Highly diastereoselective iron-mediated C(sp2)-C(sp3) cross-coupling reactions between aryl grignard reagents and cyclic iodohydrine derivatives

Article abstract of DOI:10.1002/anie.201007187

trans-2-Arylcycloalcohol derivatives are obtained in high diastereoselectivity by the iron-mediated cross-coupling of cyclic TBS-protected iodohydrines with aryl Grignard reagents (see scheme; TBS=tert- butyldimethylsilyl). The stereoconvergent cross-coupling of a chiral TBS-protected 2-iodocyclohexanol provides the 2-arylcyclohexanols with no loss of stereochemical purity, and is a valuable alternative to the enantioselective opening of symmetrical epoxides. Copyright

Full text of DOI:10.1002/anie.201007187

DOI: 10.1002/anie.201007187
Stereoselective Cross-Coupling
2
3
À
Highly Diastereoselective Iron-Mediated C(sp ) C(sp ) Cross-
Coupling Reactions between Aryl Grignard Reagents and Cyclic
Iodohydrine Derivatives**
Andreas K. Steib, Tobias Thaler, Kimihiro Komeyama, Peter Mayer, and Paul Knochel*
Transition-metal-catalyzed cross-coupling reactions have
Products of type 1 are versatile building blocks for
pharmaceuticals,[10] chiral ligands,[11] and auxiliaries.[12] They
are usually obtained by the opening of the corresponding
epoxides with aryl organometallic compounds. Enantioselec-
tive versions of this opening are of limited scope.[13] In fact,
the most efficient procedures for the desymmetrization of
oxacycles using aryl Grignard reagents have only been
reported for oxabenzonorbornadienes[14] and 2,3-disubsti-
tuted 7-oxabicyclo[2.2.1]hept-5-enes.[7a,b] These problems can
be solved by an alternative retrosynthesis involving the
diastereoselective coupling of the readily available iodohy-
drine derivative 4 with ArMgX 5 (Scheme 1).
À
become indispensible tools for C C bond-forming reactions
in modern organic synthesis.[1] Most of these reactions depend
on the use of palladium or nickel complexes as catalysts.
Although these metals are used in only catalytic amounts,
they have the disadvantage of being toxic[2] and/or expen-
sive.[3]
Iron-mediated coupling reactions[1e,4] were found to be a
valuable alternative, since iron is one of the most abundant
transition metals and its salts are inexpensive and environ-
mentally benign. Despite spectacular advances[5] and insights
into the role of iron in coupling reactions,[6] only a few
stereoselective versions of iron-mediated or -catalyzed C(sp3)
cross-coupling reactions are known.[5k,l,6f,7]
Recently, we developed a diastereoselective palladium-
catalyzed cross-coupling of various substituted cycloalkylzinc
reagents with (hetero)aryl halides[8] and bromoalkynes.[9]
However, this coupling reaction could not be used for the
preparation of a-arylated cyclohexanol derivatives of type 1,
since the required zinc reagent 2 undergoes fast elimination to
give cyclohexene (3; Scheme 1).
In preliminary experiments, we examined the cross-
coupling of the TBS-protected (TBS = tert-butyldimethyl-
silyl) iodohydrine 4 with PhMgCl in the presence of various
iron salts (Scheme 2). The addition of PhMgCl to the
Scheme 2. Cross-coupling of 4 with PhMgCl in the presence of various
iron salts.
cyclohexyl iodide 4 (75:25 cis/trans) in the presence of 10%
[Fe(salen)Cl][5n,15] salen = (R,R)-N,Nꢀ-bis(3,5-di-tert-butylsali-
cylidene)-1,2-cyclohexanediamine resulted in the exclusive
formation of protonated product (cHexOTBS; Table 1,
entry 1). Further attempts with iron salts, such as [Fe-
(acac)3][5i] (acac = acetylacetonate) and FeCl3,[5l] in catalytic
amounts furnished the desired cross-coupling product 1a in
27% yield at best and with a diastereoselectivity between
76:24 and 96:4 d.r. (entries 2–4). Significant improvements
were achieved by using substoichiometric amounts
(0.85 equiv) of the complex FeCl2·2LiCl,[6d] which is highly
soluble in THF; this complex preferentially gave the thermo-
dynamically more stable trans isomer[16] 1a in 48% yield
(59% GC yield) and 96:4 d.r. (entry 5). The addition of
N,N,N’,N’-tetramethylethylenediamine (TMEDA)[5l] led to a
deterioration of the diastereoselectivity (83:17 d.r.; entry 6).
The use of 4-fluorostyrene as the additive, which is known to
facilitate the reductive elimination step in nickel-catalyzed
cross-coupling reactions,[17] resulted in a higher yield of the
isolated product (61%; 78% GC yield) with an excellent
diastereoselectivity of 96:4 d.r. (entry 7).[18,19] To elucidate
whether traces of other transition metals present in the
Scheme 1. Retrosynthesis of 2-arylcyclohexanol derivatives 1.
[*] A. K. Steib,[+] T. Thaler,[+] Dr. P. Mayer, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
Prof. Dr. K. Komeyama
Department of Chemistry and Chemical Engineering
Graduate School of Engineering, Hiroshima University
Kagamiyama, Higashi-Hiroshima 739-8527 (Japan)
[+] These authors contributed equally to this work.
[**] Funding from the European Research Council under the European
Community’s Seventh Framework Programme (FP7/2007-2013,
ERC grant no. 227763) is acknowledged. We thank the SFB 749 and
the Fonds der Chemischen Industrie for financial support, and are
grateful to BASF AG, W. C. Heraeus GmbH, Chemetall GmbH, and
Solvias AG for the generous gift of chemicals. K.K. thanks the Japan
Society for the Promotion of Sciences (JSPS) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007187.
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Table 1: Optimization of the conditions for the diastereoselective cross- Table 2: Products of the diastereoselective cross-coupling with 4.
coupling (Scheme2).
Entry
Product
Yield [%][a]
d.r.[b]
Entry
Product
Yield [%][a]
d.r.[b]
Entry Metal mediator
Additive
Yield [%][a] d.r.[a]
1[b]
2[d]
10% [Fe(salen)Cl][5n,15]
–
0[c]
traces
n.d.
n.d.
10% [Fe(acac)3][5i]
20% TMEDA
10% HMTA[e]
TMEDA
62
95:5
65
>99:1
1
6
3[d]
5% FeCl3
17
76:24
[5l]
(1.2 equiv)
4
5
10% FeCl3
10% DPEphos 27
96:4
96:4
1b
1g
FeCl2·2LiCl
(0.85 equiv)
FeCl2·2LiCl
(0.85 equiv)
FeCl2·2LiCl
(0.85 equiv)
FeCl2·2LiCl
(0.85 equiv)
10% [Ni(acac)2]
–
59 (48)
6
TMEDA
86
83:17
96:4
96:4
n.d.
67
99:1
62
>99:1
(1.2 equiv)
4-fluorostyrene 78 (61)
(0.5 equiv)
4-fluorostyrene 73 (57)
(0.5 equiv)
10% DPEphos traces
2
3
4
5
7
7[f]
8[g]
9
1c
1h
[a] Determined by GC analysis on a capillary column. Tridecane (C13H28)
was used as the internal standard. Numbers in brackets indicate yields of
isolated products. [b] 2.0 equiv of PhMgCl were used. [c] Only cHexOTBS
was obtained. [d] 1.2 equiv of PhMgCl were used. [e] HMTA=hexame-
thylenetetramine. [f] The use of catalytic amounts of FeCl2·2LiCl did not
lead to a satisfactory conversion of 4. [g] With 99.99% Fe (Alfa Aesar).
Inductively coupled plasma (ICP) analysis showed that no traces of other
transition metals were present in the reaction mixture apart from iron.
n.d.=not determined.
75
97:3
62
95:5
8
1d
1i
90
98:2
57
>99:1
9
reaction mixture were responsible for the cross-coupling
we used FeCl2 with a purity of 99.99% (entry 8). This
resulted in 1a being obtained in a similar yield of 57%
(73% GC yield). The use of a combination of 10%
[Ni(acac)2] and 10% bis(2-diphenylphosphanylpheny-
l)ether (DPEphos)[20] as catalyst gave 1a in only trace
amounts (< 3%; entry 9).
1e
1j
80
>99:1
80
>99:1
10
1 f
1k
Next, we examined the scope of the diastereoselective
iron-mediated cross-coupling of 4 by using various aryl-
magnesium reagents (Table 2). These Grignard reagents
were prepared either by LiCl-promoted insertion of Mg[21]
or by a Br/Mg exchange using iPrMgCl·LiCl.[22] In all cases,
the thermodynamically favored trans-1,2-disubstituted cyclo-
hexanols were formed preferentially with ꢀ 95:5 d.r.[16] Aryl-
magnesium reagents bearing methyl and trifluoromethyl
groups were coupled efficiently with high diastereoselectivity
(95:5 to 99:1 d.r.; entries 1–3). The cross-coupling reactions of
the bulky naphthalen-1-ylmagnesium bromide[21] and the
sterically congested mesitylmagnesium bromide[21] with 4
gave the trans products 1e and 1 f in high yields (80 and 90%)
and excellent diastereoselectivity (98:2 and > 99:1 d.r.;
entries 4 and 5). Grignard reagents bearing sensitive cyano
functions underwent smooth coupling reactions with 4 to
furnish the respective products 1g and 1h in yields of 62 and
65% as single diastereomers (entries 6 and 7). Although a
pivaloyloxy function is a well-known leaving group in iron-
catalyzed cross-coupling reactions with Grignard reagents,[5c]
the reaction of [4-(pivaloyloxy)phenyl]magnesium bromide
(4-PivOC6H4MgBr)[21] with 4 led to the exclusive formation of
1i (62%; 95:5 d.r.; entry 8). Heteroaryl Grignard reagents,
such as 3-quinolinylmagnesium bromide[21] and 3-pyridinyl-
magnesium chloride,[22] were also coupled successfully to give
1j and 1k as single diastereomers (entries 9 and 10).
[a] Yield of analytically pure isolated product. [b] Determined by GC analysis on
a capillary column before and after purification.
Br/Mg exchange on 6 in the presence of iPrMgCl·LiCl in
THFat À788C led to the formation of the Grignard reagent 7,
which bears a sensitive ester function. The arylmagnesium
reagent 7 underwent efficient cross-coupling with 4 to give,
after desilylation with Bu4NF, the stereochemically defined
3,4-dihydroisocoumarin 8[23] in 62% overall yield and
> 99:1 d.r. (Scheme 3). 3,4-Dihydroisocoumarins often dis-
Scheme 3. Preparation of the stereochemically defined 3,4-dihydroiso-
coumarin 8.
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stereoconvergent manner with no loss of the stereochemical
purity (92–93% ee) and excellent diasteteroselectivities
(ꢀ98:2 d.r.; Table 3). Thus, the reaction is suitable for the
efficient propagation of stereoinformation and represents a
valuable alternative to the enantioselective opening of sym-
metrical epoxides.
Finally, we tried this diastereoselective iron-mediated
coupling on the TBS-protected 2-iodocyclopentanol 13 in the
presence of various (hetero)aryl Grignard reagents
(Scheme 5). To our delight, the trans coupling products[26]
14a–j were obtained with excellent diastereoselectivities of
98:2 to > 99:1 d.r. (Table 4). trans-2-Arylcyclopentanols are
Scheme 4. Preparation and cross-coupling of the chiral 2-iodocyclohex-
anol 9. NMI=N-methylimidazole.
Scheme 5. Diastereoselective cross-coupling of the 2-iodocyclopenta-
nol derivative 13.
play biological activity and their structural motifs occur in a
number of natural products.[24]
To underline its synthetic utility we applied this reaction
to the cross-coupling of the enantioenriched 2-iodocyclohex-
anol derivative 9 which was obtained in four steps from the
readily prepared mixture of (R,R)-10 and (R,R)-11[25]
(92% ee) in an overall yield of 39% (Scheme 4). The iron-
mediated cross-coupling reactions of 9 with various aryl
Grignard reagents produced the trans products 12a–d in a
Table 4: Products of the diastereoselective cross-coupling with 13 (Scheme5).
Entry
Product
Yield [%][a]
d.r.[b]
Entry
Product
Yield [%][a]
d.r.[b]
56
98:2
68
>99:1
1
6
Table 3: Products of type 12 of the iron-mediated cross-coupling with
enantioenriched 9 (Scheme4).
14a
14b
14 f
14g
Entry
Product
Yield [%][a]
d.r.[b]
ee [%][c]
80
>99:1
69
>99:1
2
3
7
8
87
98:2
1
92
12a
12b
65
>99:1
68
>99:1
64
>99:1
2
3
4
14c
14h
92
93
75
>99:1
42
>99:1
4
5
9
69
>99:1
14d
14i
12c
12d
73
>99:1
92
60
>99:1
60
>99:1
10
[a] Yield of analytically pure isolated product. [b] Determined by GC
analysis on a capillary column before and after purification. [c] The
enantiomeric excess (ee) was determined by HPLC on a chiral stationary
phase. See the Supporting Information for details.
14e
14j
[a] Yield of analytically pure isolated product. [b] Determined by GC analysis on
a capillary column before and after purification.
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Communications
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2
3
À
C(sp ) C(sp ) coupling of 2-iodocycloalcohol derivatives with
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Published online: February 14, 2011
À
Keywords: C C coupling · cross-coupling · diastereoselectivity ·
iron · synthetic methods
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