Dearomatization-Rearomatization Strategy for Synthesizing Carbazoles with 2,2′-Biphenols and Ammonia by Dual C(Ar)-OH Bond Cleavages

Article abstract of DOI:10.1021/acs.jafc.0c00644

Carbazole is an essential building block in various pharmaceuticals, agrochemicals, natural products, and materials. For future sustainability, it is highly desirable to synthesize carbazole derivatives directly from renewable resources or cheap raw materials. Phenolic compounds are a class of degradation products of lignin. On the other hand, ammonia is a very cheap industrial inorganic chemical. Herein, an efficient dearomatization-rearomatization strategy has been developed to directly cross-couple 2,2′-biphenols with ammonia by dual C(Ar)-OH bond cleavages. This strategy provides a greener pathway to synthesize valuable carbazole derivatives from phenols.

Full text of DOI:10.1021/acs.jafc.0c00644

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Dearomatization-Rearomatization Strategy for Synthesizing Carbazoles
with 2,2-Biphenols and Ammonia by Dual C(Ar)-OH Bond Cleavages
Dawei Cao, Jing Yu, Huiying Zeng, and Chao-Jun Li
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.0c00644 • Publication Date (Web): 30 Mar 2020
Downloaded from pubs.acs.org on April 8, 2020
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Dearomatization-Rearomatization Strategy for Synthesizing Carbazoles with 2,2’-Biphenols
and Ammonia by Dual C(Ar)–OH Bond Cleavages
Dawei Cao,a Jing Yu,a Huiying Zenga, *and Chao-Jun Li b, *
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a The State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China.
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b Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill
University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
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Abstract
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Carbazole is an essential building block in various pharmaceuticals, agrochemicals, natural
products, and others. For future sustainability, it is highly desirable to synthesize carbazole
derivatives directly from renewable resources or cheap raw materials. Phenolic compounds are a
class of degradation products of lignin. On the other hand, ammonia is a very cheap industrial
inorganic chemical. Herein, an efficient dearomatization-rearomatization strategy has been
developed to directly cross-couple 2,2’-biphenols with ammonia by dual C(Ar)–OH bond
cleavages. This strategy provides a greener pathway to synthesize valuable carbazole derivatives
from phenols.
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Key words: carbazoles, 2,2’-biphenols, ammonia, C(Ar)–O bond cleavage, lignin phenolic
compound
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INTRODUCTION
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Phenols are the most abundant aromatics in natural biomass and are readily available by the
degradation of lignins.1-5 Although converting phenols into anilines with ammonia at 220-250 ˚C
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is a well-known industrial procedure,
to achieve such conversions under mild conditions for
synthesizing fine chemicals, pharmaceuticals and agrochemicals are still very challenging. 2,2’-
Biphenols are 5-5’ linkage model compounds of lignin and have a fair amount of natural
abundance. Furthermore, they can be readily generated from the oxidative Cross-Dehydrogenative
Coupling (CDC) of a diverse array of phenols,8-10 which can be readily obtained from lignin
depolymerizations. Therefore, converting 2,2’-biphenols into value-added chemicals is highly
desirable.
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Carbazoles are common and important nitrogen-containing heterocyclic compounds in natural
products and bioactive molecules (Figure 1).11-16 Many carbazole-containing molecules exhibit
antimalarial, antiviral and antitumor activities.17-20 Furthermore, carbazoles are also important
skeletons in photophysical materials, such as polymeric light-emitting diodes (PLEDs) and organic
light-emitting devices (OLEDs).21-32 Given the tremendous importance and usefulness of these
carbazole based compounds, various approaches have been developed to construct functionalized
carbazoles.33 Traditionally, Fischer−Borsche reaction is the main method to synthesize carbazole
compounds,34,35 but the process requires multiple steps including condensation, cyclization and
dehydrogenation. Subsequently, a one-pot C–C and C–N bond bond-forming coupling reaction
was used to synthesize carbazole derivatives.36-51 In recent years, indole as a readily available raw
material provided an opportunity for the synthesis of carbazoles.52-62 More recently, intramolecular
C–H Amination was reported to construct carbazoles.63 Very recently, the conversion of 1,1’-bi-
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2-naphthol into 7H-dibenzo[c,g]carbazole was reported by Ito and Kawamoto’s group with
prolonged heating at 200 ℃.64,65
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As a long term objective to valorize agricultural biomass into high-valued chemical products,
we have successfully coupled phenols, the degradation products of lignin, with different
nucleophilic reagents to produce a series of useful molecular structures.66-72 However, in order to
be economically viable, it is important to use the more economical starting material ammonia to
couple with phenols. Very recently, our group has developed a dearomatization-rearomatization
strategy73 to synthesize aryl amines by reacting phenols with hydrazine (Scheme 1a).74 Moreover,
we also used this strategy to construct other amine compounds by C(Ar)–O bond cleavages of
phenols or diaryl ethers (Scheme 1b).75,76 However, it would be even more desirable and
challenging to obtain more complex and valuable structures directly from simple phenols and
simple ammonia. Herein, we report a new method of synthesizing carbazoles from 2,2’-biphenols
and ammonia by dual C(Ar)–OH bond cleavages via a dearomatization-rearomatization strategy
(Scheme 1c).
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MATERIALS AND METHODS
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In order to optimize the dearomatization-rearomatization conditions, the cross-coupling reaction
of [1,1'-biphenyl]-2,2'-diol with ammonia was carried out by using Pd(OH)2/C as catalyst and
NaBH4 as hydride source under argon atmosphere (Table 1, entry 1). Gratifyingly, the desired
carbazole 3a and by-products 4a were obtained in 43% and 22% yields, respectively. However,
other palladium catalysts such as Pd/C, Pd/Al2O3 and Pd(OAc)2 showed low or poor activity for
this transformation (Table 1, entries 2-4). When HCO2Na was used as a hydrogen source, the by-
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product 4a was significantly reduced, likely because of its weaker reducing ability compared with
NaBH4 (Table 1, entry 5). Various solvents including toluene, 1,4-dioxane, H2O and mixed
solvents were examined (Table 1, entries 6-9). These results illustrated that the addition of water
could increase the conversion of the raw materials, but the yield of by-product 4a was increased
more than the desired product 3a (Table 1, entry 9). To our gratification, adding an appropriate
amount of TFA could significantly enhance the yield of the desired product (Table 1, entries 10-
11). Surprisingly, when m-xylene alone was used as the solvent, the yield of 9H-carbazole (3a)
was raised to 80% (Table 1, entry 12). Increasing the amount of HCO2Na to 5.0 equiv, 9H-
carbazole (3a) was obtained with 93% yield (Table 1, entry 13). Reducing the amount of TFA to
0.5 equiv only slightly affected the reaction (Table 1, entry 14). However, when the amount of
ammonia was decreased, the reaction yield was also significantly reduced (Table 1, entries 15-16).
Finally, different reaction temperatures and times were investigated (Table 1, entries 17-21), with
the optimized ones being 140 oC and 24 h, respectively. Interestingly, when hydrogen atmosphere
(1 atm) was used instead of sodium formate, 62% yield of carbazole was also detected (Table 1,
entry 22).
RESULTS AND DISCUSSION
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With the optimal reaction conditions established, the scope of 2,2’-biphenols was explored
(Table 2). Symmetrical 2,2’-biphenols (1a-b) were successfully cross-coupled with ammonia to
afford the corresponding carbazoles with good yields. However, when an allyl-substituted
substrate 1b was used, the carbon-carbon double bond was also reduced under the standard
conditions. To our delight, unsymmetrical 2,2’-biphenols (1c-i) with electron-donating (Me, Et, i-
Pr, OMe,) and electron withdrawing (F, CF3) groups at different positions were well tolerated and
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generated the desired carbazoles. When fluoro- and methoxy-containing substrates (1f-i) were
used, only defluorination and demethoxylation products were obtained. Moreover, different
amines, such as methylamine and ethylamine, were also tested to explore the generality of this
reaction, and the corresponding products (3f-g) were obtained in good yields. However, when
other primary amines, such as n-hexylamine, n-octylamine, were used for this transformation, no
carbazole product was obtained; instead, these amines homocoupled to form secondary and tertiary
amines.
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Based on our previous studies, a plausible mechanism is given in Scheme 2. The H-Pd-H species
is formed when palladium reacted with sodium formate. Then, one of the phenol groups is
reductively dearomatized by this species to generate cyclohexanone A, which condenses with
ammonia to form imine B (the condensation of ketones with ammonia could be promoted by TFA).
Further reduction of B generates amine C. There are two possible pathways from C to the product
carbazole: a) One possible pathway (path a) is via an oxidative rearomatization to form aniline D,
and the other phenol group undergoes a similar reduction-condensation-rearomatization via
intermediate E and imine F to generate product 3a with the concurrent generation of by-product
4a by further reduction of imine F; b) Alternatively, the intermediate C is further reduced to form
cyclohexanone G (path b), and then intramolecular condensation forms imine H, which is
oxidatively aromatized to generate by-product 4a and further oxidatively aromatized to form the
product 3a.
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In summary, we have successfully developed a palladium-catalyzed synthesis of carbazoles
from 2,2’-biphenols and cheap industrial inorganic chemical ammonia by dual C(Ar)–OH bond
cleavages, via a dearomatization-rearomatization strategy. Various biphenols bearing substituents
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such as alkyl, alkenyl, fluoro and trifluoromethyl are readily converted into the corresponding
carbazole derivatives. Water was the sole stoichiometric waste in this synthetic protocol. This
method provides a sustainable protocol to synthesize carbazole derivatives from 2,2’-biphenols
(some are available from agricultural biomasses) and ammonia.
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ASSOCIATED CONTENT
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Supporting Information
The Supporting Information is available free of charge on the website at DOI:
https://pubs.acs.org/doi/10.1021/acs.jafc
General experimental procedures, characterization details, and copies of H and 13C NMR
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spectra of new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: zenghy@lzu.edu.cn
*E-mail: cj.li@mcgill.ca.
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ORCID
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Huiying Zeng: 0000-0002-2535-111X
Chao-Jun Li: 0000-0002-3859-8824
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We thank the NSFC (21971093), the FRFCU (lzujbky-2018-62), Gansu provincial Sci. & Tech.
Department (Nos. 2016B01017, 18JR3RA284, 18JR4RA003) and the 111 project for support of
our research. We also thank the Canada Research Chair (Tier I) foundation, the E.B. Eddy
Endowment Fund, the CFI, NSERC, and FQRNT to C.-J.L.
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R. J. K.; Unsworth, W. P., Silver(I)-Catalyzed Dearomatization of Alkyne-Tethered Indoles:
Divergent Synthesis of Spirocyclic Indolenines and Carbazoles. Org. Lett. 2015, 17, 4372-4375.
(55) Ozaki, K.; Zhang, H.; Ito, H.; Lei, A.; Itami, K., One-Shot Indole-to-Carbazole π-Extension
by a Pd-Cu-Ag Trimetallic System. Chem. Sci. 2013, 4, 3416-3420.
(56) Samala, S.; Mandadapu, A. K.; Saifuddin, M.; Kundu, B., Gold-Catalyzed Sequential Alkyne
Activation: One-Pot Synthesis of NH-Carbazoles via Cascade Hydroarylation of Alkyne/6-Endo-
Dig Carbocyclization Reactions. J. Org. Chem. 2013, 78, 6769-6774.
(57) Saravanan, V.; Mageshwaran, T.; Mohanakrishnan, A. K., Synthesis of Cyclo[b]fused
Carbazoles via SnCl4-Mediated Domino Reaction of 2-Indolylmethylpivalates with Arenes and
Heteroarenes. J. Org. Chem. 2016, 81, 8633-8646.
(58) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.; Nagase, Y.; Miyamura, T.; Shirakawa, E.,
Indium-Catalyzed Annulation of 2-Aryl- and 2-Heteroarylindoles with Propargyl Ethers: Concise
Synthesis and Photophysical Properties of Diverse Aryl- and Heteroaryl-Annulated[a]carbazoles.
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(59) Wang, S.; Chai, Z.; Wei, Y.; Zhu, X.; Zhou, S.; Wang, S., Lewis Acid Catalyzed Cascade
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Compounds by Palladium-Catalyzed Oxidative Coupling of Heteroarene Carboxylic Acids with
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Combined Experimental and Computational Investigation. Org. Biomol. Chem. 2014, 12, 4832-
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320
Figures:
Figure 1. Carbazole-containing biomolecules and materials
Me
CHO
OH
N
Me
OMe
Me
N
H
MeO
N
H
Me
N
H
Clausine V
Mukonal
Ellipticine
COOMe
OH
O
O
N
H
N
N
H
H
OH
OR
O
OMe O
R=H Causamine-A
R=Me Clausamine-B
Clausine E
Clausamine-C
R
O
N
H
OMe
O
O
O
Clausine E
O
R=Me Murrayafoline A
R=CH2OH Koenoline
R=CHO Murrayanine
R=COOH Mukoeic acid
R=CO2Me Mukonine
N
N
H
OMe
H
OMe
Furanoclausamine A
Furanoclausamine B
321
322
Schemes:
323
Scheme 1. Converting phenols into high-valued chemicals
(a) From phenols to anilines
NH2
OH
NH2NH
2 H2O
(b) From diaryl ethers or phenols to aryl amines
OH
H
N
O
NH2 NH
2 H2O
or
NH
or
3 H2O
(c) From biphenyldiols to carbazoles (this work)
OH
Pd(OH)2/C
HCO2Na
H
N
NH3 H2O
+
TFA
OH
324
325
Scheme 2. The plausible mechanism
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dearomatization
HN
O
HO
H2N
NH3
HPdH
Pd0
path b
Pd0
HPdH
Pd0
H2O
OH
OH
OH
1a
OH
A
B
C
H2N
rearomatization
H
N
HPdH
N
Pd0
HPdH
path a
Pd0
H2O
4a
O
Pd0
H
G
HPdH
H2N
H2N
H
N
N
HPdH
Pd0
rearomatization
Pd0
OH
H2O
O
3a
E
F
D
326
327
328
Tables:
Table 1. Optimization of the reaction conditionsa
NH3 H2O
catalyst
OH
+
additive, T
solvent, time
N
H
N
H
OH
1a
3a
4a
Additive
(equiv)
H Source
(equiv)
3ab
Yield/%
4ab
Yield/%
Entry
Catalyst
Solvent
1
2
Pd(OH)2/C
Pd/C
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
toluene
NaBH4 (1)
NaBH4 (1)
43
35
22
10
3
Pd/Al2O3
NaBH4 (1)
n.p.
n.p.
30
n.p.
n.p.
8
4
Pd(OAc)2
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
NaBH4 (1)
5
HCO2Na (3)
HCO2Na (3)
HCO2Na (3)
HCO2Na (3)
HCO2Na (3)
HCO2Na (3)
HCO2Na (3)
HCO2Na (3)
HCO2Na (5)
HCO2Na (5)
HCO2Na (5)
HCO2Na (5)
HCO2Na (5)
HCO2Na (5)
HCO2Na (5)
HCO2Na (5)
HCO2Na (5)
H2 (1 atm)
6
32
16
7
1,4-dioxane
H2O
n.p.
21
n.p.
49
8
9
H2O/toluene = 4/1
H2O/toluene = 4/1
H2O/toluene = 4/1
m-xylene
20
47
10
11
12
13
14
15c
16d
17e
18f
19g
20h
21i
22f
TFA (1)
TFA (1.5)
TFA (1)
TFA (1)
TFA (0.5)
TFA (1)
TFA (1)
TFA (1)
TFA (1)
TFA (1)
TFA (1)
TFA (1)
TFA (1)
43
20
47
18
80
trace
trace
16
m-xylene
93
m-xylene
75
m-xylene
48
n.p.
trace
trace
trace
trace
trace
trace
5
m-xylene
75
m-xylene
80
m-xylene
95 (91)
65
m-xylene
m-xylene
65
m-xylene
96
m-xylene
62
a
General conditions: 1a (0.2 mmol), ammonia 2a (8 equiv), catalyst (20 mol%), HCO2Na (3 equiv), and
solvent (1 mL) stirred at 150 ºC for 24 h under argon atmosphere. b Yields were determined by 1H NMR with
nitromethane as internal standard; isolated yields in brackets. c NH3•H2O (2 equiv). d NH3•H2O (5 equiv). e
160 ºC. f 140 ºC. g 120 ºC. h 12 h. i 36 h.
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329
Table 2. Substrate scope of cross-coupling of biphenols with ammoniaa
OH
R1
Pd(OH)2/C
R1
HCOONa
R2
NH3 H2O
+
R2
m-xylene
140 oC, 24 h
N
H
HO
1
2a
3
Substrates
OH
Products
Substrates
OH
Products
MeO
N
H
N
H
HO
1a
HO
3a
92%
1g
3a
88%
n-Pr
n-Pr
OH
OH
N
H
N
HO
H
F
HO
1b
3b
3c
3d
90%
3a
82%
1h
OH
OH
N
H
93%
N
HO
1c
H
F3C
HO
3c
OH
78%
1i
OH
N
H
HO
1d
88%
HO
3a
N
OH
i-Pr
CH3NH2
3f
86%
2b
N
H
i-Pr
HO
OH
1e
3e
72%
OH
N
HO
3a
N
H
CH3CH2NH2
MeO
HO
3g
72%
2c
3a
90%
1f
1
2
a General conditions: (0.2 mmol), ( (8.0 equiv), catalyst (20 mol%), HCO2Na (5.0 equiv), TFA
(1.0 equiv) and m-xylene (1.0 mL) at 140 °C for 24 h under argon atmosphere.
330
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331
TOC Graphic
H
OH
N
cat. Pd(OH)2/C
NH3 H O
+

2
TFA, HCO2Na
OH
m-xylene
cheap industrial
carbazole
inorganic chemical
derivatives
332
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