Ruthenium-Catalyzed Direct Hydroxymethylation of Aryl C-H Bonds

Article abstract of DOI:10.1021/acscatal.7b00078

An ideal addition of inert aryl C-H bonds to formaldehyde has been achieved to synthesize a variety of hydroxymethylarenes via a Ru(II)-catalyzed C-H activation. Many different directing groups (not limited to strongly heterocyclic directing groups) can be used, and this challenging C-H hydroxymethylation proceeds in the presence of water and air, without stoichiometric undesirable byproducts, thus offering an environmentally benign method of hydroxymethylarene synthesis that can be readily scaled up.

Full text of DOI:10.1021/acscatal.7b00078

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Letter
Ruthenium-Catalyzed Direct Hydroxymethylation of Aryl C-H Bonds
Yunxiang Wu, and Bing Zhou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00078 • Publication Date (Web): 15 Feb 2017
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ACS Catalysis
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Ruthenium-Catalyzed Direct Hydroxymethylation of Aryl C-H Bonds
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a, b
, a, b
Yunxiang Wu, Bing Zhou*
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a
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences,
555 Zu Chong Zhi Road, Shanghai 201203, PR China
b
University of Chinese Academy of Sciences, Beijing 100049, China
KEYWORDS: C-H Activation; Ruthenium; Hydroxymethylation; hydroxymethylarene; Formaldehyde
ABSTRACT: An ideal addition of “inert” aryl C-H bonds to formaldehyde has been achieved to synthesize a variety of hy-
droxymethylarenes via a Ru(II)-catalyzed C-H activation. Many different directing groups (not limited to strongly hetero-
cyclic directing groups) can be used and this challenging C-H hydroxymethylation proceeds in the presence of water and
air, and without stoichiometric undesirable by-products, thus offering an environmentally benign method of hy-
droxymethylarene
synthesis
that
can
be
readily
scaled-up.
Hydroxymethylated arenes are ubiquitous in many nat-
ural products, pharmaceuticals, biologically active com-
pounds, fragrances, and polymers, and they are also used
as important intermediates in synthetic organic chemistry
In this context, as a complementary method, a transi-
tion-metal-catalyzed direct nucleophilic C-H addition to
formaldehyde has its own advantages for hy-
droxymethylarene synthesis from a synthetic and envi-
ronmental point of view (Scheme 1b). Obviously, this pro-
cess would be the most step-, atom-, and redox-
economical in that substrate preactivation and manipula-
tion of air- and moisture-sensitive organometallic rea-
gents are avoided. However, to the best of our knowledge,
there is no report on the transition-metal-catalyzed direct
C-H hydroxymethylation with formaldehyde, presumably
due to the following challenges: 1) the nucleophilicity of
the C-Metal bond is low; 2) insertion of aldehyde into the
[1]
(
Figure 1). Traditionally, hydroxymethylarenes can be
synthesized by reduction of either aryl aldehydes or es-
ters. Alternatively, nucleophilic addition of highly reactive
aryl Grignard reagents and other related organometallic
reagents to formaldehyde is a fundamental and important
reaction for the introduction of a hydroxymethyl group
[2]
into an aromatic or a heteroaromatic ring (Scheme 1a).
However, this approach requires organohalides as the
starting materials to produce the organometallic reagents,
thus inevitably causing environmental problems owing to
their tedious and sluggish preparation. Moreover, this
method has some other limitations such as the need for
manipulation of air- and moisture-sensitive reagents,
poor tolerance of functional groups, and generation of
stoichiometric unwanted salt wastes. In addition, hy-
droxymethylarene could also be synthesized by a direct
electrophilic addition of arenes to formaldehyde in pres-
[
4]
C-Metal bond is reversible; 3) the rate of protonation
versus β-H-elimination of the resulting the transition-
metal alkoxide intermediates is competitive; 4) formal-
dehyde is a gas so that a mild reaction condition is neces-
sary.
[5]
[3]
ence of acid.
Scheme 1. C-H Hydroxymethylation reaction. (a) Traditional
way: halogenation, metalation, nucleophilic addition to for-
maldehyde, then hydration. (b) Catalytic direct C-H addition
toward formaldehyde.
Recently, the groups of Miura, Takai, and Shi made sig-
nificant contributions to carry out the addition of aryl C-
H bonds to aryl or alkyl aldehydes by addition of external
silanes to trap the transition-metal alkoxide intermei-
Figure 1. Representative natural products and biologically
active compounds.
[6]
dates, thus producing the corresponding silylethers.
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Alternatively, the metal alkoxide intermediates could be
trapped by directing groups to form stable cyclic prod-
(entryies 3-5) and we were pleased to observe that the
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situation changed significantly when the Ru(II) complex
was used as the catalyst, providing the desired product 3a
in 47% yield (entry 5). Screening of the solvent proved
DCE to be the optimal choice (entries 6-8). Next, some
acid additives were screened (entries 9-11) and the addi-
tion of NaH PO gave a dramatically improved yield (up
[7]
ucts. In stark contrast to these trapping strategies, only
very few examples has been reported on the direct nucle-
ophilic aryl C-H addition to aldehydes to produce desired
alcohol. Recently, a significant breakthrough was made by
Li and Shi, who independently reported the alcohol syn-
thesis by rhodium(III)-catalyzed chelation-assisted
2
4
to 87%) (entry 11). Reactions at higher temperatures re-
sulted in decreased reactivity (entry 12). To our delight,
replacement of polyformaldehyde with formalin (40%
2
C(sp )-H addition to electron-withdrawing aldehydes
[
8]
(
Scheme 2a). Very recently, the group of Wang expand-
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ed the scope of aldehydes to electron-rich aldehydes by a
manganese-catalyzed C-H activation, although stoichio-
metric ZnBr and Me Zn are required as Lewis acid to ac-
HCHO in H O) gave the 3a in 92% yield (entry 13). Con-
2
trol reaction confirmed that the transformation did not
occur in the absence of the ruthenium catalyst (entry 14)
2
2
tivate the aldehydes, thus inevitably generating stoichio-
or AgSbF (entry 15).
6
[
9]
[a]
metric unwanted wastes (Scheme 2b). Despite great
advances, all reactions were limited to aryl or alkyl alde-
hydes and C-H addition to significantly more challenging
formaldehyde have unfortunately proven elusive thus far.
Furthermore, the scope with respect to the directing
group was largely limited to strongly coordinating direct-
ing groups (eg. pyridine, pyrimidine and pyrazole) that
are difficult to remove or modify. Therefore, it remains an
unmet challenge to develop transition-metal-catalyzed
environmentally benign C-H addition to challenging for-
Table 1. Reaction optimization.
yield
entry
catalysts
additive
solvent
[b]
(%)
maldehyde.
Given
the
importance
of
hy-
1
2
3
4
5
[Cp*RhCl
Cp*Rh(MeCN)
[Cp*IrCl /AgSbF
Cp*CoI (CO)/AgSbF
2
]
2
/AgSbF
6
-
-
-
-
-
THF
THF
THF
THF
THF
8
droxymethylarenes in organic chemistry and pharmaceu-
tical industries, and with our continuing interest in the
3
(SbF
6
)
2
6
2
]
2
6
<5
<5
47
[10]
sustainable organic synthesis, we herein report the first
catalytic addition of aryl C-H bonds to formaldehyde
which proved viable with highly selective ruthenium(II)
2
6
[RuCl
2
(p-cymene)]
2
/AgSbF
6
1
,4-
[11]
catalysts (Scheme 2c). Notably, many different directing
groups (not limited to strongly heterocyclic directing
groups) can be used in the C-H hydroxymethylation reac-
tion and this protocol was carried out in the presence of
water and air, and without stoichiometric undesirable
waste under mild reaction conditions.
6
[RuCl
2
(p-cymene)]
2
/AgSbF
6
-
43
dioxane
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
7
8
9
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
[RuCl
2
2
2
2
2
2
2
(p-cymene)]
(p-cymene)]
(p-cymene)]
(p-cymene)]
(p-cymene)]
(p-cymene)]
(p-cymene)]
2
2
2
2
2
2
2
/AgSbF
/AgSbF
/AgSbF
/AgSbF
/AgSbF
/AgSbF
/AgSbF
6
-
39
60
72
71
87
70
92
0
6
-
6
AcOH
PivOH
1
0
6
1
1
[c]
[d]
6
NaH
NaH
NaH
NaH
NaH
2
2
2
2
2
PO
PO
PO
PO
PO
4
4
4
4
4
1
2
3
6
1
6
1
4
5
AgSbF
6
1
[RuCl (p-cymene)]
2
2
0
[
a] Conditions: 1a (0.2 mol), polyformaldehyde (0.6 mmol),
catalyst (2.5 mol%), AgSbF6 (10 mol%) and additive (20
mol%) were dissolved in the solvent (0.1 M) and heated at
the 60 °C for 12 h in a sealed tube. [b] Yield isolated by col-
umn chromatography. [c] The reaction was carried out at 90
o
C. [d] Replacement of polyformaldehyde with formalin (40%
HCHO in H O).
2
Scheme 2. Transition-metal-catalyzed addition of C-H bonds
to aldehydes to produce alcohols.
With the optimized reaction conditions in hand, we
embarked on an investigation of the scope of this C-H
hydroxymethylation reaction (Scheme 3). It was found
that the electronic and steric effects of the substituents at
the phenyl ring did not play key roles. Various substrates
containing electron-donating (3b, 3c, 3e and 3f) and -
withdrawing (3d, 3g-i) groups at ortho- (3b), meta- (3c
and 3d) or para- (3e-i) position on the phenyl ring were
readily coupled with formaldehyde to provide the corre-
sponding products in good to excellent yields. In particu-
lar, with a methyl group at the 2-position of the phenyl
ring (3b) or at the 3-position of the pyridine ring (3j), the
The 2-phenylpyridine (1a) was selected as a model sub-
strate. Given the remarkable ability of Cp*Rh(III) complex
[8,12]
to catalyze the C-H addition to polar multipe bonds,
we first carried out the reaction of 2-phenylpyridne (1a)
and polyformaldehyde (2a) in the presence of 2.5 mol%
(
Cp*RhCl ) , 10 mol % AgSbF at 60 °C in THF, providing
2 2 6
the hydroxymethylation product 3a in only 8% yield (Ta-
ble 1, entry 1). The prepared Rh (III) precursor
[Cp*Rh(CH CN) ](SbF ) led to a slightly decreased yield
3 3 6 2
(
entry 2). Other catalytic systems were next examined
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reactions exhibited good reactivities, thus showing high
tolerance for steric hindrance. The meta-substituted sub-
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strates (3c and 3d) gave two regioisomers in good yields.
This C-H hydroxymethylation reaction showed excellent
compatibility with various functional groups, such as
OMe (3c and 3f), Cl (3d), Br (3g), COOMe (3h) and even
the electrophilic CHO groups (3i). Of note, heterocyclic
substrates proved to be reactive, providing the product 3k
in good yield. Tricyclic benzo[h]quinoline (3l) was found
to be useful in this transformation. Arenes containing
other directing groups such as pyrimidine (3m), oxazole
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(3n) and pyrazole (3o) also worked well.
DG
[RuCl2(p-cymene)]2 (2.5 mol %)
DG
H
CH2OH
HCHO
AgSbF6 (10 mol %)
NaH2PO4 (20 mol %)
DCE, 60 oC, 12 h
2
a
1
3
N
N
N
N
CH2OH
CH2OH
CH2OH HOH2C
MeO
MeO
Scheme 4. The Scope of readily functionalizable directing
groups. Reaction Conditions: [RuCl (p-cymene)] (2.5 mol%),
3a, 92%
3b, 81%
3c, 48%
3c', 38%
2
2
AgSbF6 (10 mol%), 1 (0.1 mmol), polyformaldehyde (0.3
N
N
N
N
mmol), NaH PO (20 mol%) were dissolved in the DCE (0.1
2
4
CH2OH HOH C
2
CH OH
2
CH OH
2
M) and heated at the 60 °C for 12 h in sealed tubes. [a]
Reaction Conditions: [RuCl (p-cymene)] (2.5 mol%), AgSbF
6
2
2
Cl
Cl
(
10 mol%), 1 (0.1 mmol), formalin (0.3 mmol), CsOPiv (50
OMe
3
d, 43%
3d', 40%
3e, 92%
3
f, 88%
mol%) were dissolved in the DCE (0.1 M) and heated at the
6
0 °C for 12 h in sealed tubes.
N
N
N
N
We were pleased to find that the present C-H hy-
CH2OH
CH2OH
CH2OH
CH2OH
droxymethylation reaction is potentially applicable in
large-scale synthesis (Scheme 5a). The utility of the direct
C−H hydroxymethylation reaction as a tool for late-stage
modification of bioactive complex estrone derivative 5
was demonstrated, affording the corresponding hy-
droxymethylation product 6 in 70% yield (Scheme 5b).
The deprotection of oximes for 4k gave the 5-
Br
g, 63%
COOMe
3h, 81%
CHO
3i, 62%
3
3j, 86%
N
N
N
N
N
N
O
N
CH2OH
CH2OH
CH2OH
S
CH2OH
CH2OH
(
hydroxymethyl)chroman-4-one 7k in good yield (Scheme
3k, 78%
3l, 71%
3m, 68%
3o
,
56%
3
n, 76%
5c). To further illustrate the synthetic utility of this direct
C-H hydroxymethylation reaction, a variety of transfor-
mations of 3a are displayed. Biologically active pyrido[2,1-
a]isoindole 8a and indolizino[3,4,5-ab]isoindole 9a can be
Scheme 3. Substrate Scope. Reaction Conditions:
[RuCl2(p-cymene)]2 (2.5 mol%), AgSbF6 (10 mol%), 1 (0.2
mmol), formalin (40% HCHO in H2O) (0.6 mmol),
NaH2PO4 (20 mol%) were dissolved in the DCE (0.1 M) and
heated at the 60 °C for 12 h in sealed tubes.
[13]
easily prepared from 3a (Scheme 5d). Hydrogenation of
[14]
3
a provided the 2-Me derivative 10a (Scheme 5d).
In addition to strongly heterocyclic directing groups,
the scope of the directing group was further defined by
using various readily functionalizable directing groups
(
Scheme 4). Arenes (4a-d) bearing acylamido group un-
derwent the ortho-hydroxymethylation in acceptable
yields. Azobenzene (4e) exhibited comparable reactivity
and selectivity. Electronically modified ketoximes were
smoothly coupled with formaldehyde to give hy-
droxymethylation products 4f-k. Other directing groups
such as ketone, aldehyde, and ester were not suitable for
this transformation (4l-n).
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Scheme 5. The synthetic application of the C-H hy-
droxymethylation reaction.
A series of preliminary experiments have also been per-
formed to probe the mechanism. H–D exchange was de-
tected when treating 2-phenylpyridine with formaldehyde
2
a in the presence of D O, indicative of the reversibility of
2
2
the ortho-C(sp )-H bond cleavage process (eq 1). No deu-
terium incorporation was observed in absence of catalyst.
In the reaction of 2-phenylpyridine (1a) and 2-phenyl-
On the basis of these preliminary studies, we propose
the catalytic cycle to involve an initial reversible cy-
[
d5]pyridine (1a-d5) with formaldehyde 2a, a kinetic iso-
tope effect of 1.6 was observed(eq 2). In addition, a kinetic
isotopic effect (KIE) of 1.5 was also observed from two
cloruthenation to form five-membered complex A and the
+
[11]
release of one equivalent of proton (H ) (Scheme 6).
[11q]
side-by-side reactions using 1a and 1a-d (eq 3). Both re-
Then the nucleophilic addition (or C=O insertion)
5
sults indicated that the C−H bond cleavage might not be
takes place to form the seven-membered O-Ru species B.
The intermediate B is protonated by the acid that is gen-
erated in situ at the initiating step, thus producing the
desired product 3a and regenerates the cationic rutheni-
um species 11.
[15]
involved in the rate-determining step. The competitive
reaction of an equimolar amount of 1f, 1h, and 2a under
the standard conditions gave a mixture of 3f and 3h in a
3
:1 ratio, indicating that the electron-rich arenes
inherently react preferentially (eq 4). This observation
can be rationalized in terms of an electrophilic C-H
[11]
ruthenation. Furthermore, we prepared a ruthenacycle
[16]
1
0, which not only successfully catalyzed the current
coupling reaction (eq 5), but also reacted stoichiometri-
cally with 2a to give 3a (eq 6), indicating that this five-
membered complex was indeed an active species in the
catalytic cycle .
Scheme 6. Plausible Mechanism.
In summary, we have reported the first C-H hy-
droxymethylation reaction under chelation assistance. A
user-friendly ruthenium(II) complex efficiently catalyzed
the site-selective C-H hydroxymethylation under mild
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reaction conditions. Many different directing groups (not
b) Li, H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang, X.; Shi, Z.-J. J. Am.
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Chem. Soc. 2011, 133, 15244-15247.
limited to strongly heterocyclic directing groups) can be
used in the C-H hydroxymethylation reaction and this
protocol was carried out in the presence of water and air,
without stoichiometric undesirable waste, thus offering
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an
environmentally
benign
method
of
hy-
[
6] a) Fukumoto, Y.; Sawada, K.; Hagihara, M.; Chatani, N.;
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1
available free of charge at acs.org. Experimental details, H,
1
3
and C NMR characterization of products.
AUTHOR INFORMATION
Corresponding Author
zhoubing@simm.ac.cn; zhoubing2012@hotmail.com
Author Contributions
[8] a) Yang, L.; Correia, C. A.; Li, C.-J. Adv. Synth. Catal. 2011,
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53, 1269; b) Li, Y.; Zhang, X.-S.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett.
012, 14, 4498-4501; c) Y. Li, X.-S. Zhang, K. Chen, K.-H. He, F.
Pan, B.-J. Li, Z.-J. Shi, Org. Lett. 2012, 14, 636-639.
9] Zhou, B.; Hu, Y.; Wang, C. Angew. Chem. Int. Ed. 2015,
4, 13659-13663.
10] a) Yang, Y.; Wang, X.; Li, Y.; Zhou, B. Angew. Chem. Int.
Y. W. and B. Z. directed the project. / B. Z. wrote the manu-
script with the assistance of Y. W.. / B. Z. conceived and de-
signed the project. / All authors have given approval to the
final version of the manuscript. /
[
5
[
Ed. 2015, 54, 15400-15404; b) Zhou, B.; Chen, Z.; Yang, Y.; Ai, W.;
Tang, H.; Wu, Y.; Zhu, W.; Li, Y. Angew. Chem. Int. Ed. 2015, 54,
12121-12126; c) Zhou, B.; Hou, W.; Yang, Y.; Li, Y. Chem. Eur. J.
Notes
The authors declare no competing financial interest.
2
013, 19, 4701-4706; d) Zhou, B.; Du, J.; Yang, Y.; Feng, H.; Li, Y.
Org. Lett., 2013, 15, 6302-6305;
11] For recent reviews on ruthenium(II)-catalyzed C−H
functionalizations, see: (a) Ackermann, L. Org. Process Res. Dev.
015, 19, 260-269. (b) Bruneau, C. Top. Organomet. Chem. 2014,
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ACKNOWLEDGMENT
[
Support of this work by the CAS Pioneer Hundred Talents
Program, and "Personalized Medicines——Molecular Signa-
ture-based Drug Discovery and Development", Strategic Pri-
ority Research Program of the Chinese Academy of Sciences
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L. Adv. Synth. Catal. 2014, 356, 1461-1479. d) Kozhushkov, S. I.;
Ackermann, L. Chem. Sci. 2013, 4, 886-896 ; e) Li, B.; Dixneuf, P.
H. Chem. Soc. Rev. 2013, 42, 5744-5767; f) Arockiam, P. B.; Bru-
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Grant No. XDA12020333) is gratefully acknowledged.
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