Oxidative ortho-amino-methylation of phenols via C-H and C-C bond cleavage

Article abstract of DOI:10.1039/c3ra46373g

Initiated by CCl₃Br, phenols undergo efficient ortho-selective oxidative cross dehydrogenative coupling (CDC) with trimethylamine. When tetramethylethylenediamine (TMEDA) is used instead of trimethylamine, oxidative carbon-carbon activation coupling (CAC) could occur to give the same salicylamines together with CDC by-products. These reactions are accelerated by a gold salt.

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ARTICLE TYPE
Oxidative orthoꢀaminoꢀmethylation of phenols via C─H and C─C bond
cleavage
Wenbo Sun,a Huacan Lin,a Wenyu Zhoub* and Zigang Li a *
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Initiated by CCl3Br, Phenols undergo efficient orthoꢀselective
of phenols. Based on our knowledge, there is no previous report
oxidative cross dehydrogenative coupling (CDC) with
on salicylamine synthesis via a CAC pathway. Herein, we report
trimethylamine. When tetramethylethylenediamine(TMEDA) 50 a gold accelerated oxidative CAC process between phenols and
is used instead of trimethylamine, oxidative carbonꢀcarbon
TMEDA to afford salicylamines. Similar conditions could also
be applied to CDC reactions between phenols and trimethylamine
to yield same products.
10 activation coupling (CAC) could process to give same
salicylamines together with CDC byꢀproducts. These
reactions are accelerated by gold salt.
R2
55
R2
Ru(bpy) Cl 6H O (0.05 eq)
3
2
2
NMe2
NO2
NO2
Phenols are important building blocks in pharmaceutics,
lubricants and fine chemicals.[1] Selective alkylation of phenols is
15 of interest for many decades. For some related expamples, Pettus
et al. reported a constructing method using protected phenols
bearing an orthoꢀcarbonyl group with organoꢀmetal reagents;
Kuninobu and Takai et al. reported a Rheniumꢀcatalyzed orthoꢀ
alkylation of phenols with alkenes; in addition to early reports of
20 ortho alkylation of phenols with allyl alcohols, Yi et al. recently
reported an intriguing dehydrating coupling between phenols and
alcohols to afford orthoꢀalkylated phenols; Capdevielle et al.
reported a copper mediated oxidation of amines into amino Nꢀ
oxide to couple with electron deficient phenol; Hansen et al.
25 utilized Eschenmoser’s salt and its derivatives to react with
phenols via a Mannich process.[2] Despite of these efforts, Lack
of chemoꢀselectivity and phenol functional group tolerance is still
the main drawback of existing methodologies.
Pioneered by Li and others, the concept of cross
30 dehydrogenative coupling (CDC) is employed in synthesizing
various valuable building blocks, which generally involves a
metal mediated oxidative process intermolecularly.[3] Hansen’s
method is efficient in constructing salicylamines, however, it is
an extended classic FriedelꢀCrafts reaction and the CDC process
35 with a phenol substrate is rare and needs further exploration and
elucidation.[2g, 2i]
Comparing with C─H bonds, C─C bonds are weaker in
bond energy but much less accessible, the steric hindrance
tremendously limits their synthetic applications.[4] Intramolecular
40 C─C bond cleavage and reformation are well documented as
various rearrangement reactions from the early stage of organic
synthesis,[5] however, C─C activation coupling(CAC) via an
intermolecular manner is less developed.[6] Recently, we reported
a visible light induced Henry type reaction as shown in Scheme
45 1.[7] In this process, TMEDA could be viewed as masked
Eschenmoser’s salt[8] under oxidative conditions, which may
participate in further transformations such as aminomethylation
R1
R1
+
MeCN, r.t., 1 atm O ,
2
NMe2
H
visible light
NMe2
+
N
60 Scheme 1. Photoꢀinduced CAC between TMEDA and nitro
compounds
Table
1.
Screening
of
conditions
65
70
75
a
Reactions were performed at 0.1 mmol scale based on phenol with 3 equiv. oxidant and 10 equiv.
TMEDA in 2 ml solvent at room temperature with 5% catalyst loading except indicated otherwise.
80 Conversion based on NMR with CH2Br2 as internal standard. O2 balloon. Reaction was performed at 1
mmol scale in 5 ml solvent with 5% catalyst, 3 equiv. BrCCl3 and 10 equiv. TMEDA at room temperature,
b
c
d
which
is
set
as
the
standard
conditions.
combined
isolated
yields.
The visible lightꢀinduced conditions shown in scheme 1 was
85 first tested (entry 1, table 1). To our disappointment, only 28%
NMR yield is achieved with O2 as oxidant. The conversion
increases almost quantitatively when the oxidant is changed to
BrCCl3; however, BrCCl3 without catalyst could also mediate this
transformation with a prolonged reaction time.(entry 2, table 1)
90 Various Lewis acids/Bronsted acids are tested for their
accelerating efficiency and HAuCl4 is superior for this reaction
with improved conversion. In this reaction, we also identified
CDC coupling product between TMEDA and phenol. The
combined conversion is reported in table 1. Control reactions
95 with or without light gave similar results when gold catalys is
present, brand new reaction vessels and stir bars were used to
eliminate possible trace low valent transition metal contamination.
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Gold salt may play roles other than an optimal
Phenols with both electron withdrawing groups or electron
Lewis/Bronsted acid to mediate electrophilic aromatic 70 donating groups are all suitable substrates of this reaction. To our
substitution of in situ generated iminiums phenol addition to the
in-situ generated Eschenmoser’s salt, since phenols bearing
electron withdrawing groups react as well or better than phenols
bearing electron donating groups. The exact role of gold catalyst
in this reaction still needs further elucidation.[9]
disappointment, ethyldimethylamine or butyldimethylamine
could only give limited conversion(~10%), partly due to the
difficulty of generating corresponding iminiums.
Interestingly, when naphthaleneꢀ2ꢀol is tested, together with
75 37% expected product, we identified naphthaleneꢀfused oxazine
in 8% isolated yield, which indicates an intriguing and novel
method for fused heterocycle synthesis. Aminomethylated
naphthaleneꢀ2ꢀol couldn’t undergo this reaction. (Scheme 2)
5
Table 2. CDC reactions between trimethylamine and phenols
OH
10
15
20
25
30
35
40
45
50
OH
BrCCl3
N
N
+
R1
DCM, 5% HAuCl4
R1
80
Entrya
Phenol
OH
Product
OH
Yield(%)b
a Standard condition. b Isolated yields.
Scheme 2. Formation of naphthaleneꢀfused oxazine
I
I
Me2
N
N
85
1
2
95
61
Table 3. CAC reactions between TMEDA and phenols
OH
OH
Br
F
Br
F
Me2
OH
OH
OH
TMEDA, BrCCl3
N
R
N
+
OH
OH
OH
OH
OH
OH
R
R
DCM, HAuCl4
90
95
N
Me2
Me2
N
N
3
4
50
Entrya
Substrate
R
Yield(%)b
Ratioc
33:30
1
2
3
4
5
6
7
8
9
F
Cl
Br
I
Ph
CF3
OMe
Me
Allyl
66
81
88
76
80
68
81
62
61
78c
52:29
53:35
43:33
35:45
29:39
50:31
31:31
31:30
OH
R
OH
OH
CF3
CF3
Me2
Me2
N
N
5
6
98c
52
OH
t-Bu
100
105
110
115
10
72
49:23
I
I
t-Bu
OH
OH
OH
OH
11
12
57:21
60:0
78
60
Me2
N
NMe2
7
8
22d
86e
I
I
I
OH
OH
OH
OH
N
N
N
N
OH
Me
13
23:33
56
N
OH
Me
Br
OH
9
91
OH
N
14
15
59
38
45:14
38:0
N
OH
OH
OH
Me
Br
Me
Br
OH
N
10
88
Me
Me
N
MeOOC
a Standard condition. b Combined isolated yields. c CAC:CDC product ratio.
OH
11
80
The results between TMEDA and phenols are summarized
120 in table 3. The reactions give good yields with moderate to good
selectivity between CAC and CDC products, which varies from
1:1 to 3:1. orthoꢀSubstituted phenols show better reactivity
(entries 1ꢀ9) than simple phenol (entry 14). Highly substituted
phenols also give reasonable yields.(entries 10, 13) Interestingly,
125 comparing entry 11 with scheme 2, no oxazine product is
detected. For entries 12 and 15, only CAC products are isolated.
metaꢀSubstituted phenols are unfavourable substrates in
MeO
O
MeO
O
a Reaction condition: phenol (1.0 mmol), TMA(gas), HAuCl4.3H2O (0.05 mmol), DCM (5 mL), BrCCl3 (3
b
c
mmol), r.t. Isolated yields based on phenol. Combined with 8% for entry 4 and 11% for entry 5
ortho,paraꢀdualꢀaddition product. d Combined yields. (10% 2ꢀortho coupling, 12% 5ꢀortho coupling.) e 63%
55 monoꢀaddition
product
plus
23%
dualꢀaddition
product.
Inspired from the CDC product between TMEDA and
phenol, we tested the reactivity between trimethylamine and
phenols. Results are summarized in table 2. paraꢀ or orthoꢀ
60 Substituted phenols generally give good to excellent yields with
high orthoꢀselectivity. Dual additions to both orthoꢀ and paraꢀ
position are also found in small amounts in some cases.(entries 4
and 5) metaꢀIodoꢀphenol shows no selectivity between its two
orthoꢀpositions with low yield.(entry 7, table 2) Simple phenol
65 gives both monoꢀ and dualꢀ addition products which could be
separated in 63% and 23% respectively. (entry 8, table 2) Also,
phenols bearing a heterocycle or with poly substitutions react
well under the standard condition.(entries 9 and 10, table 2)
previous reports of phenol alkylation, which is
a major
limitation.[3] In our case, despite lower reactivity, metaꢀiodo and
130 metaꢀethyl phenol react to give moderate yields as shown in
Scheme 3. This process has excellent orthoꢀselectivity to phenols.
If both orthoꢀpositions are blocked by methyl groups, the
aminomethylation would occur at the paraꢀposition with only the
CAC product in 23% isolated yields. Various diamines with
135 similar structure as TMEDA are tested, however, they could only
afford very low conversions.(SI table1)
2
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55
OH
OH
OH
OH
Conclusions
TMEDA, BrCCl3
DCM, HAuCl4
N
N
N
+
+
In summary, we report a novel phenol aminomethylation via
either C─C or C─H bond cleavage initiated by BrCCl3 with good
orthoꢀselectivity. This reaction provides important clues for
60 further study on C─C bond cleavage and it is the first case of
CAC alkylation of phenols. We propose a radical initiated
iminium intermediate. Further applications and mechanism
elucidation of this methodology are under current investigation.
N
I
I
I
I
9%
N
18%
16%
OH
OH
OH
TMEDA, BrCCl3
DCM, HAuCl4
N
+
N
5
56%
OH
17%
OH
TMEDA, BrCCl3
DCM, HAuCl4
10
65 Experimental
N
General procedure: An ovenꢀdried round bottom flask (25
mL) was equipped with magnetic stir bar and charged with
phenol (1 mmol, 1.0 equiv.), TMEDA(10 mmol, 10.0 equiv.),
HAuCl4.3H2O (0.05 mmol, 0.05 equiv.), BrCCl3 (3 mmol, 3.0
70 equiv.) and DCM (10.0 mL). The mixture was then stirred under
a balloon nitrogen atmosphere at room temperature until the
starting material disappeared from the TLC. After that the solvent
was removed under reduced pressure, and the residue was
purified by silica gel column chromatography to afford the
75 desired pure product.
23%
Scheme 3. Reactions of substituted phenols at standard
conditions.
15
When TEMPO is added, the yield dramatically decreases and
TEMPOꢁCCl3 adduct is identified by MS, which hints that a
radical process may be involved. However, phenol bearing a
radical sensitive cyclopropane is not affected in both products
20 and recovered substrates, which suggests an iminium pathway,
shown in Scheme 4.
Acknowledgements
OH
OH
OH
We thank the National Natural Science Foundation of China
Grant 21102007, the Shenzhen Science and Technology
80 Innovation Committee SW201110060 and SW201110018, the
Shenzhen Peacock Program (KQTD201103) to Z.G.L.
I
I
I
TMEDA, BrCCl3, DCM
N
N
+
1 eq. TEMPO, 5% HAuCl4
N
36%
19%
25
OH
OH
OH
TMEDA, BrCCl3, DCM
5% HAuCl4
N
N
+
Notes and references
N
10% sm recovery
a Key laboratory of Chemical Genetics, School of Chemical Biology and
Biotechnology, Shenzhen Graduate School of Peking University,
85 Shenzhen University Town, Shenzhen, China, 518055, Fax:86-755-2603-
3174; Tel: 86-755-2603-3616; E-mail: lizg@pkusz.edu.cn
Shenzhen Second People’s Hospital, 3002, ShunGang West Road,
Shenzhen, Guangdong, 518055, P.R.C. Fax: 86-755-8336-6388; Tel: 86-
755-8307-3866; E-mail: drzhouwenyu@163.com
90 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
33%
13%
Scheme 4. The possible pathway of this reaction
30
b
A tentative mechanism is proposed in Scheme 5: BrCCl3
initiates the reaction by generating radical species, which
deprives an electron from the N atom of TMEDA to form the
radical cation. TEMPO addition could inhibit the reactivity
35 during the first two steps. Then there could be two competitive
pathways: iminiums form by C─C cleavage or by C─H cleavage,
which leads to the CAC and CDC products respectively. The
steps involving phenols are not radicalꢀnature and won’t disturb
the radical sensitive cyclopropane, and gold catalyst could
40 accelerate the last step(s). The role of gold catalyst is elusive,
gold salt could significantly increases the reaction rate, however;
the electron density of phenols doesn't play a decisive role in
these reactions. This fact weakens the assumption of gold as a
simple Lewis acid/Bronsted acid in this reaction. However, from
45 the gold salts we screened, HAuCl4 behaves better than
Ph3PAuCl, Ph3PAuCl/AgOTf and AuCl, which indicates the
importance of catalyst’s acidity. Further mechanistic study is in
designing to reveal the effect of gold salt in this reaction.
BrCCl3
‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
95 spectral data, and crystallographic data.
[1] Barclay, L. R. C.; Vinqvist, M. R. The Chemistry of Phenols (Ed: Z.
Rappoport, WileyꢀVCH, Weinheim, 2003, p840.
100 [2] (a) R. W. Van De Water, D. J. Magdziak, J. N. Chau, T. R. R. Pettus, J.
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[4] J. Halpern, Acc. Chem. Res. 1982, 15, 238.
50
[5] B. Rybtchinski, D. Milstein, Angew. Chem., Int. Ed., 1999, 38, 870 and
references therein.
[6] For recent reviews of the CꢀC cleavage, see: (a) C.ꢀH. Jun, Chem. Soc.
OH
OH
Br
N
+ CCl3
N
N
TMEDA
115
120
Rev., 2004, 33, 610. (b) T. Tobisu, N. Chatani, Chem. Soc. Rev., 2008,
37, 300. (c) T. Satoh, M. Miura, Top. Organomet. Chem. 2005, 14, 1; (d)
C.ꢀH. Jun, J. W. Park, Top. Organomet. Chem. 2007, 24, 117. (e) Z. Xi,
Acc. Chem. Res. 2010, 43, 1342.
N
+
N
OH
N
HAuCl4
N
N
[7] S. Y. Cai, X. Y. Zhao, X. B. Wang, Q. S. Liu, Z.G. Li, D. Z.ꢀG. Wang,
Angew. Chem. Int. Ed. 2012, 51, 8050.
N
Scheme 5. Tentative mechanism
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[8] J. Schreiber, H. Maag, N. Hashimoto, A. Eschenmoser, Angew. Chem. Int.
Ed. 1971, 10, 330.
[9] Goldꢀaccelerated C─C cleavage process is rare, except for some
decarboxylation processes. (a) K. Vikse, G. N. Khairallah, J. S. McIndoe,
R. A. J. O'Hair, Dalton Trans. 2013, 42, 6440. (b) J. P. Fackler, M. N. I. J.
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1359. (f) P. GarcíaꢀGarcía, M. A. FernándezꢀRodríguez, E. Aguilar,
Angew. Chem. Int. Ed. 2009, 48, 5534. (g) Y. F. Chen, M. Chen, Y. H.
Liu, Angew. Chem. Int. Ed. 2012, 51, 6493.
5
10
4
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