Cobalt-mediated diastereoselective cross-coupling reactions between cyclic halohydrins and arylmagnesium reagents

Article abstract of DOI:10.1021/ol503361m

Cyclic TBS-protected iodohydrins (and bromohydrins) undergo a highly diastereoselective cross-coupling with various aryl- and heteroarylmagnesium reagents in the presence of THF-soluble CoCl₂·2LiCl and TMEDA as a ligand leading to trans-2-arylcyclohexanol derivatives in good yields and dr up to >99:1. A range of functional groups are tolerated in the Grignard reagent (e.g., COOR, CN, CF₃, SF₅). The use of heterocyclic iodohydrins leads to trans-3,4-disubstituted pyrrolidines and tetrahydrofurans.

Full text of DOI:10.1021/ol503361m

Letter
pubs.acs.org/OrgLett
Cobalt-Mediated Diastereoselective Cross-Coupling Reactions
between Cyclic Halohydrins and Arylmagnesium Reagents
Jeffrey M. Hammann, Andreas K. Steib, and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, Haus F, 81377 Munich, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Cyclic TBS-protected iodohydrins (and bromohydrins)
undergo a highly diastereoselective cross-coupling with various aryl-
and heteroarylmagnesium reagents in the presence of THF-soluble
CoCl2·2LiCl and TMEDA as a ligand leading to trans-2-arylcyclohex-
anol derivatives in good yields and dr up to >99:1. A range of
functional groups are tolerated in the Grignard reagent (e.g., COOR,
CN, CF3, SF5). The use of heterocyclic iodohydrins leads to trans-3,4-
disubstituted pyrrolidines and tetrahydrofurans.
Scheme 1. (a) Diastereoselective α-Arylation of Alcohol
Derivatives and (b) Structure of Key NK1 Antagonists 2 and
3
ransition-metal-catalyzed cross-coupling reactions are
Tindispensable tools for the construction of C−C bonds
in organic synthesis.1 Most of these reactions are catalyzed by
Pd or Ni salts; however, these metals have the disadvantage of
toxicity2 and/or high costs.3 In contrast, cobalt is an
inexpensive and less toxic alternative for cross-coupling
reactions. Recently, there has been much progress in Co-
catalyzed coupling methods.4 However, despite the spectacular
advances and insights into the role of Co in coupling reactions,
only a few diastereoselective Co-mediated or catalyzed
transformations of this type have been described.5,6 Previously,
we have reported a diastereoselective Fe-mediated cross-
coupling of cyclic iodohydrins with aryl Grignard reagents
leading to products of type 1.7 Although very effective with
electron-poor Grignard reagents, this method displays a limited
reaction scope, and electron-rich arylmagnesium bromides give
unsatisfactory results. Additionally, cyclic bromohydrins did not
react. Herein, we report a new broadly applicable cobalt-
mediated α-arylation of TBS-protected (TBS = tert-butyldime-
thylsilyl) cyclic bromo- and iodohydrins.8 The structural unit
present in 1 is found in a range of biologically active molecules,
such as the NK1 antagonists 2 and 3 (Scheme 1).9
Thus, the dropwise addition of various Grignard reagents to
a mixture of the protected iodohydrin 4a (1.0 equiv), CoCl2·
2LiCl (0.85 equiv, 1 M in THF),16 and TMEDA (0.3 equiv) in
THF at −50 °C led to the trans-coupling products (1a−k) in
55−91% yield and excellent dr (dr >95:5, Table 2).17 Both
electron-poor or electron-rich arylmagnesium halides were used
successfully. Furthermore, heterocyclic Grignard reagents
obtained either by a directed magnesiation18 or magnesium
insertion19 led to the desired cross-coupling product in very
high diastereoselectivity (up to >99:1 dr). Thus, the
magnesiation of the uracil derivative 6 with TMPMgCl·LiCl
(1.1 equiv, THF, 0 °C, 0.5 h) led to the heterocyclic Grignard
reagent 5b (>90% yield).18 Its coupling with 4a under the
In optimization studies, we have examined the arylation of 4a
(75:25 cis/trans, X = I) with 4-anisylmagnesium bromide (5a)
in the presence of various transition-metal salts (Table 1). As
mentioned above, the use of FeCl2·2LiCl proved to be
unsatisfactory, and the coupling of 4a with 5a furnished the
expected product 1a in only 18% yield (entry 1).7 Changing the
iron salt or the ligand was not satisfactory (entries 2 and 3).10
Therefore, we examined other metallic salts. MnCl2·2LiCl11
12
and CrCl2 gave poor results (entries 4 and 5), in contrast to
cobalt salts. Thus, CoCl2·2LiCl (0.85 equiv)13 and 4-
fluorostyrene (0.5 equiv) used as an additive14 led to the
product 1a with a dr = 99:1, but with only 44% yield (entry 6).
In the absence of 4-fluorostyrene, the yield improved to 62%.
Finally, adding TMEDA as a ligand gave the best results (71%
isolated yield, dr 95:5; entry 8).5e,15
Received: November 19, 2014
© XXXX American Chemical Society
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Table 1. Optimization of the Conditions for the Diastereoselective Cross-Coupling of 4a with 5a
a
a
entry
metal mediator (equiv)
additive (equiv)
GC yield (%)
dr
1
2
3
4
5
6
7
8
FeCl2·2LiCl (0.85)
FeCl2·2LiCl (0.85)
Fe(acac)3 (0.85)
4-fluorostyrene (0.50)
TMEDA (0.30)
18
53
24
0
94:6
88:12
91:9
nd
TMEDA (0.30)
MnCl2·2LiCl (0.85)
CrCl2 (0.20)
TMEDA (0.30)
TMEDA (0.30)
5
99:1
99:1
99:1
95:5
CoCl2·2LiCl (0.85)
CoCl2·2LiCl (0.85)
CoCl2·2LiCl (0.85)
4-fluorostyrene (0.50)
44
62
b
TMEDA (0.30)
79 (71)
a
b
Determined by capillary GC analysis. Undecane (C11H24) was used as internal standard. Isolated yield. TMEDA = N,N,N′,N′-tetramethylethane-
1,2-diamine.
Table 2. Products Obtained by the Diastereoselective Cross-
Coupling of 4a with Various Grignard Reagents
Scheme 2. Preparation of Heterocyclic Grignard Reagents
and Their Diastereoselective Cross-Coupling with 4a
(9) with iPrMgCl·LiCl (1.1 equiv, THF, −20 °C, 0.5 h)20
provides the corresponding Grignard reagent 5d (>90%),
which smoothly undergoes a Co-mediated cross-coupling,
providing the cyclopentanol derivative 8a in 67% yield (dr
>99:1). Similarly, the arylmagnesium reagent 5e (>90%)
prepared from the iodobenzoate 10 by I/Mg-exchange
furnished, after cross-coupling with 4b, the cyclopentanol
derivative 8b in 52% yield (dr 97:3, Scheme 3).
The use of CoCl2·2LiCl allows further expansion of the
reaction scope of this coupling, and the iodohydrins 4a,b can be
replaced advantageously by the corresponding bromohydrin
(4c, X = Br). Using the same reaction conditions, the cross-
coupling products 11a−d were obtained with high diaster-
eoselectivities (dr >97:3, Scheme 4).
Remarkably, this cross-coupling can also be performed with
heterocyclic iodohydrins such as 12 and 13, leading to trans-
3,4-disubstituted tetrahydrofurans (14) and pyrrolidines (15)
as single diastereomers (71−74%, Scheme 5). The up-scaling of
this cross-coupling is readily performed as indicated in Table 3
(entry 7) as well as in the synthesis of 14, which has been
performed on a 4 mmol scale (gram scale).
To demonstrate the synthetic potential of this method, we
have prepared the functionalized arylated TBS-protected
cyclohexanol,16 which is a key intermediate for the synthesis
of the NK1 antagonist 2. Thus, the commercially available
ketone 17 was converted in four steps (37% overall yield) into
the silyl-protected iodohydrin 18 (Scheme 6). Co-mediated
cross-coupling with 4-fluorophenylmagnesium bromide (5f)
a
b
1
Isolated yield. Determined by capillary GC and H NMR analysis.
standard conditions furnished the pyrimidine 1b in 55% yield
(dr >99:1). Also, N-methyl 5-bromoindole 7 reacted with Mg
and LiCl (25 °C, 1 h) to produce the corresponding Grignard
reagent 5c in >90% yield.17 Coupling with 4a under our
standard conditions produced the indole 1c (60% yield, dr
98:2, Scheme 2).
Extension of this coupling to the five-membered iodohydrin
4b (X = I) led to the expected α-arylated or α-heteroarylated
cyclopentanol silyl ethers 8a−j in 52−80% yield (dr >97:3;
Table 3). The mild conditions required for this cross-coupling
allowed the presence of sensitive functional groups in the
Grignard reagent. Thus, the treatment of the bromobenzonitrile
B
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Table 3. Products Obtained by the Diastereoselective Cross-
Coupling of 4b with Various Grignard Reagents
Scheme 5. Diastereoselective Cross-Coupling of the
Heterocyclic Halohydrins 12 and 13
Scheme 6. Synthesis of Key Intermediate 16 from Ketone 17
a
b
1
Isolated yield. Determined by capillary GC and H NMR analysis.
c
Reaction performed on a 4 mmol scale.
Scheme 3. Preparation of Various Grignard Reagents and
Their Diastereoselective Cross-Coupling with 4b
improvement over the previously reported synthesis (dr
66:54).9
Preliminary mechanistic studies have shown that ArMgX and
CoCl2 readily react with each other, leading to the
homocoupling products quantitatively. However, under the
reaction conditions (slow addition of ArMgX to a mixture of
the respective halohydrin, CoCl2·2LiCl, and TMEDA), the
desired cross-coupling is much faster. The stereoconvergence of
the reaction may be the result of a radical generated at the α-
position to oxygen.4b,5
In conclusion, we have reported a highly stereoselective
cobalt-mediated arylation of TBS-protected cyclic bromo- and
iodohydrins, leading to trans-α-arylated cyclic alcohols with
high diastereoselectivity (up to dr >99:1). In contrast to the
corresponding iron-mediated arylation, both electron-with-
drawing and electron-donating substituents can be present in
the Grignard reagent. Furthermore, heterocyclic iodohydrins
are also excellent substrates for this cobalt-mediated arylation.
Further extension of this method as well as mechanistic studies
are currently underway.
Scheme 4. Products of Type 11 Obtained by the
Diastereoselective Cross-Coupling of Bromohydrin 4c with
Arylmagnesium Reagents
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Full experimental details; H, 13C, and 19F NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
furnished the desired product 16 in 61% yield (dr 85:15).
Although this diastereoselectivity is not perfect, it represents an
The authors declare no competing financial interest.
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(12) Steib, A. K.; Kuzmina, O. M.; Fernandez, S.; Flubacher, D.;
Knochel, P. J. Am. Chem. Soc. 2013, 135, 15346.
(13) Cahiez, G.; Chaboche, C.; Duplais, C.; Giulliani, A.; Moyeux, A.
ACKNOWLEDGMENTS
■
We would like to thank DFG (Deutsche Forschungsgemein-
schaft) for financial support. We also thank Rockwood Lithium
GmbH for the generous gift of chemicals.
Adv. Synth. Catal. 2008, 350, 1484.
(14) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
(15) (a) The use of triisopropylsilyl-protected (TIPS-protected) 2-
iodocyclohexanol led to a similar diastereoselectivity (dr 94:6),
whereas protection with the bulky tert-butyldiphenylsilyl (TBDPS)
group resulted in a decreased diastereoselectivity (dr 90:10). (b) The
role of N,N,N′,N′-tetramethylethane-1,2-diamine (TMEDA) is to
coordinate the low-valent cobalt intermediate.
(16) The use of catalytic amounts of CoCl2·2LiCl (0.40 equiv) did
not lead to a satisfactory conversion of 1a (54% yield).
(17) Treatment of a mixture of CoCl2·2LiCl (0.85 equiv), TMEDA
(0.3 equiv), and ArMgCl (1.7 equiv) with the protected iodohydrin (1
equiv) in THF at −50 °C did not lead to the formation of the desired
product.
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