Rh(III)-catalyzed synthesis of unsymmetrical acridines from aldehydes and azides using transient directing strategy in biomass-derived γ-valerolactone

Article abstract of DOI:10.1080/00397911.2018.1448418

An Rh(III)-catalyzed synthesis of unsymmetrical acridines from aldehydes and azides through bilateral cyclization process in biomass-derived γ-valerolactone has been developed. The in situ-generated imino directing group (DG) from aldehyde and catalytic a

Full text of DOI:10.1080/00397911.2018.1448418

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Rh(III)-catalyzed synthesis of unsymmetrical
acridines from aldehydes and azides using
transient directing strategy in biomass-derived γ-
valerolactone
Jun Shen, Xi Liu, Liang Wang, Qun Chen & Mingyang He
To cite this article: Jun Shen, Xi Liu, Liang Wang, Qun Chen & Mingyang He (2018): Rh(III)-
catalyzed synthesis of unsymmetrical acridines from aldehydes and azides using transient
directing strategy in biomass-derived γ-valerolactone, Synthetic Communications, DOI:
10.1080/00397911.2018.1448418
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SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2018.1448418
Rh(III)-catalyzed synthesis of unsymmetrical acridines from
aldehydes and azides using transient directing strategy
in biomass-derived γ-valerolactone
Jun Shen, Xi Liu, Liang Wang, Qun Chen, and Mingyang He
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of Petrochemical Engineering,
Changzhou University, Changzhou, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 19 October 2017
An Rh(III)-catalyzed synthesis of unsymmetrical acridines from
aldehydes and azides through bilateral cyclization process in
biomass-derived γ-valerolactone has been developed. The in situ-
generated imino directing group (DG) from aldehyde and catalytic
amount of BnNH2 worked as a transient directing group, thereby no
additional steps were required for installation and removal of the DG.
A series of functional groups were well tolerated, affording the desired
products in good to excellent yields. Gram-scale synthesis of the
product was also achieved.
KEYWORDS
C–H Activation; green
solvent; transient directing
groups; unsymmetrical
acridines
GRAPHICAL ABSTRACT
Introduction
Over the past decades, transition metal-catalyzed C–H functionalization has attracted
much attention. It provides a powerful and atom-economic way to construct complex
molecular scaffolds.[1] Particularly, with the assistance of suitable directing groups (DGs),
good reactivity and regioselectivity can be achieved.[2] However, the traditional C–H
activation processes still have some limitations: (i) additional steps are usually required for
installation and removal of the DGs; (ii) the direct C–H functionalization of aldehydes or
amines still remains a big challenge; and (iii) straightforward routes to highly functionalized
molecules from simple starting materials through C–H activation are still less reported.
Recently, transient directing group (TDG)-assisted C–H functionalization has shown
a promising way to overcome the aforementioned limitations.[3–17] In these reactions,
CONTACT Liang Wang
lwcczu@126.com
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology,
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

2
J. SHEN ET AL.
the TDG binds to the substrate in situ through an imine intermediate and dissociates from
the product after reaction. Thus, extra prefunctionalization steps can be avoided. The syn-
thetic values of these approaches would be further increased if the TDGs are readily available
and cost effective. Although much effort has been devoted to exploring suitable TDGs and
new C–H activation reactions in recent years, reports on bilateral cyclization between two aro-
matic substrates through intermolecular C–H functionalization are still rare.[18–20] It should
be pointed out that the bilateral cyclization reactions featured a rapid construction of highly
functionalized molecules from simple starting materials. For example, Ellman et al.[18]
reported a formal [3 þ 3] annulations of aromatic azides with aromatic imines through
in situ-generated imines to construct acridines. Shi et al.[19] demonstrated an Rh(III)-catalyzed
cross-coupling of aryl carboxylic acids and benzyl thioethers through double C–H activation.
You et al.[20] reported an Rh(III)-catalyzed ortho C–H heteroarylation of aromatic carboxylic
acids. Interestingly, this protocol provided a rapid and concise access to π-conjugated
poly-heterocycles. Just recently, Cheng et al.[21] also developed an efficient Rh(III)-catalyzed
bilateral cyclization process to access acridines from aldehydes and nitrosos (Scheme 1a).
Despite these significant advances, current C–H activation reactions have largely been
conducted in common organic solvents such as N,N-dimethylformamide (DMF), dimethyl
sulfoxide (DMSO), acetonitrile (CH3CN), or 1,2-dichloroethane (DCE), which present
major issues due to their volatility and toxicity. Recently, the use of bio-based reaction
medium such as γ-valerolactone (GVL) has become a hot field. This renewable chemical
has been recognized as a sustainable solvent due to its high boiling and flash points,
low toxicity, good chemical stability, and similar polarity compared with DMF and
N-methylpyrrolidone.[22] To our best knowledge, although several reactions have been
realized in GVL, reports on directing group-assisted C–H activation reactions are rare.
Particularly, bilateral cyclization reaction between two aromatic substrates has never been
reported. In this paper, we report an Rh(III)-catalyzed synthesis of unsymmetrical acri-
dines using aromatic aldehydes and azides as the starting materials in GVL. The aromatic
aldehydes survived well under the reaction conditions. Only catalytic amount of benzyl
amine was required as the TDG to promote this transformation (Scheme 1b).
Scheme 1. C–H activation toward highly functionalized molecules.

SYNTHETIC COMMUNICATIONS®
3
Results and discussion
At the outset of our studies, we chose benzaldehyde 1a and phenyl azide 2a as substrates to
screen the reaction conditions in the presence of [RhCp*Cl2]2 (2.5 mol%) and AgSbF6 (10
mol%) in GVL (1 mL) at 120 (C under N2 for 16 h (Table 1).
No desired product 3aa was observed under the above reaction conditions. Fortunately,
3aa was detected in 23% yield in the presence of glycine (0.2 equiv.), indicating that a
directing group was necessary for this transformation (entry 2). Switching glycine (T1)
to amino acid T2 still gave the desired product in poor yield (11%, entry 3). Different ani-
lines were then tried and 42% yield of 3aa was obtained when aniline (T3) was used as DG.
Other anilines bearing electron-donating and electron-withdrawing groups such as T4–T6
gave lower yields (37, 26, and 19%, respectively). Delightfully, benzyl amine turned out to
be a good DG, affording the desired product in 63% yield (entry 8). Similarly, inferior
yields were obtained when substituted benzyl amines were utilized (entries 9 and 10). p-
Toluenesulfonamide (TsNH2, T10) and acethydrazide (T11) were also tested, however,
only trace amount of 3aa was observed (entries 11 and 12). Different solvents were then
evaluated. Reaction in conventional solvents such as DMF, DMSO, dioxane, and DCE pro-
vided poor yields of the desired product (entries 13–16), while the use of toluene and acetic
acid led to the failure of the reaction (entries 17 and 18). Moreover, other catalysts such as
Rh(OOCCF3)2 and [RuCl2(p-cymene)]2 were ineffective for this reaction (entries 19 and
20). Meanwhile, no desired product was obtained in the absence of either [RhCp*Cl2]2
or AgSbF6 (entries 21 and 22). The survey of other parameters showed that [RhCp*Cl2]2
(5 mol%), AgSbF6 (20 mol%), 120 (C, and 0.4 equiv. of T7 were the optimized reaction
conditions, providing 3aa in 90% yield (entries 23 and 24).
Next, we explored the scope and generality of the present protocol under the optimized
reaction conditions. Initially, a series of aromatic aldehydes were evaluated (Fig. 1). In
general, aromatic aldehydes containing both electron-withdrawing groups and electron-
donating groups reacted with phenyl azide 2a smoothly to give the desired products in
good to excellent yields (3aa–3ka). For the para-substituted aldehydes, a series of func-
t
tional groups including alkyl (iPr and Bu), phenyl, methoxy, and chloro were well toler-
ated, among which the 4-chloro benzaldehyde afforded the highest yield (92%, 3fa).
Substrate 1g also showed good activity to deliver the corresponding product 3ga in 85%
yield. Notably, for meta-substituted aldehydes 1h–1k, the C–H activation occurred
exclusively at the less hindered site, and no other isomers were detected.
Different aromatic azides were then checked. A series of azides bearing either
electron-donating or electron-withdrawing groups showed good compatibilities toward
this reaction. The alkyl, methoxy, halo, and ester groups were well tolerated, affording
the corresponding products in good yields (3ib–3ii, 73–88%). Particularly, good tolerance
of halogen atoms (Cl and Br) and ester group enabled the further manipulation of initial
products. Notably, for meta-substituted azides 2h and 2i, good regioselectivity was
observed, and the cyclization process took place at the least hindered site.
Furthermore, gram-scale synthesis was performed using the model reaction. Under the
standard reaction conditions, product 3aa was isolated in 76% yield at 10 mmol scale
(Scheme 2), thereby providing a possibility for the practical scale-up synthesis of acridines.
To gain some insight into the reaction, some control experiments were performed
(Scheme 3). First, the intermolecular kinetic isotopic effect (KIE) experiment was studied

4
J. SHEN ET AL.
Table 1. Optimization of reaction conditions.a
Entry
Catalyst
[RhCp*Cl2]2
TDG
Solvent
Yield (%)b
1
2
–
GVL
0
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
Rh(OOCCF3)2
[RuCl2(p-cymene)]2
–
T1
T2
T3
T4
T5
T6
T7
T8
T9
T10
T11
T7
T7
T7
T7
T7
T7
T7
T7
T7
T7
T7
T7
GVL
23
3
GVL
11
4
GVL
42
5
GVL
37
6
GVL
26
7
GVL
19
8
GVL
63
9
GVL
44
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
GVL
39
GVL
trace
GVL
trace
DMF
DMSO
Dioxane
DCE
12
10
7
32
Toluene
AcOH
GVL
0
0
trace
GVL
trace
GVL
0
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
GVL
0c
GVL
72d, 81e, 82f
70g, 79h, 90i
GVL
aReaction conditions: 1a (0.2 mmol), 2a (1.5 equiv.), catalyst (2.5 mol%), AgSbF6 (10 mol%), TDG (0.2 equiv.), solvent (1 mL),
120 (C under N2 for 16 h in a sealed tube.
bNMR yields using 1,1,2,2-tetrachloroethane as internal standard.
cWithout AgSbF6.
dTDG (0.3 equiv.).
eTDG (0.4 equiv.).
fTDG (0.5 equiv.).
gAt 110 °C.
hAt 130 °C.
i5 mol% catalyst and AgSbF6 (20 mol%) were used.

SYNTHETIC COMMUNICATIONS®
5
Figure 1. Reaction scope. Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv.), [RhCp*Cl2]2 (5 mol%),
AgSbF6 (20 mol%), T7 (0.4 equiv.), GVL (1 mL), 120 °C under N2 for 16 h in a sealed tube, isolated yields.
(Scheme 3a). The result showed kH/kD = 3.2, indicating that the C–H bond cleavage of ben-
zaldehyde may be the rate-determining step. Second, to determine the role of benzyl amine,
imine A was prepared and reacted with azide 2a under the standard reaction conditions.
The product 3aa was isolated in 92% yield, indicating that the imine A was the key
intermediate (Scheme 3b).
Scheme 2. Gram-scale synthesis of 3aa.

6
J. SHEN ET AL.
Scheme 3. Control experiments.
Based on these results, we proposed a mechanism for this transformation. As shown
from Scheme 4, initially, aldehyde 1 condensed with BnNH2 to form intermediate A. Then
A underwent ortho C–H activation in the presence of Rh(III) catalyst to give metallacycle
B. Afterward, coordination of azide 2 to intermediate B provided intermediate C, which
released rhodacycle D and nitrogen by migratory insertion.[23] Then protonation of D
released the Rh(III) catalyst and intermediate E, which underwent intramolecular aromatic
electrophilic substitution to give intermediate F. Finally, aromatization of F delivered the
product 3 and BnNH2.
Scheme 4. Plausible mechanism.

SYNTHETIC COMMUNICATIONS®
7
Conclusion
In summary, we have developed an Rh(III)-catalyzed synthesis of unsymmetrical acridines
from aldehydes and azides utilizing inexpensive BnNH2 as a TDG and GVL as the green
reaction medium. The present C–H amination/cyclization/aromatization cascade featured
a rapid construction of highly functionalized acridines from simple starting materials. The
aldehydes could be directly used, and no additional steps were required for installation and
removal of DGs. A series of functional groups were well tolerated, affording the desired
products in good to excellent yields. KIE experiment showed that the aromatic C–H bond
cleavage of the aldehyde was the rate-determining step. Gram-scale synthesis of the
product was also achieved. Importantly, GVL could be used as a practical and efficient
alternative to the conventional organic solvents, thereby significantly reducing the
environmental impact and energy cost.
Experimental
General remarks
All reagents were obtained from local commercial suppliers and used without further
purification. The progress of the reaction was monitored by TLC using analytical grade
1
silica gel plates (GF254) under UV light. H NMR and 13C NMR spectra were recorded
at ambient temperature on a 300 or 400 MHz NMR spectrometer (75 or 100 MHz for
13C). Chemical shifts are given in parts per million (δ, ppm) and were referenced to CDCl3
(7.26 or 77.0 ppm). The coupling constants J are given in Hz. Mass spectrometry was
performed on an LCMS-2010 EV (Shimadzu) instrument with an ESI source.
General procedure for synthesis of acridines
In an N2-filled glovebox, a 10-mL Schlenk tube equipped with a stir bar was charged
with aromatic aldehyde 1 (0.2 mmol, 1.0 equiv.), aryl azide 2 (0.30 mmol, 1.5 equiv.),
[RhCp*Cl2]2 (5 mol%), AgSbF6 (20 mol%), benzyl amine (T7, 0.4 equiv.) in GVL
(1 mL). The tube was sealed, and the reaction mixture was stirred at 120 (C for 16 h in
oil bath. After completion of the reaction, the mixture was extracted by EtOAc and washed
with water for several times. The organic layer was then dried over anhydrous Na2SO4,
concentrated in vacuum, and the residue was purified by flash column chromatography
on silica gel with petroleum ether and EtOAc as the eluent to give the pure acridine
products.
Selected data: acridine (3aa).[18] Yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.78
(s, 1H), 8.26 (dd, J = 8.8, 0.8 Hz, 2H), 8.01 (dd, J = 8.5, 0.6 Hz, 2H), 7.82–7.77 (m, 2H),
7.57–7.53 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 149.0, 136.1, 130.3, 129.4, 128.2,
126.6, 125.7; MS (ESI) m/z 180 [MþH]þ.
KIE experiment
The 1a-d6 was prepared according to the previous literature.[24] In an N2-filled glovebox,
a 10-mL Schlenk tube equipped with a stir bar was charged with aromatic aldehyde 1a
(0.1 mmol), 1a-d6 (0.1 mmol), phenyl azide 2a (0.30 mmol, 1.5 equiv.), [RhCp*Cl2]2
(5 mol%), AgSbF6 (20 mol%), benzyl amine (T7, 0.4 equiv.) in GVL (1 mL). The tube
was sealed, and the reaction mixture was stirred at 120 (C for 2 h in oil bath. After that,

8
J. SHEN ET AL.
the mixture was extracted by EtOAc and washed with water for several times. The organic
layer was then dried over anhydrous Na2SO4, concentrated in vacuum, and the residue was
purified by flash column chromatography on silica gel with petroleum ether and EtOAc as
the eluent to give the products 3aa and 3aa-d5 in 28% yield. The mixture was analyzed
1
using H NMR spectrometer to calculate the kH/kD value.
Funding
We gratefully acknowledge the National Natural Science Foundation of China (21302014),
the Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110),
and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions
the Advanced Catalysis and Green Manufacturing Collaborative Innovation Center of Changzhou
University for the financial support.
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