Accepted Manuscript

One-potsynthesisofα-fluoro-β-aminoacidandindolespiro-derivativesviaC-Nbondcleavage/formation

Chen-Yu Tang, Ge Wang, Xue-Yan Yang, Xin-Yan Wu, Feng Sha

PII: S0040-4039(14)01666-9DOI: http://dx.doi.org/10.1016/j.tetlet.2014.09.130Reference: TETL 45224

To appear in: Tetrahedron Letters

Received Date: 2 July 2014Revised Date: 13 September 2014Accepted Date: 29 September 2014

Please cite this article as: Tang, C-Y., Wang, G., Yang, X-Y., Wu, X-Y., Sha, F., One-potsynthesisofα-fluoro-β-aminoacidandindolespiro-derivativesviaC-Nbondcleavage/formation, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.09.130

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One-pot synthesis of α-fluoro-β-amino acid

and indole spiro-derivatives via C-N bond

formation/cleavage

Chen-Yu Tang, Ge Wang, Xue-Yan Yang, Xin-Yan Wu*, Feng Sha*

Leave this area blank for abstract info.

1

Tetrahedron Letters j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m

One-pot synthesis of α-fluoro-β-amino acid and indole spiro-derivatives via C-

N bond cleavage/formation

Chen-Yu Tanga , Ge Wang

a , Xue-Yan Yang

a , Xin-Yan Wu

a, ∗

and Feng Sha

a, ∗

a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, P. R. China

——— ∗ Corresponding author. Tel.: +86-021-64252011; fax: +86-021-64252758; e-mail: shaf@ecust.edu.cn (F. Sha), xinyanwu@ecust.edu.cn (X.-Y. Wu)

Since N-containing aromatics are unique skeleton widely found in natural products and pharmaceutics, strategies to

construct CAr-N bond have been developed to generate useful

molecules.1 Among these reported methodologies, however,

harsh reaction conditions and stoichiometric utilization of metal

additives are usually involved, yet the yields are not satisfying.2

Therefore, it is still of great importance to develop a direct and

efficient approach to form CAr-N bond under mild reaction

conditions. To our knowledge of aryne chemistry, arynes are

unique and attractive intermediate in organic synthesis since

arynes exhibit highly electrophilic character due to their low-

lying LUMO.3 Even neutral nucleophiles can easily add to arynes

to produce zwitterions, which may act as pivotal intermediates, leading to a variety of CAr-Y bond (Y = O, S, N) containing

compounds with highly bioactive and pharmaceutical acitivity in

subsequent transformation.4

The highly strained aziridines 1 have aroused our interest as

they may react with arynes as nucleophile and generate the

zwitterion intermediate A (Scheme 1), which may be of high reactivity due to its high degree of strain. Initiated by inter- or

intramolecular nucleophilic addition, subsequent ring-opening

reaction may easily occur.5 The nucleophile (HNu) could attack

the positive aziridine moiety of A and furnished the substituted β-

amino acid derivatives B.5c, 6

Considering that the fluorine anion

introduced to generate arynes in-situ could also act as HNu, F-

anion can be easily introduced into the final product to generate

desirable fluoro-amino acid of wide application and promising

value in pharmaceutics.7

On the other hand, the ester moiety of

aziridine 1 may take part in the reaction as electrophile and

accept the intramolecular attack of the phenic anion A, furnishing aza-polycyclic ammonium salts C to undergo following ring-

opening transformation to generate D. Herein, we wish to report

the synthesis of α-fluoro-β-amino acid derivatives utilizing the

fluorine anion as the electrophile, and the approach of indole

spiro-derivatives was also described under different mild

conditions.

Scheme 1. Aziridines 1 react with arynes.

With the above hypothesis, the reaction of 2-carboxylic acid

ester substituted aziridine 1 with aryne precursor 2 was carried

out in the presence of fluoride sources (Table 1). Initially, KF/18-

Crown-6 system was employed as fluoride source and

nucleophile in the reaction of ethyl 1-butylaziridine-2-

carboxylate (1a, 1.0 equiv) with 2-(trimethylsilyl)phenyl

trifluoromethanesulfonate (2a, 2.0 equiv) in THF at room

temperature (Table 1, entry 1). Disappointingly, no desired fluoro-product 3a was generated. By changing the fluorine

source to TBAF, trace amount of fluoro-product 3a was observed

ARTIC LE INFO ABSTRACT

Article history:

Received

Received in revised form

Accepted

Available online

In this paper, the α-fluoro-β-amino acid directives were elegantly generated via a novel strategy

of the nucleophilic addition of arynes and aziridines. C-N bonds were successfully constructed

with high efficiency. With the utilization of TABF hydrate as the fluorinated reagent, fluorine

atom could be assembled into the target molecule selectively. Interestingly, under another

condition, unexpected indole spiro-derivatives could be achieved successfully.

2009 Elsevier Ltd. All rights reserved.

Keywords:

arynes

aziridines

fluorination

β-amino acids

indole spiro-derivatives

Tetrahedron

2(entry 2). Inspiringly, the yield of 3a was dramatically

enhanced to 78% by adding H2O (entry 3). This may lie in that

the proton might be essential for the formation of the product 3a

via the phenylic anion intermediate. Therefore, the TBAF

hydrated (TBAF•3H2O) was employed and the yield of 3a could

be further enhanced to 83% (entry 4). Reducing the amount of aryne precursor 2a to 1.5 equiv gave lower yield than that of 2.0

equiv (70%, compare entries 4 and 5). Increasing the amount of

precursor 2a to 2.5 equiv, however, did not improve the yield

significantly (84%, entry 6). Further investigation on the

temperature effect demonstrated that reaction at 0 oC or 40

oC did

not improve the yield of 3a (entries 7 and 8).

Table 1. Optimization of the reaction conditionsa

Entry 1a/2a (equiv)b T (

oC) F

-

Yield of 3a

(%)c

1 1.0/2.0 rt KF/18-C-6 -

2 1.0/2.0 rt TBAF trace

3d 1.0/2.0 rt TBAF/H2O 78

4 1.0/2.0 rt TBAF•3H2O 83

5 1.0/1.5 rt TBAF•3H2O 70

6 1.0/2.5 rt TBAF•3H2O 84

7 1.0/2.0 0 TBAF•3H2O 79

8 1.0/2.0 40 TBAF•3H2O 56 a The reactions were conducted using 1a (0.5 mmol), 2a and F- source (2.0 equiv, based on 2a) in 2 mL of THF under nitrogen atmosphere.

b The equiv of 2a was based on 1a.

c Isolated yield based on 1a.

d 6 Equiv of H2O based on 2a was added.

With the optimized conditions in hand, the scope of the

substrate was then explored. As shown in Table 2, these reactions

proceeded smoothly to afford corresponding fluoro-products 3 in

mild to excellent yields. Substitutents methoxy, ethoxy and iso-propoxy group with the electron-donating effect were introduced

into aziridines 1. It is observed that with increase of the electron-

donating effect, the reaction yields ascended accordingly (entries

1-3, Table 2). Up to 90% yield of 3c was observed with the

introduction of iso-propyl ester substituted aziridine 1c (entry 3).

However, tert-butyl ester substituted aziridine 1d only furnished product 3d in 65% yield (entry 4). This might lie in the great

steric effect of tert-butyl moiety, which blocked the attack of

fluorine anion to C-2 position of the three-membered ring.

Similar reaction trend occured when different N-substituted

aziridines were employed (entries 5-7). Products 3e and 3f were

generated in 90% and 92% yields with the employment of N-cyclohexyl and N-iso-propyl substituted aziridines 1e and 1f

(entries 5 and 6). However, utilization of N-tert-butyl substituted

aziridine 1g led to 3g in a relatively lower yield (82%, entry 7).

In addition, N-benzyl and N-4-methoxylbenzyl substituted

aziridines 1h and 1i could be successfully applied to afford

corresponding products 3h and 3i in good yields (88% and 84%, entries 8 and 9). On the other hand, the reaction of 4,5-dimethyl

aryne precursor 2b could be conducted smoothly and product 3j

was furnished in 86% yield (entry 10). Furthermore, 2-acetyl

group substituted aziridines 1j and 1k could also be applied in

the reaction, giving the corresponding products 3k-m in

moderate yields (entries 11-13).

Table 2. Reaction of aziridines 1 with aryne precursors 2

affording products 3a

Entry 1 2 Yield of 3

(%)b R1 R2 R3

1 n-Bu OEt (1a) H (2a) 83 (3a)

2 n-Bu OMe (1b) 2a 73 (3b)

3 n-Bu OiPr (1c) 2a 90 (3c)

4 n-Bu OtBu (1d) 2a 65 (3d)

5 c-Hex OEt (1e) 2a 90 (3e)

6 i-Pr OEt (1f) 2a 92 (3f)

7 t-Bu OEt (1g) 2a 82 (3g)

8 Bn OEt (1h) 2a 88 (3h)

9 p-OMeBn OEt (1i) 2a 84 (3i)

10 1a Me (2b) 86 (3j)

11 n-Bu Me (1k) 2a 57 (3k)

12 Bn Me (1l) 2a 60 (3l)

13 1k 2b 53 (3m)

a The reactions were conducted using 1 (1.0 equiv), 2 (2.0 equiv) and TBAF•3H2O (2.0 equiv, based on 2) in THF at room temperature.

b Isolated yield based on 1.

To our surprise, the reaction displayed excellent

regioselectivity even with the utilization of non-symmetric aryne

from ortho-OMe substituted aryne precursor 2c. The sole

regioisomer 3n was isolated in 63% yield, the structure of which

was determined by the NOESY study (Scheme 2).

Scheme 2. The reaction of 1a with 2c and the NOESY study of product 3n.

Based on the above experimental results and our previous

investigation on aryne chemistry,4,6,8

a rationale for this

fluorination reaction was proposed. Aryne was generated in-situ

in the presence of fluorine anion, and the following nucleophilic

attack from the nitrogen atom of aziridine 1 produced the

zwitterion intermediate A. Subsequently, the intermediate A

obtained proton from H2O to generate the positive nitrogen ion 4,

which was then attacked by another fluorine anion on the C-2

position. By the following C-N bond cleavage, the fluoro-product

3 was furnished (Scheme 3).

F

N

R1

O

R2

N

R2

O

R1

2a

A

H2O N

R2

O

R1

4

H

F

3

1

Scheme 3. Plausible mechanism.

As indicated by the above experimental results, H2O acted as

the key trapping agent to accelerate the formation of the fluoro-

product. We are further interested in whether the phenylic anion

3moiety would undergo intramolecular nucleophilic attack in the

absence of H2O to furnish cyclic product. Therefore, well dried

CsF was utilized to provide fluorine anion in the reaction of

aziridine 1h and 2a (Scheme 4). Surprisingly, the unknown

product 5a was isolated. As indicated by the study of the 1H

NMR spectrum, two molecules 1b and two molecules 2a were assembled into one compound.

By further X-ray investigation,

the structure of 5a was determined as an unexpected spiro-

compound, namely 1,5'-dibenzyl-4',5'-dihydro-3'H-

spiro[indoline-2,2'-pyrano [3,2-b]indol]-3-one (Figure 1).

The formation path of 5a is described in Scheme 4. After the

formation of the intermediate A, the phenylic anion moiety attacked the intramolecular carbonyl group to give the

ammonium salt C. After losing EtOH and rearrangement, 1-

benzyl-2-methyleneindolin-3-one (D) was formed. Subsequent

[4+2] annulation immediately occurred between two molecules

of intermediate D to construct the final product 5a.

Scheme 4. The reaction of 1h and 2a in the presence of CsF.

Figure 1. The X-ray crystal diffraction of product 5a.9

Considering that the skeleton of 5a is pivotal structure of

pharmaceuticals and natural products but hard to apporach10,

further optimization of reaction conditions was conducted. As

shown in Table 3, better yield was observed in case that 1.0 equiv

of aziridine 1h react with 1.2 equiv of aryne precursor 2a in the presence of 2.4 equiv of CsF in MeCN at room temperature

(entry 4).

Table 3. Optimization of reaction conditions for the synthesis

of spiro-product 5aa

Entry 2a (equiv)b T (oC) F-/Solvent Yield of 5a (%)c

1 2.0 rt TBAF/THF trace

2 2.0 rt KF/18-C-

6/THF trace

3 2.0 rt CsF/MeCN 61

4 1.2 rt CsF/MeCN 68

5 0.8 rt CsF/MeCN 52

6 1.5 rt CsF/MeCN 55

7 1.2 0 CsF/MeCN 40

8 1.2 50 CsF/MeCN 32 a The reactions were conducted using 1h (0.5 mmol), 2a and F- source (2.0

equiv, based on 2a) in 2 mL of THF or MeCN at room temperature.

b The amount of 2a was based on 1h.

c Isolated yield based on 1h.

Furthermore, a series of 5 were generated successfully by

using the optimized conditions (Figure 2). By employing N-

phenethyl-substituted aziridine, corresponding product 5b was

furnished in relatively higher yield (76%). In contrast, alkyl-

substituted aziridine 1b generated product 5c in moderate yield

(54%). In addition, other symmetric arynes could also be

employed in this reaction, giving 5d and 5e in 41% and 66%

yield, respectively. The results demonstrated that electron-

withdrawing effect on aryne ring could improve the reaction to

generate spiro-product 5.

Figure 2. The tandem reaction of aziridines and arynes froming

spiro-product 5

In summary, we have developed a facile and highly selective

approach to generate α-fluoro-β-amino acid derivatives via the

reaction of aziridine and arynes. With the utilization of TBAF

hydrate as the fluorinated reagent, fluorine anion did not only

accelerate the generation of aryne, but also elegantly played the

role of nucleophile, promoting the fluorination/ring-opening

reaction to generate the fluoro-products under mild reaction

conditions. Interestingly, by employing CsF/MeCN system,

indole spiro-derivatives, which are not easily accessible via other

approaches, could be assembled efficiently. Notably, both α-

fluoro-β-amino acids and indole spiro-skeletons are of important utilization in the synthesis of pharmaceuticals and natural

products.

Tetrahedron

4Acknowledgments

We are grateful for the financial support from National Natural

Science Foundation of China (Project Nos. 21102043, and

20122044), the China Postdoctoral Science Foundation (Project

Nos. 20110490070, and 2012T50401) and the Fundamental

Research Funds for the Central Universities.

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