Synthesis of tetrasubstituted alkenes through a palladium-catalyzed domino carbopalladation/C-H-activation reaction

Article abstract of DOI:10.1002/chem.201103209

Helical tetrasubstituted alkenes (7) were obtained in a highly efficient way through a palladium-catalyzed domino-carbopalladation/CH-activation reaction of propargylic alcohols 6 in good to excellent yields. Electron-withdrawing- and electron-donating substituents can be introduced onto the upper and lower aromatic rings. The substrates (6) for the domino process were synthesized by addition of the lithiated alkyne (20) to various aldehydes (19); moreover, the substrates were accessible enantioselectively (in 95 % ee) by reduction of the corresponding ketone using the Noyori procedure. Copyright

Full text of DOI:10.1002/chem.201103209

DOI: 10.1002/chem.201103209
Synthesis of Tetrasubstituted Alkenes through a Palladium-Catalyzed
ꢀ
Domino Carbopalladation/C H-Activation Reaction
Lutz F. Tietze,*[a] Tim Hungerland,[a] Alexander Dꢀfert,[a] Ina Objartel,[b] and
Dietmar Stalke[b]
Abstract: Helical tetrasubstituted al-
kenes (7) were obtained in a highly ef-
ficient way through a palladium-cata-
lyzed domino-carbopalladation/CH-ac-
tivation reaction of propargylic alco-
hols 6 in good to excellent yields. Elec-
duced onto the upper and lower aro-
matic rings. The substrates (6) for the
domino process were synthesized by
addition of the lithiated alkyne (20) to
various aldehydes (19); moreover, the
substrates were accessible enantioselec-
tively (in 95% ee) by reduction of the
corresponding ketone using the Noyori
procedure.
ꢀ
Keywords: C H activation · domi-
no reactions · helical structures ·
molecular switches · palladium
tron-withdrawing-
and
electron-
donating substituents can be intro-
Introduction
The development of ecologically and economically benefi-
cial procedures for the synthesis of complex natural prod-
ucts and other interesting materials is one of the key issues
in organic chemistry. In this respect, the concept of domino
reactions, as introduced by ourselves, has become highly val-
uable, because it allows the synthesis of complex compounds
in very few steps starting from simple substrates, it preserves
our resources, and it reduces the amount of waste formed as
well as the time needed.[1–3] Previously, we have prepared
several natural products, such as a-tocopherol, using an
enantioselective domino Wacker/Heck reaction.[4] We have
also reported the preparation of enantio- and diastereomeri-
cally pure helical tetrasubstituted alkenes using a domino
carbopalladation/Stille reaction.[5] Thus, the reaction of stan-
nane 1 with [Pd2dba3] (dba=dibenzylideneacetone) in the
Scheme 1. Synthesis of tetrasubstituted alkene 2 from stannane 1.
requires several additional steps. Thus, a cyclization through
ꢀ
a C H-activation pathway without introducing additional
functional groups would be more beneficial.[6–12] For this pur-
pose, we have investigated the palladium-catalyzed reaction
of compound 4a (Scheme 2).[13]
presence of PACHTUNGTRENNUNG(tBu)3 as a ligand gave compound 2 as a single
enantiopure diastereomer (Scheme 1).
Though this procedure allowed the efficient and stereose-
lective access to tetrasubstituted alkenes of type 2, the use
of stannanes is neither environmentally friendly nor appro-
priate for a large-scale synthesis, because their preparation
Scheme 2. Formation of acenaphthylene 3 by a domino carbopalladation/
ꢀ
C H-activation reaction from alkyne 4.
[a] Prof. Dr. L. F. Tietze, T. Hungerland, Dr. A. Dꢁfert
Institut fꢁr Organische und Biomolekulare Chemie
Georg-August Universitꢂt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-39-9476
However, the only product that we obtained from this re-
action was acenaphthylene 3, which was formed from the
E-mail: ltietze@gwdg.de
ꢀ
carbopalladation of the triple bond, followed by a C H acti-
[b] I. Objartel, Prof. Dr. D. Stalke
vation at the C8’ position but not at the C2’’’. All attempts
to circumvent this reaction by, for example, introducing a
methyl group at the C8ꢀ position (4b), did not lead to the
formation of the desired tetrasubstituted alkenes of type 5.
However, by omitting the second aromatic ring in the naph-
thalene moiety in compound 4, the synthesis of tetrasubsti-
Institut fꢁr Anorganische Chemie
Georg-August Universitꢂt Gçttingen
Tammannstrasse 3, 37077 Gçttingen (Germany)
Supporting information for this article, including full syntheses and
general procedures for all the of the synthesized compounds, is avail-
able on the WWW under http://dx.doi.org/10.1002/chem.201103209.
3286
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 3286 – 3291

FULL PAPER
ꢀ
Table 1. Synthesis of tetrasubstituted alkenes 7a–7k from compounds
6a–6k.
tuted alkenes via a domino carbopalladation/C H-activation
reaction could be accomplished with excellent results.
Herein, we describe the synthesis of compounds of type 7
starting from compound 6 (Scheme 3).
Entry
R (substrate)
X
Product
A[a,b]
[%]
B[a,c]
[%]
1
2
3
4
5
6
7
8
H (6a)
4-Me (6b)
4-F (6c)
4-CF3 (6d)
4-CN (6e)
4-tBu (6 f)
4-OMe (6g)
4,5-OCH2O (6h)
H (6i)
O
O
O
O
O
O
O
O
7a
7b
7c
7d
7e
7 f
7g
7h
7i
94
59
54
72
49
74
71
72
21
44
54
87
57
86
91
41
38
83
88
97
60
75
9
10
11
CH2
CH2
CH2
4-Me (6j)
4-CF3 (6k)
7j
7k
[a] Yields of isolated products. [b] method A: LiOAc, (nBu)4NOAc, Her-
mann–Beller catalyst 10, DMF/MeCN/H2O (5:5:1), 1408C, 4 h, MW.
[c] Method B: PdACTHNUTRGNEUNG(OAc)2, PPh3, K2CO3, DMF, 1008C, 2 h, MW.
reaction temperature is presumably needed because of the
steric demands of the tert-butyl groups.
Besides the introduction of a substituent onto the upper
aromatic ring (7a–7k), compounds 11–13 (which are func-
tionalized on the lower ring) can be successfully transformed
to give tetrasubstituted alkenes (E/Z)-14–(E/Z)-18
(Scheme 4). This study confirmed the activating effects of a
ꢀ
Scheme 3. Domino carbopalladation/C H-activation of compound 6a to
give compound 7a.
Helical tetrasubstituted alkenes are of great interest as
molecular switches and machines.[3,14] Thus, the development
of new small devices for efficient electronic-data storage
and processing has, in fact, been the focus of much research
in materials science and, over the last few years, a multitude
of publications have dealt with this area.[15–19]
Results and Discussion
The reaction of compound 6a, which contains a bromoarene
moiety connected to an alkyne moiety, using the Hermann–
Beller catalyst[20,21] (10) in the presence of tetrabutylammo-
nium acetate and lithium acetate under microwave irradia-
tion at 1408C (method A) led to the formation of alkene 7a
in excellent yield (94%), which is astounding, considering
that no activating substituents (such as a triazoles, fluorine
atoms, or trifluoromethyl groups) are present on the lower
aromatic moiety. We assume that this excellent result is due
to a proximity effect. Using palladium acetate in the pres-
ence of triphenylphosphine, again under microwave irradia-
tion at 1008C (method B), the yield was slightly lower but
still very good (87% yield). The scope of the reaction, in
terms of substituents on the upper aromatic ring and ex-
changing the oxygen in the side chain for a CH2 group, is
quite broad, with both electron-donating and -accepting
groups being successfully incorporated into the substituents,
although varying yields were obtained from using the two
different methods.[22] As can be seen from Table 1, method B
usually gives better than—or almost identical yields to—
method A, with the exception of substrate 7 f, where a high
Scheme 4. Palladium-catalyzed transformations of compounds 11, 12, and
13.
ꢀ
fluorine atom (11) or a CF3-group (12) on the C H-activa-
tion step in the domino process.[23] However, this reaction is
ꢀ
more complicated than that of substrate 6, because the C
H-activation can take place at the positions ortho/para to
the fluorine atom in compound 11 or ortho/para to the CF3-
group in compound 12 to give compounds 14/15 and 17/18,
respectively, or mixtures of the two products. Furthermore,
isomerization of the primarily formed E isomers to give the
corresponding Z stereoisomers is expected. Finally, one has
to assume that the steric hindrance of the products formed
is much higher than that in compounds of type 7.
Chem. Eur. J. 2012, 18, 3286 – 3291
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3287

L. F. Tietze et al.
As expected, the reaction of compound 11 using meth-
od A (1408C) gave the four compounds, (E/Z)-14 and (E/
Z)-17, in 50% yield as a 1:1 mixture of the ortho- and para-
substituted products, and the reaction of compound 12 gave
the four compounds, (E,Z)-15 and (E/Z)-18, in 44% yield as
a 1:3 mixture in favor of the para-substituted products (E/
Z)-18. These transformations show that there is an activa-
ꢀ
tion of the vicinal C H bond through the F and CF3 sub-
stituents, because products 14 and 15 are more-sterically
hindered than compounds 17 and 18. Furthermore, the CF3
group has a higher steric demand than the F atom, thereby
explaining the favored formation of the para product (18).
Interestingly, the reaction of compound 12 using method B
at 1008C only led to the para product (18), again as an E/Z
mixture (1:1) in 91% yield, whereas the reaction of com-
pound 13 afforded (E/Z)-16 (1:1) in 94% yield. The fluoro
compound (11) gave only bad results under these condi-
tions.
All of the precursors for the cyclization process contain a
stereogenic center. Although most of the investigations
were performed using racemic mixtures, the stereogenic
center can easily be introduced in an enantioselective fash-
ion. This fact was shown in an exemplary way for compound
6a (see below), which, from a reaction with palladium ace-
tate according to method B, gave compound (S)-7a in 83%
yield as a single, almost-enantiopure diastereomer.
Figure 1. Molecular structures (ORTEP plots) of (S,P)-7d (left) and
(R,P)-7j (right).
The synthesis of the substrates 6a–6k for the domino pro-
cess is straight forward; it is accomplished by the addition of
the lithiated alkyne (20) to various aldehydes 19a–19k
(Table 3). However, the yields are not always reproducible
and heavily depend on the both the quality of the metalat-
ing agent and on the speed of the addition of the aldehyde
to the lithiated alkyne. In general, a syringe pump should be
used to allow a slow and constant addition.
Table 3. Synthesis of propargylic alcohols 6a–6k from the reaction of
lithiated alkyne 20 with unpurified aldehydes 19a–19h, obtained in situ
from alcohols 23a, 23d–23h, acetals 23b and 23c, and purified aldehydes
19i–19k.
In general, the tetrasubstituted alkenes 7a–7k and com-
pounds 14–18 are helical structures and can therefore exist
in P and M forms, whereby during formation of the helix,
the existing stereogenic center in the substrates completely
controls the helicity in the products. Thus, (S)-6a–6h yields
(S,P)-7a–(S,P)-7h, whereas (R)-6i–(R)-6k leads to (R,P)-
7i–(R,P)-7k; for the enantiomers, the opposite induction is
observed (taking into account the change in the priority of
the substituents at the stereogenic center by exchanging the
oxygen atom for a CH2 group in the side-chain).[24]
Entry R (substrate)
Conditions[a] Product
X
Yield
[%]
1
2
3
4
5
6
7
H (23a)
4-Me (23b)
4-F (23c)
4-CF3 (23d)
4-CN (23e)
4-tBu (23 f)
4-OMe (23g)
A
A
B
A
B
A
B
6a
6b
6c
6d
6e
6 f
6g
O
O
O
O
O
O
O
56[b]
70[b]
38[b]
39[b]
40[b]
59[b]
60[b]
The products are not configurationally stable but can iso-
merize. However, the calculations of the ground-state ener-
gies (Table 2) show that the S,P isomers (7a and 7d) and
Table 2. DFT-calculations for ground state energies of the P and M form
of selected tetrasubstituted alkenes of type 7.[a]
8
B
6h
O
53[b]
Entry
Alkene
P form
[kJmolꢀ1
M form
[kJmolꢀ1
DErel
G
]
E
]
U
]
9
10
11
H (19i)
4-Me (19j)
4-CF3 (19k)
A
B
A
6i
6j
6k
CH2CH2 64[c]
CH2
CH2
62[c]
46[c]
1
2
3
4
(S)-7a
(S)-7d
(R)-7i
(R)-7k
ꢀ2818642.0
ꢀ3703793.6
ꢀ2724297.9
ꢀ3609451.5
ꢀ2818621.8
ꢀ3703774.5
ꢀ2724273.2
ꢀ3609425.0
20.2
19.1
24.7
26.4
[a] Reaction conditions A: nBuLi, THF, ꢀ788C, then addition of alde-
hyde and stirring at ꢀ788C overnight; conditions B: LiHMDS, Et3N,
ꢀ788C, 15 min, ꢀ788C!RT, 1.5 h, then addition of aldehyde via syringe
pump (1 mLhꢀ1) at ꢀ788C. [b] Yield of isolated products over two steps.
[c] Yield of isolated products (1 step). LiHMDS=lithium bis(trimethylsi-
lyl)amide.
[a] Parameters of the DFT calculations: dataset B3LYP/6-311G
MeCN as solvent.
ACHTUNGTRNE(NUNG d,p) in
the R,P isomers (7i and 7k) are much-more-stable than the
corresponding S,M- and R,M isomers, respectively. As an ex-
ample, the difference in energy of the P form in comparison
to the M form for (R)-7k is 26.4 kJmolꢀ1. The X-ray data of
(rac)-7d and (rac)-7j show that in the single crystal, com-
pound 7d exists as the S,P- and the R,M forms and com-
pound 7i as the R,P- and S,M forms (Figure 1).[25]
The synthesis of alkyne 20 was accomplished by a Sand-
meyer reaction of phenoxyaniline 21 to give compound 22,
followed by a Sonogashira reaction using ethynyltrimethylsi-
lane (Scheme 5). The final step was the deprotection of the
alkyne moiety; all steps proceeded with good yields.
3288
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 3286 – 3291

Synthesis of Tetrasubstituted Alkenes
FULL PAPER
Scheme 5. Synthesis of alkyne 20. Reaction conditions: a) pTsOH,
NaNO2, KI, MeCN, RT, 2 h, 79%; b) ethynyltrimethylsilane, CuI, [PdCl2-
A
2ACHTUNGTREN(NUNG 1:1), RT, 42 h,
The aldehydes 19a, and 19d–19h, which contained
oxygen-bridged tethers, were obtained by ether formation
from the reaction of phenols 24a and 24d–24h with bro-
moethanol in the presence of potassium carbonate and cata-
lytic amounts of crown ether 18-crown-6 to give alcohols
23a, 23d–23h, followed by oxidation of the hydroxy groups
using IBX (Scheme 6). For the synthesis of aldehydes 19b
Scheme 7. Enantioselective synthesis of alkene 7a. Reaction conditions:
a) DMP, CH2Cl2, RT, 25 h. [b] cat. (R,R)-26, iPrOH, MeCN, RT, 23 h.
[c] PdACTHUNGTRENUNG(OAc)2, PPh3, K2CO3, DMF, 1008C, 2 h, MW. DMP=Dess–Martin
periodinane.
sponding propargylic ketone using Dess–Martin periodinane
(Scheme 7). This oxidation was followed by transfer hydro-
genation using isopropanol in the presence of the Noyori
catalyst (R,R)-26 to give compound (S)-6a in 98% yield and
95% ee.[27,28] Finally, as we have already mentioned, the dia-
stereopure alkene (S)-7a was obtained in 83% yield and
95% ee from the domino reaction using palladium acetate
in the presence of triphenylphosphine according to method
B.[29]
Conclusion
The tetrasubstituted helical alkenes 7a–7k were obtained in
a highly efficient and diastereoselective manner through a
Scheme 6. Synthesis of aldehydes 19a–19h (with oxygen-bridged tethers)
and 19i–19k (with methylene-bridged tethers). Reaction conditions:
a) bromoacetaldehyde dimethyl acetal, KOH, DMSO, 1008C, 21 h;
b) K2CO3, [18]crown-6, MeCN, 4 ꢅ molecular sieves, 608C, 4–6 h, MW;
[c] 10% HCl, THF, 408C, 6–7 h; [d] IBX, MeCN, 4 ꢅ molecular sieves,
408C, 20 h; [e] allylic alcohol, PdACHTUNTRGNEUNG(OAc)2, (nBu)4NCl, NaHCO3, DMF,
608C, 6 h, MW. DMSO=dimethyl sulfoxide, IBX=2-iodoxybenzoic acid,
MW=microwave, DMF=N,N-dimethylformamide.
ꢀ
palladium-catalyzed domino cabopalladation/C H-activa-
tion using alkynes 6a–6k as the substrates in good to excel-
ꢀ
lent yields. A vinyl–aryl bond is formed by direct C H acti-
vation, thereby avoiding the introduction of additional func-
tional groups. This procedure also allows for the synthesis of
almost-enantiopure compounds of type 7, with the introduc-
tion of the stereogenic center in the substrate 6 by an enan-
tioselective reduction of the corresponding ketone.
and 19c, acetals 23b and 23c were prepared by the reaction
of phenols 24b and 24c using bromoacetaldehyde dimethyl
acetal, followed by an acid-catalyzed cleavage of the acetal
moiety. The aldehydes 19a–19h are quite labile and purifi-
cation by column chromatography on silica gel is not recom-
mended. Thus, in all cases, they were used as unpurified
compounds in the addition step with alkyne 20. Aldehydes
19i–19k, which contained a methylene group instead of an
oxygen atom in the tether, were formed by an intermolecu-
lar Heck reaction of the bromoiodoarenes 25a–25c with
allyl alcohol (Scheme 6).[26] These aldehydes are stable and
can be obtained in their pure form by column chromatogra-
phy on silica gel in 71-85% yield.
Experimental Section
Synthesis of 6i: General procedure for the alkynylation of aldehydes 19
(method A): A solution of alkyne 20 (663 mg, 3.42 mmol, 2.00 equiv) in
dry THF (2.2 mL) was cooled to ꢀ788C and then treated with nBuLi
(2.5m in hexanes, 1.40 mL, 3.42 mmol, 2.00 equiv). The reaction mixture
was stirred for 30 min, before being allowed to warm to RT over 30 min
and then was cooled again to ꢀ788C. The cold solution was added slowly
with stirring to
a solution of aldehyde 19i (365 mg, 1.71 mmol,
1.00 equiv) in dry THF (1.7 mL) at ꢀ788C over 30 min using a syringe
pump. After the addition had been completed, stirring was continued for
1.5 h; the mixture was allowed to warm to RT and the reaction was
quenched by addition of saturated NH4Cl (aq.) solution (30 mL). The
mixture was extracted with tBuOMe (3ꢄ50 mL) and the combined or-
ganic layers were dried over MgSO4 and concentrated in vacuo. The
For the enantioselective synthesis of compound 7a, the
racemic alcohol (rac)-6a was oxidized to give the corre-
Chem. Eur. J. 2012, 18, 3286 – 3291
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3289

L. F. Tietze et al.
crude product was purified by column chromatography on silica gel (pe-
troleum ether/tBuOMe, 5:1) to yield alcohol 6i (445 mg, 64%) as a
yellow oil. 1H NMR (600 MHz, CDCl3): d=1.76 (s, 1H), 1.89–2.01 (m,
2H), 2.84 (ddd, J=1.7, 6.9, 8.6 Hz, 2H), 4.49 (t, J=6.5 Hz, 1H), 6.93–
6.98 (m, 3H), 7.01–7.06 (m, 2H), 7.08 (dt, J=1.1, 7.6 Hz, 1H), 7.16 (m,
2H), 7.26–7.31 (m, 3H), 7.48 (dd, J=1.7, 7.7 Hz, 1H), 7.50 ppm (d, J=
7.7 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=31.7, 37.3, 62.3, 81.1, 94.8,
115.2, 118.1 (2C), 119.6, 123.0, 123.6, 124.4, 127.4, 127.7, 129.6 (2C),
129.9, 130.6, 132.8, 133.7, 140.7, 157.4 ppm (2C); IR (ATR): n˜ =
2360 cmꢀ1, 1589, 1484, 1444, 1252, 1224, 1022, 750; UV/Vis (MeCN): lmax
(lg e)=195 (4.881), 242 (4.229), 253 (4.200), 279 (2.453), 289 (3.489),
298 nm (3.405 ); MS (ESI, MeOH): m/z (%): 31.0 (24) [M+Na]+, 837.1
(100) [2M+Na]+; HRMS (ESI): m/z calcd for C23H19BrO2: 429.0461
[M+Na]+, 431.0441 [M+Na]+; found: 429.0453, 431.0441.
7.7 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=25.4, 30.8, 65.2, 116.6
(2C), 122.4, 122.5, 122.9, 124.7, 125.1, 125.0, 127.4, 127.6, 128.1 (2C),
128.3, 128.9, 130.0, 134.2, 135.1, 139.5, 154.5, 154.7 ppm; IR (ATR): n˜ =
2923, 1594, 1445, 1248, 1200, 1115, 1098, 765, 742 cmꢀ1; UV (MeCN): lmax
(lg e)=321 (3.805), 277 nm (3.857); MS (ESI, MeOH): m/z (%): 349.1
(67) [M+Na]+, 675.2 (100) [2M+Na]+; HRMS (ESI): m/z calcd for
C23H18O2: 349.1199 [M+Na]+, 350.1233 [M+Na]+; found: 349.1205,
350.1237.
Synthesis of alcohol (S)-6a: Oxidation of (rac)-6a: Dess–Martin periodi-
nane (0.256 g, 0.606 mmol, 2.50 equiv) was added to a stirring solution of
the racemic alcohol (rac)-6a (0.101 g, 0.240 mmol, 1.00 equiv) in dry
CH2Cl2 (10 mL) under an argon atmosphere. The reaction mixture was
stirred for 24 h at RT. After removal of the solvent, the crude product
was purified by column chromatography on silica gel (petroleum ether/
tBuOMe, 5:1) to yield the propargylic ketone as a brown oil (116 mg,
quant). 1H NMR (600 MHz, CDCl3): d=4.72 (s, 2H), 6.72 (dd, J=8.2,
1.2 Hz, 1H), 6.84 (td, J=7.5, 1.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.99
(dd, J=9.7, 2.0 Hz, 2H), 7.09 (t, J=7.6 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H),
7.17–7.22 (m, 1H), 7.32–7.36 (m, 2H), 7.36- 7.40 (m, 1H), 7.50 (dd, J=
7.9, 1.5 Hz, 1H), 7.58 ppm (dd, J=7.7, 1.7 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=74.1, 89.7, 91.7, 111.3, 112.3, 118.2, 119.2 (2C), 122.9, 123.2,
124.1, 128.4, 129.9 (2C), 132.9, 133.6, 135.3, 154.3, 156.2, 159.6,
182.2 ppm; IR (ATR): n˜ =2194, 1685, 1666, 1587, 1475, 1443, 1224, 1029,
744 cmꢀ1; UV (MeCN): lmax (lg e)=197 (4.887), 281 (4.134), 315 nm
(3.796); MS (ESI, MeOH): m/z (%): 431.0 (12) [M+Na]+, 837.0 (100)
[2M+Na]+; HRMS (ESI): m/z calcd for C22H15BrO3: 429.0097 [M+Na]+,
431.0077 [M+Na]+; found: 429.0089, 431.0066.
Synthesis of 6j: General procedure for the alkynylation of aldehydes 19
(Method B): Et3N (0.79 mL, 13.0 equiv) was added to a solution of
LiHMDS (1.0m in toluene, 0.88 mL, 0.88 mmol, 2.00 equiv) at RT and
the solution was cooled to ꢀ788C. A solution of alkyne 20 (169 mg,
0.880 mmol, 2.00 equiv) in toluene (20 mL) was added slowly with stir-
ring and stirring was continued for 15 min at ꢀ788C and for 15 min at
ꢀ608C; then, the mixture was allowed to warm to RT and stirred for an
additional 1 h. After cooling the mixture again to ꢀ788C, a solution of al-
dehyde 19j (100 mg, 0.440 mmol, 1.00 equiv) in toluene (10 mL) was
added with stirring via syringe pump (1 mLhꢀ1) and stirring was contin-
ued for 1 h. After the addition had been completed, the mixture was al-
lowed to warm to RT and the reaction quenched by addition of saturated
NH4Cl (aq.) solution (30 mL). The mixture was extracted with tBuOMe
(3ꢄ50 mL) and the combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by column chro-
matography on silica gel (petroleum ether/tBuOMe 10:1) to yield alcohol
6j (114 mg, 62%) as a yellow oil. 1H NMR (600 MHz, CDCl3): d=1.78
(s, 1H), 2.00–1.87 (m, 2H), 2.27 (s, 3H), 2.80 (t, J=7.9 Hz, 2H), 4.48 (t,
J=6.5 Hz, 1H), 6.98–6.93 (m, 4H), 7.10–7.02 (m, 3H), 7.32–7.26 (m,
3H), 7.33 (t, J=3.6 Hz, 1H), 7.47 ppm (dd, J=7.7, 1.7 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=20.5, 31.2, 37.5, 62.3, 81.0, 94.9, 115.2,
118.1 (2C), 119.6, 123.0, 123.6, 124.1, 128.2, 129.6 (2C), 129.9, 130.2,
133.2, 133.7, 137.4, 137.6, 157.3, 157.4 ppm; IR (ATR): n˜ =1589, 1483,
1443, 1250, 1221, 1160, 1038, 869, 749, 689 cmꢀ1; UV (MeCN): lmax (lg
e)=199 nm (4.875), 252 (4.128), 271 (3.702), 278 (3.703); MS (ESI,
MeOH): m/z (%): 443.1 (22) [M+Na]+, 865.2 (100) [2M+Na]+; HRMS
(ESI): m/z calcd for C24H21BrO2: 443.0617 [M+Na]+, 445.0598 [M+Na]+;
found: 443.0604, 445.0592.
Enantioselective transfer hydrogenation reaction: A mixture of the ob-
tained propargylic ketone (20.0 mg, 49.0 mmol, 1.00 equiv) and the ruthe-
nium catalyst (R,R)-26 (2.6 mg, 4.90 mmol, 0.10 equiv) in iPrOH/MeOH
(0.80/0.08 mL) was stirred for 22.5 h at RT under an argon atmosphere.
After removal of the solvent, the crude product was purified by column
chromatography on silica gel (petroleum ether/tBuOMe, 5:1) to yield the
propargylic alcohol (S)-6a as a brown oil (20.0 mg, 99%). HPLC: Chiral-
cel OD, eluent: iPrOH/n-hexaneACHTUNGTRNEUNG
(10:90), flow rate 0.8 mLminꢀ1, 95% ee.
a2D0 =+15.29. All other characterization data were consistent with the rac-
emic mixture.
Synthesis of (S)-7a: A solution of propargylic alcohol (S)-6a (15.5 mg,
37.9 mmol, 1.00 equiv), PPh3 (10.0 mg, 37.9 mmol, 1.00 equiv), and K2CO3
(58.0 mg, 0.424 mmol, 11.2 equiv) in DMF (1.0 mL) was thoroughly de-
gassed and then PdACTHNUTRGNEUNG(OAc)2 (2.0 mg, 7.5 mmol, 0.20 equiv) was added. The
reaction mixture was heated at 1008C for 2 h under microwave irradia-
tion. After cooling to RT and quenching by addition of saturated NH4Cl
(aq.) solution (10 mL), the mixture was extracted with tBuOMe (3ꢄ
50 mL). The combined organic extracts were dried over MgSO4 and con-
centrated in vacuo. The crude product was purified by column chroma-
tography on silica gel (petroleum ether/tBuOMe, 3:1) to yield (S)-7a as a
yellow solid (9.2 mg, 74%). HPLC analysis: Chiralcel OD, eluent:
iPrOH/n-hexane (5:95), flow rate 0.8 mLminꢀ1, 95% ee. All other char-
acterization data were consistent with the racemic mixture.
ꢀ
Synthesis of 7i: General procedure for the domino carbopalladation/C
H-activation reaction (Method A): A solution of propargylic alcohol 6i
(98.0 mg, 0.240 mmol, 1.00 equiv), nBu4NOAc (205 mg, 0.720 mmol,
3.00 equiv), and LiOAc (50.0 mg, 0.960 mmol, 4.00 equiv) in DMF/
MeCN/H2O (5:5:1, 4.8 mL) was thoroughly degassed; then, the palladium
catalyst (10; 20.5 mg, 24.0 mmol, 0.10 equiv) was added and the mixture
was heated to 1408C for 4 h under microwave irradiation. After cooling
to RT and quenching with saturated NH4Cl (aq.) solution (20 mL), the
aqueous layer was extracted with tBuOMe (4ꢄ50 mL). The combined or-
ganic extracts were dried over MgSO4 and concentrated in vacuo. The
crude product was purified by flash column chromatography on silica gel
(petroleum ether/tBuOMe, 5:1) to yield 7i (16.0 mg, 49.0 mmol, 21%) as
dark-yellow crystals. Method B: A solution of propargylic alcohol 6i
(47.0 mg, 0.115 mmol, 1.00 equiv), PPh3 (33.0 mg, 0.121 mmol,
1.05 equiv), and K2CO3 (178 mg, 1.29 mmol, 11.2 equiv) in DMF (2.0 mL)
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft, the Center for Material
Crystallography, and the Fonds der Chemischen Industriefor their gener-
ous support.
was degassed thoroughly; then, PdACHTNUTRGNEUNG(OAc)2 (6.00 mg, 23.0 mmol,
0.20 equiv) was added and the mixture was heated to 1008C for 2 h
under microwave irradiation. After cooling to RT and quenching by the
addition of saturated NH4Cl (aq.) solution (10 mL), the aqueous layer
was extracted with tBuOMe (3ꢄ50 mL). The combined organic phases
were dried over MgSO4 and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (petroleum ether/
tBuOMe, 3:1) to yield alkene 7i (36.0 mg, 97%) as a yellow solid. M.p.:
1548C; 1H NMR (600 MHz, CDCl3): d=2.25 (ddt, J=20.5, 2.6, 6.7 Hz,
1H), 2.43 (ddt, J=7.9, 4.6, 7.3 Hz, 1H), 2.99 (t, J=7.1 Hz, 2H), 5.63 (dd,
J=2.6, 4.4 Hz, 1H), 6.80 (ddd, J=1.4, 7.1, 7.8 Hz, 1H), 6.93 (m, 3H),
7.15–7.24 (m, 5H), 7.27 (m, 1H), 7.32 (m, 1H), 7.40 ppm (dd, J=1.5,
[1] a) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Or-
ganic Synthesis Wiley-VCH, Weinheim, 2006; b) L. F. Tietze, U. Bei-
fuss, Angew. Chem. 1993, 105, 137–170; Angew. Chem. Int. Ed.
Engl. 1993, 32, 131–163; c) L. F. Tietze, Chem. Rev. 1996, 96, 115–
136; d) L. F. Tietze, N. Rackelmann, Pure Appl. Chem. 2004, 76,
1967–1983; e) L. F. Tietze, N. Rackelmann, Multicomponent Reac-
tions, (Ed.: J. Zhu), Wiley-VCH, Weinheim, 2005; f) L. F. Tietze, L.
Levy, The Mizoroki–Heck Reaction, (Ed.: M. Oestreich), Wiley-
3290
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 3286 – 3291

Synthesis of Tetrasubstituted Alkenes
FULL PAPER
VCH, Weinheim, 2009, p. 281–344; g) L. F. Tietze, T. Kinzel, C.
Brazel, Acc. Chem. Res. 2009, 42, 367–378; h) L. F. Tietze, D. A.
Spiegl, C. C. Brazel, Experiments in Green and Sustainable Chemis-
try, (Eds.: H. W. Roesky, D. K. Kennepohl), Wiley-VCH, Weinheim,
2009, p. 158–167; i) L. F. Tietze, A. Dꢁfert, Catalytic Asymmetric
Conjugate Reactions 2010, p. 321–350; j) L. F. Tietze, A. Dꢁfert,
Pure Appl. Chem. 2010, 82, 1375–1392.
[23] L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. 2009, 121,
9976–10011; Angew. Chem. Int. Ed. 2009, 48, 9792–9826.
[24] The facial differentiation was identical for the reactions of 6a–6h
and 6i–6k. The different suffixes stem from a change in priority for
the substituents on the stereogenic center.
[25] A shock-cooled crystal was selected and mounted under a nitrogen
atmosphere using X-TEMP2, see: a) D. Stalke, Chem. Soc. Rev.
1998, 27, 171; b) T. Kottke, D. Stalke, J. Appl. Crystallogr. 1993, 26,
615. The data sets for 7d and 7j were collected on an INCOATEC
Micro focus with mirror optics instrument equipped with a Bruker
Apex II detector (MoKa radiation, l=0.71073 ꢅ, 100 K), see: T.
Schulz, K. Meindl, D. Leusser, D. Stern, J. Graf, C. Michaelsen, M.
Ruf, G. M. Sheldrick, D. Stalke, J. Appl. Crystallogr. 2009, 42, 885.
The integration was performed with SAINT V7.68 A, see: Bruker
SAINT v7.68A, WI, USA, Madison, 2009, which was followed by an
empirical absorption correction with SADABS 2008/1 (7d) and
2008/2 (7j), see: G. M. Sheldrick, SADABS 2008/1(SASDABS 2008/
2), Gçttingen, 2008. The structures were solved by direct methods
(SHELXS), see: Sheldrick, G. M. SHELXS in SHELXTL v2008/4,
WI, USA, Madison, 2008 and refined against F2 using the full-
matrix least-squares methods with SHELXL, see: G. M. Sheldrick,
SHELXL in SHELXTL v2008/4, WI, USA, Madison, 2008. All non-
hydrogen atoms were refined with anisotropic displacement parame-
ters. For compound 7d, the hydrogen atoms were refined isotropi-
cally on calculated positions using a riding model with their Uiso
values constrained to 1.5 Ueq of their pivot atoms for terminal sp3
carbon atoms and 1.2 times for all other carbon atoms except H100,
which was found and refined freely. For compound 7j, all hydrogen
atoms were found and refined freely except those of the methyl
group C24. 7d: C23H15F3O3; Mr =396.35; crystal size 0.15ꢄ0.1ꢄ
0.05 mm; space group P21/n; a=12.620(2), b=9.453(2), c=
14.589(3) ꢅ; b=96.09(2)8; V=1730.6(6) ꢅ3; Z=4; 1calcd =1.521
[2] a) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993–3009;
b) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006,
118, 7292–7344; Angew. Chem. Int. Ed. 2006, 45, 7134–7186.
[3] C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167–178.
[4] L. F. Tietze, K. M. Sommer, J. Zinngrebe, F. Stecker, Angew. Chem.
2005, 117, 262–264; Angew. Chem. Int. Ed. 2005, 44, 257–259.
[5] a) L. F. Tietze, A. Dꢁfert, F. Lotz, L. Sçlter, K. Oum, T. Lenzer, T.
Beck, R. Herbst-Irmer, J. Am. Chem. Soc. 2009, 131, 17879–17884;
b) L. F. Tietze, M. A. Dꢁfert, T. Hungerland, K. Oum, T. Lenzer,
Chem. Eur. J. 2011, 17, 8452–8461.
[6] G. Dyker, Handbook of C–H Transformations, Wiley-VCH, Wein-
heim, 2005.
[7] a) L. Ackermann, Modern Arylation Methods, Wiley-VCH, Wein-
heim, 2009; b) L. Ackermann, A. Althammer, Angew. Chem. 2007,
119, 1652–1654; Angew. Chem. Int. Ed. 2007, 46, 1627–1629; c) L.
Ackermann, Chem. Rev. 2011, 111, 1315–1345.
[8] a) Topics in Current Chemistry: CH-Activation, vol. 292 (Eds.: J.-Q.
Yu, Z. Shi), Springer, Berlin, 2010; b) B.-J. Li, S.-D. Yang, Z.-J. Shi,
Synlett 2008, 949–957.
[9] a) S. Pascual, P. de Mendoza, A. M. Echavarren, Org. Biomol.
Chem. 2007, 5, 2727–2734; b) A. M. Echavarren, C. Nevado, Synthe-
sis 2005, 167–182.
[10] a) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc.
Rev. 2009, 38, 3242–3272; b) X. Chen, K. M. Engle, D.-H. Wang, J.-
Q. Yu, Angew. Chem. 2009, 121, 5196–5217; Angew. Chem. Int. Ed.
2009, 48, 5094–5115.
Mgmꢀ3
; ; 2qmax =52.18; 24574 reflections
m (MoKa)=0.122 mmꢀ1
[11] H. M. L. Davies, D. Morton, Chem. Soc. Rev. 2011, 40, 1857–1869.
[12] J. K. Ray, S. Paul, R. Jana, Synlett 2010, 1463–1468.
[13] L. F. Tietze, F. Lotz, Eur. J. Org. Chem. 2006, 4676–4684.
[14] V. Balzani, A. Credi, M. Venturi, Molecular Devices and Machines:
Concepts and Perspectives for the Nanoworld, Wiley-VCH, Wein-
heim, 2008.
measured; 3542 unique reflections (Rint =0.043); R1=0.0376 (I>
2s(I)) and wR2=0.0937 (all data); max./min. density peaks: 0.279
and ꢀ0.252 eꢅꢀ3. 7j: C24H20O2; Mr =340.40; crystal size 0.18ꢄ0.08ꢄ
0.08 mm; space group P2/c; a=17.405(9), b=6.240(4), c=
16.569(9) ꢅ; b=106.89(2)8; V=1721.9(17) ꢅ3; Z=4; 1calcd
=
1.313 Mgmꢀ3
; ; 2qmax =52.78; 23358 reflec-
m (MoKa)=0.082 mmꢀ1
[15] C.-T. Chen, W.-C. Chen, Y.-W. Lee, Org. Lett. 2010, 12, 1472–1475.
[16] a) B. L. Feringa, Molecular Switches, Wiley-VCH, Weinheim, 2001;
b) B. L. Feringa, J. Org. Chem. 2007, 72, 6635–6652; c) T. C. Pijper,
D. Pijper, M. M. Pollard, F. Dumur, S. G. Davey, A. Meetsma, B. L.
Feringa, J. Org. Chem. 2010, 75, 825–838; d) J. Wang, A. Kulago,
W. R. Browne, B. L. Feringa, J. Am. Chem. Soc. 2010, 132, 4191–
4196; e) D.-H. Qu, B. L. Feringa, Angew. Chem. 2010, 122, 1125–
1128; Angew. Chem. Int. Ed. 2010, 49, 1107–1110; f) N. Ruangsupa-
pichat, M. M. Pollard, S. R. Harutyunyan, B. L. Feringa, Nat. Chem.
2011, 3, 53–60.
tions measured; 3545 unique reflections (Rint =0.073); R1=0.0487
(I>2s(I)) and wR2=0.1371 (all data); max./min. density peaks:
0.294 and ꢀ0.216 eꢅꢀ3. CCDC-826454 (7d) and CCDC-826455 (7j)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[26] a) T. Jeffery, Tetrahedron Lett. 1985, 26, 2667–2670; b) T. Jeffery,
Tetrahedron 1996, 52, 10113–10130; c) T. Jeffery, J. Chem. Soc.
Chem. Commun. 1984, 1287–1289.
[17] K. M. Gericke, M. Lautens, D. I. Chai, N. Bieler, Angew. Chem.
2009, 121, 1475–1479; Angew. Chem. Int. Ed. 2009, 48, 1447–1451.
[18] D. Hojo, K. Tanaka, K. Noguchi, Angew. Chem. 2009, 121, 8273–
8276; Angew. Chem. Int. Ed. 2009, 48, 8129–8132.
[19] a) W. R. Browne, D. Pijper, M. M. Pollard, B. L. Feringa, From Non-
Covalent Assemblies to Molecular Machines, (Ed.: J.-P. Sauvage, P.
Gaspard), Wiley-VCH, Weinheim, 2011, p. 243–289; b) J.-P. Sauv-
age, Molecular Machines and Motors, Springer, Berlin, 2001; c) J. A.
Faiz, V. Heitz, J.-P. Sauvage, Chem. Soc. Rev. 2009, 38, 422–442.
[20] a) W. A. Herrmann, C. Brossmer, K. Oefele, C.-P. Reisinger, T. Pri-
ermeier, M. Beller, H. Fischer, Angew. Chem. 1995, 107, 1989–1992;
Angew. Chem. Int. Ed. Engl. 1995, 34, 1844–1847; b) V. P. W. Bçhm,
W. A. Herrmann, Chem. Eur. J. 2001, 7, 4191–4197.
[27] The absolute stereochemistry was determined using Noyoriꢀs semi-
empiric rule by comparison with the reduction of similar compounds
and by comparing the optical rotation of related structures; see:
a) K. Matsumura, s. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem.
Soc. 1997, 119, 8738–8739; b) T. Graening, V. Bette, J. Neudçrfl, J.
Lex, H.-G. Schmalz, Org. Lett. 2005, 7, 4317–4320; c) D. P. G. Em-
merson, W. P. Hems, B. G. Davis, Org. Lett. 2006, 8, 207–210; d) S.
Takano, M. Setoh, O. Yamada, K. Ogasawara, Synthesis 1993, 1253–
1256.
[28] The ee values were determined by analytical HPLC: Chiralcel OD,
250ꢄ4.6 mm, 10 mm, eluent n-hexane/iPrOH 90:10.
[29] The ee values were determined by analytical HPLC: Chiralcel OD,
250ꢄ4.6 mm, 10 mm, eluent n-hexane/iPrOH 95:5, flow rate
0.8 mLminꢀ1, tR: 30.7 min.
[21] M. Beller, T. H. Riermeier, Eur. J. Inorg. Chem. 1998, 29–35.
[22] a) L. F. Tietze, K. Heitmann, T. Raschke, Synlett 1997, 35–37;
b) L. F. Tietze, K. Kahle, T. Raschke, Chem. Eur. J. 2002, 8, 401–
407.
Received: October 11, 2011
Published online: January 19, 2012
Chem. Eur. J. 2012, 18, 3286 – 3291
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3291