N -directing group assisted rhodium-catalyzed aryl C-H addition to aryl aldehydes

Article abstract of DOI:10.1021/ol2032784

Direct aryl C-H addition to aryl aldehydes to produce biaryl methanols was reported via Rh catalysis with an N-containing directing group. The method is highly atom-, step-, and redox-economic. The procedure is robust, reliable, and compatible with water

Full text of DOI:10.1021/ol2032784

ORGANIC
LETTERS
2012
Vol. 14, No. 2
636–639
N-Directing Group Assisted
Rhodium-Catalyzed Aryl CÀH
Addition to Aryl Aldehydes
Yang Li,† Xi-Sha Zhang,† Kang Chen,† Ke-Han He,† Fei Pan,†
Bi-Jie Li,† and Zhang-Jie Shi*,†,‡
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China, and State Key Laboratory of
Organometallic Chemistry, SIOC, CAS, Shanghai 200032, China
zshi@pku.edu.cn
Received December 8, 2011
ABSTRACT
Direct aryl CÀH addition to aryl aldehydes to produce biaryl methanols was reported via Rh catalysis with an N-containing directing group. The
method is highly atom-, step-, and redox-economic. The procedure is robust, reliable, and compatible with water and air.
The addition of highly reactive organometallic reagents,
such as Grignard reagents, to aldehydes and ketones is
a fundamental reaction and has been well investigated
and broadly applied in organic synthesis since the past
century.1 The tedious procedure from environmentally
unfriendly organic halide, metal reagents, and the manip-
ulation of air and moisture sensitive organometallic re-
agents makes such a transformation undesireable. Transi-
tion metal catalyzed direct nucleophilic addition of CÀH
bonds in hydrocarbons and their derivatives to the carbon-
yl group to produce alcohols is a dream goal in organic
synthesis. Obviously, this process would be the most step-,
atom-, and redox-economical by avoiding the preactiva-
tion of starting materials and manipulating air and mois-
ture sensitive organometallic reagents.
Significant progress has already been made to promote
the synthetic efficiency by direct CÀH transformation in
the past several decades.2À4 However, the successful ex-
amples of carrying out the direct addition of aryl CÀH to
polar multipe bonds are rarely reported.5À8 Murai, Takai,
and their co-workers made significant contributions to
carry out the addition of aryl CÀH to aldehydes with the
directing strategy by quenching the resulting alcohols
with silanes.5,6b,6d Recently, this method was successfully
extended to the addition of 3-pyridinyl CÀH bonds to
aldehydes by our group.9 With a brilliant design, another
beautiful example was reported by Takai of carrying out
the CÀH addition, followed by the intramolecular nucleo-
philic addition to form the isobenzofuran derivatives with
† Peking University.
‡ CAS.
(1) For the Grignard reaction, see: (a) Silverman, G. S.; Rakita, P. E.
Handbook of Grignard Reagents; Marcel Dekker: New York, 1996. (b)
Richey, H. G. Jr. Grignard Reagents: New Development; Wiley: Chichester,
U.K., 2000. (c) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(2) For reviews on CÀH activation, see: (a) Jia, C.; Kitamura, T.;
Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (b) Miura, M.; Nomura, M.
Top. Curr. Chem. 2002, 219, 211. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. Rev. 2002, 102, 1731. (d) Kakiuchi, F.; Chatani, N. Adv. Synth.
Catal. 2003, 345, 1077. (e) Godula, K.; Sames, D. Science 2006, 312, 67.
(f) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (g)
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (h) Chen, M. S.;
White, M. C. Science 2007, 318, 783. (i) Chen, X.; Engle, K. M.; Wang,
D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (j) Daugulis, O.;
Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (k)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009,
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Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (n) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (o) Sun, C.-L.; Li, B.-J.;
Shi, Z.-J. Chem. Commun. 2010, 46, 677. (p) Jazzar, R.; Julien, H.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010,
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J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890. (r) Gutekunst, W. R.;
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Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976. (s) Wencel-Delord, J.; Droge,
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r
10.1021/ol2032784
Published on Web 01/09/2012
2012 American Chemical Society

an N-phenyliminyl group as a directing group in the
absence of silanes.6a More recently, Ellman and our group
independentlyreportedthe Rh-catalyzedaddition reaction
of aryl CÀH bonds to aldimine derivatives in the absence
of any additives.10 Based on this observation, Ellman and
his co-workers subsequently reported the addition of aryl
CÀH to the isocyanates to produce the benzamides.11 In
this communication we demonstrated the successful direct
CÀH bond addition to aryl aldehydes with a wide sub-
strate scope in the presence of water and air. Notably,
when we were performing these studies, Li and his co-
workers reported the beautiful example of the direct addi-
tion of aryl CÀH bonds to ethyl 2-oxoacetate.12 In their
studies, they also first demonstrated the CÀH addition to
aryl aldehydes.
(1a) to various aldehydes. At that moment, we observed
the desired addition product 4-(trifluoromethyl)benzalde-
hyde (2a) albeit in 17% yield with [Cp*Rh(CH3CN)3]-
[BF4]2 (4) as a catalyst (eq 1, Scheme 1). Unfortunately,
after many tries, we failed in promoting such an addition
with 2a. To our delight, after screening many substrates with
our full efforts, we found that the reaction of 2-phenylquino-
line (1b) with highly electron-deficient 2-chloro-4-nitroben-
zaldehyde (2b) gave an excellent yield. Noteworthy, by using
the quinolinyl unit as a directing group, the CÀH at the
8-position was kept untouched although it was found active
in some transformations.13 The regioselectivity of this trans-
formation was further confirmed by obtaining the single-
crystal X-ray crystal structure of 3b.14 The intramolecular
hydrogen bond shown in the structure makes the designed
product stable under the reaction conditions.
Before we performed the addition reaction of CÀH
bonds to aldimine derivatives, we had tested the Rh-
catalyzed addition of CÀH bonds of 2-phenylpyridne
Scheme 1a
(3) For a review of rhodium catalyzed CÀH activation, see: (o)
Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212. For heterocycle
synthesis, see:(a) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
1407. (b) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008,
130, 12414. (c) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474. (d) Guimond, N.;
Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050. (e) Guimond, N.;
Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. (f)
Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
9585. (g) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565. (h)
Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 18326. (i) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2010, 12, 2068. (j) Chen, J.; Song, G.; Pan, C.-L.; Li, X. Org.
Lett. 2010, 12, 5426. (k) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett.
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Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449. (n) Hyster, T. K.; Rovis,
T. Chem. Sci. 2011, 2, 1606.
(4) For the unheterocycle synthesis by rhodium catalyzed CÀH
activation, see: (a) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew.
Chem., Int. Ed. 2008, 47, 4019. (b) Schipper, D. J.; Hutchinson, M.;
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Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc.
2011, 133, 2350. (e) Tsai, A. S.; Brasse, M.; Bergman, R. G.; Ellman, J. A.
Org. Lett. 2011, 13, 540. (f) Park, S. H.; Kim, J. Y.; Chang, S. Org. Lett.
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D.-F.; Fu, Y.; Liu, L. Org. Lett. 2011, 13, 3235.
a Thermal ellipsoids are drawn at 30% probability, and hydrogen
atoms are omitted for clarity.
To accumulate experience to explore the reactivity of
other CÀH bonds and normal aldehydes, we systemati-
cally investigated such an addition reaction with commer-
cially available 2-chloro-5-nitrobenzaldehyde (2c) as a
model substrate (Scheme 2). The selection of 2c is based
on the easy transformation of final products into different
functional groups from the nitro group through the well-
known Sandmeyer procedure15 and the potential ortho-
gonal coupling reaction of a CÀCl bond.16 To our satisfac-
tion, by using 2c as a substrate, the reaction also exhibited
good efficiency (3c).
(5) Fukumoto, Y.; Sawada, K.; Hagihara, M.; Chatani, N.; Murai, S.
Angew. Chem., Int. Ed. 2002, 41, 2779.
(6) (a) Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai, K. J. Am.
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(7) Tsuchikama, K.; Hashimoto, Y.; Endo, K.; Shibata, T. Adv.
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W. D.; Foster, G. P.; Putinas, J. M. J. Am. Chem. Soc. 1987, 109, 5047.
(b) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302. (c)
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J. Am. Chem. Soc. 2010, 132, 3650. (g) Boogaerts, I. I. F.; Nolan, S. P. J.
Am. Chem. Soc. 2010, 132, 8858.
Under the optimized conditions, the reactivity of different
2-phenylquinoline derivatives was investigated (Scheme 2).
(9) Li, B.-J.; Shi, Z.-J. Chem. Sci. 2011, 2, 488.
(13) Kwak, J.; Kim, M.; Chang, S. J. Am. Chem. Soc. 2011, 133, 3780.
(14) CCDC 856810.
(15) Hodgson, H. H. Chem. Rev. 1947, 40, 251.
(16) For reviews on this topic, see: (a) de Meijere, A.; Diederich, F.
Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH Verlag GmbH &
Co.KGaA: Weinheim, Germany, 2004. (b) Littke, A. F.; Fu, G. C. Angew.
Chem., Int. Ed. 2002, 41, 4176. (c) Suzuki, A. Angew. Chem., Int. Ed.
2011, 50, 6722. (d) Negishi, E.-i. Angew. Chem., Int. Ed. 2011, 50, 6738.
(10) (a) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2011, 133, 1248. (b) Li, Y.; Li, B.-J.; Wang, W.-H.;
Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi., Z.-J. Angew. Chem., Int. Ed.
2011, 50, 2115.
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1269.
Org. Lett., Vol. 14, No. 2, 2012
637

First, electron-donating groups are introduced to the phenyl
group. For examples, with a methyl group (3d) and a
methoxyl group (3e), the reactions showed good reactivity.
Importantly, the unprotected hydroxyl group (3f) was also
compatible. Various electron-donating and -withdrawing
groups on the phenyl unit were further tested. It was found
that the electronic nature of the substituents on the phenyl
ring did not play key roles (3c to 3k). This transformation
showed good compatibility with different functional groups,
such as MOM (3h) and ester groups (3k). Pivalate protected
hydroxyl groups exhibited good reactivity, which provided
the potential chance for further functionalization.17 More-
over, the tolerance of the halides (3i and 3j) also offers the
opportunity for further transformation.16 This transforma-
tion was also investigated using other directing groups.
Compared with quinolinyl directing groups, this CÀH addi-
tion showed slightly lower yields using pyridinyl directing
groups (3lÀ3p). Other N-based directing groups, such as
pyrazolyl groups (3q) and pyrimidinyl groups (3r), were
further tested, but the reactions gave relatively lower yields.
With 2-phenylquinoline as a substrate, different aryl
aldehydes were further explored (Scheme 3). First, 4-
nitrobenzaldehyde was tested, and the reaction gave a good
yield (3s). It was found that the meta-nitro group (3t) also
gave a comparable yield. Meanwhile, other different elec-
tron-withdrawing groups on the phenyl part of the aldehyde
were explored. Ester groups (3u), trifluoromethyl groups
(3v), and nitrile groups (3w) on substituted benzaldehydes
were suitable, although the reactions exhibited moderate
efficacy. When benzaldehyde was submitted (3x), the reac-
tion gave a low yield (11%), accompanied by a large amount
of recovered starting material 1b (86% recovery of 1b).
Notably, to date, it is the first example that the CÀH
addition to simple benzaldehyde resulted in benzyl alcohol
in the absence of any additives. Moreover, this observation
exhibited great potential in extending such an addition into
normal aryl aldehydes other than the electron-deficient
aldehydes. Further efforts to approach such a goal are being
studied in our laboratory.
Scheme 3. CÀH Adddition of 2-Phenylquinoline to Different
Aryl Aldehydesa
Scheme 2. Different 2-Phenylquinoline Derivative CÀH Bond
Additions to Aldehydesa
a If no special conditions are indicated, all the reactions were per-
formed on 0.25 mmol of 2-phenylquinoline and 0.75 mmol of aldehyde
in a sealed reaction tube. bThe reactions were performed on 1.0 mmol of
2-phenylquinoline and 3.0 mmol of aldehyde. c86% recovery of 1b
a All the reactions were performed on 0.25 mmol of 2-phenylpyridne
derivatives and 0.75 mmol of aldehyde in a sealed reaction tube.
Since chloronitrobenzaldehyde showed great reactivity,
other halides were further introduced to nitrobenzaldehyde
at different positions for the same reason we used 2c. When
a nitro group was present at the para- or meta-position and
(17) (a) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486.
(b) Huang, K.; Li, G.; Huang, W.-P.; Yu, D.-G.; Shi, Z.-J. Chem.
Commun. 2011, 47, 7224.
638
Org. Lett., Vol. 14, No. 2, 2012

recovered 2-([D1]-phenyl)pyridine (5) was decreased from
93% to34%. Intermolecularly, the content ofdeuterium at
the 2- and 6-positions of the phenyl group in 2-([D5]-
phenyl)-pyridine (7) was also decreased from 50% to 30%.
As we predicted, all of these data showed that the first step
of CÀH cleavage is reversible in this transformation.
Further studies to understand this transformation are
underway.
Scheme 4. Preliminary Mechanism Research
In conclusion, we developed a highly atom-, step-, redox-
economic method to carry out the Rh(III)-catalyzed aryl
CÀH bond addition to aldehydes to produce diarylmetha-
nols. An N-containing directing group was found essential
for this transformation. In this transformation the electron-
deficient aldehydes are highly effective. The CÀH bonds of
inert arene substrates were used instead of Grignard reagents
without the addition of any additive including any reduc-
tants and oxidants. The reaction is robust and not sensitive
to water and air. Studies to apply this method to a wider
range of substrates and realize the asymmetric synthesis are
in progress.
different halide groups were introduced at the ortho-position
(3ya, 3yb, 3za, 3zb, 3Ba, and 3Bb) or para-position (3A)
of the formyl group, the addition ran smoothly and the
desired products were isolated in good to excellent yields.
At the same time, with the combination of meta-chloro
and ortho-nitrobenzaldehyde (3C), the reaction also showed
excellent efficiency. Obviously, these studies enhanced the
potential applicability of the products in this transforma-
tion. Moreover, in the presence of an electron-donating
methyl group with the nitro group, the desired product was
isolated in good yield (3A).
Acknowledgment. Support of this work by the grant
from the “973” program from MOST of China (2009CB-
825300) and NSFC (Nos. 20821062, 20925207, and 2100-
2001) is gratefully acknowledged.
To investigate the preliminary mechanism further, intra-
and intermolecular isotopic studies were performed under
the exact reaction conditions (Scheme 4). During the
intramolecular reaction, the content of deuterium in the
Supporting Information Available. Brief experimental
details and other spectral data for products. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 14, No. 2, 2012
639