Fluorene-based compounds have been widely investigated because of their wide range
of applications as organic materials,[1 ] semiconductors,[2 ] optoelectronics,[3 ] organic dyes,[4 ] photoconductors[5 ] as well as their applications in solar cells,[6 ] fuel cells,[7 ] and materials science[8 ] as indicated in Figure [1 ]. Their highly fluorescent nature has enabled fluorene derivatives to be used in
bright and efficient displays.[9 ]
Figure 1 Selected materials and bioactive molecules based on the 9-substituted fluorene core
structure
The presence of two benzylic acidic hydrogens at the C-9 position of fluorene activates
them towards alkylation under basic conditions. Compounds with a fluorene motif such
as NPC 16570 and NPC 17923 have been used as anti-inflammatory agents and inhibitors
of leukocytes in inflamed tissue,[10 ] and also exhibit anticancer activity as well as cardiac and bone marrow toxicity.[11 ] Propargylic alcohols and their derivatives are useful precursors in organic synthesis.[12 ] Propargylic alcohols react with metal salts, iodine, and Lewis acids,[13 ] and they undergo nucleophilic substitution reactions via allene carbocation or propargyl
cation species. In these situations, the allene intermediate shows diverse reactivity
as well as selectivity.[14 ] Aryl aminoamides have been used as starting materials for the preparation of heterocyclic
compounds and aryl amino amide appended carbocycles.[15 ] We have utilised fluorenone for the synthesis of spirofluorene-based fluorescent
molecules[16 ] and we have recently reported the reaction of fluorene-9-propargylic alcohols with
isatin imines for the preparation of blue emissive compounds via highly stable propargylic
cation intermediates.[17 ] The reactions of aryl substituted propargylic alcohols with several nucleophiles
such as sulfonamides,[19 ] nitroso compounds,[20 ] acetamides,[21 ] tosylhydrazines,[12 ] and imines[22 ] have been investigated by various research groups, to provide highly functionalized
products through allenyl cation intermediates.[23 ] It should be noted that the two aryl groups in the diaryl substituted phenyl propargylic
alcohols are conformationally orthogonal and decisive in the formation, stability,
and reactivity of either carbocation or allenyl intermediate.[24 ] On the other hand, when the aryl groups are coplanar or nonplanar, the formation,
stability, and reactivity of the reactive intermediate can be modified and provide
products via the most stable intermediate. To our knowledge, the reaction of coplanar
9-(phenylethynyl)-9H -fluoren-9-ols with amino amides has not been reported. Thus, we have explored the
reaction of rigid and coplanar diaryl substituted fluorene propargylic alcohols with
substituted benzamides and sulfonamides.
In contrast to previous reports that coplanar fluorene propargylic alcohols with isatin
imine nucleophiles affords products via the propargylic cation, herein we report the
reaction with nucleophiles having labile amine protons, the reactivity being found
to be reversed to afford products via an allenyl cation. The preliminary results of
the study are presented in this manuscript.
Initially, a reaction between 1 equivalent of fluorenone propargylic alcohol 1a
[25 ] in dichloromethane and 1 equivalent of 2-aminobenzamide (2a ) and 0.1 equivalents of BF3 ·Et2 O at room temperature for 10 minutes afforded (Z )-2-((2-(9H -fluoren-9-ylidene)-1-phenylethylidene)amino)benzamide (3a ) in 65% yield (Scheme [1 ], Table [1 ], entry 1). The structure of 3a was established by FTIR, 1 H NMR, 13 C NMR, DEPT-135 and HRMS analyses.
Scheme 1 Synthesis of compound 3a
To improve the yield and to optimize the reaction conditions for the synthesis of
compound 3a , a study was carried out, varying reaction parameters such as relative quantities
and nature of the acid catalyst, solvent and reaction time. Thus, performing the reaction
using 0.3 equivalent of BF3 ·Et2 O led to the yield of the product 3a being improved to 92% and was ultimately found to be optimal (Table [1 ], entry 2). Reactions using 0.5 equivalent of catalyst slightly decreased the yield
to 89% (entry 3). Catalysts such as p -TsOH, FeCl3 , and AlCl3 , led to either decreased yields or no reaction (entries 4–7). Hence, BF3 ·Et2 O was found to be the most suitable catalyst. Other solvents such as acetonitrile,
methanol, and toluene did not improve the yield (entries 8–10). Hence, dichloromethane
was found to be the most suitable solvent. An experiment without a Lewis acid catalyst
failed to provide any product (entry 11).
Table 1 Optimization of Synthesis of Compound 3a
Entry
Catalyst
Solvent
Catalyst (equiv)
Time (min)
Yield of 3a (%)a
1
BF3 ·OEt2
DCM
0.1
10
65
2
BF3 ·OEt2
DCM
0.3
5
92b
3
BF3 ·OEt2
DCM
0.5
5
89
4
p-TsOH
DCM
0.3
30
40
5
FeCl3
DCM
0.3
30
40
6
AlCl3
DCM
0.3
30
no reaction
7
InBr3
DCM
0.3
7
80
8
BF3 ·OEt2
MeCN
0.8
0.5
decomposition
9
BF3 ·OEt2
MeOH
0.8
30
10
10
BF3 ·OEt2
toluene
0.8
5
no reaction
11
–
DCM
300
no reaction
a Isolated yield after column purification.
b Optimized conditions.
Figure 2 Various propargyl alcohols 1a –c and aryl aminoamides 2a –k
Having the optimized conditions in hand, the scope of the reaction was investigated
by using a number of propargylic alcohols 1a –d and aryl aminoamides 2a –g (Figure [2 ]). Under the optimized conditions, all reactions proceeded well to afford the corresponding
products 3a –m in excellent yields (Table [2 ], Figure [3 ]). To demonstrate the diversity of the amino derivatives in the reaction, 2-aminobenzenesulfonamide
2b was reacted with propargyl alcohol 1a to provide the sulfonamide derivative 3b in 90% yield (entry 2). Reaction of propargylic alcohol 1a with 5-iodobenzamide 2c yielded product 3c in 91% yield (entry 3). In a further exploration of various benzamides, substituted
aminoamides 2d –f were chosen to react with 1a to afford products 3d –f in good yields (entries 4–6). Substituted aminoamides 2d –f were prepared from isatoic anhydride and aryl amines in water at room temperature.[26 ] The structure and relative stereochemistry of the representative compound 3e was confirmed by single-crystal XRD analysis (Figure [4 ]).[27 ]
Figure 3 Synthesized compounds 3a –m
Figure 4 ORTEP diagram of compound 3e (CCDC-1967615)[27 ]
To study the reactivity of fluorene propargylic alcohols bearing electron-donating
groups, substrate 1b was reacted with substituted amino amides 2d –f to provide compounds 3g –i in moderate to good yields (Table [2 ], entries 7–9). Alcohol 1b , on reaction with dimethyl substituted amino amide 2g , afforded product 3j in low yield (entry 10). Furthermore, reaction of alcohol 1c with amino amides 2d –e proceeded smoothly to afford the respective products 3k and 3l (entries 11 and 12). To study the effect of substitution on the fluorenone ring,
propargylic alcohol 1d was reacted with 2e , furnishing product 3m in 72% yield (entry 13).
Table 2 Reaction Scopea
Entry
Substrate
Aminoamide
Product (Yield, %)b
1
1a
2a
3a (92)
2
1a
2b
3b (90)
3
1a
2c
3c (91)
4
1a
2d
3d (89)
5
1a
2e
3e (90)
6
1a
2f
3f (88)
7
1b
2d
3g (87)
8
1b
2e
3h (91)
9
1b
2f
3i (88)
10
1b
2g
3j (75)
11
1c
2d
3k (84)
12
1c
2e
3l (83)
13
1d
2e
3m (69)
14
1a
2h
decomposition
15
1a
2i
decomposition
16
1a
2j
decomposition
17
1a
2k
decomposition
a Reaction conditions: BF3 ·Et2 O (0.3 equiv), CH2 Cl2 , 5 min. r.t.
b Isolated yield after column purification.
It is worth noting that the reaction of alcohol 1a with meta -substituted aminobenzamide 2h and para -substituted aminobenzamide 2i failed to provide the expected product. Thus, the reaction occurs only with ortho -amino arylamides, possibly due to hydrogen bonding. On the other hand, we also wished
to test the reaction with arylamines such as aniline 2j and aliphatic amines such as isopropylamine 2k with alcohol 1a . However, both reactions failed to provide the desired product and decomposed.
Based on the structure of the products formed and on literature reports,[17 ] a plausible mechanism for the formation of product 3 is proposed in Scheme [2 ]. Accordingly, initial reaction of the fluorene derived propargylic alcohol 1 with BF3
[12e ]
[18 ] generates the propargyl cation/allenic carbocation intermediate A . Subsequent nucleophilic attack of the lone pair of electrons of the amine group
of arylaminoamide 2 onto the allenic carbocation A provides allene substituted product B . Subsequent skeletal rearrangement of B leads to product 3 .
Scheme 2 Plausible mechanism for the formation of compound 3
To explore the scope of the reaction further and to diversify the products with halogen
derivatives, the reaction shown in Scheme [3 ] in the presence of N -bromosuccinimide (NBS) was proposed. Thus, the reaction was carried out with 1 equiv
of fluorenone derived propargylic alcohol 1a in dichloromethane, 1 equiv of 2-aminobenzamide 2a , 1 equiv of NBS, and 0.3 equiv amount of BF3 ·Et2 O at room temperature for 5 minutes to afford the dibromination product, namely, (E )-5-bromo-2-((2-bromo-2-(9H -fluoren-9-ylidene)-1-phenylethylidene)amino)benzamide (4a ) in good yield (60%; Scheme [3 ]). The structure and relative stereochemistry of compound 4a was confirmed by single-crystal XRD analysis (Figure [5 ]).[27 ]
Scheme 3 Synthesis of compound 4a
Figure 5 ORTEP diagram of compound 4a (CCDC-1957144)[27 ]
Under the optimized conditions, the scope of the reaction in the presence of NBS was
demonstrated by using various propargylic alcohols 1a and 1b and aryl benzamides 2a , sulfonamide 2b and iodo-substituted aryl benzamide 2c to produce products 4a –d in 60–75% yields (Figure [6 ]). The structure of all the new compounds was established by spectroscopic analyses.[28 ]
Figure 6 Synthesized compounds 4a –d
Based on the products and on literature precedents,[17 ]
,
[19 ]
[20 ]
[21 ]
[22 ] a possible mechanism for the formation of compound 4 is shown in Scheme [4 ]. The allenic carbocation intermediate A with aminobenzamide 2 forms allene intermediate B . Meanwhile, in the presence of BF3 ·OEt2 , NBS is activated and eliminates a bromine cation. Due to the electron-donating nature
of nitrogen, the electron-rich internal carbon atom of allene intermediate B reacts with the bromine cation to form intermediate C . Elimination of a proton from intermediate C followed by aromatic electrophilic bromination forms the observed compound 4 .
Scheme 4 Plausible mechanism for the formation of compound 4
In conclusion, we have developed a procedure for the synthesis of (Z )-2-((2-(9H -fluoren-9-ylidene)-1-phenyl-ethylidene)amino)benzamides via BF3 -mediated reaction of coplanar 9-(phenylethynyl)-9H -fluoren-9-ols with various 2-aminobenzamides.[28 ] Reaction in the presence of NBS afforded (E )-5-bromo-2-((2-bromo-2-(9H -fluoren-9-ylidene)-1-ethenylethylidene)amino)benzamides. A plausible mechanism for
the formation of products via an allene carbocation intermediate is proposed. The
structure of representative compounds has been established by single-crystal XRD analysis.
