Stereoselective Retentive Domino Transmetalations of Secondary Alkyllithium Compounds to Functionalized Secondary Alkylcopper Reagents

Article abstract of DOI:10.1002/anie.201505740

Functionalized secondary alkyllithium reagents obtained by I/Li exchange from the corresponding secondary alkyl iodides undergo two successive transmetalations with Me₃SiCH₂ZnBr.LiBr and CuBr.2LiCl.Me₂S to provide functionalized secondary alkylcopper compounds with high retention of configuration. These alkylcopper derivatives react further with electrophiles such as alkynyl esters, acid chlorides, allylic chlorides, ketals, ethylene oxide, and 3-iodocyclopentanone with high retention of configuration. A related sequence of transmetalations with MeMgI and LaCl₃.2LiCl allows a retentive addition of secondary alkyllithium reagents to acetone. The influence of the solvent on the configurational stability of secondary alkylzinc reagents is described.

Full text of DOI:10.1002/anie.201505740

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505740
German Edition: DOI: 10.1002/ange.201505740
Domino Reactions
Stereoselective Retentive Domino Transmetalations of Secondary
Alkyllithium Compounds to Functionalized Secondary Alkylcopper
Reagents
Kohei Moriya, Meike Simon, Rasmus Mose, Konstantin Karaghiosoff, and Paul Knochel*
Dedicated to Professor Stephen L. Buchwald on the occasion of his 60th birthday
Abstract: Functionalized secondary alkyllithium reagents
obtained by I/Li exchange from the corresponding secondary
alkyl iodides undergo two successive transmetalations with
Me3SiCH2ZnBr·LiBr and CuBr·2LiCl·Me2S to provide func-
tionalized secondary alkylcopper compounds with high reten-
tion of configuration. These alkylcopper derivatives react
further with electrophiles such as alkynyl esters, acid chlorides,
allylic chlorides, ketals, ethylene oxide, and 3-iodocyclopenta-
none with high retention of configuration. A related sequence
of transmetalations with MeMgI and LaCl3·2LiCl allows
a retentive addition of secondary alkyllithium reagents to
acetone. The influence of the solvent on the configurational
stability of secondary alkylzinc reagents is described.
electrophile (E1), a range of products of type 3 were obtained
with an overall retention of configuration.[3] Unfortunately,
only limited classes of electrophiles (E1) can be used with
these highly reactive lithium reagents. To expand the syn-
thetic utility of this method, we envisioned performing
successive stereoselective transmetalations[4,5] of the alkyl-
lithium reagents 1 with metallic salts (Met1-X, Met2-X) to give
intermediate organometallic compounds 4 and 5 and then
products of type 6 after quenching with a new set of
electrophiles (E2; Scheme 1).[6,7]
Although the use of only one stereoselective transmeta-
lation is desirable, previous work in our laboratory as well as
stereoselective transmetalations of stabilized alkyllithium
reagents performed by the groups of Taylor,[5b] Dieter,[5c]
and Coldham[5e] indicated that a first transmetalation from
lithium to zinc, followed by a second transmetalation from
zinc to copper may give the best results. Furthermore,
transmetalations of nonstabilized alkyllithium reagents may
be difficult to realize stereoselectively, since Hoffmann has
reported that transmetalations of Grignard reagents to
alkylcopper or alkylmanganese reagents are complicated by
single electron transfer (SET) processes which depend on the
nature of the metallic salts or of the electrophiles used.[8]
Therefore, we have examined in detail the domino trans-
metalation[9] of the secondary alkyllithium reagent anti-1a
generated by I/Li exchange from the corresponding function-
alized secondary alkyl iodide anti-2a (Table 1).
O
rganolithium compounds are key intermediates for
organic synthesis.[1] Stereoselective transformations involving
chiral organolithium compounds, generally a-heteroatom-
substituted alkyllithium reagents,[2] have been used for the
stereoselective synthesis of various organic molecules. As
shown in Scheme 1, we recently developed experimental
conditions that allow the stereoselective preparation of
nonstabilized functionalized secondary alkyllithium reagents
of type 1 from the corresponding alkyl iodides of type 2
through a retentive I/Li exchange. After the addition of an
A preliminary experiment showed that the carbolithiation
of ethyl propiolate (7a) with anti-1a did not provide the
expected anti-6a (Table 1, entry 1). However, the addition of
the alkyl iodide anti-2a (d.r. = 99:1) to a solution of tBuLi
(2.5 equiv, À1008C, 1 min; inverse addition[3,10]) in Et2O
followed by the addition of CuBr·2LiCl·Me2S (2.5 equiv,
À100 to À788C, 30 min) and ethyl propiolate (7a, 5.0 equiv,
À78 to À308C, 12 h) provided the acrylate (anti-6a) in 40%
yield, but unfortunately with d.r. = 65:35 (entry 2). This result
shows that the direct transmetalation from lithium to copper
is not stereoselective under these conditions. This may be
explained by an unselective transmetalation step or by an
unselective addition reaction of anti-5a to ethyl propiolate as
a consequence of the nature of the copper species or a SET
process. Better results were obtained by using domino
transmetalations, first with the soluble stabilized zinc organ-
ometallic Me3SiCH2ZnI[11] (2.5 equiv, À1008C, 20 min) fol-
lowed by CuCl·2LiCl·Me2S. In this case, the diastereoselec-
tivity jumped to 83:17 (entry 3). Interestingly, this diastereo-
Scheme 1. Stereoselective domino transmetalations of nonstabilized
secondary alkyllithium reagents.
[*] K. Moriya, M. Simon, R. Mose, Prof. Dr. K. Karaghiosoff,
Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, 81377 München (Germany)
E-mail: knoch@cup.uni-muenchen.de
Homepage: http://www.knochel.cup.uni-muenchen.de/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505749.
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Table 1: Optimization of the domino transmetalations of a secondary
alkyllithium reagent anti-1a to an alkylcopper reagent anti-5a via an
alkylzinc reagent anti-4a.
Table 2: Scope of electrophiles for the trapping reaction with alkylcopper
reagents (anti- and syn-5a) prepared by domino transmetalations of
secondary alkylithium reagents (anti- and syn-1a).
Entry
RZnX
CuX
Yield [%][a]
d.r.[b]
Entry
1
E
From anti-1a[a,b]
From syn-1a[a,b]
1
2
3
4
5
6
–
–
–
0
–
CuBr·Me2S·2LiCl
CuCl·Me2S·2LiCl
CuBr·Me2S·2LiCl
CuI·Me2S·2LiCl
CuBr·Me2S·2LiCl
CuBr·Me2S·2LiCl
CuBr·Me2S·2LiCl
(40)
(40)
44
(46)
46
65:35
83:17
87:13
73:27
91:9
Me3SiCH2ZnI
Me3SiCH2ZnI
Me3SiCH2ZnI
Me3SiCH2ZnBr·LiBr
Me3SiCH2ZnCl·LiCl
Me3SiCH2ZnBr·LiBr
52%, d.r.=94:6
62%, d.r.=94:6
63%, d.r.=94:6
37%, d.r.=93:7
48%, d.r.=9:91
65%, d.r.=6:94
59%, d.r.=7:93
37%, d.r.=9:91
7
(51)
52
87:13
94:6
8[c]
2
[a] Yield of isolated diastereomers of 6a. NMR spectroscopic yields in
parentheses. [b] Diastereoselectivity (d.r.=anti:syn) was determined by
1H and 13C NMR spectroscopy. [c] Et2O/n-hexane=2:3 was used as
solvent mixture. TBDPS=tert-butyldiphenylsilyl.
3
selectivity was found to depend on the counterion of the
copper species. The corresponding bromide (CuBr·2
LiCl·Me2S) led to a slightly increased d.r. value of 87:13
(entry 4), but the copper iodide (CuI·2LiCl·Me2S) afforded
only d.r. = 73:27 (entry 5). These results led us to examine the
influence of the halide of the organozinc reagents used
(Me3SiCH2ZnX), and we found that Me3SiCH2ZnBr·LiBr[12]
gave an enhanced d.r. value of 91:9 (entry 6). We also noticed
that the corresponding chloride Me3SiCH2ZnCl·LiCl[12] did
not improve the diastereoselectivity (entry 7). Switching the
solvents from pure diethyl ether to a 2:3 mixture of diethyl
ether and n-hexane allowed this diastereoselectivity to be
further improved to 94:6 (entry 8). Me3SiCH2ZnBr was found
to be a much better zinc halide source for the Li/Zn
transmetalation than ZnCl2 or related zinc halides and lithium
complexes.[12]
4
5[c]
43%, d.r.=91:9
62%, d.r.=85:15
44%, d.r.=9:91
63%, d.r.=15:85
6
[a] Yield of isolated diastereomers of 6. [b] Diastereoselectivity
(d.r.=anti/syn) was determined by 1H and 13C NMR spectroscopy. [c] In
the presence of BF3·Et2O.
These conditions proved to be broadly applicable. Thus,
a secondary alkyl iodide syn-2a (d.r. = 3:97) underwent the
same reaction sequence to provide the expected acrylate syn-
6a in 48% yield and d.r. = 9:91 (Table 2, entry 1). The domino
transmetalations allowed not only carbocuprations[13] to be
performed, but also a range of typical reactions of organo-
copper derivatives.[14] Thus, whereas secondary alkyllithium
reagents required the use of Weinreb amides,[3b] the acylation
with benzoyl chloride (7b) provides the 5-hydroxy ketone
derivatives anti- and syn-6b with excellent overall retention of
the configuration (d.r. = 94:6; entry 2). An addition-elimina-
tion reaction on 3-iodocyclopentenone (7c)[15] furnished both
anti- and syn-cyclopentenones (anti-6c: d.r. = 94:6 and syn-
6c: d.r. = 7:93; entry 3). The intermediate copper reagents of
type 5 also opened ethylene oxide to provide the correspond-
ing hydroxyethylated compounds.[16] Thus, the alkyllithium
reagents syn- and anti-1a were converted through a domino
transmetalation sequence using ethylene oxide (7d) to the
selectively protected syn- and anti- 1,6-diols (syn-6d: d.r. =
93:7 and anti-6d: d.r. = 9:91). BF3-mediated acetal opening by
organocopper reagents, as pioneered by Normant and co-
workers,[17] proceeded with 2,2-dimethoxypropane (7e) to
give the 1,5-diol derivatives (anti-6e: d.r. = 91:9 and syn-6e:
d.r. = 9:91; entry 5). The highly reactive allylic reagent, ethyl
(2-bromomethyl)acrylate (7 f)[18] underwent a moderately
selective allylation, thus showing that in this case SET
pathways may compete with the nonradical substitution.[19]
This analysis was confirmed, as shown in Table 3, by
delineating the reaction scope by varying the secondary alkyl
iodides of type 2. Thus, when using allyl chloride[20] as the
electrophile, the allylation reaction had much less tendency to
undergo SETreactions, as shown by Hoffmann and Hçlzer.[19]
Starting from either a cyclic secondary alkyl iodide trans- and
cis-2b (trans-2b: d.r. = 98:2 and cis-2b: d.r. = 1:99) or an
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Table 4: Domino transmetalations of a secondary alkyllithium reagent
Table 3: Scope of substrates for domino transmetalations of secondary
anti-1a to a tentative alkyllanthanum reagent via an alkylmagnesium
reagent anti-8a.
alkylithium reagents.
Entry Substrate
E
From anti or
From syn or cis[a,b]
trans[a,b]
Entry
Conditions
Yield[a]
d.r.[b]
1
2
3
without MeMgI
without LaCl3·2LiCl
with MeMgI/LaCl3·2LiCl
54%
15%
30%
55:45
60:40
95:5
1
84%, d.r.=98:2
55%, d.r.=92:8
75%, d.r.=7:93
60%, d.r.=8:92
[a] Yield of isolated diastereomers of 6k. [b] Diastereoselectivity
1
(d.r.=anti/syn) was determined by H and 13C NMR spectroscopy.
2
tivity (d.r. = 60:40; entry 2). However, transmetalation of
alkyllithium reagent anti-1a to the corresponding alkylmag-
nesium reagent anti-8a followed by the addition of
LaCl3·2LiCl[22] and acetone led to the desired product anti-
6k with an excellent diastereoselectivity (30% yield, d.r. =
95:5; entry 3). These examples (Table 2–4) demonstrated that
sequential highly retentive transmetalations of secondary
alkyllithium reagents can be achieved with high diastereose-
lectivity under appropriate reaction conditions. The degree of
retention in transmetalations depends on the nature of the
metallic salt used (Table 1), as well as the solvent polarity and,
therefore, of the solvent mixture used.[3a,7c,23,24] The influence
of the nature of the solvent on the epimerization rate of
a secondary alkylzinc reagents is demonstrated by the case of
cyclohexylzinc iodide trans-4 f obtained by an I/Li exchange
and subsequent transmetalation with ZnI2 (Scheme 2).
3
4
37%, d.r.=89:11
40%, d.r.=94:6
40%, d.r.=11:89
35%, d.r.=5:95
[a] Yield of isolated diastereomers of 6. [b] Diastereoselectivity
(d.r.=trans/cis or anti/syn) was determined by 1H and 13C NMR
spectroscopy.
acyclic iodide anti- and syn-2c (anti-2c: d.r. = 98:2 and syn-
2c: d.r. = 1:99), we obtained high retention of the config-
uration in the allylation sequence that leads to the allylated
products (trans-6g: d.r. = 98:2 and cis-6g: d.r. = 7:93 as well as
anti-6h: d.r. = 92:8 and syn-6h: d.r. = 8:92; entries 2 and 3).
Unfunctionalized secondary alkyl iodides bearing a phenyl
substituent either at position 4 or 3 (anti-2d: d.r. = 93:7 and
syn-2d: d.r. = 5:95 as well as anti-2e: d.r. = 98:2 and syn- 2e:
d.r. = 3:97) behaved as expected, and the diastereomerically
enriched alcohol anti- and syn-6i,j were produced in 35–40%
yield and good retention of diastereoselectivity.
Domino transmetalations also proved to be efficient for
undergoing additions to the carbonyl group of an enolizable
ketone. Thus, we briefly examined the diastereoselectivity
obtained in the conversion of a diastereomerically pure
secondary alkyl iodide into the corresponding lanthanum
reagent (Table 4).[21] The secondary alkyllithium reagent anti-
1a was generated from the corresponding alkyl iodide anti-2a
(d.r. = 99:1) by known methods. A direct transmetalation to
the corresponding alkyllanthanum reagent by using
LaCl3·2LiCl[22] followed by the addition of acetone provided
the tertiary alcohol anti-6k in 54% yield, but low diastereo-
selectivity (d.r. = 55:45; entry 1). Repeating this reaction by
transmetalating the intermediate alkyllithium reagent anti-1a
to the magnesium derivative anti-8a and subsequent addition
of acetone led to a lower yield and still lower diastereoselec-
Scheme 2. Effect of solvent on the stability of the configuration of
cyclohexylzinc reagent trans-4 f.
Under these conditions, the secondary alkylzinc reagent
trans-4 f was generated in Et2O with good diastereoselectivty
(d.r. = 99:1), but we noticed that it has only a limited
configurational stability in this solvent at 258C, and signifi-
cant epimerization to a diastereomeric mixture (d.r. = 73:27)
was observed after 3.5 h at 258C. The epimerization rate was
monitored by deuterolysis of the reaction mixture with
deuterated trifluoroacetic acid. Interestingly, removal of the
Et2O and dissolution in THF resulted in a high configura-
tional stability of trans-4a (d.r. = 97:3 after 3.5 h).
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[3] a) S. Seel, G. Dagousset, T. Thaler, A. Frischmuth, K. Karaghios-
off, H. Zipse, P. Knochel, Chem. Eur. J. 2013, 19, 4614; b) G.
Dagousset, K. Moriya, R. Mose, G. Berionni, K. Karaghiosoff, P.
Knochel, Angew. Chem. Int. Ed. 2014, 53, 1425; Angew. Chem.
2014, 126, 1449; c) K. Moriya, D. Didier, M. Simon, J. M.
Hammann, G. Berionni, K. Karaghiosoff, H. Zipse, H. Mayr, P.
Knochel, Angew. Chem. Int. Ed. 2015, 54, 2754; Angew. Chem.
2015, 127, 2793.
[4] Selected examples of transmetalation to alkylcopper reagents:
a) P. Knochel, T. S. Chou, H. G. Chen, M. C. P. Yeh, M. J.
Rozema, J. Org. Chem. 1989, 54, 5202; b) T. N. Majid, P.
Knochel, Tetrahedron Lett. 1990, 31, 4413; c) W. Dohle, D. M.
Lindsay, P. Knochel, Org. Lett. 2001, 3, 2871.
[5] Stereoselective transmetalation of alkyllithium reagents: a) K.
Tomooka, H. Shimizu, T. Nakai, J. Organomet. Chem. 2001, 624,
364; b) J. P. N. Papillon, R. J. K. Taylor, Org. Lett. 2002, 4, 119;
c) R. K. Dieter, G. Oba, K. R. Chandupatla, C. M. Topping, K.
Lu, R. T. Watson, J. Org. Chem. 2004, 69, 3076; d) D. Stead, P.
OꢀBrien, A. J. Sanderson, Org. Lett. 2005, 7, 4459; e) I. Coldham,
D. Leonori, J. Org. Chem. 2010, 75, 4069; f) T. K. Beng, R. E.
Gawley, Org. Lett. 2011, 13, 394.
[6] Examples of chiral alkylmagnesium compounds: a) R. W. Hoff-
mann, B. Hçlzer, O. Knopff, K. Harms, Angew. Chem. Int. Ed.
2000, 39, 3072; Angew. Chem. 2000, 112, 3206; b) J. Beckmann,
D. Darkternieks, M. Dräger, A. Duthie, Angew. Chem. Int. Ed.
2006, 45, 6509; Angew. Chem. 2006, 118, 6659; c) A. A. Zuzek,
S. C. Reynolds, D. S. Glueck, J. A. Golen, A. L. Rheingold,
Organometallics 2011, 30, 1812.
In summary, we have developed sequential retentive
domino transmetalations of nonstabilized functionalized
secondary alkyllithium compounds prepared from the corre-
sponding secondary alkyl iodides by stereoselective I/Li
exchange. We found reaction conditions that allow two
successive transmetalations from Li to Zn and from Zn to
Cu to be performed, thereby leading to secondary alkylcop-
per reagents with high retention of configuration. This
domino transmetalation sequence allows trapping with
a new set of electrophiles to afford various polyfunctionalized
products with predictive diastereoselectivity.[25] A related
domino transmetalation involving successive Li, Mg, and La
organometallic intermediates affords the new possibility to
access diastereomerically defined tertiary alcohols.
Acknowledgements
We thank SFB 749B2 for financial support. We also thank
BASF SE (Ludwigshafen) and Rockwood Lithium GmbH
(Hoechst) for the generous gift of chemicals. K.M. thanks the
DAAD for a scholarship. We thank Dr. Guillaume Dagousset
and Dr. Dorian Didier for preliminary experiments and
Giulio Volpin for NMR measurements.
[7] Examples of chiral alkylzinc compounds: a) R. Duddu, M.
Eckhardt, M. Furlong, H. P. Knoess, S. Berger, P. Knochel,
Tetrahedron 1994, 50, 2415; b) A. Boudier, P. Knochel, Tetrahe-
dron Lett. 1999, 40, 687; c) A. Guijarro, R. D. Rieke, Angew.
Chem. Int. Ed. 2000, 39, 1475; Angew. Chem. 2000, 112, 1535;
d) A. Boudier, E, Hupe, P. Knochel, Angew. Chem. Int. Ed.
2000, 39, 2294; Angew. Chem. 2000, 112, 2396.
[8] R. W. Hoffmann, B. Hçlzer, J. Am. Chem. Soc. 2002, 124, 4204.
[9] Domino Reactions: Concept for Efficient Organic Synthesis
(Eds.: L. F. Tietze), Wiley-VCH, Weinheim, 2014.
[10] a) E. Negishi, D. R. Swanson, C. J. Rousset, J. Org. Chem. 1990,
55, 5406; b) W. F. Bailey, E. R. Punzalan, J. Org. Chem. 1990, 55,
5404.
[11] a) S. H. Bertz, M. Eriksson, G. Miao, J. P. Snyder, J. Am. Chem.
Soc. 1996, 118, 10906; b) S. Berger, F. Langer, C. Lutz, P.
Knochel, T. A. Mobley, C. K. Reddy, Angew. Chem. Int. Ed.
Engl. 1997, 36, 1496; Angew. Chem. 1997, 109, 1603; c) P. Jones,
C. K. Reddy, P. Knochel, Tetrahedron 1998, 54, 1471.
[12] See the Supporting Information for the detailed preparation and
optimization.
[13] a) M. Gardette, A. Alexakis, J. F. Normant, Tetrahedron Lett.
1982, 23, 5155; b) M. Gardette, A. Alexakis, J. F. Normant,
Tetrahedron 1985, 41, 5887.
[14] Modern Organocopper Chemistry (Ed.: N. Krause), Wiley-VCH,
Weinheim, 2002.
[15] In contrast, methyl vinyl ketone or ethyl acrylate gave the
desired products in low yield.
[16] a) A. Ghribi, A. Alexakis, J. F. Normant, Tetrahedron Lett. 1984,
25, 3075; b) A. Alexakis, D. Jachiet, N. F. Normant, Tetrahedron
1986, 42, 5607.
Keywords: configurational stability · copper ·
diastereoselectivity · lithium · zinc
How to cite: Angew. Chem. Int. Ed. 2015, 54, 10963–10967
Angew. Chem. 2015, 127, 11113–11117
[1] a) D. Hoppe, T. Hense, Angew. Chem. Int. Ed. Engl. 1997, 36,
2282; Angew. Chem. 1997, 109, 2376; b) J. Clayden, Organo-
lithiums: Selectivity for Synthesis (Eds.: J. E. Baldwin, R. M.
Williams), Pergamon, Oxford, 2002; c) M. C. Whisler, S. Mac-
Neil, V. Snieckus, P. Beak, Angew. Chem. Int. Ed. 2004, 43, 2206;
Angew. Chem. 2004, 116, 2256; d) D. B. Collum, A. J. McNeil, A.
Ramirez, Angew. Chem. Int. Ed. 2007, 46, 3002; Angew. Chem.
2007, 119, 3060.
[2] Recent examples of a-heteroatom-substituted alkyllithium
reagents: a) S. D. Rychnovsky, L. R. Takaoka, Angew. Chem.
Int. Ed. 2003, 42, 818; Angew. Chem. 2003, 115, 842; b) P.
OꢀBrien, K. B. Wiberg, W. F. Bailey, J. P. R. Hermet, M. J.
McGrath, J. Am. Chem. Soc. 2004, 126, 15480; c) F. Foubelo,
M. Yus, Chem. Soc. Rev. 2008, 37, 2620; d) G. Carbone, P.
OꢀBrien, G. Hilmersson, J. Am. Chem. Soc. 2010, 132, 15445;
e) Stereochemical Aspects of Organolithium Compounds (Eds.:
R. E. Gawley, J. S. Siegel), VHCA, Zürich, 2010; f) S. Roesner,
J. M. Casatejada, T. G. Elford, R. P. Sonawane, V. K. Aggarwal,
Org. Lett. 2011, 13, 5740; g) D. I. Coppi, A. Salomone, F. M.
Perna, V. Capriati, Chem. Commun. 2011, 47, 9918; h) T. K.
Beng, J. S. Woo, R. E. Gawley, J. Am. Chem. Soc. 2012, 134,
14764; i) A. Wieczorek, F. Hammerschmidt, J. Org. Chem. 2012,
77, 10021; j) R. Mansueto, V. Mallardo, F. M. Perna, A.
Salomone, V. Capriati, Chem. Commun. 2013, 49, 10160; k) R.
Mansueto, F. M. Perna, A. Salomone, S. Florio, V. Capriati,
Chem. Commun. 2013, 49, 4911; l) T. Boultwood, J. A. Bull, Org.
Lett. 2014, 16, 2740; m) A. Salomone, F. M. Perna, A. Falcicchio,
S. O. N. Lill, A. Moliterni, R. Michel, S. Florio, D. Stalke, V.
Capriati, Chem. Sci. 2014, 5, 528; n) X. Li, I. Coldham, J. Am.
Chem. Soc. 2014, 136, 5551; o) S. G. Koller, U. Kroesen, C.
Strohmann, Chem. Eur. J. 2015, 21, 641; p) D. M. Hodgson, C. L.
Mortimer, J. M. Mckenna, Org. Lett. 2015, 17, 330.
[17] J. F. Normant, A. Alexakis, A. Ghribi, P. Mangeney, Tetrahedron
1989, 45, 507.
[18] J. Villieras, M. Rambaud, Synthesis 1982, 924.
[19] R. W. Hoffmann, B. Hçlzer, Chem. Commun. 2001, 491.
[20] Preliminary experiments showed that the use of prenyl chloride
provided a mixture of SN2/SN2’-allylated products.
[21] A. Krasovskiy, F. Kopp, P. Knochel, Angew. Chem. Int. Ed. 2006,
45, 497; Angew. Chem. 2006, 118, 511.
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[22] Although organolithium compounds are readily transmetalated
to the corresponding lanthanum derivatives, organomagnesium
reagents are less prone to undergo this transmetalation. In this
case, LaCl3·2LiCl may also just have the role of a Lewis acid that
activates acetone.
[23] Solvent effects on the configurational stability of organometallic
compounds have been reported: a) H. J. Reich, M. A. Medina,
M. D. Bowe, J. Am. Chem. Soc. 1992, 114, 11003; b) V. Capriati,
S. Florio, F. M. Perna, A. Salomone, Chem. Eur. J. 2010, 16, 9778;
c) F. M. Perna, A. Salomone, M. Dammacco, S. Florio, V.
Capriati, Chem. Eur. J. 2011, 17, 8216; d) M. Gao, N. N.
Patwardhan, P. R. Carlier, J. Am. Chem. Soc. 2013, 135, 14390.
[24] Experiments on the configurational stability of acyclic secondary
alkylzinc reagents did not show the same behavior, for example,
we observed a higher configurational stability in Et2O than in
THF.
iodides. However, these overall yields include four reaction
steps: the first is the I/Li exchange, which under our optimized
conditions is > 80% yield, the next two reactions involve
transmetalations Li/Zn and Zn/Cu, and the last is the trapping
reaction. Thus, an overall yield of 37% corresponds to a yield of
ca. 77% yield per reaction step. Similarly, an overall yield of
65% corresponds to a yield of ca. 90% yield per step. Although
transmetalations are usually high yielding, the requirement to
prepare the transmetalation reagents (Me3SiCH2ZnBr·LiBr,
CuBr·2LiCl·Me2S) may lower the efficiency of these trans-
metalations. We observed mainly hydrolysis of the organome-
tallic reagents as typical side products for the reaction sequence.
[25] We realized that the overall yields in Tables 2 and 3 lay mostly
between 40 and 65%, despite full conversion of the starting
Received: June 22, 2015
Published online: August 14, 2015
Angew. Chem. Int. Ed. 2015, 54, 10963 –10967
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