Synthesis of polyarylated methanes through cross-coupling of tricarbonylchromium-activated benzyllithiums

Article abstract of DOI:10.1002/anie.201000957

Support group: Coordinated to the tricarbonylchromium fragment, a typically unstable benzylic organolithium can participate directly in cross-coupling reactions with aryl bromides to form polyarylated methane derivatives (see scheme). Cr(CO)₃ assistance leads to reactivity with a variety of coordinated substrates and-given multiple benzylic sites-can effect up to six coupling events per arene. Chemical equation presented

Full text of DOI:10.1002/anie.201000957

Angewandte
Chemie
DOI: 10.1002/anie.201000957
Polyarylated Methanes
Synthesis of Polyarylated Methanes through Cross-Coupling of
Tricarbonylchromium-Activated Benzyllithiums**
Genette I. McGrew, Jesada Temaismithi, Patrick J. Carroll, and Patrick J. Walsh*
Polyarylated methanes are attracting considerable attention
due to their growing importance in developing medicinal
agents for cancer[1] and vascular disease,[2,3] as well as in leuco
dye precursors,[4,5] photochromic agents, and applications in
materials science.[6,7] Most syntheses of polyarylmethanes
involve Friedel–Crafts-type (F-C) electrophilic aromatic sub-
stitution reactions,[5,6,8–13] although there are some limited
exceptions.[4,14,15] Recently, modified F-C processes,[9,16]
including a novel copper-catalyzed aza-Friedel–Crafts var-
iant,[17] have been used in the preparation of diversely
substituted triarylmethanes. The F-C approach, however, is
limited by both reactivity and selectivity: the nucleophile
must be electron-rich and unhindered for adequate reactivity
and the selectivity is controlled by the relative directing
abilities of the substituents. Thus, triarylmethanes with certain
electron withdrawing groups and those with meta substitution,
are largely inaccessible. A complementary and general route
to polyarylated methanes that enables the synthesis of
currently inaccessible members of this important structural
class is needed.
Herein we disclose a general, high-yielding cross-coupling
method between {Cr(CO)3}-activated toluene derivatives and
aryl bromides to afford a broad range of di- and triaryl-
methanes that are difficult or impossible to access by known
methods.
Our initial studies used tricarbonylchromium-complexed
diphenylmethane (1, Scheme 1) and 4-bromotoluene as
coupling partners. Use of alkoxide bases at room temperature
Scheme 1. Coupling of diphenylmethane tricarbonylchromium 1 with
aryl bromide.
resulted in no product (Table 1, entries 1 and 2). In contrast,
LiN(SiMe3)2 combined with [PdCl2(PPh3)2] (3 mol%)
afforded 70% isolated yield of the coupled product 2a after
20 h at room temperature (Table 1, entry 3) and 91% yield in
A strategy that would circumvent the limitations of the
F-C reaction is based on benzylic anion synthons. Tradition-
ally, reagents for this synthon are based on metals such as
boron, tin or zinc to temper reactivity.[18–20] An alternative
approach to attenuate the reactivity of benzylic nucleophiles
is
Table 1: Optimization of reaction conditions (Scheme 1).
Catalyst
mol%
Base
t
Yield
[%][b]
SM
[h][a]
[%][c]
h6-coordination to a metal fragment such as {Cr(CO)3}.[21–24]
Along these lines, Kalinin and co-workers generated [(h6-
C6H5CH2Li)Cr(CO)3], but were unable to effect palladium-
catalyzed cross-coupling reactions. After transmetalation to
zinc the resulting [(h6-C6H5CH2ZnCl)Cr(CO)3] underwent
palladium catalyzed single coupling with aryl halides to
furnish diarylmethanes in low yield (average 37%).[25] The
intermediate transmetalation to zinc prevents the realization
of the tricarbonylchromium groupꢀs full potential: to activate
[d]
1
2
3
4
5
6
7
8
9
10
[PdBr2(PPh3)2]
[PdBr2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[NiCl2(PPh3)2]
[Pd(PPh3)4]
10
5
3
3
3
5
5
5
5
LiOtBu
NaOtBu
24
24
20
0.75
12
18
20
20
17
19
–
–
67
trace
0
trace
38
48
29
12
14
[d]
–
LiN(SiMe3)2
LiN(SiMe3)2
LDA
NaN(SiMe3)2
KN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
70[d]
91
50
26
9
0
67
78
[PdCl2(dppf)]
5
À
more than one benzylic C H bonds and open the door to
multiple functionalizations through sequential deprotonation/
[a] Conducted at 55–608C in THF solvent, except where otherwise noted.
[b] Yields of isolated products. [c] Recovered starting material. [d] Reac-
tion conducted at room temperature.
coupling events.[26]
[*] G. I. McGrew, J. Temaismithi, Dr. P. J. Carroll, Prof. P. J. Walsh
UPenn/Merck HTE Laboratories, Department of Chemistry
University of Pennsylvania
45 min at 608C (Table 1, entry 4). On the other hand, stronger
amide bases such as lithium diisopropylamide (LDA), NaN-
(SiMe3)2, or KN(SiMe3)2 (Table 1, entries 5–7), or related
catalysts, including [Cl2Pd(dppf)] (Table 1, entries 8–10) were
less effective. The optimized conditions in entry 4, Table 1,
were used to determine the substrate scope (Table 2).
The diphenylmethane complex 1 readily undergoes cross-
coupling reactions with a variety of aryl bromides in 81–94%
isolated yield of triarylmethane complexes 2a–2k (Table 2).
231 S. 34th St, Philadelphia, PA 19104 (USA)
Fax: (+1)215-573-6743
E-mail: pwalsh@sas.upenn.edu
Homepage: http://titanium.chem.upenn.edu/walsh/index.html
[**] This research was supported by the National Institutes of Health,
General Medical Sciences (GM058101), and National Science
Foundation (CHE-0848467). J.T. is a Vagelos Scholar.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000957.
Angew. Chem. Int. Ed. 2010, 49, 5541 –5544
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5541

Communications
Table 2: Single coupling of 1 with ArBr (Scheme 1).[a]
Table 3: Double and single couplings of 3 with ArBr.[a]
Entry
2a
Ar=
Yield[b]
Entry
2 f
Ar=
Yield
91
Entry
Ar=
Yield[b]
Entry
Ar=
Yield
86
91
5a
90
5e
2b
92
2g
94
5b
5c
83
78
5 f
88
86
2c
2d
90
83
2h
2j
91
81
4g
5d
82
4h
81
2e
88
2k
89
[a] Conducted at 55–608C using 2.8 equiv LiN(SiMe3)2, 3 equiv ArBr, 4–8
mol% [PdCl2(PPh3)2], and THFas solvent. [b] Yields of isolated products.
[a] Conducted at 55–608C using 1.5 equiv LiN(SiMe3)2, 1.5 equiv ArBr,
3–5 mol% [PdCl2(PPh3)2], and THF as solvent. TIPS=triisopropylsilyl.
Electron-withdrawing (2d, 2e), -donating (2 f–2h), and ortho-
substituted aryl bromides (2h–2k) were all successful cou-
pling partners. Of medicinal relevance, our method enabled
installation of a 4-substituted indole (2k).[27] In contrast, F-C
chemistry strongly favors reaction of indole at the 3-position
(or 2-position if the 3-position is blocked).[5,11–13,17] Polyaryl-
methane derivatives bearing privileged indoles have attracted
interest due to their widespread occurrence in biologically
active compounds.
Scheme 3. Cross-coupling at multiple benzylic reaction sites. TMS=
trimethylsilyl.
complex 9 was coupled with 4-bromoanisole (Scheme 3)
resulting in formation of the hexacoupled product 10 in 43%
Next we examined reactions of [(h6-toluene)Cr(CO)3] (3,
Scheme 2). Although these reactions did not proceed well at
room temperature, conversion to triarylmethane products
À
yield (over 86% for each C C bond-forming event). The
structure of the hexacoupled product is illustrated in
Figure 1.[29] In the case of [(h6-o-xylene)Cr(CO)3] (11),
bulky 1-bromo-2,6-dimethylbenzene as coupling partner
resulted in single arylation of each benzylic methyl to give
the dicoupled product (12), in 85% yield. Use of the less
sterically demanding aryl bromide 4-bromo-N,N-dimethyla-
niline, however, led to either unsymmetrical dicoupled
product (13, in which both aryl groups couple to a single
Scheme 2. Cross-coupling reactions with [(h6-toluene)Cr(CO)3] (3).
Table 4: Coupling reaction at multiple arylation sites.[a]
5a–f (Table 3) was observed upon heating at 608C. Note that
reaction with diarylmethane intermediate 4 is faster than the
Starting
complex
Product[b]
Starting
complex
Product
first coupling with 3, probably due to the greater acidity of the
[28]
À
benzylic C H position of 4 over 3. In contrast, bulky 2,6-
disubstituted aryl bromides afforded monocoupled products
4g and 4h, likely due to steric hindrance.
Having demonstrated that two couplings could occur on a
single methyl group, we wondered if one tricarbonylchro-
mium center could activate multiple methyl groups in
complexes of xylene and mesitylene. We were concerned
that after the first methyl had undergone two arylations, the
newly formed triarylmethane moiety would be deprotonated
and the resulting anion would inhibit further deprotonation
and coupling at the remaining methyl groups. As shown in
Scheme 3 and Table 4, this was not a serious issue. Subjecting
[(h6-p-xylene)Cr(CO)3] (6) to cross-coupling conditions with
the bulky 1-bromo-2,4,6-triisopropylbenzene furnished dicou-
pled 7 in 73% yield. Employing 4-bromofluorobenzene gave
tetracoupled 8 in 70% yield. Furthermore, the mesitylene
6
11
11
[a] Conducted at 50–608C using 4–11 equiv LiN(SiMe3)2, 3–10 equiv
ArBr, 10–20 mol% [PdCl2(PPh3)2], and THF as solvent. [b] Yields of
isolated products.
5542
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 5541 –5544

Angewandte
Chemie
amines 20a–d in 68–82% yield. No doubly coupled products
were observed, possibly due to larger size of the dimethyla-
mino group over the n-propyl ether in 15. It is noteworthy that
diarylmethylamines are important pharmacophores and are
present in numerous medications.[30] Ethylbenzene complex
17 underwent single-coupling to generate the 1,1-diarylethane
derivative 21 in 70% yield, despite the presence of b-
hydrogens in the intermediate palladium complex. Interest-
ingly, this reaction also produced 6% of the triarylmethane
quaternary product 22.
To exploit of the ability of {Cr(CO)3} to shield one face of
the coordinated arene,[21] we also examined cross-coupling
reactions with complexes of indane (23) and tetrahydronaph-
thalene (24) (Scheme 5). By adjusting the conditions, either
Figure 1. ORTEP diagram (thermal ellipsoids at 50% probability) of
hexa-arylated product (10).
methyl), or unsymmetrical tricoupled product (14) by varying
the amount of base and reaction time. Steric barriers to both
deprotonation and transmetalation likely account for the
absence of tetraarylated (symmetrical) coupling product.
These polyarylation reactions highlight a significant advant-
age of this approach over others: the possibility of multiple
coupling reactions.[16]
We also examined the possibility of coupling in the
presence of a-heteroatoms and b-hydrogens using tricarbo-
nylchromium-coordinated benzyl ether (15), N,N-dimethyl-
benzylamine (16), and ethylbenzene (17). Benzyl ether
complex 15 underwent coupling employing conditions similar
to those in Scheme 2 to afford monocoupled products 18a–e
in 58–80% yield (Scheme 4). Surprisingly, further reaction,
whether in the presence of the original aryl bromide or with a
different aryl bromide after isolation, was found to give
triarylmethyl ether complexes 19a–f. N,N-Dimethylbenzyl
amine complex 16 underwent single coupling to form diaryl-
Scheme 5. Access to 1-arylindanes and 1,3-cis-diarylindanes. [a] 40:60
toluene/THF was used instead of pure THF to improve selectivity for
monoarylation. [b] From isolated 25b.
mono- or diarylated product could be obtained, though yields
of 25 and 26 were diminished due to partial conversion to
diarylated product. In the case of the diarylation reactions to
form 27 and 28, cis-diaryl products were obtained in all cases
(determined by 1H NMR and X-ray diffraction of 27b,[29] see
Supporting Information).
To demonstrate the practical advantages to our method,
double coupling of indane tricarbonylchromium (23) with
PhBr, followed by exposure to light and air provided 79%
isolated yield of cis-1,3-diphenylindane (29, Scheme 6).
Existing syntheses of 1,3-diaryl indanes provide cis/trans
mixtures.[31] The cis-1,3-diarylindane moiety is present in
potent nonpeptide endothelin receptor antagonists.[2,3] Per-
forming the coupling of [(h6-toluene)Cr(CO)3] (3) with
3-bromoanisole on a 5 mmol scale, followed by exposure to
air and light afforded 1.4 g PhCH(3-C6H4-OMe)2 (30) in 93%
yield, a product inaccessible by standard F-C procedures with
anisole.[32]
In summary, we have introduced an efficient method for
benzylic coupling reactions leading to polyarylated methanes.
This method is complementary to F-C approaches and
enables the synthesis of polyarylmethanes that are not
accessible through electrophilic aromatic substitution reac-
Scheme 4. Coupling in the presence of heteroatoms and b-H atoms.
[a] Product obtained directly from 15. [b] From isolated 18b. [c] From
isolated 18a. [d] 6% doubly coupled product was also isolated.
Angew. Chem. Int. Ed. 2010, 49, 5541 –5544
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5543

Communications
[6] D. F. Duxbury, Chem. Rev. 1993, 93, 381.
[7] M. S. Shchepinov, V. A. Korshun, Chem. Soc. Rev. 2003, 32, 170.
[8] V. Nair, S. Thomas, S. C. Mathew, K. G. Abhilash, Tetrahedron
2006, 62, 6731.
[9] S. Lin, X. Lu, J. Org. Chem. 2007, 72, 9757.
[10] S. K. Das, Shagufta, G. Panda, Tetrahedron Lett. 2005, 46, 3097.
[11] J. S. Yadav, B. V. S. Reddy, S. Sunitha, Adv. Synth. Catal. 2003,
345, 349.
[12] C. Ramesh, J. Barerjee, R. Pal, B. Das, Adv. Synth. Catal. 2003,
345, 557.
[13] V. Nair, K. G. Abhilash, N. Vidya, Org. Lett. 2005, 7, 5857.
[14] For a complementary procedure involving vicarious nucleophilic
substitution of nitroarenes see: A. R. Katritzky, D. Toader,
J. Org. Chem. 1997, 62, 4137.
[15] A. R. Katritzky, X. Lan, J. N. Lam, Chem. Ber. 1991, 124, 1809.
[16] Y.-Z. Li, B.-J. Li, X.-Y. Lu, S. Lin, Z.-J. Shi, Angew. Chem. 2009,
121, 3875; Angew. Chem. Int. Ed. 2009, 48, 3817.
[17] J. Esquivias, R. G. Arrayꢁs, J. C. Carretero, Angew. Chem. 2006,
118, 645; Angew. Chem. Int. Ed. 2006, 45, 629.
[18] G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275.
[19] B. Liꢂgault, J.-L. Renaud, C. Bruneau, Chem. Soc. Rev. 2008, 37,
290.
[20] D. Imao, B. W. Glasspoole, V. S. Laberge, C. M. Crudden, J. Am.
Chem. Soc. 2009, 131, 5024.
[21] M. Uemura in Organic Reactions, Vol. 67 (Ed.: L. E. Overman),
Wiley, New York, 2006, p. 217.
[22] C. A. Merlic, J. C. Walsh, D. J. Tantillo, K. N. Houk, J. Am.
Chem. Soc. 1999, 121, 3596.
[23] A. Pfletschinger, T. K. Dargel, J. W. Bats, H.-G. Schmalz, W.
Koch, Chem. Eur. J. 1999, 5, 537.
Scheme 6. One-pot coupling and direct decomplexation of [(h6-ar-
ene)Cr(CO)3]complexes. [a] Reaction is exposed to light prior to
purification. [b] Single (cis-) isomer observed. [c] Reaction was con-
ducted on a 5 mmol scale.
tions alone. Activation of the benzylic protons of
[(h6-arene)Cr(CO)3] allows a base of moderate strength,
LiN(SiMe3)2, to be used for the in situ generation of the
benzyllithiums,[33] which directly participate in a palladium-
catalyzed coupling reaction. Coordinated complexes can
undergo multiple arylations, furnishing polyarylated products
including unsymmetrically substituted triarylmethanes with
quaternary carbon centers. Currently, efforts are underway to
broaden the application of our method to the generation of
quaternary polyarylmethanes and their enantioselective syn-
theses.
[24] E. P. Kꢃndig in Topics in Organometallic Chemistry, Vol. 7,
Springer, Berlin, 2004.
[25] V. N. Kalinin, I. A. Cherepanov, S. K. Moiseev, J. Organomet.
Chem. 1997, 536–537, 437.
Received: February 16, 2010
Revised: May 4, 2010
Published online: July 2, 2010
[26] A. R. E. Brewer, A. F. Drake, S. E. Gibson, J. T. Rendell, Org.
Lett. 2007, 9, 3487.
À
Keywords: C C coupling · chromium · organolithium ·
palladium · triarylmethanes
.
[27] R. J. Sundberg, Indoles, Academic Press, San Diego, 1996.
1
[28] When H NMR deprotonation studies were conducted in THF
with 1 equiv LiN(SiMe3)2, 1 exhibited approximately 50%
deprotonation, whereas 3 was only 10% deprotonated.
[29] CCDC 775771 (10) and 765716 (27b) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[30] K.-i. Yamada, K. Tomioka, Chem. Rev. 2008, 108, 2874.
[31] B. Lantaꢄo, J. Aguirre, M. L. Finkielsztein, E. Alesso, E. Brunet,
G. Y. Moltrasio, Synth. Commun. 2004, 34, 625.
[32] Alternatively, the coordinated arene can be purified first and
then simply decomplexed by exposure to light and air. A
solution of coordinated arene 2a exposed to light and air
provided triphenylmethane in 98% isolated yield.
[33] For cross-coupling reactions with organolithium reagents see: S.-
I. Murahashi, J. Organomet. Chem. 2002, 653, 27.
[1] R. Palchaudhuri, V. Nesterenko, P. J. Hergenrother, J. Am.
Chem. Soc. 2008, 130, 10274.
[2] J. D. Elliott, M. A. Lago, R. D. Cousins, A. Gao, J. D. Leber,
K. F. Erhard, P. Nambi, N. A. Elshourbagy, C. Kumar, J. Med.
Chem. 1994, 37, 1553.
[3] E. H. Ohlstein, P. Nambi, S. A. Douglas, R. M. Edwards, M.
Gellai, A. Lago, J. D. Leber, R. D. Cousins, A. M. Gao, J. S.
Frazee, C. E. Peishoff, J. W. Bean, D. S. Eggleston, N. A.
Elshourbagy, C. Kumar, J. A. Lee, T. L. Yue, C. Louden, D. P.
Brooks, J. Weinstock, G. Feuerstein, G. Poste, R. R. Ruffolo,
J. G. Gleason, J. D. Elliott, Proc. Natl. Acad. Sci. USA 1994, 91,
8052.
[4] R. Muthyala, A. R. Katritzky, X. Lan, Dyes Pigm. 1994, 25, 303.
[5] A. R. Katritzky, V. Gupta, C. Garot, C. V. Stevens, M. F.
Gordeev, Heterocycles 1994, 38, 345.
5544
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 5541 –5544