Cobalt-Catalyzed Diastereoselective Cross-Couplings between Alkynylzinc Pivalates and Functionalized Cyclic Iodides or Bromides

Article abstract of DOI:10.1021/acs.orglett.8b00784

Various 1,2-, 1,3-, and 1,4-substituted cyclic iodides or bromides undergo highly diastereoselective cross-couplings (diastereoselectivity (dr) up to 99:1) with a range of alkynylzinc pivalates, using CoCl₂ (20 mol%) and trans-N,N,N′,N′-tetrame

Full text of DOI:10.1021/acs.orglett.8b00784

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Diastereoselective Cross-Couplings between
Alkynylzinc Pivalates and Functionalized Cyclic Iodides or Bromides
Lucie Thomas, Ferdinand H. Lutter, Maximilian S. Hofmayer, Konstantin Karaghiosoff,
and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstraße 5-13, 81377 Munchen, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Various 1,2-, 1,3-, and 1,4-substituted cyclic iodides or bromides undergo highly diastereoselective cross-couplings
(diastereoselectivity (dr) up to 99:1) with a range of alkynylzinc pivalates, using CoCl2 (20 mol %) and trans-N,N,N′,N′-
tetramethylcyclohexane-1,2-diamine as a catalytic system.
Table 1. Optimization of the Conditions for the
Diastereoselective Cross-Coupling of 1,3-Disubstituted
Cyclohexyl Iodide (2a) with Alkynylzinc Pivalate (1a)
ransition-metal-catalyzed diastereoselective cross-cou-
Tplings represent an excellent way for the stereoselective
synthesis of organic molecules.1 Although palladium has been
employed for such stereoselective cross-couplings,2 the use of
alternative, less-expensive, and less-toxic metals, such as iron3 or
cobalt,4 has recently attracted a lot of attention. In most cross-
coupling reactions, organomagnesium reagents, including
alkynylmagnesium halides, are the preferred nucleophile-
s.2e,3e,4g,h,5 Recently, we have shown that the use of organozinc
reagents can be advantageous for such cross-couplings, because
of the high tolerance of functional groups of these organo-
metallics.6 Particularly, the use of organozinc pivalates of the
type RZnOPiv·MgX27 enables fast and efficient cobalt-catalyzed
cross-couplings.8 We have also reported that alkynylzinc
pivalates are readily prepared from the corresponding alkynes.
After solvent evaporation, solid organozinc pivalates are
obtained with enhanced air and moisture stability.9 Also,
these organozinc pivalates undergo convenient cobalt-catalyzed
cross-couplings with aryl halides and heteroaryl halides.10
Herein, we report a new, diastereoselective cross-coupling
between alkynylzinc pivalates of type 1 and various function-
alized cyclic iodides or bromides of type 2. In preliminary
experiments, 3-isopropylcyclohexyl iodide (2a) was treated
with 2-phenylethynylzinc pivalate (1a) at 0 °C under various
conditions (Table 1). First, we tested some low-cost transition-
metal salts. NiCl2,5c,11 MnCl2,12 FeCl2,3e,5a,b and CuCl2,13
without any additive or in the presence of TMEDA
(N,N,N′,N′-tetramethylethylendiamine), were unsuitable
metal catalysts for this coupling (entries 1−4 in Table 1).
However, using 20 mol % of CoCl2 and TMEDA as an additive
provided 3a in 67% yield, but with moderate diastereoselec-
tivity (dr = 85:15, entry 6 in Table 1).
a
a
entry
catalyst
NiCl2
additive
yield (%)
dr
b
b
b
b
b
1
2
0 (0)
n.d. (n.d.)
n.d. (n.d.)
n.d. (n.d.)
n.d. (n.d.)
80:20
b
MnCl2
FeCl2
0 (0)
b
3
0 (0)
b
4
CuCl2
0 (0)
5
CoCl2
CoCl2
CoBr2
CoCl2·2LiCl
CoCl2
CoCl2
CoCl2
5
67
11
62
2
6
TMEDA
TMEDA
TMEDA
L1
85:15
7
85:15
8
85:15
9
n.d.
10
11
12
L2
38
88:12
c
L3
86 (78)
92:8
d
CoCl2
L3
85
92:8
a
As determined by GC analysis. Tetradecane (C14H30) was used as
b
internal standard. Only the major diastereomer is shown. 2.0 equiv of
TMEDA were used. Isolated yield. CoCl2 (99.99% purity).
c
d
diastereoselectivity was improved by screening various N-
ligands (entries 9−11 in Table 1). Clearly, trans-N,N,N′,N′-
tetramethylcyclohexane-1,2-diamine (L3) gave the best results
(entry 11 in Table 1). Also, varying the solvent system did not
improve the reaction outcome.14 At this point, we verified that
Other cobalt sources, such as CoBr2 or CoCl2·2LiCl, did not
Received: March 9, 2018
have beneficial effects (see entries 7 and 8 in Table 1). The
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00784
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
no other metal contaminations are responsible for this catalysis.
Thus, using CoCl2 (99.99% purity) led to 3a in 85% yield (dr =
92:8, entry 12 in Table 1). With these optimized reaction
conditions in hand, we performed a range of coupling reactions
of various alkynylzinc pivalates of type 1 with 1,3-substituted
cyclic alkyl iodides of type 2, furnishing the thermodynamically
favored cis-isomer (see Table 2).15
Table 3. Products (3) Obtained by the Diastereoselective
Cross-Coupling of 1,4-Disubstituted Cyclohexyl Halides (2)
with Various Alkynylzinc Pivalates (1)
Table 2. Products (3) Obtained by the Diastereoselective
Cross-Coupling of 1,3-Disubstituted Cyclohexyl Iodides (2)
with Various Alkynylzinc Pivalates (1)
a
Isolated yield. The diastereoselectivity (dr) was determined by GC
b
c
a
analysis. The major diastereomer is shown. dr = 99:1. dr = 85:15.
Isolated yield. The diastereoselectivity (dr) was determined by GC-
b
c
d
analysis. The major diastereomer is shown. dr = 92:8. dr = 68:32. dr
= 90:10. dr = 99:1.
e
The coupling of 2a with bulky alkynes, such as zinc pivalates
1b or 1c, resulted in the corresponding coupling products (3b
or 3c) in 91%−95% yield and high diastereoselectivity (dr =
95:5−98:2, entries 1 and 2 in Table 2). Also, the propargylic
alcohol derivative 1d was successfully coupled with cyclic
iodides bearing a trifluoromethyl 2b and an aryl group 2c, to
provide 3d and 3e in 62%−78% yield, respectively, with a dr up
to 98:2 (entries 3 and 4 in Table 2). Pyran 3f was obtained by
coupling of the heterocyclic iodide 2d with 1a in 76% yield and
dr = 93:7 (entry 5 in Table 2). Remarkably, the cross-coupling
of iodide 2e, derived from the natural product (+)-nootka-
tone,16 proceeded smoothly with alkynylzinc pivalate 1e,
leading to the coupling product 3g in 60% yield (dr = 96:4,
entry 6 in Table 2). In addition, this cobalt-catalyzed cross-
coupling was applied to 1,4-disubstituted cyclohexyl halides,
leading to trans-coupling products (see Table 3).17 Thus, 4-
phenyl cyclohexyl iodide (2f) reacted smoothly with various
alkynylzinc pivalates (1b, 1f, 1g, 1h), resulting in the products
3h−3k in 68%−96% yield (dr = 90:10−99:1, entries 1−4 in
Table 3). Also, an ester function was tolerated in these
couplings, and the iodoester 2g was converted to the trans-
alkyne 3l in 71% yield (dr = 90:10, entry 5 in Table 3).
Furthermore, pyrrole derivative 2h was coupled with 1j,
furnishing the trans-pyrrole-substituted cyclohexane derivative
3m in 83% yield and a dr of 95:5 (entry 6 in Table 3). 4-(tert-
Butyl)cyclohexyl bromide (2i) reacts readily with the silylated
alkynylzinc pivalate 1k, leading to the trans-1,4-cyclohexane
derivative 3n (71%, dr = 90:10, entry 7 in Table 3). Also, the
corresponding cyclohexyl iodide 2j undergoes such couplings
with alkynylzinc pivalates 1k and 1l, providing the products 3n
B
DOI: 10.1021/acs.orglett.8b00784
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and 3o in 73%−84% yields and a dr up to 94:6 (entries 8 and 9
in Table 3).
In addition, this cross-coupling was performed with 1,2-
substituted cyclic halides and bromo-glycosides (see Table
4).3f,4e TBS-protected iodo or bromohydrins 2k and 2l were
affords the desired substituted tetrahydrofuran 3s in 63% yield
(dr = 99:1, entry 5 in Table 4). Coupling of the iodopyrrolidine
derivative 2o with 1l affords the trans-1,2-disubstituted
heterocycle 3t in 75% yield and high diastereoselectivity (dr
= 99:1, entry 6 in Table 4). Remarkably, this diastereoselective
cross-coupling could also be performed using the bromo-
glycoside 2p. Thus, galactose derivative 2p was successfully
cross-coupled under cobalt catalysis with alkynylzinc pivalates
1k and 1l, furnishing the α-C-glycosides 3u and 3v in 52%−
54% yields and high α/β-selectivity (α/β = 94:6−95:5, entries 7
and 8 in Table 4). The stereochemical outcome of these cobalt-
catalyzed cross-couplings with bromo-glycosides could be
explained with the formation of an anomeric α-radical
intermediate.3e,f,4a,e,19 The reaction between the allyl-protected
iodohydrin 2q and the alkynylzinc pivalate 1k led to the bicyclic
product 3w in 68% yield (dr = 95:5; see Scheme 1).20 This
result confirms a radical pathway for this cross-coupling.
Table 4. Products (3) Obtained by the Diastereoselective
Cross-Coupling of 1,2-Disubstituted Cyclic (Hetero)alkyl
Halides (2) with Alkynylzinc Pivalates (1)
Scheme 1. Diastereoselective Cyclization of Iodide 2q with
Alkynylzinc Pivalate 1k
Finally, silylated alkynylzinc reagent 1k was coupled with
various steroid derivatives (Scheme 2). Using cholesteryl iodide
Scheme 2. Diastereoselective Cross-Coupling of Steroid
Derivatives 2r and 2s with Alkynylzinc Pivalate 1k
a
Isolated yield. The diastereoselectivity (dr) was determined by GC-
b
c
analysis. The major diastereomer is shown. dr = 99:1. 5 mmol scale.
(2r) led to the alkynylated steroid 3x in 75% yield (dr =
98:2).21 Remarkably, the use of an iodo epiandrosterone
derivative containing a ketone moiety also proceeded smoothly
in 84% yield (dr = 92:2).
In conclusion, we have shown that a cobalt-catalyzed cross-
coupling reactions of 1,2- 1,3-, and 1,4-substituted 5- and 6-
membered cyclic (hetero)alkyl halides with alkynylzinc
pivalates proceed with high and predictable diastereoselectivity.
Also, alkynyl-substituted glycosides were prepared with
excellent α-selectivity. Further mechanistic studies and
applications to more functionalized ring systems and hetero-
cycles are currently underway in our laboratories.
successfully coupled with alkynylzinc pivalate 1b, leading to the
thermodynamically preferred trans-substituted product 3p in
60%−78% yield (dr = 99:1, entry 1 in Table 4).18 Similarly,
iodohydrin 2k reacted with 1a to give the trans-1,2-
disubstituted cyclohexane derivative 3q in 72% yield (dr =
94:6, entry 3 in Table 4). Bicyclic bromide 2m was converted
to the alkynylated product 3r in 62% yield (dr = 99:1, entry 4 in
Table 4). This cobalt-catalyzed cross-coupling was further
extended to five-membered heterocyclic halohydrins 2n and 2o
(entries 5 and 6 in Table 4). The coupling of the TBS-
protected cyclic iodohydrin 2n with alkynylzinc pivalate 1n
C
DOI: 10.1021/acs.orglett.8b00784
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(h) Hammann, J.; Haas, D.; Tullmann, C.-P.; Karaghiosoff, K.;
Knochel, P. Org. Lett. 2016, 18, 4778.
̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00784.
■
S
(5) (a) Hatakeyama, T.; Okada, Y.; Yoshimoto, Y.; Nakamura, M.
Angew. Chem., Int. Ed. 2011, 50, 10973−10976. (b) Cheung, C.; Ren,
P.; Hu, X. Org. Lett. 2014, 16, 2566. (c) Vechorkin, O.; Godinat, A.;
Scopelliti, R.; Hu, X. Angew. Chem., Int. Ed. 2011, 50, 11777.
(6) Haas, D.; Hammann, J. M.; Greiner, R.; Knochel, P. ACS Catal.
2016, 6, 1540.
(7) (a) Bernhardt, S.; Manolikakes, G.; Kunz, T.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 9205. (b) Manolikakes, S.; Ellwart, M.;
Stathakis, C.; Knochel, P. Chem.Eur. J. 2014, 20, 12289. (c) Chen,
Y.-H.; Ellwart, M.; Malakhov, V.; Knochel, P. Synthesis 2017, 49, 3215.
(8) Hammann, J. M.; Lutter, F. H.; Haas, D.; Knochel, P. Angew.
Chem., Int. Ed. 2017, 56, 1082.
Full experimental details and H NMR and 13C NMR
spectra (PDF)
1
Accession Codes
CCDC 1826096 and 1826097 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
(9) Chen, Y.; Tullmann, C.; Ellwart, M.; Knochel, P. Angew. Chem.,
̈
Int. Ed. 2017, 56, 9236.
(10) Hammann, J. M.; Thomas, L.; Chen, Y.-H.; Haas, D.; Knochel,
P. Org. Lett. 2017, 19, 3847.
́
(11) (a) Gong, H.; Gagne, M. R. J. Am. Chem. Soc. 2008, 130, 12177.
AUTHOR INFORMATION
(b) Caeiro, J.; Perez-Sestelo, J.; Sarandeses, L. Chem.Eur. J. 2008,
14, 741. (c) Xu, G.; Li, X.; Sun, H. J. Organomet. Chem. 2011, 696,
3011.
■
Corresponding Author
*E-mail: Paul.Knochel@cup.uni-muenchen.de.
ORCID
(12) Cahiez, G.; Duplais, C.; Buendia, J. Angew. Chem. 2009, 121,
6859.
(13) Thapa, S.; Shrestha, B.; Gurung, S. K.; Giri, R. Org. Biomol.
Chem. 2015, 13, 4816.
(14) See the Supporting Information for more details.
(15) The stereochemistry of 3a and 3b was confirmed by literature
NMR data. See: Thaler, T.; Guo, L.; Mayer, P.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 2174.
(16) Mu, X.; Shibata, Y.; Makida, Y.; Fu, G. C. Angew. Chem., Int. Ed.
2017, 56, 5821.
(17) The stereochemistry of the product 3o was determined by
crystal structure analysis.
(18) The stereochemistry of 3p was confirmed by literature NMR
Paul Knochel: 0000-0001-7913-4332
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the DFG (SFB 749) for financial support. We also
thank Albemarle (Hoechst, Germany) for the generous gift of
chemicals.
data. Hammann, J.; Haas, D.; Tullmann, C.-P.; Karaghiosoff, K.;
Knochel, P. Org. Lett. 2016, 18, 4778.
(19) (a) Adlington, R. M.; Baldwin, J. E.; Basak, A.; Kozyrod, R. P. J.
Chem. Soc., Chem. Commun. 1983, 944. (b) Dupuis, B.; Giese, D.;
̈
REFERENCES
■
(1) (a) Chemler, S. R.; Trauner, D.; Danishefsky, J. Angew. Chem., Int.
Ed. 2001, 40, 4544. (b) Powell, D.; Maki, T.; Fu, G. C. J. Am. Chem.
Soc. 2005, 127, 510. (c) Rudolph, A.; Lautens, M. Angew. Chem., Int.
Ed. 2009, 48, 2656. (d) Cherney, A. H.; Kadunce, N. T.; Reisman, S.
E. Chem. Rev. 2015, 115, 9587.
Ruegge, D.; Fischer, H.; Korth, H. G.; Sustmann, R. Angew. Chem., Int.
̈
Ed. Engl. 1984, 23, 896. (c) Abe, H.; Shuto, S.; Matsuda, A. J. Am.
Chem. Soc. 2001, 123, 11870. (d) Li, G.; Xiong, D. C.; Ye, X. S. Synlett
2011, 2011, 2410. (e) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J.
Am. Chem. Soc. 2001, 123, 5374. (f) Tsuji, T.; Yorimitsu, H.; Oshima,
K. Angew. Chem., Int. Ed. 2002, 41, 4137.
(2) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442. (b) Thaler, T.; Haag, B.; Gavryushin, A.; Schober,
K.; Hartmann, E.; Gschwind, R.; Zipse, H.; Mayer, P.; Knochel, P. Nat.
Chem. 2010, 2, 125. (c) Thaler, T.; Guo, L.; Mayer, P.; Knochel, P.
Angew. Chem., Int. Ed. 2011, 50, 2174. (d) Seel, S.; Thaler, T.; Takatsu,
K.; Zhang, C.; Zipse, H.; Straub, B.; Mayer, P.; Knochel, P. J. Am.
Chem. Soc. 2011, 133, 4774. (e) Knappke, C. E. I.; von Wangelin, A. J.
Chem. Soc. Rev. 2011, 40, 4948. (f) Li, L.; Wang, C.-Y.; Huang, R.;
Biscoe, M. Nat. Chem. 2013, 5, 607−612.
(20) The stereochemistry of 3w was determined by NOESY-NMR
spectroscopy.
(21) The stereochemistry of 3x was determined by crystal structure
analysis.
(3) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
104, 6217. (b) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41,
̈
1500. (c) Bauer, I.; Knolker, H.-J. Chem. Rev. 2015, 115, 3170. For
̈
diastereoselective reactions, see: (d) Nakamura, M.; Matsuo, K.; Ito,
S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. (e) Steib, A.;
Thaler, T.; Komeyama, K.; Mayer, P.; Knochel, P. Angew. Chem., Int.
Ed. 2011, 50, 3303. (f) Adak, L.; Kawamura, S.; Toma, G.; Takenaka,
T.; Isozaki, K.; Takaya, H.; Orita, A.; Li, H.; Shing, T.; Nakamura, M. J.
Am. Chem. Soc. 2017, 139, 10693.
(4) (a) Cahiez, C.; Moyeux, A. Chem. Rev. 2010, 110, 1435.
(b) Hammann, J. M.; Hofmayer, M. S.; Lutter, F. H.; Thomas, L.;
Knochel, P. Synthesis 2017, 49, 3887. For stereoselective reactions,
see: (c) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2006, 128, 1886. (d) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett.
2006, 8, 3093. (e) Nicolas, L.; Angibaud, P.; Stansfield, I.; Bonnet, P.;
Meerpoel, L.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed. 2012, 51,
11101. (f) Nicolas, L.; Izquierdo, E.; Angibaud, P.; Stansfield, I.;
Meerpoel, L.; Reymond, S.; Cossy, J. J. Org. Chem. 2013, 78, 11807.
(g) Hammann, J. M.; Steib, A.; Knochel, P. Org. Lett. 2014, 16, 6500.
D
DOI: 10.1021/acs.orglett.8b00784
Org. Lett. XXXX, XXX, XXX−XXX