Traceless directing group for stereospecific nickel-catalyzed alkyl-alkyl cross-coupling reactions

Article abstract of DOI:10.1021/ol300891k

Stereospecific nickel-catalyzed cross-coupling reactions of benzylic 2-methoxyethyl ethers are reported for the preparation of enantioenriched 1,1-diarylethanes. The 2-methoxyethyl ether serves as a traceless directing group that accelerates cross-coupling. Chelation of magnesium ions is proposed to activate the benzylic C-O bond for oxidative addition.

Full text of DOI:10.1021/ol300891k

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4293–4296
Traceless Directing Group for
Stereospecific Nickel-Catalyzed
AlkylÀAlkyl Cross-Coupling Reactions
Margaret A. Greene, Ivelina M. Yonova, Florence J. Williams, and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697-2025,
United States
erjarvo@uci.edu
Received April 6, 2012
ABSTRACT
Stereospecific nickel-catalyzed cross-coupling reactions of benzylic 2-methoxyethyl ethers are reported for the preparation of enantioenriched
1,1-diarylethanes. The 2-methoxyethyl ether serves as a traceless directing group that accelerates cross-coupling. Chelation of magnesium ions
is proposed to activate the benzylic CÀO bond for oxidative addition.
Nickel-catalyzed alkylÀalkyl cross-coupling reactions
are emerging as powerful new methods for the construc-
tion of tertiary stereogenic centers.1 Our laboratory has
reported stereospecific cross-coupling reactions of enan-
tioenriched ethers as one approach to achieve such
transformations.2 The use of enantioenriched ethers in
cross-coupling reactions is limited, however, by the diffi-
culty of oxidative addition into sp3 CÀO bonds. In this
communicationwedescribeanew tracelessdirectinggroup
that accelerates oxidativeaddition reactions of less reactive
electrophiles and application of this method toward synth-
esis of 1,1-diarylethanes containing a range of functional
groups including N-heterocycles.
cross-coupling reactions, pendant ligands can increase the
rate of reductive elimination by coordination to the nickel
catalyst.3,4 Pendant ligands can also accelerate transmeta-
lation of nickel complexes after oxidative addition of CÀS
bonds by coordinating to the transmetalation partner.5,6
Our previously reported stereospecific cross-coupling re-
actions required an adjacent extended aromatic ring to
accelerate oxidative addition. Naphthylic ether 1 under-
goes facile cross-coupling, likely due to participation of the
extended aromatic ring, stabilizing the transition state for
oxidative addition (Scheme 1a). In contrast, benzylic ether
2 provides a low yield under our reported reaction condi-
tions (Table 1, entry 1).
The field of transition metal catalysis is rich with exam-
ples where rate acceleration is afforded by strategically
placed directing groups. In the context of nickel-catalyzed
(3) Devasagayaraj, A.; Studemann, T.; Knochel, P. Angew. Chem.,
Int. Ed. 1995, 34, 2723. (b) Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H.
Tetrahedron 1996, 54, 1117.
(4) Interaction between the nickel catalyst and functional groups on
the substrate are important during enantioselective nickel-catalyzed
cross-coupling of alkyl halides. For a lead reference, see: Zhe, L.; Wilsily,
A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154.
(5) (a) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. J. Am. Chem.
Soc. 1999, 121, 9449. (b) Ni, Z. J.; Mei, N. W.; Shi, X.; Tzeng, Y. L.;
Wang, M. C.; Luh, T. Y. J. Org. Chem. 1991, 56, 4035.
(1) For reviews of stereospecific and stereoselective nickel-catalyzed
alkylÀalkyl cross-coupling reactions, see: (a) Taylor, B. L. H.; Jarvo,
E. R. Synlett 2011, 19, 2761. (b) Jana, R.; Pathak, T. P.; Sigman, M. S.
Chem. Rev. 2011, 111, 1417. (c) Glorius, F. Angew. Chem., Int. Ed. 2008,
47, 8347.
(2) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am.
Chem. Soc. 2011, 133, 389.
(6) For substrate-directed reactions of cuprates, see: Hanessian, S.;
Thavonekham, B.; DeHoff, B. J. Org. Chem. 1989, 54, 5831.
r
10.1021/ol300891k
2012 American Chemical Society
Published on Web 05/08/2012

To increase the reactivity of nonextended aromatic
systems for cross-coupling, a new strategy was required.
We developed a traceless directing group that would
accelerate oxidative addition but not be present in the
reaction products, by incorporating the directing group on
the ether substituent (Scheme 1b). We envisioned that
ethers that contain pendant ligands would chelate the
magnesium salts present in the reaction mixture, thus
activating the CÀO bond for oxidative addition and
accelerating the rate of the desired cross-coupling reaction.
Unlike typical directed reactions where the directing func-
tional group is present in the reaction product, this strategy
allows for a wider substrate scope and precludes the
necessity for further modification of the product to remove
the directing group.7
promise, identification of new medicinal agents based on
the 1,1-diarylalkane framework is held back because gen-
eral methods for their enantioselective preparation do not
exist. These compounds are typically prepared and tested
for biological activity as racemic mixtures or are resolved
using classical resolution by crystallization of diastereo-
meric salts. While there have been creative approaches to
enantioselective syntheses of these compounds,9 control of
stereochemistry without directing groups that must later
be removed remains a challenge.
Scheme 1. Traceless Directing Group Used To Accelerate Oxi-
dative Addition
Figure 1. Bioactive diarylalkanes.
By starting with enantioenriched ethers and utilizing a
traceless directing group for substrate activation, we envi-
sioned a straightforward strategy for enantioselective
synthesis of 1,1-diarylethanes. This methodology does
not rely on steric bulk or electronic differentiation at the
stereocenter because stereochemistry is set before the
cross-coupling reaction, allowing diarylethanes with sub-
stitution far removed from the stereocenter to be synthe-
sized in high enantiopurity.
We examined cross-coupling reactions of diphenyl carbinol
derivatives to evaluate the influence of the ether substituent on
the cross-coupling (Table 1). 2-Methoxyethyl ether 5 reacts
more rapidly than methyl, MOM, or MEM ethers (cf. entries
1À4). These results are consistent with acceleration of oxida-
tive addition by formation of an optimal five-membered ring
chelate with magnesium salts (Scheme 1b).
Once we had identified a suitable directing group, we
optimized the reaction conditions to further improve the
yield of the desired product (Table 1). While other ligands
were examined, DPEphos generally provided the highest
yield (e.g., entries 4À6).10 The precatalyst, Ni(cod)2, could
be replaced with more stable Ni(acac)2 providing an im-
proved yield (entry 7). Extending the reaction time to 48 h
further improved the yield to 80% (entry 8).
As a test application to determine the feasibility of this
strategy, we targeted the enantiospecific synthesis of 1,1-
diarylethanes (Figure 1). 1,1-Diarylalkanes are active
against cancer, osteoporosis, smallpox, tuberculosis, and
insomnia.8 Furthermore, the diarylmethine pharmaco-
phore is present in natural products and drugs including
podophyllotoxin, peperomin B, kadangustin J, zoloft,
tolterodine, lasofoxifene, and centchroman. Despite their
(7) For a representative example of an alternative type of traceless
directing group, where a functional group is used first as a directing
group and second as a leaving group, see: Wang, C.; Rakshit, S.; Glorius,
F. J. Am. Chem. Soc. 2010, 132, 14006.
(8) (a) For a discussion, see: Kainuma, M.; Kasuga, J.-i.; Hosoda, S.;
Wakabayashi, K.-i.; Tanatani, A.; Nagasawa, K.; Miyachi, H.;
Makishima, M.; Hashimoto, Y. Bioorg. Med. Chem. Lett. 2006, 16,
3213. (b) Anti-lung cancer agent, see: Alami, M.; Messaoudi, S.; Hamze,
A.; Provot, O.; Brion, J.-D.; Liu, J.-M.; Bignon, J.; Bakala, J. Patent
WO/2009/147217 A1, Dec 10, 2009. (c) Anti-viral agent: Cheltsov, A. V.;
Aoyagi, M.; Aleshin, A.; Yu, E. C.-W.; Gilliland, T.; Zhai, D.; Bobkov,
A. A.; Reed, J. C.; Liddington, R. C.; Abagyan, R. J. Med. Chem. 2010,
53, 3899. (d) Anti-prostate cancer agent: Hu, Q. Z.; Yin, L. N.; Jagusch,
C.; Hille, U. E.; Hartmann, R. W. J. Med. Chem. 2010, 53, 5049. (e)
(9) For representative examples, see: (a) Hatanaka, Y.; Hiyama, T.
J. Am. Chem. Soc. 1990, 112, 7793. (a) Wang, X.; Guram, A.; Caille, S.;
Hu, J.; Preston, J. P.; Ronk, M.; Walker, S. Org. Lett. 2011, 13, 1881. (b)
Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J. Am.
Chem. Soc. 2009, 131, 5024. (c) Paquin, J.-F.; Defieber, C.; Stephenson,
C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850. (d) Nave,
S.; Sonawane, R. P.; Elford, T. G.; Aggarwal, V. K. J. Am. Chem. Soc.
2010, 132, 17096. (e) Lewis, C. A.; Chiu, A.; Kubryk, M.; Balsells, J.;
Pollard, D.; Esser, C. K.; Murry, J.; Reamer, R. A.; Hansen, K. B.;
Miller, S. J. J. Am. Chem. Soc. 2006, 128, 16454. (f) Bolshan, Y.; Chen,
C.-y.; Chilenski, J. R.; Gosselin, F.; Mathre, D. J.; O’Shea, P. D.; Roy,
A.; Tillyer, R. D. Org. Lett. 2004, 6, 111. (g) Podhajsky, S. M.; Iwai, Y.;
Cook-Sneathen, A.; Sigman, M. S. Tetrahedron 2011, 67, 4435.
(10) Alternative ligands, including Xantphos, rac-BINAP, dppb, and
dppf provided <5% product.
ꢀ
Messaoudi, S.; Hamze, A.; Provot, O.; Treguier, B.; De Losada, J. R.;
Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.;
Brion, J.-D.; Alami, M. Chem. Med. Chem. 2011, 6, 488. (f) Shagufta;
Srivastava, A. K.; Sharma, R.; Mishra, R.; Balapure, A. K.; Murthy,
P. S. R.; Panda, G. Bioorg. Med. Chem. 2006, 14, 1497. (g) Pathak, T. P.;
Gligorich, K. M.; Welm, B. E.; Sigman, M. S. J. Am. Chem. Soc. 2010,
132, 7870. (h) Moree, W. J.; Li, B. F.; Zamani-Kord, S.; Yu, J. H.; Coon,
T.; Huang, C.; Marinkovic, D.; Tucci, F. C.; Malany, S.; Bradbury,
M. J.; Hernandez, L. M.; Wen, J. Y.; Wang, H.; Hoare, S. R. J.; Petroski,
R. E.; Jalali, K.; Yang, C.; Sacaan, A.; Madan, A.; Crowe, P. D.; Beaton,
G. Bioorg. Med. Chem. Lett. 2010, 20, 5874.
4294
Org. Lett., Vol. 14, No. 16, 2012

Table 1. Identification of Traceless Directing Group
Table 2. Scope of Cross-Coupling Reaction
1
a Determined by H NMR spectroscopy by comparison to internal
standard (PhTMS). b Ni(cod)2 replaced with Ni(acac)2. c 48 h reaction
time.
a Isolated yield after silica gel chromatography. Yields in paren-
theses are determined by NMR spectroscopy relative to an internal
standard (PhTMS). b Determined by chiral SFC chromatography.
c 100 Â eeproduct/eestarting
.
d 5% Ni(cod)2, 10% DPEphos, 1.5 equiv
We designed a series of chiral substrates to test the
enantiospecificity (es) of the reaction (Table 2).11 Each
substrate was prepared by enantioselective arylation of an
aldehyde with the requisite boronic acid.12 The nickel-
catalyzed cross-coupling reaction is highly enantiospecific
across a range of substitution patterns. As expected,
cross-coupling proceeds with inversion at the stereogenic
center.13 For most substrates, the background reaction in
the absence of nickel catalyst does not occur.14
To highlight the synthetic advantages of our method,
our preliminary studies have focused on the synthesis of
1,1-diarylethanes where the arenes have similar steric
properties and are only differentiated by distal substituents
(e.g., products 6À10). This type of tertiary stereocenter is
very challenging to prepare using alternative methods.
Electron-donating and electron-withdrawing groups15 on
the aromatic rings are well-tolerated (entries 2 and 3). A
protected phenol (entry 4) and pendant alcohol (entry 5)
material
of MeMgI. Average of four experiments. e 24% dimer product observed.
f 15% Ni(acac)2, 30% DPEphos, 3 equiv of MeMgI. g Enantiomers of
product 12 were not separable by chiral SFC or GC.
are also competent substrates and provide functional
group handles for further chemical modification of the
products. Inclusion of a strong electron-donating p-OMe
group provides a moderate yield of desired product 8
despite competitive dimerization of the starting material.16
As anticipated, this method also provides access to com-
pounds containing arenes with similar electronic proper-
ties. For example, compound 12 contains m- and p-CF3
substituted arenes.
N-Heterocycles are another challenging class of com-
pounds that we envisioned could undergo cross-coupling
reactions using this traceless directing group strategy.
N-Heterocyclic motifs are often present in biologically
activecompounds17 and, therefore, represent an important
set of targets. These substrates had proven recalcitrant
under our original cross-coupling conditions: when sub-
strates such as quinoline 13, containing the simple methyl
ether, are subjected to our previously reported reaction
(11) For definition of the term enantiospecificity (es), see: (a)
Denmark, S. E.; Vogler, T. Chem.ÀEur. J. 2009, 15, 11737. (b)
Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010,
132, 1232.
(12) (a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850. (b)
~
Braga, A. L.; Paixao, M. W.; Westermann, B.; Schneider, P. H.;
Wessjohan, L. A. J. Org. Chem. 2008, 73, 2879. (c) Moro, A. V.; Tiekink,
(16) 24% dimer observed. See Supporting Information for more
information. The mechanism of formation of this dimer is under
investigation. Related palladium-catalyzed cross-coupling of 1,1-
diaryl-1-haloalkanes with aryl BF3K salts also results in dimerization
of starting material. See: Molander, G. A.; Elia, M. D. J. Org. Chem.
2006, 71, 9198.
(17) (a) Pathak, T. P.; Gligorich, K. M.; Welm, B. E.; Sigman, M. S.
J. Am. Chem. Soc. 2010, 132, 7870. (b) Moree, W. J.; Li, B.-F.; Jovic, F.;
Coon, T.; Yu, J.; Gross, R. S.; Tucci, F.; Marinkovic, D.; Zamani-Kord,
S.; Malany, S.; Bradbury, M. J.; Hernandez, L. M.; O’Brien, Z.; Wen, J.;
Wang, H.; Hoare, S. R. J.; Petroski, R. E.; Sacaan, A.; Madan, A.;
Crowe, P. D.; Beaton, G. J. Med. Chem. 2009, 52, 5307. (c) Little, P. J.;
Ryan, A. J. Biochem. Pharmacol. 1982, 31, 1795.
€
E. R. T.; Zukerman-Schpector, J.; Ludtke, D. S.; Correia, C. R. D.
Eur. J. Org. Chem. 2010, 3696.
(13) Comparison of optical rotations for synthesis of compound 8 to
literature values demonstrates that the reaction proceeds with inversion
at the stereogenic center. See Supporting Information for more detail.
(14) For all substrates in Table 2, reactions run without nickel
catalyst, in the presence and absence of phosphine ligand, provide
<5% product, except for entry 3 where 24% product 8 was observed.
(15) The yields of compounds 7 and 12 are high as measured by 1H
NMR spectroscopy; decreased isolated yields for these substrates are
due to the challenging separation from starting material by silica gel
column chromatography.
Org. Lett., Vol. 14, No. 16, 2012
4295

Table 3. Effect of Traceless Directing Group in Cross-Coupling
Reactions of N-Heterocyclic Compounds
Table 4. Reactivity of N-Heterocyclic Compounds
temp
starting
material (%)a
product
(%)a
entry
R
(°C)
1
-CH3, 13
22
5
<5
<5
<5
<5
<5
2
-CH3, 13
18
3
4c
-(CH2)2OCH3, 14
-(CH2)2OCH3, 14
5
50b
62b
5
1
a Determined by H NMR spectroscopy by comparison to internal
standard (PhTMS). b Isolated yield after silica gel chromatography.
c Slow addition of starting material.
conditions the rate of decomposition of starting material is
much faster than that of product formation (Table 3, entry
1). Decreasing the reaction temperature provides a slight
improvement in product distribution to afford quinoline
15 in 18% yield (entry 2). Employing the traceless directing
group substantially improves the transformation and
provides a 50% yield of the desired product (entry 3).
We hypothesize that the 2-methoxyethyl ether accelerates
oxidative addition, allowing the desired transformation
to out-compete decomposition. Further optimization of
the reaction conditions by slow addition of the starting
material further suppressed decomposition pathways and
afforded the desired product in 62% yield (entry 4).
A range of N-heterocyclic substrates react smoothly and
with high levels of enantiospecificity under the optimized
reaction conditions. Both 3- and 4-substituted quinolines
underwent cross-coupling (Table 4, entries 1 and 2). Sub-
stituted pyridines are also well-tolerated and provided
excellent yields (entries 3 and 4). Notably, substrates that
contain a naphthalene ring in addition to the heteroaro-
matic ring are sufficiently reactive that the simple methyl
ether 19 also provides desired product 18 in good yield.18
This result is consistent with participation of the naptha-
lene ring as shown in Scheme 1a.
a Isolated yield after silica gel chromatography. b Determined by
chiral SFC chromatography. c 100 Â eeproduct/eestarting
.
d 10%
material
Ni(cod)2, 20% dppf, 5 °C. e Enantiomers of product 16 were not
separable by chiral SFC or GC.
enantiospecificity, where the newly formed stereogenic cen-
ter is flanked by arenes with similar steric and electronic
properties. The use of the methoxyethyl ether as a directing
group also promotes reactions of substrates containing
sensitive N-heterocycles that did not provide the desired
cross-coupling under our previously reported reaction con-
ditions. Further expansion of the scope and elucidation of
the mechanistic details of this reaction is an ongoing project
in our group.
Acknowledgment. This work was supported by Univer-
sity of California, Cancer Research Coordinating Com-
mittee. We thank Frontier Scientific and Sigma-Aldrich
for gifts of boronic acids and catalysts, respectively.
Note Added after ASAP Publication. There were errors
in the version published ASAP May 8, 2012. Figure 1 was
corrected. Reference 8 was rearranged for clarity, and two
references to the work of Alami (8b and 8e) were added;
the correct version reposted May 15, 2012.
In conclusion, we report a new traceless directing group
that accelerates cross-coupling for unreactive oxidative addi-
tion partners. This strategy is demonstrated by developing
new methods for nickel-catalyzed sp3Àsp3 cross-coupling.
Enantioenriched 1,1-diarylethanes are formed with high
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(18) For more details, see the Supporting Information.
The authors declare no competing financial interest.
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