Ru-Catalyzed Regioselective Direct Hydroxymethylation of (Hetero)Arenes via C-H Activation

Article abstract of DOI:10.1021/acs.orglett.7b00183

An efficient and direct ruthenium-catalyzed regioselective hydroxymethylation of (hetero)arenes via C-H activation with paraformaldehyde as a hydroxymethylating reagent is described. The corresponding products can be obtained in good to excellent yield. A number of aryl aldehydes can also be used in place of paraformaldehyde giving the desired alcohol products with similarly good results.

Full text of DOI:10.1021/acs.orglett.7b00183

Letter
pubs.acs.org/OrgLett
Ru-Catalyzed Regioselective Direct Hydroxymethylation of
(Hetero)Arenes via C−H Activation
Guo-Fu Zhang, Yue Li, Xiao-Qiang Xie, and Cheng-Rong Ding*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and direct ruthenium-catalyzed
regioselective hydroxymethylation of (hetero)arenes via C−H
activation with paraformaldehyde as a hydroxymethylating
reagent is described. The corresponding products can be
obtained in good to excellent yield. A number of aryl aldehydes
can also be used in place of paraformaldehyde giving the
desired alcohol products with similarly good results.
he methylol functional group (−CH2OH) is present in a
broad range of natural products and biologically active
Scheme 1. Previous Work and This Work
T
compounds. The physical properties of molecules, including
lipophilicity, can be altered by the methylol functional group,
greatly influencing the activity of the compound.1 Furthermore,
the CH2OH group can be readily manipulated and converted
into other functional groups allowing for the use of numerous
syntheticprotocols. Therefore, over thepastfew decades, hydroxy-
methylation has been a prominent research topic in drug
discovery, material science, and the chemical industry.2 Among
the various hydroxymethylation reactions, a radical pathway
has displayed encouraging versatility for the preparation of
benzylalcohol and pyridylalcohol. Minisci3 and other groups4−6
have reported several significant developments in this area.
Although a number of different approaches have been reported,
the application of these reactions remains limited due to poor
substrate scope and regioselectivity.
Recently, transition-metal-catalyzed C−H functionalization
using a directing group has emerged as a very attractive strategy
for structure elaboration because of its high efficiency and
regioselective control. Among the many reported procedures,7
the directing group assisted metal-catalyzed C−H addition of
arenes to aldehydes represents a unique strategy for accessing a
variety of alcohol-containing structures. Significant progress has
been made on this front. For example, the Li,8 Shi,9 and Chen
groups10 have independently reported a Rh-catalyzed C−H
addition to aldehydes. The Wang group11 recently extended a
Mn-catalyzed direct nucleophilic C(sp2)−H addition to alde-
hydes using a wide range of substrates. Kim12 and co-workers
reported addition reactions with indoles and indolines which use
ethyl glyoxalate and ethyl trifluoropyruvate as raw materials.
Murai,13 Takai,14 and Shi15 have independently developed
alternative methodologies which utilize C−H addition to
aldehydes and silyl capture, in which the aldehydes are activated
by silicon and a catalyst. Although the aforementioned reactions
provide separate routes for the preparation of various alcohol
products, hydroxymethylation via directing C−H addition has
not yet been reported (Scheme1) and remains challenging.
Herein we report a highly efficient Ru-catalyzed regioselective
direct hydroxymethylation using paraformaldehyde as a hydroxy-
methylating reagent via C−H activation.16 The catalyst system is
suitable for a broad range of substrates, and various electron-
deficient aldehydes can be used in place of paraformaldehyde
giving the desired alcohol products with similarly good results.
Initially, a Ru-catalyzed directed hydroxymethylation of
2- phenylpyridine 1 with paraformaldehyde was performed
(Table 1). After catalyst screening, the hydroxymethyl product 2
was obtained in 35% yield by using [Ru(p-cymene)Cl2]2 and
ZnBr2 inCHCl3 under anatmosphere of N2 (entry 2). Encouraged
by this result, a series of solvents were screened. DCE was found to
be the most efficient solvent (entry 7). We next screened a number
of Lewis acids as additives and found that FeF3 exhibited the best
effect (entry 9). A number of bases, which are helpful during the
C−H bond cleavage, were also examined. The addition of AcONa
(0.5 equiv) significantly improved the yield of the desired product
Received: January 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00183
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope Hydroxymethylation of Substrates
entry
[Ru]
additive
solvent
yield (%)
1
Ruthenocene
CH3Cl
CH3Cl
t-BuOH
THF
N.R.
35
2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
3
trace
trace
trace
53
4
5
MeOH
DCM
DCE
6
7
61
8
AlBr3
DCE
trace
75
9
FeF3
DCE
10
11
12
FeCl3
AcOK
AcONa
AcONa
DCE
33
DCE
85
DCE
96
c
13
DCE
N.R
a
Reaction conditions: all reactions were performed with 1 (0.2 mmol),
(HCHO)n (3 equiv), [Ru] (5 mol %), ZnBr2 (0.5 equiv), and additive
b
(0.5 equiv) in solvent (2.0 mL) at 60 °C under N2 for 24 h. Isolated
c
yield. Without ZnBr2.
to 96% (entry 12). It is also worth noting that the reaction was
highly monoselective, giving solely the monosubstituted product,
most likely due to the intramolecular coordination of OH to N of
the product.
With the optimized reaction conditions in hand, we proceeded
to survey the scope of the reaction with substrates bearing
substituted 2-phenylpyridine groups. As shown in Scheme 2, a
wide variety of 2-phenylpyridine derivatives undergo hydrox-
ymethylation efficiently, irrespective of the electronic character
of the substituents. For example, electron-rich substituents
bearing methyl-, methoxy-, trifluoromethyl-, and hydroxymethyl-
substituted arenes all gave their corresponding products with
good yields (2a−e). Additionally, halogen and vinyl substituents
were well tolerated (2f, 2g, 2m, 2n, 2o). Of particular interest
were the products of substrates bearing hydroxymethyl and
chlorine or vinyl groups (2d, 2g, 2m), which allow for further
derivatization. Electron-deficient arenes also underwent C−H
activation smoothly, giving the desired hydroxymethylated
products in moderate yield albeit requiring a prolonged reaction
time (2i). A substrate bearing a disubstituted phenyl ring was also
amenable to the reaction conditions providing the corresponding
product in good yield (2h). The successful use of this method
prompted us to examine the compatibility of hydroxymethyla-
tion with aromatic heterocycle substrates. We were pleased to
discover that hydroxymethylation of furan (2u), thiophene (2t),
and benzothiophene (2v) proceeded smoothly to give the cor-
responding hydroxmethyl heterocyclic products. Pyrimidine and
pyrazole heterocycles could also be used as directing groups but
were not as effective as pyridine (2r, s).
a
Reaction conditions: all reactions were performed with 1 (0.2 mmol),
(HCHO)n (3 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), ZnBr2 (0.5 equiv),
and AcONa (0.5 equiv) in DCE (2.0 mL) at 60 °C under N2 for 24 h.
b
c
Isolated yield. For 48 h.
bromine (3f), and chorine (3j, h) groups on the aryl ring. A tri-
fluoromethyl group at the para-position did not have a significant
impact on product yield (3i). Gratifyingly, 2,5-dichlorobenzaldehyde
also underwent addition giving the corresponding product in 83%
yield (3h). C−H addition with methyl 4-formylbenzoate occurred
with good yield under identical reaction conditions (3k). A nitrile
group was also tolerable to the reaction conditions (3l).
Studies were conducted to elucidate the mechanism of the
reaction. A H/D exchange experiment of 2-phenylpyridine was
carried out to investigate the reversibility of the C−H activation
step (Scheme 4). As expected, 93% deuterium incorporation at
the ortho-position was observed, supporting the hypothesis that
the C−H activation step may be reversible. In addition, an
intermolecular kinetic isotope effect value of 1.2 was observed,
implying that cleavage of the C−H bond is not involved in the
rate-determining step.
We subsequently investigated the use of other aldehydes in our
reaction (Scheme 3). Addition of glyoxylate also proceeds in
good yield (3a) as did the addition of terephthalaldehyde (3b).
We discovered that the use of electron-deficient benzaldehydes
bearing nitro, cyano, and methoxycarbonyl groups also provided
the desired products in good yields. Both para- and ortho-
substituted nitroaldehydes also underwent reaction with good
yields (3c, d). The reaction was compatible with fluorine (3e),
Based on the above results, the mechanism shown in Figure 1
has been proposed. Coordination of 2-phenylpyridine to the
[Ru] catalyst is followed by ortho C−H activation to give a
corresponding [Ru-substrate] intermediate. A hydrogen on the
B
DOI: 10.1021/acs.orglett.7b00183
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 3. Scope of Aldehydes
Figure 1. Proposed mechanism.
seven-membered metallocycle. After proton transfer, the catalyst
[Ru] is released for the next catalytic cycle.
In summary, we have developed an efficient, direct regioselective
Ru-catalyzed hydroxyseven-metallocyclemethylation of (hetero)-
arenes via C−H activation using paraformaldehyde as a hydro-
xymethylating reagent. The reaction shows good atom efficiency
and is suitable for a broad range of substrates. Other electron-
deficient aldehydes could also be used in place of paraformaldehyde
to give the addition adducts in good to excellent yields.
a
Reaction conditions: all reactions were performed with 1 (0.1 mmol),
RCHO (3 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), ZnBr2 (0.5 equiv),
and AcONa (0.5 equiv) in DCE (1.0 mL) at 60 °C under N2 for 24 h.
b
c
Isolated yield. For 48 h.
Scheme 4. Mechanism Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00183.
Typical experimental procedure and characterization data
for all products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dingcr@zjut.edu.cn.
ORCID
Cheng-Rong Ding: 0000-0001-6000-3965
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Supported by the National Natural Science Foundation of China
(No. 20702051) and the Natural Science Foundation of Zhejiang
Province, China (No. LY13B020017)
a
b
c
On 0.2 mmol scale. Isolated yield. General conditions: all reactions
were performed with substrates (0.2 mmol), (HCHO)n (3 equiv),
[Ru(p-cymene)Cl2]2 (5 mol %), ZnBr2 (0.5 equiv), and AcONa
(0.5 equiv) in DCE (2.0 mL) at 60 °C under N2 for 2 h.
REFERENCES
(1) Sloan, K. B.; Bodor, N. Int. J. Pharm. 1982, 12, 299.
(2) For selected recent examples, see: (a) Smejkal, T.; Han, H.; Breit,
■
benzene ring is removed under the influence of [Ru] and base.17
Activation of the aldehyde with ZnBr2 and insertion give a
B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 10366. (b) Liu, X. L.; Liao,
C
DOI: 10.1021/acs.orglett.7b00183
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Y. H.; Wu, Z. J.; Cun, L. F.; Zhang, X. M.; Yuan, W. C. J. Org. Chem.
2010, 75, 4872. (c) Kobayashi, S.; Kawamoto, T.; Uehara, S.; Fukuyama,
T.; Ryu, I. Org. Lett. 2010, 12, 1548. (d) Pasternak, M.; Paradowska, J.;
Rogozinska, M.; Mlynarski, J. Tetrahedron Lett. 2010, 51, 4088. (e) Jin,
H. S.; Zhao, L. M. Chin. Chem. Lett. 2010, 21, 568. (f) Chen, A.; Xu, J.;
Chiang, W.; Chai, C. L. L. Tetrahedron 2010, 66, 1489. (g) Mukherjee,
C.; Kitanosono, T.; Kobayashi, S. Chem. - Asian J. 2011, 6, 2308.
(h) Kuhl, N.; Glorius, F. Chem. Commun. 2011, 47, 573. (i) Ji, C. B.; Liu,
Y. L.; Cao, Z. Y.; Zhang, Y. Y.; Zhou, J. Tetrahedron Lett. 2011, 52, 6118.
(j) Shanmuganathan, S.; Natalia, D.; Greiner, L.; de Maria, P. D. Green
Chem. 2012, 14, 94. (k) Shirakawa, S.; Ota, K.; Terao, S. J.; Maruoka, K.
Org. Biomol. Chem. 2012, 10, 5753. (l) Krishnaraj, T.;
Muthusubramanian, S. Tetrahedron Lett. 2012, 53, 1149. (m) Murai,
N.; Yonaga, M.; Tanaka, K. Org. Lett. 2012, 14, 1278. (n) Kawamoto, T.;
Fukuyama, T.; Ryu, I. J. Am. Chem. Soc. 2012, 134, 875. (o) Slattery, C.
N.; Deasy, R. E.; Maguire, A. R. J. Org. Chem. 2013, 78, 5955.
(p) Kawamoto, T.; Okada, T.; Curran, D. P.; Ryu, I. Org. Lett. 2013, 15,
2144. (q) Garza, V. J.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 3655.
(3) (a) Buratti, W.; Gardini, G. P.; Minisci, F. Tetrahedron 1971, 27,
3655. (b) Minisci, F.; Citterio, A.; Vismara, E.; Giordano, C. Tetrahedron
1985, 41, 4157.
(4) (a) Ishida, A.; Toki, S.; Takamuku, S. J. Chem. Soc., Chem. Commun.
1985, 1481. (b) Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.;
Serravalle, M.; Giordano, C. J. Org. Chem. 1986, 51, 4411. (c) Minisci, F.;
Porta, O.; Recupero, F.; Punta, C.; Gambarotti, C.; Pruna, B.; Pierini,
M.; Fontana, F. Synlett 2004, 874. (d) Neubert, T. D.; Schmidt, Y.;
Conroy, E.; Stamos, D. Org. Lett. 2015, 17, 2362.
(5) Li, H.-J.; Wu, Y.-Y.; Wu, Q.-X.; Wang, R.; Dai, C.-Y.; Shen, Z.-L.;
Xie, C.-L.; Wu, Y.-C. Org. Biomol. Chem. 2014, 12, 3100.
(6) Huff, C. A.; Cohen, R. D.; Dykstra, K. D.; Streckfuss, E.; DiRocco,
D. A.; Krska, S. W. J. Org. Chem. 2016, 81, 6980.
(7) For selected reviews: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (c) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (d) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (e) Arockiam, P. B.; Bruneau,
C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (f) Engle, K. M.; Mei, T.-
S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (g) Ackermann, L.
Acc. Chem. Res. 2014, 47, 281. (h) Huang, Z.; Lim, H. N.; Mo, F.; Young,
M. C.; Dong, G. Chem. Soc. Rev. 2015, 44, 7764. (i) Su, B.; Cao, Z.-C.;
Shi, Z.-J. Acc. Chem. Res. 2015, 48, 886. (j) Chen, Z.-K; Wang, B.-J;
Zhang, J.-T; Yu, W.-L; Liu, Z.-X; Zhang, Y.-H. Org. Chem. Front. 2015, 2,
1107. (k) Fabry, D. C.; Rueping, M. Acc. Chem. Res. 2016, 49, 1969.
(l) He, G.; Wang, B.; Nack, W. A.; Chen, G. Acc. Chem. Res. 2016, 49,
635. (m) Rao, W.-H.; Shi, B.-F. Org. Chem. Front. 2016, 3, 1028.
(8) Yang, L.; Correia, C. A.; Li, C.-J. Adv. Synth. Catal. 2011, 353, 1269.
(9) (a) Li, Y.; Zhang, X.-S.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett. 2012, 14,
4498. (b) Li, Y.; Zhang, X.-S.; Chen, K.; He, K.-H.; Pan, F.; Li, B.-J.; Shi,
Z.-J. Org. Lett. 2012, 14, 636.
(10) Chen, J.; Chen, P.; Song, C.; Zhu, J. Chem. - Eur. J. 2014, 20,
14245.
(11) Zhou, B.; Hu, Y.; Wang, C. Angew. Chem., Int. Ed. 2015, 54, 13659.
(12) Jo, H.; Park, J.; Choi, M.; Sharma, S.; Jeon, M.; Mishra, N. K.;
Jeong, T.; Han, S.; Kim, I. S. Adv. Synth. Catal. 2016, 358, 2714.
(13) Fukumoto, Y.; Sawada, K.; Hagihara, M.; Chatani, N.; Murai, S.
Angew. Chem. 2002, 114, 2903; Angew. Chem., Int. Ed. 2002, 41, 2779.
(14) (a) Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai, K. J. Am.
Chem. Soc. 2006, 128, 12376. (b) Kuninobu, Y.; Nishina, Y.; Takai, K.
Tetrahedron 2007, 63, 8463. (c) Kuninobu, Y.; Matsuki, T.; Takai, K.
Org. Lett. 2010, 12, 2948. (d) Kuninobu, Y.; Nishina, Y.; Takeuchi, T.;
Takai, K. Angew. Chem. 2007, 119, 6638; Angew. Chem., Int. Ed. 2007, 46,
6518.
(15) Li, B.-J.; Shi, Z.-J. Chem. Sci. 2011, 2, 488.
(16) Recently Kim’s group reported a similar catalysis system
containing [Ru(p-cymene)Cl2]2, NaOAc, and AgSbF6 which is suitable
with indoles and indolines and use of ethyl glyoxalate and ethyl
trifluoropyruvate as raw materials.
(17) Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am.
Chem. Soc. 2011, 133, 10161.
D
DOI: 10.1021/acs.orglett.7b00183
Org. Lett. XXXX, XXX, XXX−XXX