Green Organocatalytic Synthesis of Indolines and Pyrrolidines from Alkenes

Article abstract of DOI:10.1002/adsc.201601262

Employing a green and efficient 2,2,2-trifluoroacetophenone-catalyzed oxidation of alkenes, which utilizes H₂O₂ as the green oxidant, a novel and sustainable synthesis of indolines and pyrrolidines was developed. This constitutes a cheap, general and environmentally-friendly protocol for the synthesis of substituted nitrogen-containing heterocycles. A variety of substitution patterns, both aromatic and aliphatic moieties, are well tolerated leading to the desired nitrogen heterocycles in good to excellent yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201601262

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DOI: 10.1002/adsc.201601262
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Green Organocatalytic Synthesis of Indolines and Pyrrolidines
from Alkenes
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Alexis Theodoroua and Christoforos G. Kokotosa,*
a
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens,
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Panepistimiopolis 15771, Athens, Greece
Fax.: (+30) 2107274761
Phone: (+30) 2107274281
E-mail: ckokotos@chem.uoa.gr
Received: November 12, 2016; Revised: January 18, 2017; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601262
Abstract: Employing a green and efficient 2,2,2-
trifluoroacetophenone-catalyzed oxidation of al-
kenes, which utilizes H2O2 as the green oxidant, a
novel and sustainable synthesis of indolines and
pyrrolidines was developed. This constitutes a
cheap, general and environmentally-friendly proto-
col for the synthesis of substituted nitrogen-con-
taining heterocycles. A variety of substitution
patterns, both aromatic and aliphatic moieties, are
well tolerated leading to the desired nitrogen
heterocycles in good to excellent yields.
Keywords: Organocatalysis; Oxidation; Pyrrolidine;
Green Chemistry; H2O2
37 Pyrrolidines and indolines are widely existing struc-
38 tural motifs in a number of pharmaceuticals, bio-
39 logically important molecules and natural products
40 (Figure 1).[1] The indoline moiety constitutes a very
41 useful and versatile scaffold in organic synthesis, since
42 it is usually embedded in a wide range of designed
43 bioactive compounds and natural products (Figure 1).
Figure 1. Representative molecules containing the indoline
or the pyrrolidine moiety.
44 In the former case, an indoline derivative has been proaches have been devised for the synthesis of both
45 proven to exhibit anticancer properties,[2] while strych- indolines and pyrrolidines (Scheme 1). One of the
46 nine is a notorious natural product bearing the indo- most common synthetic approaches to these nitrogen
47 line scaffold (Figure 1).[1,3] Furthermore, the simpler heterocycles constitutes the oxidative difunctionaliza-
48 structure of pyrrolidine is also present in the natural tion of unactivated alkenes. Among the most powerful
49 amino acid proline, which except from its role in transformations in modern organic chemistry are
50 enzymes and proteins, is being considered as a key alkenes’ vicinal difunctionalization.[7] It comes as no
51 molecule in Organocatalysis.[4] In addition, pyrrolidine surprise that metal-catalyzed processes have the lion’s
52 is encountered in numerous natural products, such as share towards the synthesis of these nitrogen hetero-
53 kainic acid[5] and coccinine[6] (Figure 1).
54
cycles (indolines and pyrrolidines) involving either
As a consequence of their vivid occurrence in osmium,[8] palladium,[9] copper[10] or gold[11] (Scheme 1,
55 numerous compounds, their existence in a significant A). Despite the widespread popularity of these
56 proportion of biologically active molecules and due to protocols, metal toxicity and high levels of inorganic
57 their synthetic utility, a plethora of synthetic ap- waste make their application harmful for the environ-
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ment. A few metal-free approaches for the synthesis consideration the orthogonal choice of the nitrogen
of these nitrogen heterocycles have also emerged in protecting group, so that in situ deprotonation will
the literature,[12] but they heavily depend on the occur, an intramolecular ring opening reaction would
stoichiometric use of iodine reagents[12a,b,d] or Oxo- afford the desired cyclized compound bearing a
ne[12c] (Scheme 1, B). Although no metal contamina- hydroxy moiety (Scheme 1, bottom and Table 1). In
tion can be expected by these transformations, the general, this oxidation protocol would be environ-
stoichiometric amount of acid waste remains. To our mentally friendly, having as the only byproduct, water.
surprise, there is no single literature report (stoichio- In addition, this will lead to an unprotected alcohol
metric or catalytic) employing H2O2 as the oxidant for that can be easily transformed to a variety of func-
10 such a transformation, although this will have as an tional groups.
11 obvious advantage that the only byproduct of the
12 method would be water. Probably, this is due to the
Table 1. Optimization of the reaction conditions for the
synthesis of indoline 2a from 1a.a)
13 inability of H2O2 to perform oxidations by itself and it
14 has to be activated by a catalyst.[13]
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Entry Catalyst
(mol%)
MeCN/H2O2
(equiv.)
Solvent Yieldb)
(%)
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0
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tBuOH 68
tBuOH traces
tBuOH 93
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MeCN
91
EtOAc 65
MeOH 11
THF
CHCl3
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[a] All reactions were carried out with 1a (0.50 mmol), 2,2,2-
trifluoro-1-phenylethanone (10 mol%, 0.05 mmol), solvent
(0.4 mL), aqueous buffer solution (0.4 mL, 0.6 M K2CO3–
43 10À4 M EDTA disodium salt), acetonitrile and 30%
aqueous H2O2. The reaction mixture was left stirring for
18 hours.
[b] Isolated yield.
Scheme 1. Synthetic approaches for the synthesis of indolines
and pyrrolidines.
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Surprisingly, there are only sparse reports for the
synthesis of indolines and pyrrolidines bearing a free
hydroxyl moiety.[11,12a,c,15]
We initiated our study utilizing mesyl-protected
We have been actively involved in the field of allyl aniline 1a, easily-prepared from aniline, in our
45 Organocatalysis and very recently reported a cheap, optimized reaction conditions for the epoxidation
46 green and environmentally friendly protocol for vari- reaction (Table 1, entry 1).[14c] At the beginning, the
47 ous oxidations employing H2O2 as the green oxidant, alkene is epoxidized, while in the basic pH of aqueous
48 whose only by-product is water and 2,2,2-trifluoroace- buffer, mesyl aniline is deprotonated (pKa of MeSO2
49 tophenone as the organocatalyst.[14] We envisaged we Ph ~12.9 DMSO, usually lower in H2O) and thus
50 could extend this organocatalytic oxidative protocol subsequent ring opening of the epoxide leads to
51 via the introduction of an one-pot procedure for the cyclization to 2a in good yield without requiring
52 isolation of indolines and pyrrolidines (Scheme 1, additional reagents or heating (Table 1, entry 1). The
53 bottom).
choice of the mesyl-group was not made in vain, since
54
We envisaged that, H2O2 could be activated by additionally to the appropriate adjustment to the
55 2,2,2-trifluoroacetophenone to perform an epoxida- acidity of the NH for the deprotonation and the
56 tion. Once the intermediate epoxide is formed, and subsequent cyclization, it is thought to be a “difficult”
57 upon the basic conditions of the reaction, taking into substrate for this reaction. In most literature reports,
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the Ts- or the Ns-protecting group is employed, while transferred. When the Boc-group was employed, as a
the mesyl-group is known to lead to poor yield or no typical member of the urethane protecting groups, the
reaction.[9,10] 2,2,2-Trifluoroacetophenone is indispen- epoxidation took place, but the BocNH is not acidic
sable for this protocol, since if it is omitted, traces of enough to be deprotonated, and thus no cyclization
the product are observed (Table 1, entry 2). Increasing occurs. Thus, the intermediate epoxide can be isolated.
the amount of MeCN and H2O2 led to almost Alternatively, once the epoxidation reaction is com-
quantitative reaction yield (Table 1, entry 3). Various pleted, addition of tBuOK performs the deprotonation
organic co-solvents were tested along with the aque-
ous buffer and only MeCN led to similar high yield
10 (Table 1, entries 4–8).
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Having in hand the optimum reaction conditions,
12 we further explored how the nature of the protecting
13 group affects the reaction outcome (Scheme 2).
14 Although the tosyl-protecting group is frequently
15 employed in literature, in our case the indoline 3 was
16 isolated in slightly lower yield than 2a. This can be
17 attributed to the fact, that some deprotection of the
18 tosyl group was observed under the reaction condi-
19 tions, while no reaction takes place when the amine is
20 unprotected (Scheme 2). Other-sulfonyl based protect-
21 ing groups can be also employed with similar success
22 (4–6). It has to be noted that when the enantiopure
23 camphorsulfonate was used, no selectivity was ob-
24 served (1:1 dr of 6), which is probably due to the fact
25 that the chiral center is not in close proximity to the
26 generated chiral center and thus no chiral induction is
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Scheme 3. Green Organocatalytic synthesis of indolines and
pyrrolidines – substrate scope.
and furnishes the cyclized product 7. When benzoyl or
p-nitrobenzoyl protection was employed, after epox-
idation and cyclization, an additional deprotection is
taking place leading to unprotected aminoalcohol 8 in
good yields in both cases. Again, deprotection occurs
after epoxidation and cyclization, since the free allyl-
aniline does not undergo the cyclization step. Unfortu-
nately, simple acetyl protection cannot be employed,
since no cyclized product is formed.
Once the optimum protecting group was found, we
focused on exploring the substrate scope of this new
green and sustainable protocol (Scheme 3). Initially, a
number of substituted aromatic allyl-mesyl-protected
anilines (1a–g) were utilized (Scheme 3). In all cases,
Scheme 2. Green Organocatalytic synthesis of indolines –
nature of the protecting group.
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the products were isolated in high to excellent yields. conditions, deprotonation occurs leading to a ring
Attempts to render the process asymmetric, utilizing opening of the epoxide with simultaneous cyclization
the commercially available Shi’s epoxidation catalyst, to indoline 2a.
led to poor asymmetric induction.[16] Halogen substitu-
tion at the para position led to substituted indolines
2b–d in good yields. Electron donating groups, such as
alkyl or methoxy were well tolerated leading to
compounds 2e and 2f in similarly good yields. If the
substitution is moved to the ortho position, indoline
10 2g was isolated in excellent yield. Next, a series of
11 aliphatic mesyl-protected homoallyl amines were
12 employed leading to substituted pyrrolidines 2h–l
13 (Scheme 3). In some cases in these aliphatic mesyl
14 amines, a mixture of cyclized product and epoxide was
15 present in crude NMR. Thus, to ensure cylization and
16 higher yield of the pyrrolidine, the reaction mixture
17 was treated with DBU to ensure cyclization. In the
18 case of 2h, a mixture of diastereomers was isolated in
19 high yield. Again, attempts to render the process
20 asymmetric led to poor yield and low enantioselectiv-
21 ity.[16] One can envisage an easy access to 4-substituted
22 proline derivatives after oxidation of the hydroxy
23 group to acid. When the alkene is a,a-disubstituted, as
24 the case of 1i, trisubstituted pyrrolidine 2i that carries
Scheme 4. Proposed reaction mechanism.
In conclusion, a highly sustainable and green
25 a tetrasubstituted carbon atom was isolated as a single protocol was developed for the conversion of alkenyl
26 diastereomer in moderate yield. Probably a preferred protected anilines into polysubsituted indolines or
27 cyclization is taking place, leading to the cyclization of pyrrolidines using H2O2 as the oxidant. Since H2O2 is
28 only one diastereomer. Trisubstituted alkene 1j led to poor by itself to perform oxidations, our synthetic
29 high yield of pyrrolidine 2j, albeit with low diaster- approach utilizes a cheap and commercially available
30 eoselectivity. Pyrrolidine 2j closely resembles Jorgen- metal-free organic molecule (2,2,2-trifluoroacetophe-
31 sen-Hayashi’s diaryl prolinols, which are known to be none) as the catalyst to activate H2O2. Our approach
32 potent organocatalysts.[4] This approach can lead to reports the one-pot epoxidation of alkenyl-protected
33 substituted derivatives on the pyrrolidine ring of these amines followed by an in situ ring opening/cyclization
34 molecules. When cyclic alkene 1k (1:1 mixture of process leading to nitrogen heterocycles in good to
35 diastereomers) was employed, bicyclic compound 2k excellent yields. After an extensive study of the nature
36 was isolated in high yield as a mixture of diastereom- of the protecting group, a variety of substitution
37 ers. This constituted an interesting entry in the rapid patterns is well tolerated leading to indolines and
38 assembly of polyfunctionalized bicyclic scaffolds for pyrrolidines in good to high yields. This novel
39 numerous applications, such as bioactive compounds approach of combining our organocatalytic oxidation
40 or new catalysts and ligands. Finally, trisubstiuted protocol in one-pot transformations leading to prod-
41 pyrrolidines, such as 2l that carries a quaternary ucts of high molecular complexity is currently being
42 center on the pyrrolidine ring can be formed by this pursued in our laboratories.
43 protocol in almost quantitative yield.
44
To summarize the events that take place in this
Experimental Section
45 procedure, a proposed reaction mechanism is shown
46 in Scheme 4. In the aqueous environment of the
47 reaction, 2,2,2-trifluoroacetophenone affords diol I.
48 Then, and in the appropriate pH, MeCN reacts with
49 H2O2 to afford II, which in conjunction with H2O2
50 oxidizes I to perhydrate IV.[14] Then, another molecule
51 of II reacts with IV affording the active oxidant of the
52 protocol, which epoxides alkenyl-mesyl-protected ani-
53 line 1a. The structure of the active oxidant of the
54 oxidation protocol is still unknown. The possibility of
55 a dioxirane intermediate cannot be ruled out,[17]
56 although we have recently reported that this is highly
57 unlikely to be true.[14e] Then, and upon the basic
Experimental DetailsAlkene (0.50 mmol) was placed in a
round bottom flask and dissolved in tert-butanol (0.4 mL).
2,2,2-Trifluoro-1-phenylethanone (8.7 mg, 0.05 mmol), aque-
ous buffer solution (0.4 mL, 0.6 M K2CO3–43 10À4M EDTA
disodium salt), acetonitrile (0.40 mL, 8.00 mmol) and 30%
aqueous H2O2 (0.84 mL, 8.00 mmol) were added consecu-
tively. The reaction mixture was left stirring for 18 hours at
room temperature. The product was purified by column
chromatography (30–50% EtOAc in Pet. Ether). For ali-
phatic substrates, after reaction completion, DBU
(1.00 mmol) was added and the reaction mixture was left
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Acknowledgements
The authors would like to thank Dr. Maroula Kokotou for
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