Cine substitution of arenes using the aryl carbamate as a removable directing group

Article abstract of DOI:10.1021/ol301275u

An efficient and controlled means to achieve a rare cine substitution of arenes is reported. The methodology relies on the strategic use of aryl O-carbamates as readily removable directing groups for arene functionalization. The removal of aryl carbamates is achieved by employing an air-stable Ni(II) precatalyst, along with an inexpensive reducing agent, to give synthetically useful yields across a range of substrates. The net cine substitution process offers a new strategy for analogue synthesis, which complements the well-established logic for achieving arene functionalization by ipso substitution.

Full text of DOI:10.1021/ol301275u

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2918–2921
Cine Substitution of Arenes Using the
Aryl Carbamate as a Removable
Directing Group
Tehetena Mesganaw, Noah F. Fine Nathel, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles,
California 90095-1569, United States
neilgarg@chem.ucla.edu
Received May 8, 2012
ABSTRACT
An efficient and controlled means to achieve a rare cine substitution of arenes is reported. The methodology relies on the strategic use of aryl
O-carbamates as readily removable directing groups for arene functionalization. The removal of aryl carbamates is achieved by employing an air-
stable Ni(II) precatalyst, along with an inexpensive reducing agent, to give synthetically useful yields across a range of substrates. The net cine
substitution process offers a new strategy for analogue synthesis, which complements the well-established logic for achieving arene
functionalization by ipso substitution.
Arene substitution processes are some of the most
important and frequently used transformations in organic
synthesis.1 Whereas ipso substitution can be readily
achieved through numerous means, including metal-
catalyzed cross-coupling2 and nucleophilic aromatic
substitution,3 methods to achieve other patterns of arene
substitution are rare. For example, cine substitution of
aromatics,4 where a new substituent is introduced adjacent
to the position of the departing leaving group, has seen
little use beyond reactions of nitroaromatics5 and in reac-
tions that invoke aryne6 intermediates. A controlled and
selective method to achieve the net cine substitution of
arenes would provide a valuable means for arene functio-
nalization and a versatile new tool for analogue synthesis.
(1) (a) Olah, G., Ed. FriedelÀCrafts and Related Reactions; Inter-
science: New York, 1963; Vols. IÀIV. (b) Pearson, D. E.; Buehler, C. A.
Synthesis 1972, 533–542. (c) Effenberger, F. Angew. Chem., Int. Ed. Engl.
1980, 19, 151–171. (d) Franck, H. G.; Stadelhofer, J. W. Industrial
Aromatic Chemistry; Springer-Verlag: Berlin, New York, 1987. (e) Kobayashi,
M., Ed. Chemical Resources. New Developments in Organic Chem-
istry; Scientific Publishing Division of MY K. K.: Tokyo, Japan, 1988;
Chapters 1, 2, 5.
(5) Nitroarenes can be converted to aryl carboxylic acid derivatives
via the von Richter reaction; for a pertinent study, see: Bunnett, J. F. Q.
Rev. Chem. Soc. 1958, 12, 1–16.
(6) Arynes may give rise to products of net ipso or cine substitution.
For reviews of aryne chemistry, see: (a) Sanz, R. Org. Prep. Proced. Int.
~
ꢀ
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2008, 40, 215–291. (b) Pena, D.; Perez, D.; Guitian, E. Heterocycles
2007, 74, 89–100. (c) Dyke, A. M.; Hester, A. J.; Lloyd-Jones, G. C.
Synthesis 2006, 4093–4112. (d) Pellissier, H.; Santelli, M. Tetrahedron
2003, 59, 701–730. (e) Wenk, H. H.; Winkler, M.; Sander, W. Angew.
Chem., Int. Ed. 2003, 42, 502–528. For recent studies of regioselectivity
in additions to unsymmetrical arynes, see: (f) Cheong, P. H.-Y.; Paton,
R. S.; Bronner, S. M.; Im, G.-Y. J.; Garg, N. K.; Houk, K. N. J. Am.
Chem. Soc. 2010, 132, 1267–1269. (g) Im, G.-Y. J.; Bronner, S. M.;
Goetz, A. E.; Paton, R. S.; Cheong, P. H.-Y.; Houk, K. N.; Garg, N. K.
J. Am. Chem. Soc. 2010, 132, 17933–17944.
(2) For recent reviews of transition metal-catalyzed cross-couplings,
see: (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340–348. (b) Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
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Wiley-VCH: New York, 1998. (c) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1469. (d) Topics in
Current Chemistry, Vol. 219; Miyaura, N., Ed.; Springer-Verlag:
New York, 2002. (e) Corbet, J.; Mignani, G. Chem. Rev. 2006, 106,
2651–2710. (f) Negishi, E. Bull. Chem. Soc. Jpn. 2007, 80, 233–257.
(3) For reviews, see: (a) Terrier, F. Nucleophilic Aromatic Displace-
ment, The Influence of the Nitro Group; VCH Publishers Inc.: New York,
1991. (b) van der Plas, H. C.; Chupakhin, O. N.; Charushin, V. N. Nucleo-
philic Aromatic Substitution of Hydrogen; Academic Press: San Diego,
1994. (c) Makosza, M. Russ. Chem. Bull. 1996, 45, 491–504.
(7) A Reaxys search shows that over 500 examples of ortho-functio-
nalization of N,N-dialkyl carbamates have been reported on aryl or
heteroaryl substrates, using directed ortho-lithiation or transition-
metal-catalyzed CÀH functionalization methodologies.
(4) For a review of cine substitution, see: Suwinski, J.; Swierczek, K.
Tetrahedron 2001, 57, 1639–1662.
(8) Of the various phenol derivatives, the aryl carbamate possesses
superior ability in directed metallation reactions (see ref 10).
r
10.1021/ol301275u
Published on Web 05/21/2012
2012 American Chemical Society

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).
Org. Lett., Vol. 14, No. 11, 2012
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meta-substituted products 5b and 5c, respectively. Given
the rich precedent for the controlled ortho-functionaliza-
tion of aryl carbamates and the efficiency of the carbamate
removal methodology (vida infra), this cine substitution
process provides a useful tool for the conversion of para- to
meta-substituted arenes.
Figure 4 highlights the ability to employ carbamates in
either ipso or cine substitution reactions, in a highly
controlled manner, using transition metal-catalyzed reac-
tions. Using Ni-catalysis, direct coupling of carbamate 6
affords products 14 or 15, via CÀN18c or CÀC18a,b bond
formation, respectively. Alternatively, borylation of 6 with
cine substitution provides boronic ester 13. Boronate 13
could be elaborated to either amine 16 or arylated pro-
duct 17, via ChanÀLam26 or SuzukiÀMiyaura coupling,
Figure 2. Cine substitution of para-methoxycarbamate 3 to give
meta-substituted products 5aÀc.
The cine substitution sequence was also tested on 5-hy-
droxyindole derivative 6 (Figure 3). Lithiation of 6 pro-
ceeded selectively at C4; subsequent functionalization of
the resulting organolithium species gave ortho-substituted
carbamate products 7À9. Amide 7 was obtained through a
Fries rearrangement/carbamoylation sequence, whereas
products 8 and 9 came from direct quenching of the
intermediate lithiated species with MeI or TMSCl, respec-
tively. Reductive cleavage of 7À9 under our Ni-catalyzed
reaction conditions furnished the desired products 10À12.
The cine substitution of indolylcarbamate 6 demonstrates
(a) the unrivaled directing group ability of the N,N-
diethylcarbamate, as competitive C2 lithiation was not
observed;24 (b) that the Ni-catalyzed carbamate removal
methodology may be used on heterocyclic, ortho-substituted
substrates; and (c) that C4-substituted indoles can be readily
synthesized from more accessible C5-substituted precursors.25
Figure 4. Cross-coupling approaches to ipso or cine substituted
products from carbamate 6.
respectively. Given the widespread use of transition metal-
catalyzed reactions in medicinal chemistry,27 we expect the
complementary means to achieve CÀC and CÀN bond
formation using aryl carbamates, with controlled ipso or
cine substitution, will add to the arsenal of tools needed to
efficiently synthesize analogues of lead compounds.
Finally, we explored the generality of our reaction
conditions for the reductive cleavage of various carbamate
substrates, as no general methodology exists for this
transformation (Figure 5). Fused aromatics were excellent
substrates, giving rise to products 18À21. Of note, a
double-decarbamoylation proceeded smoothly to give
naphthalene (18) in 82% yield. Nonfused aromatics were
also tolerated, as were a variety of functional groups.
For instance, an electron-deficient ester survived the trans-
formation to provide 20, and electron-donating sub-
stituents did not cause difficulty as suggested by the
smooth formation of 21 and 22. The successful reduction
of an estrone derivative demonstrates the use of this
methodology on a complex system bearing a ketal protect-
ing group to furnish 23. Several heterocyclic substrates
Figure 3. Cine substitution of indolylcarbamate 6.
(24) The acidity of C2ÀH of N-methylindole is approximately 107
times greater than the acidity of C4ÀH according to computational
studies; see: Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron
2007, 63, 1568–1576.
(26) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829–856.
(27) (a) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027–
3043. (b) Modern Drug Synthesis; Li, J. J., Johnson, D. S., Eds.; Wiley:
New York, 2010. (c) Djakovitch, L.; Batail, N.; Genelot, M. Molecules 2011,
16, 5241–5267.
(25) The ability to access C4 substituted indoles is of importance for
natural product synthesis and drug discovery. A Reaxys search indicates
that more than 600 C4-substituted indole-containing natural products
exist and nearly 10 000 bioactive C4-substituted indoles have been
reported.
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Org. Lett., Vol. 14, No. 11, 2012

substituents positioned ortho to the carbamate are toler-
ated by this methodology.
In summary, we have developed an efficient means
to achieve a rare arene cine substitution process. The
methodology relies on the strategic use of aryl O-carba-
mates as readily removable directing groups for arene
functionalization. We expect that our parent method
for carbamate removal will prove useful for aryl CÀO
bond cleavage reactions. Moreover, the cine substitution
process offers a new tool for arene functionalization that is
intended to complement the prevalent logic of arene ipso
substitution as a means to prepare analogues of important
scaffolds.
Acknowledgment. The authors are grateful to Boehrin-
ger Ingelheim, DuPont, Eli Lilly, Amgen, AstraZeneca,
NOBCChE/GlaxoSmithKline (T.M.), Roche, the A. P.
Sloan Foundation, and the University of California, Los
Angeles for financial support. We thank the GarciaÀ
Garibay laboratory (UCLA) for access to instrumenta-
tion, Dr. John Greaves (UC Irvine) for mass spectra, and
Materia Inc. for chemicals. These studies were supported
by shared instrumentation grants from the NSF (CHE-
1048804) and the National Center for Research Resources
(S10RR025631).
Figure 5. Reductive cleavage of aryl carbamates. Reaction con-
ditions: Aryl carbamate (1 equiv), NiCl2(PCy3)2 (5À20 mol %),
TMDSO (2.5 equiv), K3PO4 (4.5 equiv), toluene (0.27 M),
115À125 °C for 15 h (see Supporting Information). Isolated
yields provided.
Supporting Information Available. Experimental de-
tails and compound characterization data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
were evaluated to provide 24À26 in synthetically useful
yields. Two additional ortho-substituted carbamates were
examined, which demonstrate that both phenyl and fluoro
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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