Highly regioselective and chemoselective titanocene mediated Barbier-type allylation reactions

Article abstract of DOI:10.1039/c3cc49230c

Titanocene carboxylate 1 is an excellent chemoselective reagent for unprecedented α-regioselective Barbier-type reactions. It constitutes the first titanocene(iii) able to tolerate epoxides and readily reduced carbonyl compounds, such as aromatic and α,β-unsaturated aldehydes. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc49230c

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Highly regioselective and chemoselective
titanocene mediated Barbier-type allylation
reactions†
Cite this: Chem. Commun., 2014,
50, 2211
Received 4th December 2013,
Accepted 24th December 2013
a
a
b
c
´
Sara P. Morcillo, Angela Martınez-Peragon, Verena Jakoby, Antonio J. Mota,
´
´
Christian Kube,b Jose Justicia,a Juan M. Cuerva*a and Andreas Gansauer*b
´
¨
DOI: 10.1039/c3cc49230c
www.rsc.org/chemcomm
Titanocene carboxylate 1 is an excellent chemoselective reagent for
unprecedented a-regioselective Barbier-type reactions. It constitutes the
first titanocene(III) able to tolerate epoxides and readily reduced carbonyl
compounds, such as aromatic and a,b-unsaturated aldehydes.
Titanocene(III) complexes are useful tools for mediating and catalyzing
a number of useful transformations,1 such as homolytic epoxide
opening,2 pinacol coupling reactions,3 and Barbier-type additions of
allylic and propargylic halides or carbonates to carbonyl compounds.4
A drawback of these procedures is the lack of chemoselectivity in the
electron transfer step. For this reason, aromatic and a,b-unsaturated
carbonyl compounds are usually unsuitable substrates in Barbier-type
reactions.4 Here, we demonstrate that this shortcoming can be
resolved in the case of complex 1 (Scheme 1) in the presence of Mn
dust via complex 2a (Fig. 1).5,6
Fig. 1 CV of 2 mM solution of 1 (red) and Mn–1 (black) recorded at n =
100 mV sÀ1 in 0.2 M TBAPF6–THF.
could be maintained.4a,6 Remarkably, in the absence of 5, no pinacol
Gratifyingly, 3 and 4, model compounds for aromatic and products are formed.7 Further exploring this new reactivity con-
a,b-unsaturated aldehydes, reacted with 5 in the presence of complex cluded that epoxides were also tolerated by this reagent. This
1 and Mn dust to exclusively yield a-prenylated compounds 6 and 7. suggests that the aldehydes or epoxides cannot bind to Mn–1.
Thus, the highly useful a-regioselectivity of prenylation noted earlier
To rationalize these findings, cyclic voltammograms (CVs) of 1
and Mn–1 in THF were recorded (Fig. 1). The oxidation of electro-
chemically reduced 1 reveals the presence of two species. 1À (Epc
=
À1.38 V vs. Fc+/Fc) is formed via electron transfer at the electrode.
The process is irreversible due to the formation of 2a (Epa1 = À1.00 V)
through loss of chloride. For Mn–1, 2a (Epa1 = À0.95 V) is formed as
expected, due to the more efficient abstraction of the chloride and
formation of MnCl2. The more negative value of Epa1 compared to
Cp2TiCl (Epa1 = À0.83 V) is in line with the carboxylate that is a better
donor ligand than chloride. The second peak (Epa2 = À0.65 V) is also
observed at higher sweep rates (n = 1–50 V sÀ1). Thus, the species
being oxidized is an initial component8 of Mn–1 in THF and is not
formed during the sweep. We suggest that 2b and not cationic 2c is
the second component of Mn–1 for a number of reasons. 2c should
Scheme 1 Ti-mediated regioselective a-prenylation of benzaldehyde (3)
and citral (4).
a Department of Organic Chemistry, University of Granada, Fuentenueva Campus,
t
Granada 18071, Spain. E-mail: jmcuerva@ugr.es
have a potential similar to that of [Cp(C5H4 Bu)Ti]+ (Epa = À0.47 V). It
b
´
¨
¨
Kekule-Institut fur Organische Chemie und Biochemie, Universitat Bonn, Gerhard-
Domagk-Strasse 1, 53121 Bonn, Germany. E-mail: andreas.gansaeuer@uni-bonn.de
c Department of Inorganic Chemistry, University of Granada, Fuentenueva Campus,
Granada 18071, Spain
has been recently shown that cationic titanocene(III) complexes open
epoxides.9 Both findings are in contradiction to the behavior of
Mn–1. In agreement with the observations, 2b is more difficult to
oxidize than 2a because the electron density is withdrawn from Ti
through carboxylate coordination. The steric shielding of Ti in 2b will
† Electronic supplementary information (ESI) available: Experimental methods
and characterisation of new compounds. See DOI: 10.1039/c3cc49230c
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be similar to that in 2a and thus epoxide and aldehyde binding is as
difficult for 2b as for 2a.
To understand the unprecedented chemoselectivity, we carried
out the model reactions with Mn-reduced Cp2TiCl(OMe),10
Cp2TiCl(OAc),11 and Cp2TiCl(OBz).12 Unselective electron transfer
reactions with Cp2TiCl2 were observed. This suggests that the
tethering of the carboxylate to the ligand is essential.
To highlight this point, the coordination of 2a to THF, benzalde-
hyde, and trimethyloxirane was studied by DFT calculations (Table 1).7
The generation of these coordination complexes is characterized
by: (a) a only slightly negative enthaply of formation and (b) a highly
unfavorable entropy of formation. This results in DG values of about
Scheme 2 Ti-mediated regioselective a-prenylation of aromatic and
a,b-unsaturated carbonyl compounds. Conditions: for aromatic aldehydes:
1 (1 mmol), Mn dust (8 mmol), aldehyde (1 mmol), and activated halide
(2 mmol) in THF. Otherwise: 1 (1.5 mmol), Mn dust (8 mmol), carbonyl
compound (1 mmol), and activated halide (3 mmol) in THF. aPrenyl chloride
can be used with similar yield (77%).
+8 to +12 kcal mol .
À1 13 Therefore, aldehyde and epoxide complexa-
tion seems to be precluded as observed experimentally.
Next, we explored the chemoselectivity of electron transfer further
(Scheme 2 and Table 2). Gratifyingly, our Barbier-type reactions using
activated halides as pronucleophiles are general and take place with
moderate to excellent yields.7 A variety of aromatic and a,b-unsaturated
aldehydes are suitable. Even acetophenone, as an example of aromatic
ketones, is an excellent substrate (Scheme 2). All products are valuable
building blocks for terpene synthesis.1d Even more interesting and
demanding are Barbier-type reactions with electrophiles (19–20) or
nucleophiles (23), incorporating epoxides (Table 2).
In agreement with our DFT calculations, epoxides are readily
tolerated by Mn–1.7 Thus, functionalized epoxypolyprenes that are
highly attractive intermediates for synthesis of natural products1d
can be prepared from either epoxide containing carbonyl com-
pounds or activated halides. As an attractive additional feature, our
novel method allows the elimination of the often difficult regio-
selective epoxidation step of the polyprenic starting materials.
An important aspect of this study is the regioselectivity of the
addition of the allylic nucleophile. In contrast to the numerous
g-selective additions, a-regioselective additions are considerably
less common.14 Here, we obtained the a-regioisomers in very
high selectivity (492: o8) when prenyl derivatives 5, 8 and 23
were used as pronucleophiles. Moreover, commercially available
Mn dust could be used at room temperature.
Table 1 Structures and energies of the interactions of THF, benzaldehyde
(B), and trimethyloxirane (Ep) with 2a (for computational details see ESI,
energies are in kcal molÀ1
)
Finally, we also investigated Wurtz-type coupling reactions mediated
by Mn–1. Such reactions can be carried out in the presence of
Cp2TiCl.15 However, the chemoselectivity of these reactions is low. This
is not the case in our system and, hence, epoxide containing substrates
can be readily coupled (Table 2, entry 8). The reaction took place with
excellent yield and also with a high a,a-regioselectivity (86 : 14).
In summary, we have demonstrated that Mn–1 is a reagent for
Barbier-type allylation reactions delivering the a-addition products
with almost complete regioselectivity. The reactions proceed with an
unprecedented chemoselectivity because epoxides and readily reduced
carbonyl compounds, such as aromatic and a,b-unsaturated alde-
hydes, are tolerated. The compounds obtained are difficult to prepare
using other methodologies and are valuable substrates in terpene
synthesis. Moreover, the reactions can be performed at room tem-
perature and no preformed organometallic reagents (B or Li) or
especially activated metals (Ba) have to be employed.
Complex
DH
ÀTDS
DG
0.0
+10.9
+8.3
2a
2a-THF
2a-B
0.0
À2.8
À4.2
À0.5
0.0
+13.7
+12.5
+12.5
2a-Ep
+12.0
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Table
2
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Product
Yield (%)
76
˜
´
´
´
1
2
5
5
´
´
¨
˜
68
42
´
´
´
˜
´
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´
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´
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´
3
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5
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7
20
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63
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7 See ESI† for details.
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8
—
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¨
9 A. Cangonu¨l, M. Behlendorf, A. Gansauer and M. van Gastel, Inorg.
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zwitterion is too high in energy to be a real intermediate, as CV
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We thank the Spanish MICINN (Grants CTQ-2011.22455 and
PRI-AIBDE-2011-1122) and SFB 813 ‘Chemistry at Spin Centers’
for financial support. SPM thanks Regional Government of
´
Andalucıa for her contract. We also thank the Centro de Super-
´
computacion de la Universidad de Granada (UGRGRID) for
computational time.
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This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 2211--2213 | 2213