When employed subsequently to carbamate-directed arene
functionalization, this methodology provides an efficient
means to achieve the desired arene cine substitution process.
Our approach provides a new method for analogue synth-
esis, which augments the conventional logic for achieving
arene functionalization by ipso substitution.
We first explored the sequential ortho-functionalization/
reduction of methoxycarbamate 3 to give cine substituted
products 5 (Figure 2). Carbamate-directed lithiation of 3
proceeded smoothly, without competitive metallation ortho
to the methoxy substituent. This observation, which is
consistent with literature data,17 reflects the superior direct-
ing group ability of carbamates compared to ethers.
Quenching of the lithiated intermediate with various elec-
trophiles gave products 4aÀc.
Figure 1. Cine substitution of aryl O-carbamates.
Bearing in mind the unique ability of aryl carbamates7,8
to participate efficiently in directed metallation reactions,9
most commonly using organolithium chemistry pioneered
by Snieckus,10 we considered the net arene cine substitu-
tion process shown in Figure 1. Aryl carbamates 1 would
undergo ortho-functionalization, followed by reductive
aryl CÀO bond cleavage, to afford the net cine substituted
products 2. Although methods for aryl CÀO bond clea-
vage of aryl sulfonates are well-known,11 and recent
examples pertaining to phenol-derived esters12,13 and
ethers have been reported,12,14,15 no methodology exists
for the reductive removal of synthetically useful aryl carba-
mates. In fact, the cleavage of aryl carbamates through
CÀO bond reduction has only been observed as a minor
undesired reaction pathway in the attempted coupling of
aryl carbamates with alkyl Grignard reagents.16
Next, we developed conditions for the unexplored aryl
carbamate cleavage. We,18 and others,16,19 have shown
that the aryl CÀO bond of aryl carbamates may be
activated by specific Ni/ligand combinations to ultimately
construct CÀC or CÀN bonds.20 The Ni(II) precatalyst
NiCl2(PCy3)2,21 which was used in the SuzukiÀMiyaura
coupling of aryl carbamates, was considered ideal because
of its low cost and pronounced stability to air and water.22
Despite the fact that this complex has not been used in
reductive aryl CÀO bond cleavage reactions, we tested its
performance in the desired transformation using 4a as the
substrate, in conjunction with various reducing agents.
After considerable experimentation, it was found that
reductive cleavage occurred efficiently using cat. NiCl2-
(PCy3)2, 1,1,3,3-tetramethyldisiloxane (TMDSO),23 and
K3PO4 in toluene at 115 °C to afford meta substituted
arene 5a in 69% yield (Figure 2). Of note, the methoxy
substituent remainedintactdespite the removability of aryl
ethers under Ni-based reductive conditions.14 Removal
of the carbamate from ortho-substituted substrates
4b and 4c using our Ni-catalyzed conditions provided
We report the first method to achieve the reductive
cleavage of aryl O-carbamates, which utilizes an air-stable
Ni(II) precatalyst and an inexpensive silane reducing agent.
(9) For Pd-, Ir-, or Rh-based methods for carbamate-directed arene
functionalization, see: (a) Bedford, R. B.; Webster, R. L.; Mitchell, C. J.
Org. Biomol. Chem. 2009, 7, 4853–4857. (b) Zhao, X.; Yeung, C. S.;
Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837–5844. (c) Nishikata, T.;
Abela, A. R.; Huang, S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132,
4978–4979. (d) Yamazaki, K.; Kawamorita, S.; Ohmiya, H.; Sawamura,
M. Org. Lett. 2010, 12, 3978–3981. (e) Feng, C.; Loh, T.-P. Chem.
Commun. 2011, 47, 10458–10460. (f) Gong, T.-J.; Xiao, B.; Liu, Z.-J;
Wan, J.; Xu, J.; Luo, D.-F.; Fu, Y.; Liu, L. Org. Lett. 2011, 13, 3235–
3237.
(10) (a) Snieckus, V. Chem. Rev. 1990, 90, 879–933. (b) Hartung,
C. G.; Snieckus, V. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: New York, 2002; pp 330À367. (c) Macklin, T.; Snieckus, V. In
Handbook of CÀH Transformations; Dyker., G., Ed.; Wiley-VCH: New
York, 2005; pp 106À119. (d) Snieckus, V. Beilstein J. Org. Chem. 2011,
1215–1218.
(11) For selected methodology studies and an example in total
synthesis, see: (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1986, 27, 5541–5544. (b) Mori, A.; Mizusaki, T.;
Ikawa, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Chem.;Eur. J.
2007, 13, 1432–1441. (c) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran,
P. G. Angew. Chem., Int. Ed. 2003, 42, 4961–4966.
(12) Tobisu, M.; Yamakawa, K.; Shimasaki, T.; Chatani, N. Chem.
Commun. 2011, 47, 2946–2948.
(13) Aryl pivalate esters can be employed in Pd-catalyzed ortho
arylation reactions: Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.;
Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468–469. However,
o-lithiation/functionalization of phenol-derived esters is not possible
because of the Fries rearrangement.
(17) Kalinin, A. V.; Da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.;
Snieckus, V. Tetrahedron Lett. 1998, 39, 4995–4998.
(18) For Ni-catalyzed couplings of aryl carbamates, see: (a)
Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am. Chem.
Soc. 2009, 131, 17748–17749. (b) Quasdorf, K. W.; Antoft-Finch, A.;
Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren,
S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011,
133, 6352–6363. (c) Mesganaw, T.; Silberstein, A.; Ramgren, S. D.; Fine
Nathel, N. F.; Hong, X.; Liu, P.; Garg, N. K. Chem. Sci. 2011, 2, 1766–
1771. For the related Ni-catalyzed coupling of aryl pivalates, see: (d)
Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130,
14422–14423.
(19) (a) Dallaire, C.; Kolber, I.; Gingras, M. Org. Synth. 2002, 78, 42.
(b) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem. Soc.
2009, 131, 17750–17752. (c) Xu, L.; Li, B.-J.; Wu, Z.-H.; Lu, X.-Y.;
Guan, B.-T.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Org. Lett. 2010, 12,
884–887. (d) Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem.
2011, 76, 1507–1510.
(20) For a pertinent review, see: Rosen, B. M.; Quasdorf, K. W.;
Wilson, D. A.; Zhang, B.; Resmerita, A.-M.; Garg, N. K.; Percec, V.
Chem. Rev. 2011, 111, 1346–1416.
(21) NiCl2(PCy3)2 is commercially available from Strem Chemicals
Inc. or Sigma-Aldrich (CAS #19999-87-2). For more information on this
catalyst, see: Quasdorf, K. W.; Garg, N. K. Encyclopedia of Reagents for
Organic Synthesis 2010, DOI: 10.1002/047084289X.rn01201.
(22) Current methods for the reductive removal of aryl esters or
ethers utilize Ni(cod)2 as the precatalyst, which requires glovebox
handling; see refs 12 and 14.
(14) (a) Ivarez-Bercedo, P. A.; Martin, R. J. Am. Chem. Soc. 2010,
132, 17352–17353. (b) Sergeev, A. G.; Hartwig, J. F. Science 2011, 332,
439–443. (c) Kelley, P.; Lin, S.; Edouard, G.; Day, M. W.; Agapie, T.
J. Am. Chem. Soc. 2012, 134, 5480–5483.
(15) Aryl ethers are modest directing groups for ortho-metallation;
see ref 10 for a discussion.
(16) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus,
V. J. Org. Chem. 1992, 57, 4066–4068.
(23) TMDSO was also an effective reducing agent for the reductive
removal of aryl ethers reported by Martin et al. (see ref 14a).
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