Photodecarboxylation of N-Adamantyl- and N-phenylphthalimide

CROATICA CHEMICA ACTA

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CCACAA, ISSN 0011-1643, e-ISSN 1334-417X

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Croat. Chem. Acta 87 (4) (2014) 431-446.

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http://dx.doi.org/10.5562/cca2482

Original Scientific Article

Photodecarboxylation of /V-Adamantyl- and /V-Phenylphthalimide

Dipeptide Derivatives1

Margareta Sohora, Tatjana Šumanovac Ramljak, Kata Mlinarić-Majerski, and Nikola Basarić*

Department o f Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia

RECEIVED MAY 22,2014; REVISED SEPTEMBER 8,2014; ACCEPTED SEPTEMBER 11, 2014

Abstract. New dipeptide derivatives 1 and 3 were synthesized and their reactivity in the photochemical re-

action of decarboxylation was investigated. The photodecarboxylation of A-adamantyl derivatives la and

lb and A-phenylphthalimide derivatives 3a and 3b probably takes place from the triplet excited state. The

triplet excited state of la, 3a and 3b was characterized by laser flash photolysis. A-phenylphthalimides 3a

and 3b undergo 2-5 times more efficient photodecarboxylation than /V-adamantylphthalimides la and lb.

The aminoacid residue (Phe or Gly) at the C-terminus of the dipeptide does not influence the photodecar-

boxylation efficiency. Product selectivity in the photoreactions is determined by the conformation of the

molecules. A'-phenylphthalimides with the separated electron donor (carboxylate) and acceptor moiety

(phthalimide) give only simple decarboxylation products, whereas iV-adamantyl derivatives also give cy-

clization products.

Keywords: photodecarboxylation, dipeptides, phthalimides

INTRODUCTION

tochemical reactions giving rise to complex hetero-

polycyclic derivatives.12 These reactions include photocy-

cloadditions,13 cyclizations initiated by H-abstraction,14 or

photoinduced electron transfer (PET).15 In the PET reac-

tions, the phthalimide is an electron acceptor, whereas a

donor of an electron can be carboxylate16 or silyl deriva-

tive.17 Using photoinduced decarboxylation initiated by

the phthalimide chromophore, Griesbeck et al. developed

synthetic methods for the preparation of medium and

large-cyclic ethers18 and cyclic peptides,19 and developed

novel chiral photocages.20 Later, Oelgemoller et al. used

photoinduced decarboxylation for the acetate,21 benzyl,22

or a-amino acid addition to the phthalimide,23 or for the

formation of cyclic aryl ethers,24which was also conduct-

ed in the microflow reactors.25 We have recently demon-

strated that photoinduced decarboxylation of 3-(N-

phthalimi-do)-l-adamantane carboxylic acid initiate addi-

tion of the photogenerated radical to electron deficient

alkenes.26 The latter photoaddition is feasible only in the

systems wherein the phthalimide is separated by a rigid

spacer from the electron donor to prevent the cyclization

reaction. In the flexible systems, cyclization takes place,

and we have recently shown that it takes place with high

enantioselectivity due to memory of chirality. Thus, cy-

clization of dipeptide la containing L-phenylalanine gives

2a as the major product in 65 % yield with the ee > 99 %

(Eq. I).27

Photodecarboxylation is an important photochemical

reaction with many applications in organic synthesis.1

For example, photodecarboxylation of Barton esters can

induce radical chain reactions,2 whereas degradation of

some classes of organic compounds can be carried out

by photo-Colbe reaction.3 Photodecarboxylation is also

important for the chromophores that compose nonstere-

oidal non-inflammatory drugs such as ketoprofen, and

naproxen. Since these drugs are known to induce pho-

toalergy, their photochemistry has been thoroughly

investigated.4 Generally, the mechanism of photodecar-

boxylation can take place via homolytic cleavage giving

radicals.5 The other suggested mechanism includes

photoejection of an electron from the carboxylates and

formation of radicals.6 A special interest was directed to

the photodecarboxylation of ketoprofene and similar

derivatives.7 Although some controversy was encoun-

tered regarding the reactive excited state of ketoprofen,8

it is generally accepted that the decarboxylation gives

carbanionic species.9

Synthesis of phthalimide derivatives attracts organic

chemists due to their application in the amine protection,10

as well as their biological activity.11 Furthermore,

phthalimide has shown a potential as a useful chromo-

phore that can initiate many synthetically applicable pho-

1 Dedicated to Dr. Mirjana Eckert-Maksić on the occasion of her 70thbirthday.

* Author to whom correspondence should be addressed. (E-mail: nbasaric@irb.hr)

M. Sohora et al., Photodecarboxylation ofDipeptides

432

2a

Chart 1.

Herein we investigate further the scope of the pho-

todecarboxylation in a series of dipeptide derivatives

wherein the N-terminus is activated by phthalimide. The

investigated molecules comprise of A-adamantyl-

phthalimide derivatives la, lb, and jV-phenylphtha-

limide derivatives 3a, 3b (Chart 1). The molecules are

designed to probe for the efficiency of photode-

carboxylation depending on the spacer between the

electron donor (carboxylate) and the acceptor (phthali-

mide). Although photochemistry of TV-alkylphthalimides

has been well documented, reports on photochemistry of

TV-phenylphthalimides are scarce.28 The C-terminus of

the dipeptides bears two distinctly different amino acids,

glycine and phenylalanine. The anticipated photodecar-

boxylation should give rise to two different radical spe-

cies, and therefore, it is anticipated to proceed with

different efficiency. We performed preparative pho-

tolyses and isolated or characterized primary photo-

products and determined quantum efficiency of their

formation. In addition, to get more information about

the mechanism of the photochemical reactions and to

characterize the excited states involved, we carried out

laser flash photolysis (LFP).

RESULTS AND DISCUSSION

Synthesis

Adamantyl dipeptide derivatives la and lb were syn-

thesized from the A-phthalimide derivative of 3-

aminoadamantane-1-carboxylic acid, prepared as previ-

ously described.26,27 The acid was activated with /V,/V-

Dicyclohexylcarbodiimide (DCC) and treated with N-

hydroxysuccinimide (NHS) to give iminoester deriva-

tive27 which was treated with unprotected L-phe-

nylalanine or glycine in the presence of a base to afford

the desired peptides la and lb in good yields, that were

purified by column chromatography.

TV-phenylphthalimide dipeptides 3a and 3b were

prepared from acid 4.26 Attempts to activate acid 4 by

DCC and NHS failed. Therefore, we used a stronger

activation reagent, A,A,A',A'-tetramethyl-C-(l//-benzo-

triazol-l-yl)uronium hexafluorophosphate (HBTU).29

The acid was activated in situ and reacted with ethyl or

benzyl ester L-phenylalanine or glycine (Scheme 1).

The esters 5a and 5b, as well as the corresponding ethyl

-c n -^N ^ C O O B n

_________R_________

X

COOBn

H B T U ,T E A

DMF

5a R= -CH2-C 6H5

5b R= H

CO OH

6a R= -CH2-C6H 5

6b R= H

3 a R= -CH2-C6H 5

3b R= H

Scheme 1.

Croat. Chem. Acta 87 (2014) 431.

M. Sohora et al., Photodecarboxylation ofDipeptides

433

Table 1. Photolysis ofphthalimides la, lb, 3a, and 3b under different conditions^

Products(c)

Cyclization

Product

40

Cone.

(mg/mL)

Time

(min)

Reactant

(%)<d>

Comp.

Solvent

Decarboxylation

Product

« 10

(8a)

Unidentified

Products

35

la

acetone-H20

(3:1)

acetone-IEO

(3:1)

CH3CN-H2O

(3:1)

acetone-H20

(3:l)(b)

acetone-H20

(3:1)

acetone-H20

(3:1)

CH3CN-H2O

(3:1)

acetone-H20

(3:1)

CH3CN-H2O

(3:1)

acetone-H20

(3:1)

acetone-H20

(3:1)

CH3CN-H2O

10/20

100/100

10/20

30

20

30

21

20

15

20

3

15

(la)

70

(la)

90

(la)

70

(lb)

21

(lb)

65

(lb)

>90

(lb)

60

(3a)

85

(3a)

40

(3b)

10

(2a)

13

(2a)

10

Traces

(8a)

Traces

(8a)

Traces

(8b)

10

(8b)

5

(8b)

Traces

(8b)

20

(7a)

10

17

-

(2a)

lb

78/185

20/20

15 (9b)

8 (2b)

Traces

(9b+2b)

Traces

(9b+2b)

Traces

(9b+2b)

0

7

69

30

<10

20

5

200/100

20/20

3a

3b

20/20

3

0

(7a)

15

(7b)

5

(7b)

20/20

10

45

85

25

100/100

20/20

(3b)

60

15

_____(3:1)

____

m

___________(7b)

(a)Irradiations were carried out in N2-purged solutions in the presence of 0.5 equivalents of K2CO3. Luzchem or Rayonet reactor

was equipped with 8 or 16 lamps, respectively, with the irradiation maximum at 300 nm.

(b) Irradiation was carried out in Luzchem reactor equipped with 3 lamps (300 nm).

(c) The ratio of products determined from the NMR spectra of crude mixture. The number in parenthesis corresponds to the ob-

tained cyclization product.

(d)The conversion was obtained by the weight of the photoproducts after separation from the unreacted acids la,b and 3a,b.

ester 5bEt, were prepared in good to moderate yields.

Using the same activation protocol we also prepared the

corresponding ethyl and benzyl gylcine esters of the

adamantane derivative (IbEt, lbBz). However, all

attempts to perform basic or acidic hydrolysis of these

esters failed, mostly due to the competitive ring-opening

of the phthalimide moiety. Therefore, the benzyl protec-

tion of the esters was inferred to be more rewarding,

enabling the selective deprotection by hydrogenolysis.

However, the usual protocol by use of Pd/C, in addition

to the cleavage of the esters, gave phthalides 6a and 6b.

A successful benzyl ester deprotection was achieved in

a reaction of triethylsilane and Pd/C (5 %) with in situ

formed H-radicals.30 The deprotection was carried out in

methanol-DMF and furnished desired products 3a and

3b in good yields (Scheme 1).

efficient intra- or intermolecular electron transfer and

photodecarboxylation. 18-26 However, under these con-

ditions, irradiation of the phenyl derivatives 3a and 3b

gave complex mixtures of many products. Chromato-

graphic isolation of the photoproducts was problematic

due to their poor solubility in most of the commonly

used solvents. However, photolyses (10 min, 16

lamps) taken to lower conversion gave photode-

carboxylation products 7a and 7b (formed as major

products in small amounts, < 2 0 %) which were de-

tected by NMR and HPLC (Eq. 2, Table 1). To fully

characterize 7a and 7b, they were prepared by an in-

dependent synthetic method, by applying the above-

described protocol (HBTU activation, Scheme 1), from

acid 4 phenylethylamine and methylamine, respective-

ly (see the experimental). Irradiation of the isolated

derivatives 7a and 7b, under the same conditions as

used in the photolysis of 3a and 3b, lead to a fast for-

mation of numerous products and high-weight materi-

al. All attempts to isolate some of the secondary pho-

toproducts failed due to the problems of solubility, the

material was lost on the column chromatography on

silica or alumina.

Photochemistry

To isolate and characterize photoproducts, preparative

irradiations of lb, 3a, and 3b were carried out. Irradia-

tions were carried out in acetone-HiO (3:1) in the

presence of 0.5 equivalents of K2CO3 as a base, ac-

cording to the previously documented conditions for

Croat. Chem. Acta 87 (2014) 431.

M. Sohora el al., Photodecarboxylation ofDipeptides

434

3a R= -CH2-C6H5

3b R= H

7a R= -CH2-C6H5

7b R= H

techniques (COSY, NOESY, HSQC and HMBC). In the

'H NMR spectrum of the glycine product 9b, a charac-

teristic singlet corresponding to the methoxy group was

observed at d 3.88 ppm, whereas in the 13C NMR, the

corresponding quartet was observed at 52.80 ppm. Fur-

ther, in the aliphatic part of the l3C NMR spectrum, in

addition to 7 signals of the adamantane C-atoms, a dou-

blet at 44.8 ppm can be seen corresponding to the gly-

cine CH²after the loss of the carboxylate. In the 'H

NMR the glycine CH2 appears as a singlet at 3.73 ppm.

In the aromatic part of the spectrum four different C-H

signals were observed, indicating a loss of the symmetry

of the phthalimide moiety. Interactions seen in 2D NMR

were fully in agreement with the assigned structure. The

methoxy group was probably introduced in the molecule

during the chromatographic separation on a thin layer of

silica using CH2CI2/CH3OH/TFA as eluent.

The assignation of the structure to the cyclization

product 2b was straightforward from its !H and 13C

NMR spectra. In the 13C NMR spectra three characteris-

tic singlets in low magnetic field can be seen corre-

sponding to three carbonyl groups; they appear at §

187.7, 179.1 and 171.7 ppm. In addition, a characteristic

singlet at 3.74 ppm in ’H, and a triplet at 43.77 ppm in

the 13C NMR correspond to the glycine CH2. All inter-

actions seen in the 2D NMR fully corroborate the as-

signed structures.

Irradiation of the adamantane derivatives la and

lb under the same conditions as used for the phenyl

derivatives, taken to low conversion, gave cleaner

photochemical reactions and furnished two types of

products, decarboxylation 8, and cyclization products

9 and 2 (Eq. 3). The photolysis of the glycine deriva-

tive lb taken to a low conversion (30 %) gave the

cyclization products ( 8 % of 2b and 15 % of 9b), and

traces of 8b. Irradiation to the conversion of 80 %

gave 8b ( 1 0 %), along with numerous unidentified

products. Attempts to isolate these products failed due

to high adsorptivity on silica and alumina. To charac-

terize the decarboxylation product 8b which was

formed in low yield, it was prepared in the independ-

ent synthetic method. The succinimide ester27 was

treated with methylamine to afford 8b in good yield.

Irradiation of 8b under the same conditions as lb gave

numerous products. Furthermore, the photodecomposi-

tion of 8b proceeded ten times slower than the decar-

boxylation of lb. Attempts to isolate some of the sec-

ondary products from 8b failed.

Irradiation of the isolated 8a and 8b, similar to the

photolysis of 7a and 7b, gave many products. However,

photodecomposition was much slower with the adaman-

tyl derivatives (conversion 5-10 % after 15 minutes),

than with the phenyl derivatives (conversion ~ 30 %

after 10 minutes). The secondary photochemical reac-

tion of adamantyl derivatives 8a and 8b are anticipated,

probably involving intramolecular H-abstractions from

the adamantyl moiety, as previously reported. 14 Howev-

er, it is not yet clear which photochemical transfor-

mations are involved in the photodecomposition of the

phenyl derivatives 7a and 7b.

To further investigate the photochemical reactivity

of phthalimides la, lb, 3a and 3b irradiations were

carried out in different solvents: acetone, CH3CN, ace-

tone-H20 (3:1) and CH3CN-H2O (3:1). In all aqueous

solvents the irradiation experiments were conducted in

the presence of 0.5 equivalents of base (K2CC>3) to as-

sure deprotonation of the acid moiety. After irradiations,

a composition of the photolysates was analyzed by

The structures of the cyclization photoproducts 9b

and 2b were determined by use of ID and 2D NMR

H

fry

! '

+

acetone-H20

A p

U

<

-

v

1-1

1a R=CH2-C6H5

1b R= H

2a R= CH2-C6H5

2b R= H

9a R= CH2-C6H5, R

9b R= H, R' = CH3

Croat. Chem. Acta 87 (2014) 431.

M. Sohora et al., Photodecarboxylation ofDipeptides

435

HPLC, NMR, and in some cases a chromatographic

separation was carried out. Due to the solubility prob-

lems, irradiations in the presence of the base could be

conducted only in the presence of H2O, since K-salts

were not soluble in neat CH3CN or acetone. Neverthe-

less, NMR and HPLC analysis after irradiations of the

colloidal solutions of the K-salts in CH3CN or acetone

indicated formation of the same products as in the aque-

ous solvents, but with significantly lower efficiency

(100 times). The highest photoreactivity for all deriva-

tives was observed in acetone-H20 (3:1) in the presence

of K2CO3 which is in agreement with the sensitization

mechanism of photoexcitation and anticipated electron

transfer from carboxylate to phthalimide.26,27 In addi-

tion, for la and lb a difference in the product distribu-

tion was observed when the irradiation was performed

in acetone-H20 (3:1) and CH3CN-H2O (3:1). In ace-

tone-H20 the cyclization products were predominantly

formed, whereas in CH3CN-H2O cyclization and simple

decarboxylation products were formed in comparable

yields. For 3a and 3b we could not observe a difference

in the product distribution, but the process was more

efficient in acetone. The findings clearly indicate that

acetone acts as a triplet sensitizer and induce photo-

chemical reactions of la, lb, 3a, and 3b. Moreover, a

different ratio between the cyclization and the simple

decarboxylation photoproducts obtained from la and lb

in CH3CN-H2O and acetone-H20 (Table 1) suggests

involvement of singlet and triplet excited states, with

the cyclization taking place via the triplet.

It is known that phthalimides are unstable under

basic conditions and undergo ring opening. Therefore,

the stability of phthalimides lb and 3b (c = 2.0 MCT3

M) in CH3CN-H2O was tested in the presence of differ-

ent concentrations of K2CO3 (c = 1.0 *10~3 and 1.0

x10”2 M). The progress of the reaction was monitored

by UV-vis spectroscopy (see the supporting info.)

Whereas decomposition of lb at c(K2CC>3) = 1.0 *10-3

M after 20 h did not take place, a slow decomposition

at 10”2 M was observed (pseudounimolecular k ~

8 x10~5 s”1). On the contrary, a slow decomposition of

3b was observed already at c(K2C0 3 ) = 1.0 *](T3 M

(pseudounimolecular k ~ lxl() 5 s”1). These results

indicate that under the irradiation conditions adamantyl

derivatives la and lb probably did not undergo ring

opening, whereas for the phenyl derivatives 3a and 3b

competitive base promoted ring opening could take

place.

tions 0.1-0.4 M, indicating involvement of the triplet

excited state in the photoproducts formation.

Irradiation of 3-(iV-phthalimido)-1-adamantane

carboxylic acid in the presence of a base and electron

deficient alkenes gave rise to photodecarboxylation and

radical addition of the adamantane to the alkene double

bond^.26We attempted to perform the analogous addition

to acrylonitrile with the photogenerated radicals from

la, lb, 3a, and 3b. Irradiations were performed in the

presence of 1 0 0 equivalents of acrylonitrile, but no

addition products were detected. Since the adamantyl

derivatives la and lb after the initial decarboxylation

give the cyclization products, the finding is logical. We

have already reported that the separation of the electron

donor and the acceptor is essential to enable the addi-

tion.26 However it is yet not clear why radical addition

cannot take place from the phenyl derivatives 3a and

3b. Probably, the anticipated radicals from 3a and 3b

(vide infra), are stabilized by the amino substituent, and

therefore, less reactive. Hence, only photodecarboxyla-

tion products 7a and 7b can be detected, and the addi-

tion does not take place.

On attempts to perform photoaddition to acryloni-

trile we observed quenching of the photoreaction of la

and lb with acrylonitrile. With the phenyl derivatives

3a and 3b, no quenching was observed. This observa-

tion can be rationalized by the quenching of the triplet

excited state of N-alkylphthalimides by acrylonitrile.

The triplet energy of acrylonitrile is 297 kJ mol-1 ,32

which is similar to the triplet energy of N-

methylphthalimide, 293 kJ mol” 1.33 Furthermore, this

finding suggests that A'-phenylphthalimides have lower

triplet energy than the analogous N-alkylphthalimides.

The energy transfer to acrylonitrile induces polymeriza-

tion consuming the alkene, and therefore, the addition to

the double bond does not take place. It is interesting to

note that quenching of the triplet state of 3-(N-

phthalimido)-l-adamantane carboxylic acid by acryloni-

trile was not observed.26

Quantum efficiency for the photodecomposition

(&d) of la, lb, 3a, and 3b was determined in CH3CN-

H2O (3:1) and acetone-HzO (3:1) in the presence of

K2CO3 as a base. For the determination of 4>d in

CH3CN-H2O (3:1), a primary actinometer was used,

photolysis of valerophenone in aqueous solvent giving

acetophenone.34 For the photoreaction in acetone-H2 0

(3:1) we used a secondary actinometer, photocyclization

of 6 -[(yV-phthalimido)methyl]cyclohexane carboxylic

acid.35 The photosensitized reaction (irradiation in ace-

tone-H2 0 ) gave mostly the cyclization products in case

of 1, or photodecarboxylation products in case of 3.

Direct excitation (irradiation in CH3CN-H2O) gave

photodecarboxylation products in case of 1 and 3. From

the values compiled in Table 2 it is evident that photo-

transformation is more efficient in acetone-^O than in

To investigate which excited state is involved in

the formation of the photoproducts, irradiation of lb (c

= 7 xl0“4 M) was performed in CH3CN-H2O in the

presence of K2CO3 and potassium sorbate, an ubiquitous

quencher of the triplet excited state (Et = 246 kJ

mol-1) .31 The quenching of the photoreaction of lb was

accomplished with potassium sorbate in the concentra-

Croat. Chem. Acta 87 (2014) 431.

M. Sohora et al., Photodecarboxylation ofDipeptides

436

Table 2. Quantum yields for the decomposition (<£d) of la,

lb, 3a and 3b in CH3CN-H2O (3:1) and acetone-H20 (3:1)

triplet excited states we carried out LFP measurements.

The measurements were conducted in N2- and O2-

purged CH3CN and CH3CN-H2O solutions. For the

excitation of samples, a frequency quadrupled Nd:YAG

laser with the output at 266 nm was used. LFP for 3b in

CH3CN gave transient absorption spectra characterized

by two bands, a stronger absorption with a maximum at

330-340 nm, and a weaker broad band at 530 nm, both

decaying with the rate constant 1 = 4.4 x 10⁵s_1 (Figure

1 right). The observed transient was quenched by O2

with the rate constant kq= 2.8 x 109 M_1 s_1. According

to the precedent spectra36 and quenching with 0 2, the

transient was assigned to the triplet state of N-

phenylphthalimide. Similarly, L-phenylalanine deriva-

tive 3a showed transient spectra with a maximum at

330-340 nm, and a weaker band at 530 nm, both as-

signed to the triplet-triplet absorption of N-

phenylphthalimide. In N2-purged CH3CN solution the

triplet of 3a decayed slower (compared to 3b) with the

rate constant k = 1.1 x 1 0 s s_1.

Compound

acetone-H2 0 (a)

0.06±0.002 <c>

0.3±0.02 <c>

CH3CN-H20<b>

O.OlliO.OOl <d>

0.0135±0.0005<d>

0.015±0.003 <d>

0.005±0.003 <d>

la

lb

3a

3b

0.28±0.02 (d)

0.38±0.06 <d>

(a) Photocyclization of 6 -[(/V-phthalimido)methyl]cyclohexane

carboxylic acid was used as a secondary actinometer (<Pr =

0.3).35 Photoconversion was determined from 'H NMR spectra

of the crude photolysis mixture.

(b) Photolysis of valerophenone in aqueous CH3CN was used

as an actinometer (formation of acetophenone, (Z> =

0.65±0.03).34Photoconversion was determined by HPLC.

(c) Quantum yield for the formation of cyclization products.

(d) Quantum yield for the formation of decarboxylation prod-

ucts.

CH3CN-H2O. Lower efficiency of the reaction in

CH3CN-H2O is probably due to a low efficiency of

intersystem crossing (ISC). Furthermore, it is interesting

to note a higher efficiency for the aceton-sensitized

reaction for the phenyl, than for the adamantyl deriva-

tives. This observation could be rationalized with signif-

icantly different photophysical properties of N-

phenylphthalimide derivatives36 compared to A-alkyl

derivatives.35 The difference in the reactivity of la vs

lb, may be explained by an energy transfer from the

triplet excited state of phthalimide to phenylalanine,

giving rise to non-productive deactivation from the

excited state. Such an energy transfer is not feasible

with the glycine derivative lb.

The adamantyl derivative la gave rise to distinctly

different transient absorption spectra in CH3CN then the

phenyl derivatives, with only one maximum at 340 nm.

The transient decayed in N2-purged solution with the

rate k = 1.5 x 106 s-1, and was quenched by O2 (kq= 1.4

x 109 M-1 s_I). Based on the quenching with 0 2 and

precedent spectra,14f it was assigned to the triplet state

of phthalimide. The lifetime of the triplet of la is signif-

icantly shorter than for 3-(/V-phthaIimido)-1-adamantane

carboxylic acid (Table 3). This observation could be

explained by intramolecular energy transfer from the

triplet state of phthalimide to the phenylalanine. How-

ever, due to the overlapping of the absorption of the

phthalimide and phenylalanine triplet,37 we could not

resolve the signals. The quenching of the triplet by phe-

nylalanine is also in agreement with the observed lower

quantum efficiency of decomposition for la compared

to lb (vide supra, Table 2).

Laser Flash Photolysis (LFP)

To get a better insight into the mechanism of the photo-

chemical transformations of 1 and 3 and characterize the

0.03 -

A

S

— ■— 0 .6 iis

^0.02-A i

“\

—

•

—

3.9 n s

-A 9.3 |aS

<

16 fiS

/* 1

0.01 -

▼

V « • x-

n nn -

300

400

500

600

700

W avelength / nm

Figure 1. Transient absorption spectra of la (left) and 3a (right) in N2-purged CH3CN.

Croat. Chem. Acta 87 (2014) 431.

M. Sohora et al., Photodecarboxylation o fDipeptides

437

Table 3. Properties of triplet excited state of la, 3a and 3b obtained by LFP

Compound

r / p s(a)

0.66±0.01

8.5±0.3

2.27±0.02

13

kq / M 's 1(c)

1.4X109

0ISC (b)

0.1U0.02

0.07±0.01

O.lOiO.Ol

0.22

la

3a

2.1*109

3b

2.8xl09

3-(Af-phthalimido)adamantane-1-carboxylic acid(d)

A-PhePhth

2.0xl09

11.5

0.03

-

(a) Lifetime of the triplet excited state in N2-purged solution.

(b) Oise in CLbCN, determined by comparing intensity of the signal with the optically matched solution of 7V-methylphthalimide in

CHsCN ((Disc = 0.8)35

(c) Rate constant for the quenching of the triplet with O2 in CH3CN.

(d) Taken from the Ref. 26.

(e)A-phenylphthalimide, the values taken from the Ref. 36.

The addition of K2CO3 to the aqueous solution

leads to a change of the observed transient absorption

spectrum of la (Figure 2) and increase of the lifetime (r

> ms, due to low intensity of the signal and long lifetime

we could not determine its decay precisely). The new

species is assigned to the radical-anion formed by PET,

in accordance with the precedent literature.14f LFP ex-

periments for 3a and 3b in the presence of K2CO3 (c =

0.01 M) gave no transient absorption signal, suggesting

that triplet and subsequent transient species have very

short lifetimes under these conditions. Short lifetime of

the jV-phenylphthalimide triplets can be rationalized by

a fast electron transfer from carboxylate, which is also

demonstrated by efficient photodecarboxylation quan-

tum yield (vide supra). However, it should be noted that

/V-phenylphthalimides are very sensitive to basic condi-

tions, undergoing ring opening. Thus, absence of signal

in the transient absorption is due to competative fast

decomposition of the sample.

Photochemical Reaction Mechanism

Based on the preparative photolyses and LFP measure-

ments the photochemical reaction mechanisms for the

transformations of 1 and 3 can be proposed. On direct

excitation, /V-alkyl and TV'-phenylphthalimides undergo

ISC with a low quantum efficiency of 10 % and popu-

late triplet excited states. Photodecarboxylation and

formation of photoproducts from 1 and 3 probably takes

place from the triplet excited state, as suggested by the

quenching with potassium sorbate and acrylonitile. One

of the deactivation channels from the triplet excited

state is PET, followed by a rapid irreversible decarboxy-

lation. LFP measurement in the presence of K2CO3

strongly indicated presence of the phthalimide radical-

anion. The biradical anion 10 can be protonated to bi-

radical 11, or undergo ring closure to anion 12 (Scheme

2). Nevertheless, the ring closure to 12 or 9 is enantiose-

lective (in case of la) due to the memory of chirality.27

Biradical 11 probably undergoes unimolecular or bimo-

lecular H-transfer and give simple decarboxylation

products 8a or 8b. Although these products are formed

in higher yields in CH3CN-H2O than in acetone-H2 0 ,

they are probably formed from the triplet excited state

via some other low efficient mechanism known in the

photochemistry of carboxylic acids.2-8 In addition to

PET, the other channel for the deactivation from the

triplet excited state is probably energy transfer from the

phthalimide to the phenylalanine, not leading to any

stable product.

Photophysical properties of N-phenylphthalimides

are different from the adamantyl analogues. ISC and

population of the triplet excited state takes place with

the similar efficiency. However, the deactivation from

the triplet by electron transfer probably takes place more

efficiently, as suggested by higher quantum efficiency

of decarboxylation. It gives biradical-anion 13. Contrary

to the adamantane derivatives, 13 cannot undergo in-

tramolecular cyclization. Most probably it decays by

Figure 2. Transient absorption spectra of 3a in N2-purged

CH3CN-H2O (1:1) at pH 7 and in the presence of K2CO3, c =

0.01 M.

Croat. Chem. Acta 87 (2014) 431.

438

M. Sohora et al., Photodecarboxylation ofDipeptides

8a R= -CH2-C6H5

8b R= H

1a R= -CH2-C6H5

1b R =H

2a R= -CH2-C6H5

2b R =

H

Scheme 2.

protonation giving biradical 14 (Scheme 3). Since in-

tramolecular H-transfer in 14 is not possible, only bimo-

lecular reactions give rise to the decarboxylation prod-

uct. Furthermore, biradical probably undergo many

competitive intermolecular H-abstractions giving rise to

a number of unidentified products. As discussed above,

nonreactivity of 13 or 14 in the radical additions to

double bonds could possibly be attributed to lower reac-

tivity of the radical due to the presence of N-substituent.

The other option for the decay of biradical-anion 13

would be back electron transfer giving carbanion. How-

ever the latter pathway is less likely due to poor electron

accepting properties and low reduction potential of the

acetamido group.

R

3a R= -CH2-C6H5

3b R=H

H+

R

7b R= H

Scheme 3.

Croat. Chem. Acta 87 (2014) 431.

M. Sohora et al., Photodecarboxylation ofDipeptides

439

2-{[3-(H-phthalimido)-l-adamantyl]carboxamido}ace-

CONCLUSION

tic acid (lb)

We have prepared new dipeptide derivatives activated

by the phthalimide chromphore. On irradiation of these

dipeptides photoinduced decarboxylation takes place.

The efficiency of the process depends on the spacer

between the electron donor (carboxylate) and the elec-

tron acceptor (phthalimide in the triplet excited state).

A'-phenylphthalimides undergo 2-5 times more effi-

A round bottom flask was charged with of glycine (5

mmol) and TEA (triethylamine, 0.697 mL, 5 mmol),

and dissolved in a mixture of THF-H2O (1:1, 20 mL).

To the reaction mixture, a solution of A-succimidyl[3-

(yV-phthalimido)-1-adamantyljformiate27 (1.990 g, 4.5

mmol) in THF (15 mL) was added dropvise, and the

reaction was stirred at rt for 3 days. When the reaction

was finished, IM HC1 (20 mL) was added, and the

product was extracted with ethyl acetate (3^20 mL).

The extracts were dried over anhydrous MgSCL, the

solution was filtered and the solvent removed on a rota-

ry evaporator to afford crude products. The product was

purified by column chromatography on silica gel with

5-10 % MeOH/CH2Cl2 and 10 % MeOH/EtOAc. The

pure product was obtained in the yield of 60-80 %.

Colourless oil; IR (KBr) v „Jem "1: 3412 (m),

2917 (m), 2852 (w), 2360 (w), 1707 (s), 1654 (m), 1540

(m), 1458 (w), 1369 (m), 1316 (m), 1078 (w), 875 (w),

720 (m), 6 6 8 (w); ’H NMR (300 MFIz, CD3OD) d/ppm:

7.78 (s, 4H), 3.87 (d, J = 4.0 Hz, 2H), 2.62-2.56 (m,

4H), 2.50 (d, J= 12.3 Hz, 2H), 2.31 (s, 2H), 2.05-1.80

(m, 5H), 1.74 (d, J = 12.4 Hz, 1H); 13C NMR (150

MHz, CD3OD) d/ppm: 170.9 (s, 1C), 135.2 (d, 2C),

133.1 (s, 1C), 123.5 (d, 2C), 61.4 (s, 1C), 44.1 (s, 1C),

42.7 (t, 1C), 42.3 (t, 1C), 40.4 (t, 2C), 38.9 (t, 2C), 36.3

(t, 1C), 31.1 (d, 2C); HRMS ealed. for C2,H22N20 5

421.1160, obsd. 421.1161.

cient photodecarboxylation

than A-adamantyl-

phthalimides. The photodecarboxylation and cycliza-

tion of jV-adamantyl derivatives la and lb and photo-

decarboxylation of .V-phenylphthalimide 3a and 3b

probably proceeds from triplet excited state. The ami-

no acid residue (Phe or Gly) at the C-terminus of the

dipeptide does not influence the photodecarboxylation

efficiency. Product selectivity in the photoreactions is

mostly determined by the molecular conformation.

Due to the rigid geometry /V-phenylphthalimide de-

rivatives with the separated donor and acceptor moiety

gave only simple decarboxylation products. On the

contrary, A-adamantyl derivatives wherein the donor

and acceptor can get in close contact gave cyclization

products. Formation of cyclic products with adaman-

tylphenylalanine takes place with the memory of chi-

rality and ee > 99 %. Therefore, it is anticipated that

this cyclization will have an important impact to the

future photochemical synthetic methods for the for-

mation of cyclic peptidomimetics.

p-(N-phthalimido)benzoic Acid (4)38

EXPERIMENTAL

General

A round bottom flask was charged with phthalic anhy-

dride (6.0 g, 0.041 mol) and melted. To the melt p-

aminobenzoic acid (4.40 g, 0.032 mol), suspended in

DMF (10 mL) was added in several portions. The reac-

tion mixture was heated and stirred for 2 0 minutes

without stopper with occasional addition of DMF (~2x2

mL). When the reaction was finished and when all DMF

evaporated, the mixture was cooled and suspended in

EtOAc (100 mL). The suspension was washed with 10

% HOAc (70 mL), and then with 10 % NaHCCfi (70

mL). During this washing, the product was suspended

between the organic and the aqueous layer in a form of

colourless solid. The suspended product in EtOAc was

filtered through a sinter (D-4) and dried in vacuum oven

at 60 °C and 10 mbar. The pure product 7 was obtained

(7.1 g, 83 %) in a form of colourless crystals.

'H and 13C NMR spectra were recorded on a on a

Broker Avance Spectrometer at 300 or 600 MHz. All

NMR spectra were measured in CDCI3, DMSO-cfe or

CD3OD using tetramethylsilane as a reference. High-

resolution mass spectra (HRMS) were measured on an

Applied Biosystems 4800 Plus MALDI TOF/TOF in-

strument. IR spectra were recorded on FT-IR ABB

Bonem MB 102 spectrophotometer. Melting points

were obtained using an Original Kofler Mikroheitztisch

apparatus (Reichert, Wien) and are uncorrected. Silica

gel or alumina was used for the chromatographic purifi-

cations. Solvents were purified by distillation. The

chemicals for the synthesis were obtained from the

usual commercial sources. Photochemical reactions

were carried in a Rayonet or a Luzchem reactor in

quartz cuvettes. CH3CN used in the irradiation experi-

ments was of HPLC purity, whereas acetone was of p.a.

purity. They were used as received, and were not further

purified. Synthesis and characterization of la, 2a, and

9a has been reported.27

General Procedure for the Synthesis of Benzyl Esters

5a and 5b

A round bottom flask was charged with 4 (534 mg, 2

mmol), dry DMF (10 mL), TEA (0.557 mL, 4 mmol),

and HBTU (796 mg, 2.1 mmol). After stirring at rt for

10 min., 2.1 mmol of benzyl ester of glycine or L-

Croat. Chem. Acta 87 (2014) 431.

M. Sohora et al., Photodecarboxylation ofDipeptides

440

'H NMR (300 MHz, CD3OD) <S/ppm: 8.05-7.96 (m,

4H), 7.94-7.88 (m, 2H), 7.65 (d, J = 8 .8 Hz, 2H), 4.25

(q, J =1.1 Hz, 2H), 4.16 (s, 2H), 1.31 (t, J = 7.1 Hz,

3H); l3C NMR (150 MHz, CDC13) <5/ppm: 169.8 (s, 1C),

166.7 (s, 1/2C), 166.4 (s, 1/2C), 134.9 (s, 1C), 134.5 (d,

2C), 133.0 (s, 1C), 131.6 (s, 2C), 127.8 (d, 2C), 126.2

(d, 2C), 123.8 (d, 2C), 61.6 (t, 1C), 41.9 (t, 1C), 14.1 (q,

1C); HRMS calcd. for Ci9H,6N20 5 375.0951, obsd.

375.0948.

phenylalanine hydrochloride were added, and the reac-

tion mixture was stirred for 1 day in the case of 5a and 4

days in the case of glycine derivative 5b. To the reac-

tion mixture brine (50 mL) was added and extraction

with diethyl ether was carried out (1><50 mL). The prod-

uct in a form of colourless solid was suspended between

the organic and aqueous layers. After removal of the

aqueous layer, the suspension of solid in ether was

washed with 1M HC1 (50 mL), H2O (50 mL), saturated

aqueous NaHCCL (50 mL), and again with H2O (50

mL). The suspension was filtered through a sinter (D-4)

and the solid product was dried in a vacuum oven at 60

°C and 10 mbar to afford the pure products.

Benzyl-2-{[3-(H-phthalimido)-1-adamantyl]carboxa-

mido}acetate (IbBz)

A

round bottom flask was charged with 3-(N-

phthalimido)-l-adamantane carboxylic acid (400 mg,

1.23 mmol), HBTU (490 mg, 1.29 mmol), TEA (351

pL, 2.52 mmol) and CH2CI2 (3 mL), and stirred at rt for

10 min. Then, benzyl ester of glycine hydrochloride

(231 mg, 1.29 mmol) was added and stirring was con-

tinued for 3 days. When the reaction was completed,

brine (50 mL) was added, resulting in a white suspen-

sion which was extracted with diethyl ether (1x50 mL).

The organic layer was washed with IM HC1 (50 mL),

H²O (50 mL), saturated NaHCCft (50 mL), and again

with H2O (50 mL), and dried over anhydrous MgS0 4 .

The solution was filtered and the solvent was removed

on a rotary evaporator to afford the crude product that

was purified by column chromatography on silica gel

with 1 0 % EtOAc/CH2Cl2.

552 mg (95 %); colorless solid; mp, 136-138 °C;

IR (KBr) v max/cnT1: 3437 (m), 2941 (m), 2854 (m),

1709 (s), 1639 (m), 1522 (m), 1369 (m), 1318 (m), 1221

(m), 1080 (w), 974 (m), 839 (s), 756 (m), 723 (m), 642

(w); >H NMR (600 MHz, CDC13) <5/ppm: 7.73-7.70 (m,

2H), 7.66-7.62 (m, 2H), 7.36-7.24 (m, 5H), 6.35 (t, J =

5.0 Hz, 1H), 5.15 (s, 2H), 4.05 (d, J= 5.2 Hz, 2H), 2.60

(s, 2H), 2.54 (d, J= 12.0 Hz, 2H), 2.44 (d, J= 12.0 Hz,

2H), 2.28 (s, 2H), 1.92 (d, J= 12.2 Hz, 2H), 1.85 (d, J=

12.2 Hz, 2H), 1.75 (d, J = 12.6 Hz, 1H), 1.64 (d, J =

12.6 Hz, 1H); ,3C NMR (75 MHz, CDC13) <S/ppm: 176.4

(s, 1C), 169.8 (s, 1/2C), 169.3 (s, 1/2C), 135.1 (s, 1C),

133.6 (d, 2C), 131.7 (s, 2C), 128.4 (d, 2C), 128.3 (d,

1C), 128.1 (d, 2C), 122.4 (d, 2C), 66.9 (t, 1C), 60.1 (s,

1C), 42.6 (s, 1C), 41.2 (t, 1C), 41.1 (t, 1C), 39.1 (t, 2C),

37.8 (t, 2C), 34.9 (t, 1C), 29.3 (d, 2C); HRMS calcd. for

C28H28N20 5495.1890, obsd. 495.1885.

N-{4-[N-(benzyloxycarbonyl-2-phenylethan-l-yl)carba-

moyl]phenyl}phthalimide (5a)

707 mg (75 %); colourless solid; mp, 204-206 °C; IR

(KBr) i/max/cnT1: 3326 (m), 3062 (w), 3029 (w), 1707

(s), 1637 (m), 1506 (m), 1389 (m), 1084 (w), 849 (w),

718 (m), 528 (w); 'H NMR (300 MHz, d6-DMSO)

3/ppm: 8.96 (d, J = 7.7 Hz, IH, NH), 8.08-7.86 (m,

6H), 7.54 (d, J = 8.6 Hz, 2H), 7.40-7.15 (m, 10H),

5.30-5.00 (m, 2H), 4.76-4.68 (m, 1H), 3.27-3.01 (m,

2H); 13C NMR (75 MHz, <4-DMSO) <S/ppm: 171.5 (s,

1C), 166.7 (s, 1C), 166.0 (s, 2C), 137.6 (s, 1C), 135.9 (s,

1C), 134.8 (d, 2C), 134.6 (s, 1C), 133.1 (s, 1C), 131.5

(s, 2C), 129.1 (d, 2C), 128.4 (d, 2C), 128.3 (d, 2C),

128.0 (d, 1C), 127.9 (d, 2C), 127.7 (d, 2C), 126.9 (d,

2C), 126.5 (d, 1C), 123.5 (d, 2C), 66.0 (t, 1C), 54.5 (d,

1C), 36.2 (t, 1C); HRMS calcd. for C31H24N2O5

527.1577, obsd. 527.1569.

N-{4-[N-((benzyloxycarboyl)methyl)carbamoyl]phe-

nyl}phthalimide (5b)

503 mg (65 %); colourless solid; mp, 245-247 °C; IR

(KBr) Vmax/cnT1: 3337 (w), 1759 (m), 1701 (s), 1647

(m), 1506 (m), 1391 (m), 1312 (w), 1207 (m), 1119 (w),

887 (w), 719 (m), 530 (w); ’H NMR (300 MHz, d6-

DMSO) (5/ppm: 9.11 (t, J= 5.7 Hz, IH, NH), 8.14-7.89

(m, 6H), 7.60 (d, J = 8.5 Hz, 2H), 7.40-7.25 (m, 5H),

5.18 (s, 2H), 4.12 (d, J = 5.7 Hz, 2H); 13C NMR (75

MHz, ^6-DMSO) (5/ppm: 169.7 (s, 1C), 166.7 (s, 1C),

166.1 (s, 2C), 134.8 (d, 2C), 134.6 (s, 1/2C), 133.0 (s,

1/2C), 131.5 (s, 2C), 128.4 (d, 2C), 128.1 (d, 1C), 127.9

(d, 2C), 127.8 (d, 2C), 127.0 (d, 2C), 123.5 (d, 2C), 65.9

(t, 1C), 41.4 (t, 1C); HRMS calcd. for C24H18N2O5

437.1108, obsd. 437.1099.

General Procedure for the Hydrogenolysis on Pd/C

N-{4-[N-((ethyloxycarbonyl)methyl)carbamoyl]phe-

nyljphthalimide (5bEt)

In a vessel for hydrogenation was placed 5a (500 mg, 1

mmol) or 5b (500 mg, 1.2 mmol) and dissolved in a

mixture of dry DMF (75 mL) and aps. EtOH (40 mL),

and 10 % Pd/C (300 mg) was added. The hydrogenation

was carried out, for 1 day at 55 psi. The crude reaction

mixture was filtered, and the solvent was evaporated on

a rotary evaporator. The residue was dissolved in

EtOAc (20 mL) and extracted with 10 % NaHCCE

The compound was prepared according to the general pro-

cedure for the preparation of benzyl esters 5a and 5b, but

the ethyl ester of glycine was used instead of the benzyl.

The reaction furnished pure product (332 mg, 36 %).

Colourless solid; mp, 202-204 °C; IR (KBr) v

max/cnT1: 3421 (s), 3315 (s), 2916 (m), 1709 (s), 1639

(m), 1508 (m), 1389 (m), 1097 (w), 856 (w), 719 (m);

Croat. Chem. Acta 87 (2014) 431.

M. Sohora et al., Photodecarboxylation ofDipeptides

441

(3x15 mL). Combined aqueous layers were acidified to

pH 3 with IM HC1, and then extracted with EtOAC

(3x15 mL). The organic layers were dried over anhy-

drous MgSCL, filtered and the solvent was removed.

The pure product was obtained after crystallization from

EtOAc/MeOH in a form of colourless crystals in ~ 30 %

yield.

Hz, 1H); 13C NMR (75 MHz, 76-DMSO) (5/ppm: 166.8

(s, 1C), 165.3 (s, 2C), 138.8 (s, 1C), 134.8 (d, 2C),

134.3 (s, 1C), 133.9 (s, 1C), 131.5 (s, 2C), 129.1 (d,

2C), 128.0 (d, 2C), 127.7 (d, 2C), 126.9 (d, 2C), 126.1

(d, 1C), 123.5 (d, 2C), 55.1 (d, 1C), 36.8 (t, 1C).

N-{4~[N-(carboxymethyl)carbamoyl]phenyl}phthali-

mide (3b)41

2-[4-(l-Oxoisoindolin-2-yl)benzamidoJ-3-

phenylpro-panoic Acid (6a)40

Colourless solid; ’H NMR (300 MHz, <f6-DMSO)

(5/ppm: 12.74 (br s, 1H), 8.66 (d, J= 7.5 Hz, 1H), 8.01

(d, J= 8.7 Hz, 2H), 7.89 (d, J= 8.7 Hz, 2H), 7.81 (d, J

301 mg (77 %); colourless solid; 'H NMR (600 MHz,

CD3OD) (5/ppm: 8.00 (d, 2H, J= 8.5 Hz), 7.99-7.96 (m,

2H), 7.91-7.87 (m, 2H), 7.62 (d, 2H, J= 8.5 Hz), 4,12

(s, 2H); >H NMR (600 MHz, cfe-DMSO) 6/ppm: 12.59

(br. s, 1H), 8.92 (t, J= 5.7 Hz, 1H), 8.06-7.90 (m, 6H),

7.59 (d, J = 8.4 Hz, 2H), 3.96 (d, J = 5.8 Hz, 2H); 13C

NMR (150 MHz, J6-DMSO) (5/ppm: 171.1 (s, 1C),

166.7 (s, 2C), 165.5 (s, 1C), 134.8 (d, 2C), 134.5 (s,

1C), 133.2 (s, 1C), 131.5 (s, 2C), 127.8 (d, 2C), 126.9

(d, 2C), 123.5 (d, 2C),41.3(t, 1C).

=

7.4 Hz, 1H), 7.72-7.67 (m, 2H), 7.57 (t, J = 7.0 Hz,

1H), 7.32-7.09 (m, 5H), 5.07 (s, 2H), 4.64-4.60 (m,

1H), 3.23-3.02 (m, 2H); 13C NMR (75 MHz, cfe-DMSO)

(5/ppm: 173.2 (s, 1C), 167.0 (s, 1C), 165.6 (s, 1C), 142.1

(s, 1C), 141.1 (s, 1C), 138.2 (s, 1C), 132.6 (d, 1C),

132.2 (s, 1C), 129.1 (d, 2C), 128.3 (d, 3C), 128.2 (d,

2C), 126.3 (d, 1C), 123.4 (d, 2C), 118.1 (d, 2C), 54.2 (d,

2C), 50.4 (t, 1C), 36.3 (t, 1C).

General Procedure for the Synthesis of Decarboxyla-

tion Products 7a and 7b

2-[4-(l-Oxoisoindolin-2-yl)benzamido]

acetic Acid (6b)39

A round bottom flask was charged with acid 4 (200 mg,

0.748 mmol), HBTU (298 mg, 0.786 mmol), TEA (for

7a 0.104 mL, 0.748 mmol, 1 equivalent, and for 7b

0.208 mL, 1.496 mmol, 2 equivalents) and DMF (10

mL), and stirred for 10 min. After activation of the acid,

HC1xNH2CH3 (50 mg, 0.748 mmol) or 2-

phenylethylamine (94 pL, 0.748 mmol) was added. The

reaction mixture was stirred at rt for 4 days. After the

reaction was completed, DMF was removed on a rotary

evaporator. To the crude reaction mixture brine (30 mL)

and EtOAc (50 mL) were added. The product was sus-

pended in a form of white solid between the aqueous

and organic layer. After filtration of this mixture

through a sinter, the precipitate was three times washed

with ethyl acetate (3x15 mL) and dried over P 2O 5.

Colourless solid; ‘H NMR (300 MHz, d6-DMSO)

(5/ppm: 12.59 (s, 1H), 8.86 (t, J = 5.8 Hz, 1H),

8.07-7.95 (m, 4H), 7.85-7.52 (m, 4H), 3.94 (d, J= 5.8

Hz, 2H); 13C NMR (75 MHz, (4-DMSO) (5/ppm: 171.3

(s, 1C), 166.9 (s, 1C), 165.7 (s, 1C), 142.0 (s, 1C), 141.0

(s, 1C), 132.5 (d, 1C), 132.1 (s, 1C), 128.9 (s, 1C),

128.2 (d, 3/2C), 123.3 (d, 2/3C), 118.2 (d, 2C), 50.4 (t,

1C), 41.2 (t, 1C).

General Procedure for the Synthesis of Acids 3a and

3b

A two neck round bottom flask was charged with benzyl

ester 5a (500 mg, 1 mmol) or 5b (500 mg, 1.2 mmol),

10 % Pd/C (100 mg) and abs MeOH (30 mL). The flask

was closed with a septum and purged with nitrogen in

order to remove air. The the suspension 10 equivalents

of Et3SiH were added during one hour. The reaction was

monitored on TLC. After the reaction was finished, the

reaction mixture was filtered, and the solvent was re-

moved on a rotary evaporator. To the residue cold

MeOH (25 mL) was added to precipitate the product.

The product was filtered off through a Hirsch funnel

and dried in a vacuum oven at 60 °C and 10 mbar.

1A-{4-[N-(2-phenylethan-l-yl)carbamoyl]phenyl}phtha-

limide (7a)40

275 mg (100 %); colourless solid; mp, 322-324°C,

sublimation at 268-270 °C; 'H NMR (600 MHz, d6-

DMSO) (5/ppm: 8.71 (s, IH, NH), 8.01-7.91 (m, 6H),

7.55 (d, J= 8.2 Hz, 2H), 7.33-7.25 (m, 4H), 7.21 (t, J =

6.9 Hz, 1H), 3.53-3.51 (m, 2H), 2.88 (t, J = 7.4 Hz,

2H); 13C NMR (150 MHz, ^-DMSO) (5/ppm: 166.8 (s,

1C), 165.5 (s, 2C), 139.5 (s, 1C), 134.8 (d, 2C), 134.2

(s, 1C), 134.0 (s, 1C), 131.5 (s, 2C), 128.6 (d, 2C),

128.3 (d, 2C), 127.7 (d, 2C), 126.9 (d, 2C), 126.1 (d,

1C), 123.5 (d, 2C), 40.9 (t, 1C), 35.0 (t, 1C); HRMS

calcd. for C23H18N2O3 393.1209, obsd. 393.1206.

'N-{4-[N-(l-carboxy-2-phenylethan-l-yl)carbamo-

yljphenyljphthalimide (3a)40

267 mg (65 %); colourless solid; 'H-NMR (600 MHz,

t/e-DMSO) (5/ppm: 8.36 (d, J = 7.2 Hz, IH, NH),

7.99-7.96 (m, 2H), 7.93-7.89 (m, 4H), 7.54 (d, J= 8.5

Hz, 2H), 7.32-7.29 (d, J= 7.3 Hz, 2H), 7.25 (t, J = 7.4

Hz, 2H), 7.16 (t, J= 7.3 Hz, 1H), 4.60-4.55 (m, 1H),

3.23 (dd, 7=4.2, 13.3 Hz, 1H), 3.07 (dd, J = 10.3, 13.3

N-{4-[(N-methyl)carbamoyl]phenyl}phthalimide (7b)40

182 mg (87 %); colourless solid; mp, 303-305 °C, sub-

limation at 238-240°C; 'H NMR (300 MHz, (ftf-DMSO)

c5/ppm: 8.56 (d, J = 4.5 Hz, 1H), 8.04-7.87 (m, 6H),

7.55 (d, J = 8.6 Hz, 2H), 2.81 (d, J = 6.4 Hz, 3H); 'H

Croat. Chem. Acta 87 (2014) 431.

442

M. Sohora et al., Photodecarboxylation ofDipeptides

NMR (300 MHz, MeOD) ć/ppm: 8.01-7.95 (m, 4H),

7.93-7.90 (m, 2H), 7.64-7.60 (m, 2H), 2.94 (s, 3H); 13C

NMR (150 MHz, MeOD) <S/ppm: 170.1 (s, 1C), 168.4

(s, 2C), 137.8 (s, 1C), 135.9 (d, 2C), 133.1 (s, 2C),

128.8 (d, 2C), 127.7 (d, 2C), 124.7 (d, 2C), 27.0 (q, 1C),

one singlet (1C) is not detected; HRMS calcd. for

Ci6H,2N20 3 303.0740, obsd. 303.0744.

equipped in the reactor. After irradiation, solvent was

removed by evaporation, and crude reaction mixture

was chromatographed on column and/or thin layer of

silica gel.

Decarboxylation product 8b (5 mg, 5 %) was iso-

lated from the crude photoreaction mixture after several

column chromatographies on silicagel EtOAc/CH2Cl2

and MeOH/EtOAc as eluent, and rechromatography on

TLC with EtOAc/MeOH/CH2Cl2(5:10:85).

N-[3-(N-methyl)carbamoyl-l-adamantyl]phthalimide

(8b)

Glycine derivatives 12a and 13a were isolated af-

ter preparative thin layer chromatography of the crude

A round bottom flask was charged with a solution of

methylamine hydrochloride (62 mg, 0.922 mmol),

TEA (257 pL, 1.844 mmol) and THF (5 mL). To the

solution succinimide (428 mg, 1.014 mmol) was added

during 30 minutes. The reaction was conducted at rt

for 2 days. The solvent was removed on a rotary evap-

orator and 0.5M HC1 (10 mL) was added. The extrac-

tion with ethyl acetate (3><10 mL) was carried out, and

the extracts were dried over MgSCfi. After filtration

and removal of the solvent the crude product was ob-

tained that was purified by column chromatography on

silicagel with CH2CI2 and 2-5 % MeOH/CH2Cl2 as

eluent, and cristallization from hexane/CH2Cl2/MeOH

mixture. The pure product was isolated in a form of

colourless crystals.

73 mg (23 %); colourless crystals; mp, 205-207

°C; IR (KBr) v mJ c r n u. 3348 (m), 2914 (m), 2850

(m), 1707 (s), 1635 (m), 1541 (m), 1466 (w), 1364

(m), 1313 (m), 1078 (m), 974 (w), 872 (w), 719 (m),

640 (w), 534 (w); 'H NMR (600 MHz, CD3OD)

<5/ppm: 7.73 (s, 4H), 2.85-2.68 (m, 3H), 2.58-2.53 (m,

4H), 2.47 (d, J = 12.2 Hz, 2H), 2.27 (br. s, 2H), 1.91

(d,J = 12.4 Hz, 2H), 1.87-1.78 (m, 3H), 1.70 (d, J =

1.8 Hz, 1H); I3C NMR (75 MHz, J 5-DMSO) <S/ppm:

176.1 (s, 1C), 169.0 (s, 2C), 134.3 (d, 2C), 131.2 (s,

2C), 122.5 (d, 2C), 59.8 (s, 1C), 42.0 (s, 1C), 41.2 (t,

1C), 38.8 (t, 2C), 37.6 (t, 2C), 34.8 (t, 1C), 29.0 (q,

1C), 25.9 (d, 2C); HRMS, calcd. for C20H22N2O3

339.1703, obsd. 339.1707.

photoreaction

mixture

on

silica

gel

with

CH2Cl2/TFA/MeOH (30:0.07:69.93).

2.12- Diaza-l 0-methoxy-hexacyclo[12.5.1.11'16.114-18.

04'9]doeicosa-4,6,8-trien-3,13-dion (9b)

Colourless oil; IR (KBr) v max/cm-1: 3421 (s), 2917

(m), 2852 (m), 2361 (m), 1718 (m), 1654 (m), 1399

(w), 1314 (w), 1090 (w), 668 (w); 'H NMR (600 MHz,

CD3OD) <5/ppm: 7.89 (dd, J = 0.6, 7.7 Hz, 1H), 7.59

(td, J= 7.6, 1.2 Hz, 1H), 7.50 (td, J= 7 .7 , 1.2 Hz, 1H),

7.42 (dd, J = 0.6, 7.6 Hz, 1H), 3.88 (s, 3H), 3.73 (s,

2H), 2.26-2.20 (m, 7H), 2.11 (d, J = 11.2 Hz, 2H),

1.91 (d, J = 12.1 Hz, 2H), 1.88 (d, / = 12.1 Hz, 2H),

1.76 (d, J = 12.5 Hz, 1H), 1.71 (d, J= 12.5 Hz, 1H);

13C NMR (150 MHz, CD3OD) <5/ppm: 178.9 (s, 1C),

171.9 (s, 1C), 168.5 (s, 1C), 140.8 (s, 1C), 133.2 (d,

1C), 131.0 (d, 1C), 130.2 (d, 1C), 129.9 (s, 1C), 128.9

(d, 1C), 54.0 (s, 1C), 52.8 (q, 1C), 44.8 (t, 1C), 43.8 (s,

1C), 43.6 (t, 1C), 41.2 (t, 2C), 39.2 (t, 2C), 36.5 (t,

1C), 30.9 (d, 2C).

2.12- Diaza-pentacyclo[12.5.1.1'■16.114,18.04,9]doeicosa-

4,6,8-trien-3,10,13-trion (2b)

Colourless oil; IR (KBr) v max/cm_l: 3394 (s), 2916 (s),

2850 (m), 1617 (s), 1593 (s), 1566 (s), 1388 (m), 1321

(w), 718 (w), 608 (w); >H NMR (300 MHz, CD3OD)

<5/ppm: 7.61-7.50 (m, 2H), 7.46-7.33 (m, 2H), 3.74 (s,

2H), 2.32 (s, 2H), 2.27-2.06 (m, 6H), 1.93-1.88 (m,

4H), 1.81-1.68 (m, 2H); 13C NMR (75 MHz, CD3OD)

<5/ppm: 187.7 (s, 1C), 179.1 (s, 1C), 171.7 (s, 1C), 140.8

(s, 1C), 136.1 (s, 1C), 130.6 (d, 1C), 129.1 (d, 1C),

129.0 (d, 1C), 128.9 (d, 1C), 53.8 (s, 1C), 44.7 (s, 1C),

43.8 (t, 1C), 43.1 (t, 1C), 41.3 (t, 2C), 39.2 (t, 2C), 36.6

(t, 1C), 30.8 (d, 2C).

Stability of Phthalimides in the Presence of K2CO3

To the solutions of lb and 3b in CH3CN-H2O (3:1, c =

lxlO-3 M) were added aqueos solutions of K2CO3 to

reach the final concentration of K2CO3 c = lxlO-3 M or

lxlO-2 M. The LTV-vis spectra were recorded prior to

the addition of base, and afterwards in the intervals of 1

hour (see the supporting info.).

Irradiation in the Presence of Acrylonitrile

A quartz vessel was charged with a solution of la, lb,

3a or 3b (10 mg/20 mL) in acetone-water (3:1), and 0.5

equivalents of K2C0 3 were added. The solution was

purged with N2 for 15 minutes. After the purging, acry-

lonitrile (100 pL) was added and the solution was irra-

diated at 300 nm in Luzchem reactor (8 lamps) for

10-30 min. After the irradiation, the solvent was re-

moved on a rotary evaporator and 'H NMR spectrum

was recorded.

Irradiation Experiments, General

In a quartz vessel a solutions of acids la, lb, 3a, or 3b

(c ~ 5-7 x io-3 M) and 0.5 equivalents of K2CO3 in

acetone-H20 (3:1) or CH3CN-H2O (3:1) were prepared.

After purging with N2 for 20 minutes, the solutions were

irradiated at 300 nm in a Luzchem reactor with 8 lamps.

During the irradiation the solution was cooled with a fan

Croat. Chem. Acta 87 (2014) 431.

M. Sohora et al., Photodecarboxylation ofDipeptides

443

Irradiation in the Presence of Potassium Sorbate

These data can be found on the website of Croatica Chemica

Acta (http://public.camet.hr/ccacaa).

A solution of lb in CH3CN-water (3:1, 10 mg/20 mL)

was placed to three quartz cuvettes (5 mL to the each

cuvette. To the cuvettes an aqueous solution of K2C 03

(0.5 equivalents) and potassium sorbate were added, and

the solutions were diluted with CH3CN-water (3:1) to

Acknowledgements. These materials are based on work fi-

nanced by the Ministry of Science Education and Sports of the

Republic of Croatia (grant No. 098-0982933-2911), National

Foundation for Science, (HrZZ grant no. 02.05/25) We thank

Professors Peter Wan and Cornelia Bohne, and the University

of Victoria (Victoria, Canada, BC) for the use of nanosecond

LFP.

reach the final concentrations of lb, c

-

7 x 10“4M, and

the sorbate in the concetrations 0, 0.010 M and 0.035 M.

The solutions were purged with N2 for 15 minutes and

irradiated at 300 nm in Luzchem reactor (6 lamps) for

30 min. After the irradiation, the solvent was removed

on a rotary evaporator and 'H NMR spectra were rec-

orded.

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Photodecarboxylation of N-Adamantyl- and N-phenylphthalimide

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