Ni-catalyzed stereoselective arylation of inert C-O bonds at low temperatures

Article abstract of DOI:10.1021/ol4031815

A Ni-catalyzed arylation of inert C-O bonds that operates at temperatures as low as -40 C is described. Unlike other methods for C-O bond cleavage utilizing organometallic species, this protocol operates at low temperatures, thus allowing the presence of sensitive functional groups with exquisite site-selectivity and stereoselectivity.

Full text of DOI:10.1021/ol4031815

ORGANIC
LETTERS
2013
Vol. 15, No. 24
6298–6301
Ni-Catalyzed Stereoselective Arylation of
Inert CꢀO bonds at Low Temperatures
Josep Cornella† and Ruben Martin*,†,‡
Institute of Chemical Research of Catalonia (ICIQ), Av Paısos Catalans 16,
¨
43007 Tarragona, Spain, and Catalan Institution for Research and Advanced Studies
(ICREA), Passeig Lluıs Companys, 23, 08010 Barcelona, Spain
¨
rmartinromo@iciq.es
Received November 4, 2013
ABSTRACT
A Ni-catalyzed arylation of inert CꢀO bonds that operates at temperatures as low as ꢀ40 °C is described. Unlike other methods for CꢀO bond
cleavage utilizing organometallic species, this protocol operates at low temperatures, thus allowing the presence of sensitive functional groups
with exquisite site-selectivity and stereoselectivity.
Metal-catalyzed cross-coupling reactions rank among
the most widely employed synthetic methodologies for
CꢀC bond-forming processes.1 While organic halides are
typically employed as coupling partners, the readily avail-
ability of phenol and its low toxicity as compared to the
arylhalidesmakeCꢀO electrophilesparticularly attractive
counterparts for cross-coupling reactions.2 Although
formidable advances have recently been described in
the literature employing activated CꢀOTs, CꢀOMs, or
CꢀOPiv derivatives, the coupling of rather inert CꢀO
(alkyl) bonds still constitutes a considerable synthetic
challenge in modern cross-coupling methodologies.3 Not
surprisingly, a rather limited number of protocols invol-
ving the cleavage of CꢀO(alkyl) bonds have been reported
to date, most requiring high temperatures.3,4 Although the
high activation energy for CꢀO cleavage can be overcome
by using Grignard reagents,3e‑i their low tolerance toward
functional groups prompted chemists to use organozinc5
or organoboron reagents.6 Still, the use of these organo-
metallicspecies isnotideal from a step-economical point of
view due to their high cost and low availability; indeed,
† Institute of Chemical Research of Catalonia.
‡ Catalan Institution for Research and Avanced Studies.
(1) In Metal-catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998.
Scheme 1. Low-Temperature CꢀO(Alkyl) Bond Cleavage
(2) (a) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013,
19. (b) Correa, A.; Cornella, J.; Martin, R. Angew. Chem., Int. Ed. 2013,
52, 1878. (c) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346.
(d) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486.
(3) For selected Ni-catalyzed C(sp2)ꢀO(alkyl) activation methodo-
logies, see: (a) Cornella, J.; Gomez-Bengoa, E.; Martin, R. J. Am. Chem.
Soc. 2013, 135, 1997. (b) Alvarez-Bercedo, P.; Martin, R. J. Am. Chem.
Soc. 2010, 132, 17352. (c) Tobisu, M.; Yamakawa, K.; Shimasaki, T.;
Chatani, N. Chem. Commun. 2011, 47, 2946. (d) Sergeev, A. G.; Hartwig,
J. F. Science 2011, 332, 439. (e) Guan, B.-T.; Xiang, S.-K.; Wang, B.-Q.;
Sun, Z.-P.; Wang, Y.; Zhao, K.-Q.; Shi, Z.-J. J. Am. Chem. Soc. 2008,
130, 3268. (h) Dankwart, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428. (i)
Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org. Chem.
1984, 49, 4894. (j) Wenkert, E.; Ferreira, T. W. Organometallics 1982, 1,
1670. (k) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem.
Soc. 1979, 101, 2246.
(4) For Ru-catalyzed C(sp2)ꢀO(alkyl) activation methodologies, see:
(a) Ueno, S.; Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem.
Soc. 2006, 128, 16516. (b) Kakiuchi, F.; Usui, M.; Ueno, S.; Chatani, N.;
Murai, S. J. Am. Chem. Soc. 2004, 126, 2706.
(5) Wang, C.; Ozaki, T.; Takita, R.; Uchiyama, M. Chem.;Eur. J.
2012, 18, 3482.
(6) (a) Shimasaki, T.; Konno, Y.; Tobisu, M.; Chatani, N. Org. Lett.
2009, 11, 4890. (b) Tobisu, M.; Shimasaki, T.; Chatani, N. Angew.
Chem., Int. Ed. 2008, 47, 4866.
r
10.1021/ol4031815
Published on Web 11/19/2013
2013 American Chemical Society

organozinc and organoboron derivatives are typically pre-
pared from Grignard reagents via a transmetalation event.7
We hypothesized that a low-temperature Ni-catalyzed
C(sp2)ꢀO(alkyl) cleavage would allow the use of Grignard
reagents in a chemoselective fashion, thus achieving an
elusive goal in the CꢀO bond-cleavage arena.8 Herein, we
describe a method that not only meets this challenge, but
also provides a new route to homoallylic alcohols with
high Z-selectivity (Scheme 1). Importantly, the targeted
C(sp2)ꢀO(alkyl) bond cleavage can be performed, for the
first time, in the presence of commonly more reactive CꢀO
electrophiles such as aryl tosylates or aryl pivalates,2 thus
becoming a powerful strategy for our ever-growing syn-
thetic repertoire.
Table 1. Stereoselective Arylation of 1aa
Figure 1. Scope of the Grignard reagent. Reaction conditions as
for Table 1, entry 8 (no E-isomer was detected in the crude
reaction mixtures); Yields are of isolated pure material (average
of at least two runs). (a) reaction conducted at ꢀ40 °C; (b)
Grignard reagent prepared according to Knochel’s procedure;
see ref 12; (c) using 4-[bis(trimethylsilyl)amino]phenylmagnesium
bromide; (d) Z:E ratio 20:1.
addition of LiCl allowed for the reaction to operate at
ꢀ30 °C, affording 3a in quantitative yields (entry 8).10 To
the best of our knowledge, this is the lowest temperature
achieved for an unactivated CꢀO(alkyl) bond-cleavage
event reported to date. It is noteworthy that, under the
limits of detection, only the Z-isomer was detected by 1H
NMR spectroscopy of the crude material. These results are
in sharp contrast with the ability of other organometallic
species to deliver E-configured isomers using related cou-
pling approaches.11
With these conditions in hand, we set out to explore the
generality of our protocol by using differently substituted
Grignard reagents (Figure 1). As depicted, high yields were
obtained when using either electron-rich or electron-
deficient Grignard reagents. The use of LiCl as additive
suggested that Knochel-type Grignards could be employed
under our protocol;12 as shown for 3d and 3e, this was
a 1a (0.50 mmol), 2a (1.00 mmol), Ni(COD)2 (10 mol%), L (10mol%),
additive (x %), THF (2 mL). b GC yield using dodecane as internal
standard; in all cases, 3a was obtained with >95:5 (Z:E) selectivity.
c Isolated yield. d Ni(COD)2 (5 mol %). e NiCl2(glyme) was utilized.
We started our investigation with 1a as the model sub-
strate and using phenylmagnesium bromide (2a) as the
coupling partner (Table 1). We anticipated that a particu-
larly electron-rich ligand would be critical for activating
the rather inert CꢀO(alkyl) bond. Toward this end, we
turned our attention to easily tuned N-heterocyclic car-
benes (NHC) since these ligandsare strongσ-donors with a
remarkable solubility and stability (entries 1ꢀ6).9 Among
all ligands examined, L5 provided the best results at 0 °C
(entry 5). While the use of other Ni sources or additives
had a deleterious effect on reactivity (entries 7ꢀ13), the
(10) LiCl might break the polymeric aggregates of the Grignard
reagent, producing more reactive monomeric ArMgBr LiCl species.
3
See: (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Buttrees, N. H.; Eaborn, C.; EꢀKhely, M. N. A.; Hitchcock,
P. B.; Smith, J. D.; Tavakkoli, K. J. Chem. Soc., Dalton Trans. 1988, 381.
(11) See, for example: (a) Le Menez, P.; Brion, J.-D.; Lensen, N.;
Evelyne, C.; Pancrazi, A.; Ardisson, J. Synthesis 2003, 2530. (b) Le
Menez, P.; Fargeas, V.; Poisson, J.; Ardisson, J.; Lallemand, J.ꢀJ.;
Pancrazi, A. Tetrahedron Lett. 1994, 35, 7767. (c) Fujisawa, T.; Kurita,
Y.; Kawashima, M.; Sato, T. Chem. Lett. 1982, 1641.
(7) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(8) For a low temperature KumadaꢀCorriu reaction employing aryl
iodides or bromides as substrates, see: (a) Joshi-Pangu, A.; Wang, C.-Y.;
Biscoe, M. R. J. Am. Chem. Soc. 2011, 133, 8478. (b) Martin, R.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844.
(12) (a) Piller, F, M.; Metzger, A.; Schade, M. A.; Haag, B. A.;
Gavryushin, A.; Knochel, P. Chem.ꢀEur. J. 2009, 15, 7192. (b) Piller, F.;
Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel, P. Angew.
Chem., Int. Ed. 2008, 47, 6802.
€
(9) For recent reviews, see: (a) Droge, T.; Glorius, F. Angew. Chem.,
Int. Ed. 2010, 49, 6940. (b) Kantchev, E. A. B.; O’Brien, C. J.; Organ,
M. G. Angew. Chem., Int. Ed. 2007, 46, 2768.
Org. Lett., Vol. 15, No. 24, 2013
6299

corresponding Z-configured homoallylic alcohol. As for
Figure1, the high reaction rates translatedintoanexcellent
chemoselectivity profile including functional groups that
are susceptible to nucleophilic attack by Grignard reagents
(1p). As shown for 1r, the reaction was not limited to
aromatic-substituted 2,3-dihydrofurans. Interestingly, our
methodology could also be extended to 3,4-dihydro-2H-
pyran derivatives (1t); although in this case the reaction
required a slightly higher temperature, the Z-isomer was
exclusively formed as well. Strikingly, the E-isomer was
only obtained when benzo[d]furan was utilized at 80 °C
(3s). Such structure was unambiguously characterized by
X-ray crystallography. In line with these observations, we
anticipated that the E-selectivity might be a thermal- and
catalyst-dependent event. We confirmed this hypothesis
upon raising the temperature of a crude reaction of 1a with
2a at ꢀ30 °C to þ40 °C, exclusively obtaining 3a-E.17,18
We believe this result illustrates the simplicity, robustness,
and synthetic potential of our protocol for controlling the
diastereoselectivity of the double-bond geometry.
Figure 2. Scope of the dihydrofuran backbone. Reaction conditions
as for Table 1, entry 8 (no E-isomer was detected in the crude
reaction mixtures); Yields are of isolated pure material (average of at
least two runs). (a) 80 °C; no Z isomer was detected; (b) 0 °C.
indeed the case, and we obtained high yields and stereo-
selectivities of the corresponding coupling products. Inter-
estingly, the presence of aryl methyl ethers (3h and 3l) as
well as aryl halides (3d, 3f, and 3m) was perfectly tolerated.
These results illustrate the selectivity of our protocol in
the presence of groups that have shown to be reactive
under other related Ni-catalyzed arylation events at
higher temperatures.3,13 In line with the same notion, while
thiophene motifs have shown to rapidly undergo CꢀS
bond-cleavage with Ni catalysts,14 we found that 3k was
exclusively obtained atꢀ30 °C, albeit in lower yields.15 It is
noteworthy that the reaction can even be conducted at
temperatures as low as ꢀ40 °C (3h). Substrates containing
labile OTHP ethers (3g) and amino groups (3c) were also
perfectly accommodated. As shown for 3l and 3m, the
presence of ortho substituents on the Grignard reagent did
not have a negative impact on reactivity. Importantly, we
could extend the scope of our reaction to alkyl Grignard
reagents as well (3n). As judged by 1H NMR spectroscopy
of the crude reaction mixtures for all compounds in
Figure 1, a complete control of the diastereoselectivity
was observed in favor of the less stable Z-isomer. X-ray
diffraction analysis of 3h confirmed our initial assignment
of the double bond geometry.
Scheme 2. Mechanistic Hypothesis
Next, we decided to conduct preliminary mechanistic
experiments to shed light on the striking high reactivity at
low temperatures. Thus, we monitored by 1H NMR spectro-
scopy a reaction of 1a with stoichiometric Ni(COD)2, SIPr,
and LiCl in THF-d8 at ꢀ30 °C.17 Interestingly, no oxidative
addition of the initially formed Ni(0)/L5 species into the
CꢀO bond was observed, even after prolonged reaction
times. In sharp contrast, the addition of 2a to this mixture
allowed for the rapid formation of 3a. This result leaves a
reasonable doubt that the reaction is initiated by “classical”
oxidative addition and advocates the notion that a different
mechanism comes into play.19 In light of these observations,
we propose a mechanism based upon a Lewis acid aided
oxidative addition (Scheme 2).20 Additional support for such
We next turned our attention to study the scope on the
2,3-dihydrofuran backbone.16 As depicted in Figure 2,
a wide variety of substitution patterns could all be
accommodated, invariably affording high yields of the
(17) See the Supporting Information for details
(18) Upon exposure of analytically pure Z-configured 3a to catalytic
amounts of Ni(COD)2/L5 at 50 °C in the absence of 2a, we found that
3a-E was obtained in >98:2 selectivity after 8 h reaction time. Interest-
ingly, no apparent Z/E isomerization was observed when 3a was
simply treated with 2a at 40 °C. Such experiments likely suggest the
intermediacy of nickel π-allyl complexes that are responsible for the
stereoselectivity switch at 40 °C.
(13) For reviews on CꢀF activation, see: (a) Torrens, H. Coord.
Chem. Rev. 2005, 249, 1957. (b) Jones, W. D. Dalton Trans. 2003, 3991.
(c) Mazurek, U.; Schwarz, H. Chem. Commun. 2003, 1321. (d) Murphy,
E. F.; Murugavel, R.; Roesky, H. W. Chem. Rev. 1997, 97, 3425.
(14) For selected examples, see: (a) Hintermann, L.; Schmitz, M.;
Chen, Y. Adv. Synth. Catal. 2010, 352, 2411. (b) Kanemura, S.; Kondoh,
A.; Yorimitsu, H.; Oshima, K. Synthesis 2008, 2659. (c) Torres-Nieto, J.;
(19) For a mechanistic study that rules out a “classical” oxidative
addition of Ni(0) into CꢀO(alkyl) bonds, see ref 3a.
Arevalo, A.; Garcıa, J. J. Organometallics 2007, 26, 2228. (d) Shimada,
´
T.; Cho, Y.-H.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 13396.
(15) No arylation via CꢀS bond-cleavage was observed by NMR
spectroscopy of the crude reaction mixture
(16) Substituted 2,3-dihydrofurans are either commercially available
or easily obtained in one step from dihydrofuran. See ref 17.
(20) Selected examples: (a) Hirata, Y.; Yada, A.; Morita, E.; Nakao,
Y.; Hiyama, T.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2010, 132,
10070. (b) Nakao, Y.; Yada, A.; Hiyama, T. J. Am. Chem. Soc. 2010,
132, 10024. (c) Matsubara, R.; Jamison, T. F. J. Am. Chem. Soc. 2010,
132, 6880. (d) Ghosh, I.; Jacobi, P. A. J. Org. Chem. 2002, 67, 9304.
6300
Org. Lett., Vol. 15, No. 24, 2013

suggesting that an orthogonal reactivity with commonly
more reactive electrophilic counterparts could be possible.
Gratifyingly, we found that the coupling of substrates
containing pivaloyl or tosylate motifs resulted in the clean
formation of Z-configured 3u and 3v in high yields
(Scheme 3). To the best of our knowledge, this is the first
time that a Ni-catalyzed methodology favors the coupling
of inert CꢀO(alkyl) bonds in the presence of a priori more
reactive CꢀOPiv and CꢀOTs bonds.
Scheme 3. Selectivity Issues with Other CꢀO Electrophiles
In summary, we have developed a Ni-catalyzed direct
CꢀO arylation of 2,3-dihydrofurans and Grignard re-
agents at temperatures as low as ꢀ40 °C. The high reaction
rates are translated into an excellent chemoselectivity
profile, allowing for the preparation of Z-configured
homoallylic alcohols. Preliminary mechanistic studies sug-
gest a Lewis acid-aided oxidative addition, an issue that
can be turned into a strategic advantage in the presence of
more reactive electrophilic counterparts. Further mechan-
istic studies and the extension to other substrates are
currently underway in our laboratories.
scenario comes from the observation that PhMgCl failed to
provide 3a, indicating that the nature of the counterion on
the Grignard reagent plays a critical role. At present, we
believe the reaction is initiated by coordination of the Lewis
basic oxygen donor to the Mg center,21 thus forming I and
significantly weakening the CꢀO bond. Subsequently, the
electron-rich Ni(0) center would be capable of promoting an
oxidative addition (II) followed by a fast transmetalation
and reductive elimination with concomitant regeneration of
the active Ni(0) catalyst. At present, we can not rule out an
alternate pathway consisting of the intermediacy Ni(0)-ate
complexes formed by reacting Ni(COD)2/L5 with 2a.22,23
Although premature, we anticipate that other related CꢀO
bond-cleavage reactions might follow a similar mechanistic
scenario.24
Acknowledgment. We thank the ICIQ Foundation, the
European Research Council (ERC-277883), and MI-
CINN (CTQ2012-34054) for financial support. Johnson
Matthey, Umicore, and Nippon Chemical Industrial are
acknowledged for gifts of metal and ligand sources. R.M
and J.C sincerely thank MICINN for a RyC and the
European Union for a Marie Curie fellowship (FP7-PEO-
Our mechanistic data indicated that a Lewis basic oxy-
gen donor was required for the CꢀO bond cleavage,
(21) Hill, C. M.; Walker, R. A.; Hill, M. E. J. Am. Chem. Soc. 1951,
73, 1663.
(22) For Niꢀate complexes in cross-coupling events, see: (a) Yu, D.-G.;
Li, B.-J.; Zheng, S.-F.; Guan, B.-T.; Wang, B.-Q.; Shi, Z.-J. Angew. Chem.,
Int. Ed. 2010, 49, 4566. (b) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.;
PLE-2012-IEF-328381). We thank Marta Martınez and
´
Eduardo Escudero-Adan for X-ray crystallographic ana-
lysis. We also thank Kerman Gomez and Israel Macho for
insightful NMR discussions.
ꢀ
Nakamura, M. J. Am. Chem. Soc. 2009, 131, 11949. (c) Campora, J.; Reyes,
M. L.; Hackl, T.; Monge, A.; Ruiz, C. Organometallics 2000, 19, 2950. (d)
Poerschke, K. R.; Klaus, J.; Wilke, G.; Benn, R.; Mynott, R.; Goddard, R.;
Krueger, C. Chem. Ber. 1985, 118, 275.
(23) For other cross-coupling reactions involving ate complexes, see:
€
(a) Furstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.;
€
Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773. (b) Furstner, A.;
Majima, K.; Martin, R.; Krause, H.; Kattnig, E.; Goddard, R.; Lehmann,
Supporting Information Available. Experimental pro-
cedures, spectral data, and crystallographic data (CIF)
for compounds 3h and 3s. This material is available free of
charge via the Internet at http://pubs.acs.org.
€
C. W. J. Am. Chem. Soc. 2008, 130, 1992. (c) Furstner, A.; Martin, R.;
€
Majima, K. J. Am. Chem. Soc. 2005, 127, 12236. (d) Martin, R.; Furstner,
A. Angew. Chem., Int. Ed. 2004, 43, 3955. (e) Amatore, C.; Jutand, A. Acc.
Chem. Rev. 2000, 33, 314.
(24) We found no reaction using 2-methoxynaphthalene, 2-(meth-
oxymethyl)naphthalene, or butyl vinyl ether as substrate.
The authors declare no competing financial interest.
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