poration (DI) was higher than 95%. These DI values are signifi-
cant because high DI percentages are characteristic for radical
reductions by D-atom transfer (DAT) from [Ti(OD2)ClCp2] but
not for the hydrolysis of alkyl-TiIV complexes with D2O (DI
ꢀ60%).[8] Thus, the generation of free radicals in the first
mechanistic step was confirmed.
Once primary propargyl halides demonstrated to be suitable
substrates for the synthesis of exocyclic allenes, we investigat-
ed the secondary ones. Nevertheless, treatment of secondary
propargyl chloride 34 with a substoichiometric quantity of
[TiClCp2] gave dehalogenated alkyne 35 (98% yield) and no
cyclization product was detected. Moreover, similar treatment
of secondary chloride 36 gave alkyne 37 accompanied by
a minor amount of dimeric allene 38 (Scheme 2).
The unexpected behavior shown by secondary propargyl
halides was intriguing and, consequently, we tackled the study
of the mechanism involved in these processes.
Mechanistic studies and discussion
On the basis of our previous experience on intermolecular pro-
pragylations,[8,12] we hypothesized that the cyclization mecha-
nism would take place in three steps: 1) free-radical genera-
In spite of the great advances in free-radical chemistry ach-
ieved in the last decades,[23] the structure and chemical behav-
ior of secondary propargyl radicals is still poorly understood. In
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
803
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
to steric factors. Consequently, TiIII-catalyzed synthesis of exocy-
clic allenes is limited to primary propargyl halides due to the
inherent reactivity of secondary propargyl-TiIV complexes.
TiIII-Catalyzed enantioselective synthesis of exocyclic allenes
Asymmetric catalysis plays a crucial role in contemporary or-
ganic synthesis.[27] Therefore, we decided to assay an enantio-
merically pure titanium catalyst to check the possibility of ach-
ieving an unprecedented TiIII-catalyzed procedure for the enan-
tioselective synthesis of exocyclic allenes. To this end we chose
the commercially available Brintzinger’s complex (+)-dichloro-
(R,R)-ethylenebis(4,5,6,7-tetrahydro-1-indenyl)titanium(IV) (43)
as the precatalyst. In situ generation of the corresponding TiIII
enantiopure catalyst (44) was carried by simple stirring of 43
with Mn dust (Scheme 5).
Scheme 4. a) In situ-generation of [Ti(OD2)ClCp2] and D-atom transfer (DAT)
to free radicals; b) Deuterium labeling of the primary propargyl radical de-
rived from 12; c,d) Deuterium labeling of secondary propargyl radicals de-
rived from compounds 34 (c) and 36 (d).
Scheme 5. In situ-generation of enantiopure titanocene(III) catalyst 44 from
commercially available 43.
contrast, both spectroscopic techniques and theoretical calcu-
lations have shown that primary propargyl radicals are stabi-
lized by resonance but with unequal distribution of spin densi-
ties between the sp2 carbon (65%) and the sp one (35%),[24]
which is consistent with the 2.3:1 mixture of alkyne 39 and
allene 40 obtained in the deuterium-labeling experiment de-
picted in Scheme 4b.[25] To the best of our knowledge, howev-
er, no theoretical calculations on secondary propargyl radicals
have been reported so far. Thus, although a relative increase in
the spin density on the sp2 carbon has been suggested, there
are no conclusive data for these secondary radicals.[26] In this
scenario, results depicted in Scheme 4c and d suggest that on
the sp2 carbon of secondary propargyl radical might be a spin
density higher than 65%, giving a considerable radical reactivi-
ty to this position.
To our satisfaction, cyclization of ketone 6, catalyzed by
titanocene(III) complex 44, gave optically active cycloalkanol
(À)-20 (Table 2, entry 1). Chiral HPLC analysis indicated a mod-
Table 2. Enantioselective synthesis of exocyclic allenes catalyzed by
titanocene(III) complex 44.
Entry
Substrate
Product
Yield
[%]
ee[a]
[%]
1
2
3
4
5
6
6
7
9
10
12
15
(À)-20
(+)-21
(+)-23
(À)-24
(+)-26
(À)-29
70
71
71
78
75
72
15
29
36
39
17
43
[a] Determined by chiral HPLC analysis.
Despite of this reactivity, however, when 34 was treated
with [TiClCp2] in dry [D8]THF, dehalogenated product 35 was
obtained and no any deuterium-labeled derivative was detect-
ed, indicating that the secondary radical was not reduced by
hydrogen abstraction from the solvent and suggesting that
the radical was quickly trapped by [TiClCp2], as depicted in the
second step of Scheme 3.
erate 15% enantiomeric excess (ee). This is the first metal-cata-
lyzed enantioselective synthesis of an exocyclic allene reported
to date.
Subsequent cyclization of substrates 7, 9, 10, 12, and 15 cat-
alyzed by 44 gave optically active allenes (+)-21, (+)-23, (À)-
24, (+)-26, and (À)-29 in yields ranging from 71 to 78% and
ee values from 15 to 43% (Table 2, entries 2–6). Despite the
moderate ee values obtained, these results confirm that the ti-
tanocene catalyst participates in the key CÀC bond-forming
step and, consequently, paves the way for the development of
more efficient catalysts.
Finally, when 34 was treated with [TiClCp2] in THF and after
6 h reaction DCl/D2O was added, the deuterium-labeled prod-
uct 41 was formed. This result should be attributed to the deu-
terolysis of a propargyl-TiIV complex, which supports the mech-
anism depicted in Scheme 3 for primary propargyl halides and
strongly suggests that secondary propargyl-TiIV complexes are
not capable of reacting with the carbonyl group, possibly due
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
804
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
TiIII-Catalyzed synthesis of stemoamide
lysts. The utility of this method has been proved in the synthe-
sis of the natural alkaloid stemoamide. At the moment we are
engaged in the design and synthesis of more efficient chiral
titanocene(III) complexes and the total synthesis of terpenoid
1 and carotenoid 2.
The synthesis of natural products constitutes one of the most
demanding tests of the viability of a new method in organic
synthesis. Therefore, we decided to try out the Ti-catalyzed
synthesis of exocyclic allenes for preparing natural products. To
this end we chose the alkaloid stemoamide as target molecule.
Due to its biological properties, stemoamide, isolated from the
traditional Chinese medicine plant Stemona tuberosa, has been
the subject of several synthetic efforts.[28] Among them, Hong
and co-workers have recently reported a bio-inspired synthesis
through the key intermediate 3. We have prepared this inter-
mediate following Scheme 6. The required starting product
Experimental Section
General procedure A for the synthesis of carbocycles with
an exocyclic allene
Deoxygenated, dry THF (20 mL) was added to a mixture of
[TiCl2Cp2] (0.2 equiv) and Mn dust (8 equiv) under an Ar atmos-
phere and the suspension stirred at room temperature until it
turned lime green (after about 15 min). Then, a mixture of 2,4,6-
collidine (7 equiv) and Me3SiCl (4 equiv) in THF was added. Subse-
quently, a solution of the corresponding substrate (1 equiv) in THF
(2 mL) was slowly added over a period of 15 min and the mixture
was stirred for 6 h. The reaction was then quenched with 2n HCl
and the organic solvent removed. The residue was diluted in Et2O,
washed with brine, dried (anhydrous Na2SO4) and the solvent re-
moved. The products were purified by flash chromatography
(hexane/EtOAc mixtures).
Diethyl 3-hydroxy-4-vinylidenecyclopentane-1,1-dicarboxylate
(19): Reaction of diethyl 2-(4-chlorobut-2-yn-1-yl)-2-(2-oxoethyl)-
malonate (5; 104 mg, 0.360 mmol) according to the general proce-
dure A afforded 68 mg (74%) of product 19, isolated as colorless
Scheme 6. Formal synthesis of (Æ)-stemoamide through the key intermedi-
ate 3. a) i) propargyl chloride, nBuLi, THF, 50 8C; ii) NaBH3CN, MeOH, AcOEt,
78 8C, 50%; b) OsO4 catalyst, KIO4, THF/H2O, 0 to 5 8C, 59%; c) [TiCl2Cp2], Mn,
2,4,6-collidine, TMSCl, THF, reflux, 76%.
1
oil. H NMR (300 MHz, CDCl3): d=5.03–4.87 (m, 2H), 4.78–4.71 (m,
1H), 4.25 (q, J=7.5 Hz, 2H), 4.23 (q, J=7.5 Hz, 2H), 3.24 (dtt, J=
16.5, 4.1, 1.2 Hz, 1H), 2.97 (dt, J=16.5, 4.9 Hz, 1H), 2.55–2.35 (m,
2H), 1.29 (t, J=7.5 Hz, 3H), 1.27 ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3, DEPT): d=203.3 (C), 172.2 (C), 171.0 (C), 104.6 (C),
79.0 (CH2), 73.4 (CH), 61.9 (CH2), 61.7 (CH2), 58.5 (C), 42.7 (CH2), 36.4
(CH2), 13.9 (CH3), 13.9 ppm (CH3); IR (film): n˜ =3376, 2926, 2854,
2253, 1964, 1728, 1192, 903, 726 cmÀ1; HRMS (QTof): m/z calcd for
C13H19O5 255.1232; found: 255.1233 [M+1]+.
was obtained by alkylation of the sodium salt of commercial
succinimide with 5-bromo-1-pentene, which afforded 45 in
a near quantitative yield as previously described.[29] Selective
monopropargylation was achieved in a quite straightforward
way. Thus, treatment of propargyl chloride with n-BuLi and ad-
dition to 45 gave a hydroxy derivative, which was immediately
reduced with NaBH3CN to give the desymmetrized succinimide
derivative 46. After chemoselective oxidative cleavage of the
terminal olefin of 46, the aldehyde 47 was obtained. Finally,
[TiClCp2]-catalyzed cyclization of 47 gave exocyclic allene 3 as
a 2.7:1 mixture of diasteromers.[30] This mixture can be directly
used to give a single isomer of stemoamide as has been previ-
ously reported.[3] By using this procedure, the formal synthesis
of stemoamide is achieved with a considerably shorter synthe-
sis for the preparation of key intermediate 3, thus proving the
synthetic utility of our method.
Dimethyl 3-hydroxy-3-methyl-4-vinylidenecyclopentane-1,1-di-
carboxylate (20): Reaction of dimethyl 2-(4-chlorobut-2-yn-1-yl)-2-
(2-oxopropyl)malonate (6; 300 mg, 1.09 mmol) according to the
general procedure A afforded 223 mg (85%) of product 20, isolat-
ed as colorless oil. 1H NMR (500 MHz, CDCl3): d=4.94 (br t, J=
4.5 Hz, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.39 (dtd, J=16.6, 4.0, 1.5 Hz,
1H), 2.96 (dt, J=16.6, 5.0 Hz, 1H), 2.63 (d, J=14.0 Hz, 1H), 2.30 (d,
J=14.0 Hz, 1H), 1.41 ppm (brs, 3H); 13C NMR (125 MHz, CDCl3,
DEPT): d=201.9 (C), 172.9 (C), 171.6 (C), 108.4 (C), 80.0 (CH2), 78.8
(C), 58.3 (C), 53.0 (CH3), 52.9 (CH3), 48.5 (CH2), 36.9 (CH2), 26.4 ppm
(CH3); IR (film) n˜ =3509, 2954, 2928, 1962, 1728, 1434, 1261, 1061,
801 cmÀ1; HRMS (QTof): m/z calcd for C12H17O5 241.1076 [M+H]+;
found: 241.1077.
Dimethyl
3a-hydroxy-3-vinylidene-3,3a,8,8a-tetrahydrocyclo-
Conclusion
penta[a]indene-1,1(2H)-dicarboxylate (22): Reaction of dimethyl
2-(4-bromobut-2-yn-1-yl)-2-(1-oxo-2,3-dihydro-1H-inden-2-yl)malo-
nate (8; 300 mg, 0.76 mmol) according to the general procedure A
afforded 209 mg (87%) of product 22, isolated as a white solid.
We present the first general procedure for the straightforward
synthesis of exocyclic allenes reported to date. The reaction,
catalyzed by titanocene(III) complexes, proceeds under mild
conditions compatible with different functional groups and
provides good yields of five-, six-, and seven-membered carbo-
cycles and nitrogen-containing heterocycles bearing an exocy-
clic allene group. Therefore, this method affords a new retro-
synthetic disconnection in the a-position of an exocyclic
allene. Additionally, this procedure can be carried out in an
enantioselective manner by using chiral titanocene(III) cata-
1
M.p.: 134–1368C; H NMR (300 MHz, CDCl3): d=7.47 (m, 1H), 7.28
(m, 2H), 7.16 (m, 1H), 5.13–5.05 (m, 1H), 4.98–4.88 (m, 1H), 4.08 (s,
1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.55 (t, J=8.8 Hz, 1H), 3.32–3.17 (m,
2H), 2.97 (d, J=16.4 Hz, 1H), 2.64 ppm (dd, J=16.6, 7.5 Hz, 1H);
13C NMR (75 MHz, CDCl3, DEPT): d=203.5 (C), 173.8 (C), 169.9 (C),
145.1 (C), 139.6 (C), 128.5 (CH), 127.6 (CH), 124.1 (CH), 123.4 (CH),
107.7 (C), 90.8 (C), 79.9 (CH2), 61.8 (C), 57.0 (CH), 53.4 (CH3), 52.7
(CH3), 37.0 (CH2), 33.6 ppm (CH2); 1D NOESY: proton irradiated:
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
805
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
4.08 (H-8a), 3.55 (OH-3a); IR (film): n˜ =3514, 2954, 1960, 1722,
1608 cmÀ1; HRMS (QTof): m/z calcd for C18H19O5: 315.1232 [M+H]+;
found 315.1237.
(dt, J=14.2, 1.3 Hz, 1H), 2.21–1.96 (m, 3H), 1.85–1.74 (m, 1H),
1.67–1.55 ppm (m, 2H); 13C NMR (75 MHz, CDCl3, DEPT): d=207.1
(C), 172. (C), 171.9 (C), 102.1 (C), 77.2 (CH2), 71.7 (CH), 57.2 (C), 52.4
(CH3), 52.2 (CH3), 36.1 (CH2), 34.9 (CH2), 31.3 (CH2), 19.2 ppm (CH2);
IR (film): n˜ =3505, 2952, 1729, 1434, 1200 cmÀ1; HRMS (QTof): m/z
calcd for C13H18O5Na: 277.1052; found: 277.1057 [M+Na]+.
Diethyl
4-hydroxy-3-vinylidenecyclohexane-1,1-dicarboxylate
(23): Reaction of 2-(4-chlorobut-2-yn-1-yl)-2-(3-oxopropyl)malonate
(9; 82 mg, 0.272 mmol) according to the general procedure A af-
forded 56 mg (77%) of product 23, isolated as colorless oil.
1H NMR (300 MHz, CDCl3): d=4.91–4.90 (m,2H), 4.27–4.10 (m, 5H),
3.02 (dd, J=13.8, 1.6 Hz, 1H), 2.58 (dt, J=13.8, 2.9 Hz, 1H), 2.42–
2.34 (m, 1H), 2.11–2.02 (m, 1H), 1.97–1.88 (m, 1H), 1.79 (brs, 1H),
1.75–1.63 (m, 1H), 1.29–1.23 ppm (m, 6H); 13C NMR (75 MHz, CDCl3,
DEPT): d=202.3 (C), 170.9 (C), 170.3 (C), 101.8 (C), 78.4 (CH2), 67.7
(CH), 61.5 (CH2), 61.3 (CH2), 55.2 (C), 33.2 (CH2), 31.7 (CH2), 28.1
(CH2), 14.0 (CH3), 14.0 ppm (CH3); IR (film) n˜ =3512, 2939, 2859,
2253, 1964, 1650, 903, 726 cmÀ1; HRMS (QTof): m/z calcd for
C14H21O5: 269.1389; found: 269.1381 [M+1]+.
Dimethyl 4-hydroxy-4-methyl-3-vinylidenecycloheptane-1,1-di-
carboxylate (30) and methyl 5-methyl-7-oxo-9-vinylidene-6-
oxabicyclo[3.2.2]nonane-1-carboxylate (31): Reaction of dimethyl
2-(4-bromobut-2-yn-1-yl)-2-(4-oxopentyl)malonate (16; 300 mg,
0.86 mmol) according to the general procedure A afforded the
products 30, isolated as a white solid (111 mg, 48%) and 31, isolat-
ed as a white solid (49 mg, 24%). 30: M.p.: 47–488C; 1H NMR
(500 MHz, CDCl3): d=4.83 (dt, J=10.7, 1.5 Hz, 1H), 4.80 (dt, J=
10.6, 1.5 Hz, 1H), 3.70 (brs, 3H), 3.69 (brs, 3H), 2.98 (br d, J=
13.9 Hz, 1H), 2.60 (dt, J=14.1, 1.5 Hz, 1H), 2.21–2.12 (m, 2H), 1.90–
1.78 (m, 2H), 1.69–1.58 (m, 2H), 1.34 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3, DEPT): d=206.3 (C), 172.2 (C), 171.7 (C), 106.3 (C),
77.8 (CH2), 73.0 (C), 57.5 (C), 52.3 (CH3), 52.1 (CH3), 41.7 (CH2), 35.7
(CH2), 32.2 (CH2), 29.8 (CH3), 20.1 ppm (CH2); IR (film) n˜ =3412,
2923, 1955, 1734, 1309 cmÀ1; HRMS ES: m/z calcd for C14H21O5
269.1389 [M+H]+; found: 269.1393; 31: M.p.: 87–918C; 1H NMR
(500 MHz, CDCl3): d=5.02 (dt, J=10.9, 4.6 Hz, 1H), 4.96 (dt, J=
10.8, 4.5 Hz,1H), 3.80 (s, 3H), 3.40 (dtd, J=17.0, 5.0, 1.3 Hz, 1H),
2.79 (dt, J=17.0, 4.0 Hz, 1H), 2.29–2.21 (m, 1H), 2.11 (dt, J=9.7,
4.6 Hz, 1H), 2.03–1.78 (m, 4H), 1.52 (brs, 3H); 13C NMR (125 MHz,
CDCl3, DEPT): d=202.6 (C), 172.0 (C), 170.9 (C), 99.2 (C), 83.6 (C),
79.9 (CH2), 52.9 (CH3), 52.3 (C), 39.9 (CH2), 30.20 (CH2), 30.19 (CH2),
Methyl 1-methyl-3-oxo-6-vinylidene-2-oxabicyclo[2.2.2]octane-4-
carboxylate (24): Reaction of dimethyl 2-(4-chlorobut-2-yn-1-yl)-2-
(3-oxobutyl)malonate (10; 300 mg, 1.03 mmol) according to the
general procedure A afforded 175 mg (76%) of product 24, isolat-
1
ed as a colorless oil. H NMR (500 MHz, CDCl3): d=5.03 (dt, J=9.3,
4.5 Hz, 1H),4.97 (dt, J=9.3, 4.4 Hz, 1H), 3.82 (brs, 3H), 3.17 (ddd,
J=16.4, 8.0, 4.6 Hz, 1H), 2.73 (dt, J=16.5, 4.5 Hz, 1H), 2.52–2.44
(m, 1H), 2.12–1.93 (m, 3H), 1.50 ppm (s, 3H); 13C NMR (125 MHz,
CDCl3, DEPT): d=202.2 (C), 171.7 (C), 169.6 (C), 99.4 (C), 82.4 (C),
80.5 (CH2), 52.8 (CH3), 49.4 (C), 32.7 (CH2), 31.8 (CH2), 26.3 (CH2),
22.4 ppm (CH3); IR (film) n˜ =2987, 2939, 2255, 1964, 1753, 1735,
1270, 1084, 906, 728 cmÀ1; HRMS (QTof): m/z calcd for C12H15O4
223.0970: [M+H]+; found: 223.0977.
27.1 (CH3), 20.9 ppm (CH2); IR (film) n˜ =2921, 1958, 1738 cmÀ1
;
HRMS ES: m/z calcd for C13H17O4: 237.1127 [M+H]+; found:
1-Ethyl-4,4-bis(phenylsulfonyl)-2-vinylidenecyclohexanol
(25):
237.1135.
Reaction of 10-bromo-6,6-bis(phenylsulfonyl)dec-8-yn-3-one (11;
300 mg, 0,59 mmol) according to the general procedure A afforded
223 mg (88%) of product 25, isolated as a colorless oil. 1H NMR
(400 MHz, CDCl3): d=8.10–7.99 (m, 4H), 7.69 (dd, J=13.9, 7.4 Hz,
2H), 7.57 (dd, J=13.8, 7.6 Hz, 4H), 5.02–4.97 (m, 1H), 4.97–4.91 (m,
1H), 3.31 (dt, J=15.6, 3.1 Hz, 1H), 2.93 (d, J=15.5 Hz, 1H), 2.63
(ddd, J=15.2, 10.3, 5.0 Hz, 1H), 2.39 (dt, J=15.0, 5.0 Hz, 1H), 2.07
(dt, J=13.6, 5.2 Hz, 1H), 1.91 (dt, J=13.7, 5.3 Hz, 1H), 1.71–1.60 (m,
2H), 0.89 ppm (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, DEPT):
d=204.3 (C), 136.5 (C), 136.2 (C), 134.52 (CH), 134.49 (CH), 131.46
(CH), 131.41 (CH), 128.6 (CH), 128.5 (CH), 101.7 (C), 86.8 (C), 79.7
(CH2), 70.4 (C), 32.5 (CH2), 32.3 (CH2), 28.0 (CH2), 23.3 (CH2), 7.6 ppm
(CH3); IR (film): n˜ =3508, 2934, 1961, 1729 cmÀ1; HRMS ES: m/z
calcd for C22H24O5S2: 432.1065 [M+H]+; found: 432.1079.
1-Methyl-4,4-bis(phenylsulfonyl)-2-vinylidenecycloheptanol (32):
Reaction of 10-bromo-6,6-bis(phenylsulfonyl)dec-8-yn-2-one (17;
300 mg, 0.59 mmol) according to the general procedure A afforded
230 mg (90%) of product 32, isolated as a colorless oil. 1H NMR
(400 MHz, CDCl3): d=8.10 (d, J=8.5 Hz, 2H), 8.05 (d, J=8.5 Hz,
2H), 7.70 (t, J=7.4 Hz, 2H), 7.58 (t, J=7.7 Hz, 4H), 4.94 (brs, 2H),
3.58 (d, J=15.9 Hz, 1H), 3.02 (d, J=15.8 Hz, 1H), 2.53 (dd, J=15.6,
7.9 Hz, 1H), 2.43 (dd, J=15.7, 10.1 Hz, 1H), 1.88–1.57 (m, 4H),
1.40 ppm (brs, 3H); 13C NMR (100 MHz, CDCl3, DEPT): d=208.2 (C),
136.8 (C), 136.6 (C), 134.5 (CH), 134.3 (CH), 131.7 (CH), 131.4 (CH),
128.6 (CH), 128.5 (CH), 103.1 (C), 90.3 (C), 78.1 (CH2), 71.9 (C), 44.0
(CH2), 29.8 (CH3), 29.4 (CH2), 27.4 (CH2), 18.7 ppm (CH2); IR (film) n˜ =
3509, 2923, 1955, 1309 cmÀ1; HRMS ES: m/z calcd for C22H25O5S2:
433.1143 [M+H]+; found: 433.1132.
Dimethyl 5-hydroxy-4-vinylidenebicyclo[3.3.1]nonane-2,2-dicar-
boxylate (28): Reaction of dimethyl 2-(4-bromobut-2-yn-1-yl)-2-(3-
oxocyclohexyl)malonate (14; 300 mg, 0.84 mmol) according to the
general procedure A afforded 191 mg (81%) of product 28, isolat-
Dimethyl 2-(3-oxobutyl)-2-(pent-2-yn-1-yl)malonate (37) and tet-
ramethyl
2,13-dioxo-7,8-di(prop-1-en-1-ylidene)tetradecane-
5,5,10,10-tetracarboxylate (38): Reaction of dimethyl 2-(4-chloro-
pent-2-yn-1-yl)-2-(3-oxobutyl)malonate (36; 300 mg, 0.99 mmol) ac-
cording to the general procedure A afforded products 37, isolated
as a colorless oil (106 mg, 40%), and 38, isolated as a colorless oil
1
ed as a colorless oil. H NMR (400 MHz, CDCl3): d=4.96 (dd, J=9.9,
5.3 Hz, 1H), 4.87 (dd, J=9.9, 5.8 Hz, 1H), 3.71 (brs, 6H), 3.39 (dt,
J=16.5, 5.5 Hz, 1H), 3.05 (d, J=16.6 Hz, 1H), 2.05–1.80 (m, 4H),
1.74–1.67 (m, 3H), 1.59–1.53 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3, DEPT): d=201.5 (C), 171.1 (C), 170.7 (C), 106.7 (C), 79.6
(CH2), 67.6 (C), 58.3 (C), 52.8 (CH3), 52.7 (CH3), 40.6 (CH2), 39.2 (CH2),
36.6 (CH), 33.0 (CH2), 26.7 (CH2), 21.5 ppm (CH2); IR (film) n˜ =3162,
2857, 1957, 1724 cmÀ1; HRMS ES: m/z calcd for C15H21O5: 281.1389
[M+H]+; found: 281.1398.
1
(54 mg, 10%). 37: H NMR (400 MHz, CDCl3): d=3.72 (brs, 6H), 2.76
(t, J=2.4 Hz, 2H), 2.48 (t, J=7.4 Hz, 2H), 2.30 (t, J=7.2 Hz, 2H),
2.14 (brs, 3H), 2.16–2.08 (m, 2H), 1.07 ppm (t, J=7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3, DEPT): d=207.1 (C), 170.7 (C), 85.3 (C),
73.2 (C), 56.4 (C), 52.6 (CH3), 38.6 (CH2), 29.8 (CH3), 26.4 (CH2), 24.1
(CH3), 14.1 (CH2), 12.3 ppm (CH2); IR (film): n˜ =2954, 1949,
1733 cmÀ1; HRMS ES: m/z calcd for C14H21O5: 269.1389 [M+H]+;
found: 269.1398. 38: 1H NMR (400 MHz, CDCl3): d=5.53–5.49 (m,
1H), 5.48–5.45 (m, 1H), 3.71 (brs, 12H), 3.01 (d, J=2.2 Hz, 4H),
2.46–2.39 (m, 4H), 2.33–2.26 (m, 4H), 2.13 (s, 6H), 1.73 ppm (d, J=
7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3, DEPT): d=206.8 (C), 201.4
(C), 170.7 (C), 170.6 (C), 98.8 (C), 95.7 (CH), 56.0 (C), 52.6 (CH3), 39.7
Dimethyl 4-hydroxy-3-vinylidenecycloheptane-1,1-dicarboxylate
(29): Reaction of dimethyl 2-(4-chlorobut-2-yn-1-yl)-2-(4-oxobutyl)-
malonate (15; 70 mg, 0.242 mmol) according to the general proce-
dure A afforded 46 mg (75%) of product 29, isolated as colorless
1
oil. H NMR (300 MHz, CDCl3): d=4.83–4.81 (m, 2H), 4.37–4.27 (m,
1H), 3.73 (s, 3H), 3.72 (s, 3H), 2.93 (dt, J=14.2, 1.7 Hz, 1H), 2.68
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
806
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(CH2), 38.6 (CH2), 29.8 (CH3), 25.8 (CH2), 14.7 ppm (CH3); IR (film) n˜ =
2953, 2229, 1728 cmÀ1; HRMS ES: m/z calcd for C28H39O10: 535.2543
[M+H]+; found: 535.2549.
13.6, 1.7 Hz, 1H), 3.40 (ddd, J=13.6, 6.3, 3.2 Hz, 1H), 3.18 (ddd, J=
13.5, 9.9, 5.5 Hz, 1H), 2.42 (s, 3H), 1.93–1.59 (m, 4H), 1.38 ppm (s,
3H); 13C NMR (100 MHz, CDCl3, DEPT): d=205.7 (C), 143.3 (C), 136.0
(C), 129.5 (CH), 127.3(CH), 106.6 (C), 78.3 (CH2), 72.2 (C), 48.1 (CH2),
47.4 (CH2), 41.5 (CH2), 28.8 (CH3), 24.8 (CH2), 21.5 ppm (CH3); IR
(film) n˜ =3505, 2954, 1956, 1336, 1160 cmÀ1; HRMS (TOF MS ES+):
m/z calcd for C16H22NO3S: 308.1320; found: 308.1309.
General procedure B for the synthesis of heterocycles with
an exocyclic allene
N-(3-Oxobutyl)-N-(pent-2-yn-1-yl)-p-toluenesulfonamide (35): Re-
action of N-(4-chloropent-2-yn-1-yl)-N-(3-oxobutyl)-p-toluenesulfon-
amide (34; 300 mg, 0.88 mmol) according to the general procedure
B afforded 260 mg (98%) of product 35, isolated as a light-yellow
oil. 1H NMR (500 MHz, CDCl3): d=7.73 (d, J=8.3 Hz, 2H), 7.29 (d,
J=8.0 Hz, 2H), 4.08 (t, J=2.2 Hz, 2H), 3.40 (t, J=7.2 Hz, 2H), 2.84
(t, J=7.2 Hz, 2H), 2.42 (s, 3H), 2.18 (s, 3H), 1.93 (qt, J=7.5, 2.2 Hz,
2H), 0.90 ppm (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3, DEPT):
d=206.7 (C), 143.5 (C), 135.6 (C), 129.4 (CH), 127.8 (CH), 87.5 (C),
71.9 (C), 43.0 (CH2), 41.8 (CH2), 38.1 (CH2), 30.2 (CH3), 21.5 (CH3),
13.4 (CH3), 12.1 ppm (CH2); IR (film) n˜ =2925, 2358, 1717, 1349,
Deoxygenated, dry THF (20 mL) was added to a mixture of
[TiCl2Cp2] (0.2 equiv) and Mn dust (8 equiv) under an Ar atmos-
phere. The suspension was stirred at room temperature until it
turned lime green (after about 15 min). Then, a mixture of 2,4,6-
collidine (7 equiv) and Me3SiCl (4 equiv) in THF was added. Subse-
quently, a solution of propargyl halide (1 mmol) in THF (2 mL) was
slowly added over a period of 1 h and the mixture was stirred for
4 h. The reaction was then quenched with 2n HCl and the organic
solvent removed. The residue was diluted in AcOEt, washed with
brine, dried (anhydrous Na2SO4) and the solvent removed. Products
were purified by flash chromatography of the residues on silica gel
(hexane/EtOAc mixtures).
1160 cmÀ1
; HRMS (TOF MS ES+): m/z calcd for C16H22NO3S:
308.1320; found: 308.1326.
3-Methyl-1-tosyl-4-vinylidenepyrrolidin-3-ol (21): Reaction of N-
(4-chlorobut-2-yn-1-yl)-N-(2-oxopropyl)p-toluenesulfonamide
(7;
300 mg, 0.96 mmol) according to the general procedure B afforded
208 mg (78%) of product 21, isolated as a light-yellow oil. H NMR
General procedure C for the treatment of nitrogen-
containing propargyl halides with [Ti(OD2)ClCp2]
1
(400 MHz, CDCl3): d=7.70 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.0 Hz,
2H), 5.14–4.86 (m, 2H), 4.10 (dt, J=13.1, 4.5 Hz, 1H), 3.83 (dt, J=
13.1, 4.3 Hz, 1H), 3.41 (d, J=10.1 Hz, 1H), 3.07 (d, J=10.1 Hz, 1H),
2.42 (s, 3H), 1.35 ppm (s, 3H); 13C NMR (100 MHz, CDCl3, DEPT): d=
199.9 (C), 143.7 (C), 132.7 (C), 129.7 (CH), 127.8 (CH), 105.6 (C), 82.0
(CH2), 76,9 (C), 60.7 (CH2), 48.6 (CH2), 23.9 (CH3), 21.7 ppm (CH3); IR
(film) n˜ =3478, 2926, 1968, 1345, 1160 cmÀ1; HRMS (TOF MS ES+):
m/z calcd for C14H18NO3S: 280.1007; found: 280.1001.
Deoxygenated, dry THF (20 mL) was added to a mixture of
[TiCl2Cp2] (2.5 equiv) and Mn dust (8 equiv) under an Ar atmos-
phere. The suspension was stirred at room temperature until it
turned lime green (after about 15 min) and, then, deoxygenated
D2O (50 equiv) was added. Thus the solution turned dark blue and
was stirred for 15 min. Subsequently, a solution of propargyl halide
(1 equiv) in THF (1 mL) was slowly added over a period of 20 min.
and the mixture was stirred for 5 h. The solvent was removed and
the suspension was then diluted with AcOEt. The organic layer was
washed with brine, dried (anhydrous Na2SO4). The solvent was re-
moved and the residue submitted to flash chromatography
(hexane/EtOAc mixtures) to give the corresponding product.
4-Methyl-1-tosyl-3-vinylidenepiperidin-4-ol (26): Reaction of N-(4-
chlorobut-2-yn-1-yl)-N-(3-oxobutyl)p-toluenesulfonamide
(12;
300 mg, 0.92 mmol) according to the general procedure B afforded
1
215 mg (80%) of product 26, isolated as a light-yellow oil. H NMR
(400 MHz, CDCl3): d=7.64 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.1 Hz,
2H), 4.87 (ddd, J=27.9, 10.9, 2.5 Hz, 2H), 4.00 (d, J=12.4 Hz, 1H),
3.49 (ddd, J=7.8, 5.6, 2.7 Hz, 2H), 2.93 (ddd, J=14.4, 8.0, 2.9 Hz,
1H), 2.42 (s, 3H), 1.74–1.64(m, 2H), 1.28 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3, DEPT): d=202.7 (C), 143.6 (C), 133.6 (C), 129.4
(CH), 127.6 (CH), 101.8 (C), 78.4 (CH2), 67.6 (C), 46.1 (CH2), 42.5
(CH2), 37.9 (CH2), 27.9 (CH3), 21.6 ppm (CH3); IR (film): n˜ =3503,
2925, 1962, 1347, 1158 cmÀ1; HRMS (TOF MS ES+): m/z calcd for
C15H20NO3S 294.1164; found: 294.1151.
N-(4-Deuteriobut-2-yn-1-yl)-N-(3-oxobutyl)p-toluenesulfonamide
(39) and N-(2-deuteriobuta-2,3-dien-1-yl)-N-(3-oxobutyl)-p-tolu-
enesulfonamide (40): Reaction of N-(4-chlorobut-2-yn-1-yl)-N-(3-
oxobutyl)-p-toluenesulfonamide (12; 200 mg, 0.61 mmol) accord-
ing to the general procedure C afforded a mixture of deuterium-la-
beled products 39 (2.3 parts) and 40 (1 part). 39: 1H NMR
(500 MHz, CDCl3): d=7.73 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.5 Hz,
2H), 4.06 (t, J=2.3 Hz, 2H), 3.40 (t, J=7.2 Hz, 2H), 2.84 (t, J=
7.1 Hz, 2H), 2.43 (s, 3H), 2.18 (s, 3H). 1.55 ppm (brs, 2H); 13C NMR
(125 MHz, CDCl3, DEPT): d=206.8 (C), 143.2 (C), 135.6 (C), 129.4
(CH), 127.9 (CH), 87.4 (C), 71.9(C), 43.1 (CH2), 41.9 (CH2), 38.4 (CH2),
30.1 (CH3), 21.6 (CH3), 11.8 ppm (t, 1JC,D =21.2 Hz, CH2D); IR (film)
n˜ =2923, 1946, 1715, 1340, 1160 cmÀ1; HRMS (TOF MS ES+): m/z
calcd for C15H19DNO3S 295.1227; found: 295.1220. 40: 1H NMR
(500 MHz, CDCl3): d=7.70 (d, J=8.3 Hz, 2H), 7.31 (d, J=7.9 Hz,
2H), 4.72 (t, J=2.5 Hz, 2H), 3.84 (s, 2H), 3.39 (t, J=7.2 Hz, 2H), 2.85
(t, J=7.2 Hz, 2H), 2.44 (s, 3H), 2.17 ppm (s, 3H); 13C NMR (125 MHz,
CDCl3, DEPT): d=209.2 (C), 206.5 (C), 143.3 (C), 136.4 (C), 129.8
4-Ethyl-1-tosyl-3-vinylidenepiperidin-4-ol (27): Reaction of N-(4-
bromobut-2-yn-1-yl)-N-(3-oxobutyl)p-toluenesulfonamide
(13;
300 mg, 0.77 mmol) according to the general procedure B afforded
1
170 mg (71%) of product 27, isolated as a light-yellow oil. H NMR
(400 MHz, CDCl3): d=7.66 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.0 Hz,
2H), 4.90 (ddd, J=25.8,10.6, 2.4, Hz, 2H), 3.85 (dd, J=12.6, 1.1 Hz,
1H), 3.68 (dt, J=12.6, 2.5 Hz, 1H), 3.49–3.33 (m, 1H), 3.23–3.03 (m,
1H), 2.42 (s, 3H), 1.88–1.46 (m, 4H), 0.84 ppm (t, J=7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3, DEPT): d=202.6 (C), 143.5 (C), 134.0 (C),
129.6 (CH), 127.7 (CH), 101.5 (C), 78.8 (CH2), 69.9 (C), 46.6 (CH2),
42.7 (CH2), 35.3 (CH2), 31.9 (CH2), 21.5 (CH3), 7.3 ppm (CH3); IR (film):
n˜ =3501, 2924, 1961, 1344, 1162 cmÀ1; HRMS (TOF MS ES+): m/z
calcd for C16H22NO3S: 308.1320; found: 308.1305.
1
(CH), 127.3 (CH), 85.7 (t, JC,D =19.9 Hz, CD), 76.6 (CH2), 47.9 (CH2),
43.0 (CH2), 42.0 (CH2), 29.9 (CH3), 21.6 ppm (CH3); IR (film): n˜ =2924,
2360,2332, 1715, 1347, 1159 cmÀ1; HRMS (TOF MS ES+): m/z calcd
for C15H18DNO3S: 295.1227; found: 295.1219.
4-Methyl-1-tosyl-3-vinylideneazepan-4-ol (33): Reaction of N-(4-
chlorobut-2-yn-1-yl)-N-(4-oxopentyl)p-toluenesulfonamide
300 mg, 0.88 mmol) according to the general procedure B afforded
200 mg (74%) of product 33, isolated as a light-yellow oil. H NMR
(400 MHz, CDCl3): d=7.68 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.0 Hz,
2H), 5.00–4.78 (m, 2H), 4.05 (dt, J=13.7, 2.1 Hz, 1H), 3.81 (dt, J=
(18;
N-(4-Deuteriopent-2-yn-1-yl)-N-(3-oxobutyl)-p-toluenesulfon-
amide (41): Reaction of N-(4-chloropent-2-yn-1-yl)-N-(3-oxobutyl)
p-toluenesulfonamide (34; 200 mg, 0.59 mmol) according to the
general procedure C afforded 177 mg (98%) of product 41, isolat-
1
1
ed as a light-yellow oil. H NMR (400 MHz, CDCl3): d=7.72 (d, J=
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
807
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
8.2 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 4.07 (d, J=1.9 Hz, 2H), 3.40 (t,
J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H), 2.41 (s, 3H), 2.17 (s, 3H),
1.97–1.81 (m, 1H), 0.89 ppm (d, J=7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3, DEPT): d=206.5 (C), 143.4 (C), 135.4 (C), 129.3 (CH), 127.8
(CH), 87.4(C), 72.1 (C), 42.9 (CH2), 41.7 (CH2), 32.8 (CH2), 29.9 (CH3),
21.1 (CH3), 13.3 (CH3), 11.8 ppm (t, JC,D =19.3 Hz, CHD); IR (film) n˜ =
2923, 2264, 2235, 1716, 1347, 1159 cmÀ1; HRMS (TOF MS ES+): m/z
calc. for C16 H21DNO3S: 309.1383; found: 309.1374.
excess (ee) determined by chiral HPLC (CHIRALPACK IA, hexane/
iPrOH 95:5) was 15%. ; [a]2D3 =À3.7 (c=0.003 gmLÀ1, MeOH).
(+)-3-Methyl-1-tosyl-4-vinylidenepyrrolidin-3-ol (+)-21: Reaction
of N-(4-chlorobut-2-yn-1-yl)-N-(2-oxopropyl)p-toluenesulfonamide
(7; 113 mg, 0.360 mmol), according to the general procedure D, af-
forded 71 mg (71%) of product (+)-21, isolated as colorless oil.
The ee value, determined by chiral HPLC (CHIRALPACK IA, hexane/
iPrOH 7:3), was 29%. [a]2D3 = +17.6 (c=0.012 gmLÀ1, MeOH).
1
Treatment of propargyl halide 36 with [Ti(OD2)ClCp2]: Deuteri-
um-labeled ketone 42: Deoxygenated, dry THF (20 mL) was added
to a mixture of [TiCl2Cp2] (2.47 mmol, 615 mg) and Mn dust
(7.92 mmol, 434.8 mg) under an Ar atmosphere, the suspension
stirred at room temperature until it turned lime green (after about
15 min) and then, deoxygenated D2O (49.5 mmol, 990 mg) was
added. At this point the solution turned dark blue, and it was
stirred for 15 min. Subsequently, a solution of compound 36
(300 mg, 0.99 mmol) in THF (1 mL) was slowly added over a period
of 20 min. and the mixture stirred for 5 h. The solvent was re-
moved in vacuo and Et2O was added to the residue. The organic
layer was washed with brine and dried (anhydrous Na2SO4). The
solvent was removed and the residue submitted to flash chroma-
tography (hexane/EtOAc mixtures) to give product 42, isolated as
(+)-Diethyl
4-hydroxy-3-vinylidenecyclohexane-1,1-dicarboxy-
late, (+)-23: Cyclization of diethyl 2-(4-chlorobut-2-yn-1-yl)-2-(3-
oxopropyl)malonate (9; 82 mg, 0.211 mmol) catalyzed by 43, ac-
cording to the general procedure D, afforded 40 mg (71%) of
product (+)-23, isolated as colorless oil. The ee value determined
by chiral HPLC (CHIRALPACK IA, hexane/iPrOH 95:5) was 36%.
[a]2D3 = +9.2 (c=0.009 gmLÀ1, MeOH).
(À)-Methyl
1-methyl-3-oxo-6-vinylidene-2-oxabicyclo[2.2.2]-
octane-4-carboxylate, (À)-24: Cyclization of dimethyl 2-(4-chloro-
but-2-yn-1-yl)-2-(3-oxopropyl)malonate (10; 102 mg, 0.371 mmol),
according to the general procedure D, afforded 64 mg (78%) of
product (À)-24, isolated as colorless oil. The ee value, determined
by chiral HPLC (CHIRALPACK IA, hexane/iPrOH 94:6), was 39%
[a]2D3 =À16.9 (c=0.011 gmLÀ1, MeOH).
1
a colorless oil. Yield: 94%, 251 mg. H NMR (400 MHz, CDCl3): d=
3.72 (brs, 6H), 2.76 (d, J=2.3 Hz, 2H), 2.48 (t, J=7.3 Hz, 2H), 2.30
(t, J=7.4 Hz, 2H), 2.14 (s, 3H), 2.13–2.09 (m, 1H), 1.06 ppm (d, J=
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, DEPT): d=207.1 (C), 170.7
(C), 85.3 (C), 73.2 (C), 56.4 (C), 52.6 (CH3), 38.6 (CH2), 29.8 (CH3), 26.4
(CH2), 24.1 (CH2), 13.9 (CH3), 12.1 ppm (CDH, t, J=20.1 Hz); IR (film)
n˜ =2944, 2245, 1738 cmÀ1; HRMS (TOF MS ES+): m/z calcd for
C14H20DO5: 270.1452 [M+H]+; found: 270.1474.
(+)-4-Methyl-1-tosyl-3-vinylidenepiperidin-4-ol, (+)-26: Reaction
of
N-(4-chlorobut-2-yn-1-yl)-N-(3-oxobutyl)p-toluenesulfonamide
(12; 174 mg, 0.724 mmol), according to the general procedure D,
afforded 159 mg (75%) of product (+)-26, isolated as colorless oil.
The ee value, determined by chiral HPLC (CHIRALPACK IA, hexane/
iPrOH 8:2), was 17%. [a]2D3 = +5.5 (c=0.010 gmLÀ1, MeOH).
(À)-Dimethyl 4-hydroxy-3-vinylidenecycloheptane-1,1-dicarbox-
ylate, (À)-29: Cyclization of dimethyl 2-(4-chlorobut-2-yn-1-yl)-2-(4-
oxobutyl)malonate (15; 57 mg, 0.197 mmol), according to the gen-
eral procedure D, afforded 36 mg (72%) of product (À)-29, isolated
as colorless oil. The ee value, determined by chiral HPLC (CHIRAL-
PACK IA, hexane/iPrOH 95:5), was 43%. [a]2D3 =À7.9 (c=
0.016 gmLÀ1, MeOH).
Control experiment on substrate 34 using [D8]THF: Reaction of
N-(4-chloropent-2-yn-1-yl)-N-(3-oxobutyl)-p-toluenesulfonamide
(34; 56 mg, 0.202 mmol) according to the general procedure B, but
using dry, deoxygenated [D8]THF (7 mL), afforded 60 mg (97%) of
the non-deuterated product 35.
Control experiment on substrate 34 using DCl/D2O: Reaction of
N-(4-chloropent-2-yn-1-yl)-N-(3-oxobutyl)-p-toluenesulfonamide
(34; 167 mg, 0.51 mmol) according to the general procedure B, but
quenching the reaction with 2n DCl, afforded 156 mg (98%) of
the deuterium-labeled product 41.
Synthesis of 5-(3-chloroprop-1-yn-1-yl)-1-(pent-4-en-1-yl)pyrroli-
din-2-one (46): n-BuLi (6.8 mL, 1.44m solution in hexane,
9.80 mmol) was added dropwise to a solution of propargyl chloride
(1.06 mL, 9.2m solution in toluene, 9.80 mmol) in THF (20 mL) at
À508C. Then, a solution of 1-(pent-4-en-1-yl)pyrrolidine-2,5-dione
(45)[28] (546 mg, 3.27 mmol) in THF (19 mL) was slowly added. After
15 min, water (8 mL) was added and the reaction mixture was
stirred for additional 10 min. The layers were separated and the
aqueous layer was extracted with Et2O. The combined organic
layers were washed with brine, dried over anhydrous MgSO4, and
the solvent was removed. The residue was suspended in MeOH/
General procedure D for the enantioselective synthesis of
exocyclic allenes
Deoxygenated, dry THF (20 mL) was added to a mixture of Brint-
zinger’s complex (+)-dichloro(R,R)-ethylenebis(4, 5, 6, 7-tetrahydro-
1-indenyl)titanium(IV) (43; 0.2 equiv) and Mn dust (8 equiv) under
an Ar atmosphere, and the suspension was stirred at room temper-
ature for 15 min. Then, a mixture of 2,4,6-collidine (7 equiv) and
Me3SiCl (4 equiv) in THF was added. Subsequently, a solution of
the corresponding substrate (1 mmol) in THF (2 mL) was slowly
added over a period of 15 min and the mixture was stirred for 6 h.
The reaction was then quenched with 2n HCl and the organic sol-
vent removed. The residue was diluted in Et2O, washed with brine,
dried (anhydrous Na2SO4) and the solvent removed. Products were
purified by flash chromatography of the residues on silica gel
(hexane/AcOEt mixtures).
AcOEt (2.3:1, 23 mL) and
a solution of NaBH3CN (164 mg,
2.61 mmol) in MeOH (3 mL) was added during 15 min at À788C.
The mixture was stirred during 15 min at this temperature. The sol-
vent was removed and the residue dissolved in AcOEt and washed
with water. The aqueous layer was extracted with AcOEt. The com-
bined organic layers were washed with a saturated solution of
NaHCO3, dried over anhydrous MgSO4, and concentrated under re-
duced pressure. The crude material was purified by using column
chromatography on silica gel (gradient: hexane/AcOEt from 7:3 to
3:7) to afford pure 46 (370 mg, 1.64 mmol, 50%). 1H NMR
(300 MHz, CDCl3): d=5.90–5.76 (m, 1H), 5.09–4.97 (m, 2H), 4.43–
4.37 (m, 1H), 4.17 (d, J=3.0 Hz, 2H), 3.63 (ddd, J=13.9, 8.8, 7.1 Hz,
1H), 3.13 (ddd, J=13.9, 8.6, 5.5 Hz, 1H), 2.60–2.29 (m, 3H), 2.16–
2.05 (m, 3H), 1.78–1.56 ppm (m, 2H); 13C NMR (75 MHz, CDCl3,
DEPT): d=174.0 (C), 137.6 (CH), 115.1 (CH2), 84.1 (C), 79.9 (C), 49.2
(CH), 40.7 (CH2), 31.0 (CH2), 30.0, (CH2), 29.8 (CH2), 26.4 (CH2),
(À)-Diethyl 3-hydroxy-3-methyl-4-vinylidenecyclopentane-1,1-di-
carboxylate, (À)-20: Cyclization of dimethyl 2-(4-chlorobut-2-yn-1-
yl)-2-(2-oxopropyl)malonate (6; 109 mg, 0.397 mmol) catalyzed by
43, according to the general procedure D, afforded 67 mg (70%)
of product (À)-20, isolated as colorless oil. The enantiomeric
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
808
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Angew. Chem. 2013, 125, 4978–4982; Angew. Chem. Int. Ed. 2013, 52,
4878–4882.
[3] Y. Wang, L. Zhu, Y. Zhang, R. Hong, Angew. Chem. 2011, 123, 2839–
2842; Angew Chem. Int. Ed. 2011, 50, 2787–2790.
26.1 ppm (CH2); IR (film) n˜ =3077, 2928, 2863, 1687, 1415, 1237,
914, 698 cmÀ1; HRMS (QTof): m/z calcd for C12H17ClNO: 226.0999
[M+H]+; found: 226.0996.
Synthesis of 4-(2-(3-chloroprop-1-yn-1-yl)-5-oxo-pyrrolidin-1-yl)-
butanal (47): Compound 46 (157 mg, 0.7 mmol) was dissolved in
THF/H2O (1:1, 18 mL) in a flask protected from light. NaIO4
(1200 mg, 5.22 mmol) and 2.5% solution of OsO4 (174 mL,
0.03 mmol) were added at 08C. The mixture was stirred for 4 h be-
tween 0 and 58C. Then, the layers were separated and the aque-
ous layer was extracted with Et2O. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, and con-
centrated under reduced pressure. The crude material was purified
by column chromatography on silica gel (AcOEt/acetone, 8:2) to
[4] a) Alkyne isomerization: W. M. Braje, J. Frackenpohl, O. Schrake, R.
Wartchow, W. Beil, H. M. R. Hoffmann, Helv. Chim. Acta 2000, 83, 777–
792; b) electrocyclic ring-opening: J. E. Ezcurra, C. Pham, H. W. Moore, J.
Org. Chem. 1992, 57, 4787–4789; c) transformation of propargyl alco-
hols: A. G. Myers, B. Zheng, J. Am. Chem. Soc. 1996, 118, 4492–4493;
d) 1,4-addition to conjugated enynes: T. Kusumoto, K. Ando, T. Hiyama,
Bull. Chem. Soc. Jpn. 1992, 65, 1280; e) copper-catalyzed reduction of
propargyl oxiranes: C. Deutsch, B. H. Lipshutz, N. Krause, Angew. Chem.
2007, 119, 1677–1681; Angew. Chem. Int. Ed. 2007, 46, 1650–1653;
f) Zn-promoted condensations of terminal alkynes: M. Periasamy, N.
Sanjeevakumar, M. Dalai, R. Gurubrahamam, P. O. Reddy, Org. Lett. 2012,
14, 2932–2935; g) for an excellent overview on allene synthesis:
Modern Allene Chemistry, Vol. 1 (Eds.: N. Krause, S. K. Hashmi), Wiley-
VCH, Weinheim, 2004.
[5] In fact, exocyclic allene 3 was prepared by a quite sophisticated 7-
endo-cyclization of an iminium ion (see Ref. [3]), which can be hardly
used for the synthesis of carbocyclic allenes.
[6] T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116, 986–997;
and references therein.
[7] D. J. Ramꢀn, M. Yus, Chem. Rev. 2006, 106, 2126–2208.
[8] J. MuÇoz-Bascꢀn, I. Sancho-Sanz, E. ꢃlvarez-Manzaneda, A. Rosales, J. E.
Oltra, Chem. Eur. J. 2012, 18, 14479–14486.
[9] A. F. Barrero, A. Rosales, J. M. Cuerva, J. E. Oltra, Org. Lett. 2003, 5,
1935–1938.
[10] It should be noted that the excess of Mn and 2,4,6-collidine can be re-
covered at the end of the experiments by a simple filtering and an
acid/base extraction, respectively. Subsequently, both the recovered
collidine and Mn dust can be reused in further experiments.
[11] J. Justicia, I. Sancho-Sanz, E. ꢃlvarez-Manzaneda, J. E. Oltra, J. M. Cuerva,
Adv. Synth. Catal. 2009, 351, 2295–2300.
[12] Moreover, the potential capacity of [TiClCp2] to facilitate lactonization
processes should be also taken into account. In fact, lactonization reac-
tions in the presence of [TiClCp2] have been previously reported, see:
R. E. Estꢅvez, J. Justicia, B. Bazdi, N. Fuentes, M. Paradas, D. Choquecillo-
Lazarte, J. M. Garcꢂa-Ruiz, R. Robles, A. Gansꢆuer, J. M. Cuerva, J. E. Oltra,
Chem. Eur. J. 2009, 15, 2774–2791.
[13] B. M. Trost, in Handbook of Green Chemistry, Vol. 7: Green Processes,
Green Synthesis (Ed.: P. T. Anastas), Wiley-VCH, Weinheim, 2012, pp. 1–
33.
[14] E. L. Eliel, S. H. Wilen, M. P. Doyle, Basic Organic Stereochemistry, Wiley-In-
terscience, New York, 2001.
1
afford pure 47 (94 mg, 0.41 mmol, 59%). H NMR (300 MHz, CDCl3):
d=9.77 (t, J=1.1 Hz, 1H), 4.43–4.38 (m, 1H), 4.15 (d, J=1.8 Hz,
2H), 3.61–3.51 (m, 1H), 3.24–3.15 (m, 1H), 2.53–2.27 (m, 5H), 2.17–
2.04 (m, 1H), 1.94–1.84 ppm (m, 2H); 13C NMR (75 MHz, CDCl3,
DEPT): d=201.3 (CH), 174.4 (C), 83.9 (C), 80.1 (C), 49.2 (CH), 41.2
(CH2), 40.5 (CH2), 30.0 (CH2), 29.7 (CH2), 26.1 (CH2), 19.7 ppm (CH2);
IR (film) n˜ =2932, 1719, 1676, 1414, 1262, 1237, 1172, 866,
730 cmÀ1; HRMS (QTof): m/z calcd for C11H15ClNO2: 228.0791; found:
226.0792 [M+H]+.
Synthesis of 8-hydroxy-9-vinylidenehexahydro-1H-pyrrolo[1,2-
a]azepin-3(2H)-one (3): Deoxygenated, dry THF (7 mL) was added
to a mixture of [TiCl2Cp2] (64 mg, 0.281 mmol) and Mn dust
(123 mg, 2.248 mmol) under an Ar atmosphere, and the suspen-
sion was stirred at room temperature until it turned lime green
(after about 15 min). Then, a mixture of 2,4,6-collidine (238 mg,
1.967 mmol) and Me3SiCl (122 mg, 1.124 mmol) in THF was added.
Subsequently, the reaction mixture was heated at reflux and a solu-
tion of 4-(2-(3-chloroprop-1-yn-1-yl)-5-oxopyrrolidin-1-yl)butanal
(47; 64 mg, 0.281 mmol) in THF (4 mL) was slowly added over
a period of 15 min and the mixture was stirred for 6 h. The reaction
was then quenched with 2N HCl and the organic solvent was re-
moved. The residue was diluted in Et2O, washed with brine, dried
(anhydrous Na2SO4) and the solvent removed. The crude material
was purified by column chromatography on silica gel (AcOEt/Ace-
tone, from 1:0 to 9:1) to afford pure 3 (41 mg, 0.214 mmol, cis/
trans 2.7:1, 76%). Spectroscopic data matched those quoted in the
bibliography.[3]
[15] J. Mann, R. S. Davidson, J. B. Hobbs, D. V. Banthorpe, J. B. Harborne, Nat-
ural Products: Their Chemistry and Biological Significance, Longman Sci-
entific & Technical, Harlow, 1994.
[16] J. Justicia, J. L. Oller-Lꢀpez, A. G. CampaÇa, J. E. Oltra, J. M. Cuerva, E.
BuÇuel, D. J. Cꢁrdenas, J. Am. Chem. Soc. 2005, 127, 14911–14927, and
references therein.
[17] During the redaction of this paper, Ashfeld and co-workers reported an
analogous cyclization of 16, presumably through an organozinc re-
agent, to only give a 35% yield of 30; see: L. M. Fleury, A. D. Kosal, J. T.
Masters, B. L. Ashfeld, J. Org. Chem. 2013, 78, 253–269.
[18] J. Marco-Contelles, M. C. Carreiras, C. Rodrꢂguez, M. Villarroya, A. G.
Garcꢂa, Chem. Rev. 2006, 106, 116–133.
Acknowledgements
We thank the Spanish “Ministerio de Economꢂa y Competitivi-
dad” (Project CTQ2011-24443) and the “Junta de Andalucꢂa”
(Project P10.FQM.6050) for their generous financial support.
C.H-C. acknowledges MECD and N.M.P. Junta de Andalucꢂa for
scholarships. We also acknowledge our English colleague
Ms. Angela Tate for the revision of the English version of the
manuscript.
[19] R. A. Pilli, M. C. F. de Oliveira, Nat. Prod. Rep. 2000, 17, 117–127.
[20] For a review on alkaloids showing the azepane unit, see: D. O’Hagan,
Nat. Prod. Rep. 1997, 14, 637–651.
Keywords: allenes
heterocycles · synthetic methods · titanium
·
cyclization
·
enantioselectivity
·
[21] Bis(cyclopentadienyl)titanium(III) chloride, generated in situ by stirring
commercial [TiCl2Cp2] with Zn or Mn dust in THF, exists as an equilibri-
um mixture of the monomer [TiClCp2] and the dinuclear species
[TiClCp2]2; see: a) R. J. Enemærke, J. Larsen, T. Skrydstrup, K. Daasbjerg,
J. Am. Chem. Soc. 2004, 126, 7853–7864; b) K. Daasbjerg, H. Svith, S.
Grimme, M. Gerenkamp, C. Mꢇck-Lichtenfeld, A. Gansꢆuer, A. Barchuck,
F. Keller, Angew. Chem. 2006, 118, 2095–2098; Angew. Chem. Int. Ed.
2006, 45, 2041–2044; c) A. Gansꢆuer, A. Barchuk, F. Keller, M. Schmitt, S.
Grimme, M. Gerenkamp, C. Mꢇck-Lichtenfeld, K. Daasbjerg, H. Svith, J.
Am. Chem. Soc. 2007, 129, 1359–1371. For the sake of clarity, we usual-
[1] For an excellent review, see: A. Hoffmann-Rçder, N. Krause, Angew.
Chem. 2004, 116, 1216–1236; Angew. Chem. Int. Ed. 2004, 43, 1196–
1216.
[2] For a recent review, see: S. Yu, S. Ma, Angew. Chem. 2012, 124, 3128–
3167; Angew. Chem. Int. Ed. 2012, 51, 3074–3112; For a recent gold-cat-
alyzed allene cyclization see: N. Cox, M. R. Uehling, K. T. Haelsig, G. Lalic,
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
809
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ly represent this complex as [TiClCp2], except in the case in which the
dimer character of the species involved is relevant.
[26] R. M. Fantazier, M. L. Poutsma, J. Am. Chem. Soc. 1968, 90, 5490–5498.
[27] For a Nobel Lecture on this topic, see: a) R. Noyori, Angew. Chem. 2002,
114, 2108–2123; Angew. Chem. Int. Ed. 2002, 41, 2008–2022. For recent
reviews highlighting the growing impact of asymmetric catalysis, see:
b) B. M. Trost, D. R. Fandrick, Aldrichimica Acta 2007, 40, 59–72; c) T.
Ooi, K. Maruoka, Aldrichimica Acta 2007, 40, 77–86. For recent reviews
on enantioselective radical processes, see: d) M. P. Sibi, S. Manyem, J.
Zimmerman, Chem. Rev. 2003, 103, 3263–3295; e) H. Miyabe, Y. Take-
moto, Chem. Eur. J. 2007, 13, 7280–7286.
[22] a) A. F. Barrero, J. E. Oltra, J. M. Cuerva, A. Rosales, J. Org. Chem. 2002,
67, 2566–2571; b) J. M. Cuerva, A. G. CampaÇa, J. Justicia, A. Rosales,
J. L. Oller-Lꢀpez, R. Robles, D. Cꢁrdenas, E. BuÇuel, J. E. Oltra, Angew.
Chem. 2006, 118, 5648–5652; Angew. Chem. Int. Ed. 2006, 45, 5522–
5526; c) J. Jin, M. Newcomb, J. Org. Chem. 2008, 73, 7901–7905; d) M.
Paradas, A. G. CampaÇa, T. Jimꢅnez, R. Robles, J. E. Oltra, E. BuÇuel, J.
Justicia, D. J. Cꢁrdenas, J. M. Cuerva, J. Am. Chem. Soc. 2010, 132,
12748–12756; e) A. Gansꢆuer, M. Behlendorf, A. Cangçnffll, C. Kube,
J. M. Cuerva, J. Friedrich, M. van Gastel, Angew. Chem. 2012, 124, 3320–
3324; Angew. Chem. Int. Ed. 2012, 51, 3266–3270.
[28] For a recent synthesis of 9,10-diepi-stemoamide, see: X. Zheng, X. J.
Dai, H. Q. Yuan, C. X. Ye, J. Ma, P. Q. Huang, Angew. Chem. 2013, 125,
3578–3582; Angew. Chem. Int. Ed. 2013, 52, 3494–3498.
[23] a) Radicals in Organic Synthesis, Vols. 1, 2 (Eds.: P. Renaud, M. P. Sibi),
Wiley-VCH, Weinheim, 2001; b) D. B. Guthrie, S. J. Geib, D. P. Curran, J.
Am. Chem. Soc. 2011, 133, 115–122.
[29] S. P. Marsden, A. D. McElhinney, Beilstein J. Org. Chem. 2008, 4, 8.
[30] A 2.7:1 cis/trans ratio of adducts was formed as deduced by 1H NMR
analysis.
[24] a) P. H. Kasai, J. Am. Chem. Soc. 1972, 94, 5950–5956; b) E. B. Jochno-
witz, X. Zhang, M. R. Nimlos, M. E. Verner, J. F. Stanton, G. B. Ellison, J.
Phys. Chem. A 2005, 109, 3812–3821; c) D. W. Rogers, N. Matsunaga,
A. A. Zavitsas, J. Org. Chem. 2006, 71, 2214–2219.
Received: October 15, 2013
[25] Steric factors might also contribute to the 2.3:1 ratio.
Published online on December 12, 2013
Chem. Eur. J. 2014, 20, 801 – 810
www.chemeurj.org
810
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim