Preparation of photoactivable amino acid derivatives

Article abstract of DOI:10.1021/jo900442p

(Chemical Equation Presented) A range of N-protected-R-amino acyl-5,7-dinitroindolines 3a-z were prepared in good yields from commercially available N-protected-R-amino acids 1a-z by a two-step sequence of acylation and intramolecular amide N-arylation. S

Full text of DOI:10.1021/jo900442p

Preparation of Photoactivable Amino Acid Derivatives
Jean-Luc De´bieux and Christian G. Bochet*
Department of Chemistry, UniVersity of Fribourg, 9 Chemin du Muse´e, CH-1700 Fribourg, Switzerland
christian.bochet@unifr.ch
ReceiVed February 26, 2009
A range of N-protected-R-amino acyl-5,7-dinitroindolines 3a-z were prepared in good yields from
commercially available N-protected-R-amino acids 1a-z by a two-step sequence of acylation and
intramolecular amide N-arylation. Subsequent photochemical acylation of the N-protected-R-amino acyl-
5,7-dinitroindolines 3e,g,r afforded the corresponding N-protected-R-amino acid amides 22e,g,r (77-92%)
under mild conditions. All these reactions occurred with complete retention of chirality as evidenced by
NMR analysis. This scheme provides an attractive and alternative method to the conventional acylation
of R-amino acids, especially in cases where the amide bond needs to be formed without the use of a
coupling reagent.
Introduction
triggering the process at the appropriate time. The photoacylation
reaction fulfills most of these requirements. It was developed a
few decades ago by Amit and Patchornik,12 with the introduction
of the 5-bromo-7-nitroindolinyl (Bni) photoactivable leaving
group, initially designed to block a carboxylic function through
the formation of its amide derivative, the N-acyl-5-bromo-7-
nitroindoline. Irradiation at 420 nm or below activates the acyl
function toward nucleophilic attack. Later, the Bni group was
employed both to mask and to activate a terminal carboxylic
function in order to assemble two peptide units.13 We recently
pointed out several advantages of the 5,7-dinitroindolinyl (Dni)
group over its Bni analogue;14 in particular shorter reaction times
(up to a factor of 4) and a significantly higher quantum yield
for its photocleavage.15 In this context, we elaborated a
convenient method, using N-acyl-5,7-dinitroindolines as more
efficient agents for the photochemical acylation of amines14 and
alcohols16 under exceptionally mild and practical conditions.
We now extend the N-acyl-5,7-dinitroindoline chemistry to
prepare stable N-protected-R-amino acyl-5,7-dinitroindolines
3a-z derived from N-protected-R-amino acids 1a-z and their
utilization in the synthesis of N-protected-R-amino acid amides
22e,g,r by photochemical acylation.
R-Amino amides, the fundamental functional group in
naturally occurring peptides and proteins, are important synthetic
targets, as they have been claimed to show anti-inflammatory,1,2
antibacterial,3 anticonvulsant,4 cerebroprotective, and anti-HIV
activity,5,6 and have been utilized as local anesthetics,7 anal-
gesics,8 and melanocortin agonists.9
Many methods have been developed for the formation of
amide bonds, most of them involving the reaction between an
activated carboxylic acid as an electrophile and a free amine as
a nucleophile.10 However, many of these reactions have various
drawbacks, extensively described by Katrizky et al.11 A desirable
feature for this reaction would be a neutral medium, mild
temperature, great tolerance toward nucleophiles other than
amines, and the possibility of mixing both reactants and
(1) Chemistry and Biochemistry of Amino Acids; Barrett G. C., Ed.; Chapman
and Hall: London, UK, 1985.
(2) Marcincal-Lefebvre, A.; Gesquiere, J. C.; Lemer, C.; Dupuis, B. J. Med.
Chem. 1981, 24, 889.
(3) Joshi, K. C.; Pathak, V. N.; Jain, S. K. Pharmazie 1980, 35, 677.
(4) (a) Bachir, M.; Riffaud, J.-P.; Lacolle, J.-Y.; Lemoine, J.; De Almeida,
A.; Houziaux, P.; Danree, B. Eur. J. Med. Chem. 1990, 25, 71. (b) Chiesi, P.;
Ventura, P.; Delcanale, M.; De Fanti, R.; Armani, E.; Villetti, G.; Pietra, C.
PCT Int. Appl. WO 9803472, 1998.
(5) Oshiro, Y.; Sakurai, Y.; Tanaka, T.; Kikuchi, T.; Hirose, T.; Tottori, K.
J. Med. Chem. 1991, 34, 2014.
(6) Song, Y.; et al. Bioorg. Med. Chem. 2002, 10, 1263–1273.
(7) Dullenkopf, A.; Borgeat, A. Anaesthesist 2003, 52, 329.
(8) Salvati, P.; Veneroni, O.; Maj, R.; Fariello, R.; Benatti, L. Int. Pat. WO
03020273, 2003.
(9) Poindexter, G. S.; Luo, G.; Chen, L. U. S. Pat. 20030232807, 2003.
(10) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–
10852.
(12) (a) Amit, B.; Patchornik, A. Tetrahedron Lett. 1973, 24, 2205–2208.
(b) Amit, B.; Ben-Efraim, D. A.; Patchornik, A. J. Am. Chem. Soc. 1976, 98,
843–844.
(13) Pass, S.; Amit, B.; Patchornik, A. J. Am. Chem. Soc. 1981, 103, 7674–
7675.
(14) Helgen, C.; Bochet, C. G. Synlett 2001, 1968–1970.
(15) Adams, S. R.; Kao, J. P. Y.; Tsien, R. Y. J. Am. Chem. Soc. 1989, 111,
7957–7968.
(16) De´bieux, J.-L.; Cosandey, A.; Helgen, C.; Bochet, C. G. Eur. J. Org.
Chem. 2007, 207, 3–2077.
(11) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210.
10.1021/jo900442p CCC: $40.75
Published on Web 05/28/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4519–4524 4519

De´bieux and Bochet
SCHEME 1. Attempt of Direct Acylation of Cbz-L-Leu-OH
with 5,7-Dinitroindoline
The synthesis of phenylethylamine derivatives 4-7 was
attempted from commercially available 2-methoxyphenethy-
lamine (12, Scheme 3), but only 2 appears as a product with
any yield to speak of (Scheme 3). After protection of the amine
12 with a trifluoroacetyl group, the aromatic part was doubly
nitrated by electrophilic aromatic substitutions. Subsequent
demethylation of the intermediate 14 with LiCl in DMF at reflux
furnished phenol 15. This phenol was then converted to the
corresponding aryl bromide 16, iodide 18, and triflate 17
(Scheme 4). When the trifluoroacetamide was removed under
basic conditions (K2CO3 in MeOH/H2O) to liberate the amines
5-7, DniH (2) was directly formed; unfortunately, a spontane-
ous cyclization occurred by intramolecular amine arylation
without catalyst, clearly due to the strong electron-withdrawing
character of the aromatic part. To circumvent that problem, the
trifluoroacetyl protecting group was replaced by a Boc group,
labile under acidic conditions. It was introduced on bromoaryl
derivative 16 by reaction with di-tert-butyl dicarbonate and a
catalytic amount of DMAP in acetonitrile at room temperature
(Scheme 5). It was then removed with HCl in ethanol to form
the stable amine hydrochloride salt 20.
As test substrate, Cbz-L-Leu-OH (1a) was coupled to amine
hydrochloride salt 20 with isobutyl chloroformate (IBCF) and
N-methylmorpholine (NMM), providing in 86% yield the
acylated compound 9a, which was subsequently submitted to
an intramolecular Buchwald-Hartwig amidation24 under mi-
crowave irradiation, using 2-dicyclohexylphosphino-2′-meth-
ylbiphenyl (Me-Phos) as the ligand and Pd(dba)2 as the catalyst
(Scheme 6). Thus, Cbz-L-Leu-Dni (3a) was obtained in high
yield (94%). Microwave heating was necessary to accelerate
the reaction and to improve its efficiency. Initial experiments
with either a copper catalyst25 or Xantphos (9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene) as a ligand and Pd2(dba)3 as
a palladium source26 or only a strong base like NaH and LDA
did not afford the cyclization.
As shown in Table 1, various amino acids were tested, all of
them giving good to excellent yields (82-97%) for the acylation
(step 1); on the other hand, different problems were observed
for the intramolecular amide N-arylation (step 2). Indeed, the
reaction conditions for the cyclization, using K2CO3, are not
compatible with the Fmoc protecting group due to its cleavage
in basic medium (entries 3 and 10). Moreover, a free alcohol
group is not tolerated, as it results essentially in the formation
of DniH (entry 6). On the other hand, its protection allowed
satisfactory yields (>80%) for that step (entries 7 and 13) to be
attained. In the case of cysteine amino acids 1k and 1l, where
the thiol group is protected with the benzyl (Bzl) or acetoami-
domethyl (Acm) group, respectively, no desired product was
formed and essentially starting material was recovered (entries
11 and 12). We suspected initially that the sulfur atom on the
cysteine might act as a poison to the catalyst, but strangely,
methionine cyclized with an 80% yield (entry 9). Nevertheless,
common amino acid protecting groups other than Fmoc, such
as Boc, Cbz, and OtBu, are well tolerated under the current
conditions.
Results and Discussion
I. Preparation of N-Protected-r-Amino Acyl-5,7-Dinitroin-
dolines. Our first approach to prepare N-protected-R-amino acyl-
5,7-dinitroindolines 3a-z was a direct acylation between
commercially available N-protected-R-amino acids 1a-z, such
as Cbz-L-Leu-OH (1a), and 5,7-dinitroindoline (DniH) (2)
(Scheme 1). DniH is easily synthesized in 3 steps from indoline
by successive reactions of acetylation, dinitration, and deacety-
lation in a 58% overall yield.17
Different classical methods for direct acylation proved
unsuccessfull due to the very poor nucleophilicity of the amine
group of 5,7-dinitroindoline (DniH, 2). Amino acid halides,
which are generated in situ and frequently used as intermediates
for peptide coupling,18 gave no acylation product, even when
used in conjunction with a Lewis acid to activate the acid halide.
Standard coupling reagents for peptide bond formation such as
EDC/DMAP, BOP, DCC/HOBt, HBTU, or POCl3/pyridine were
also inefficient.19 Deprotonation of DniH (2) with strong bases
like NaH or n-BuLi and successive reaction with the pivaloyl
anhydrides or fluorides of amino acids, or with the amino acid
themselves in the presence of coupling reagents such as EDC/
DMAP, was unsuccessful. Neither the polymer-supported Mu-
kaiyama reagent,20 which is a useful coupling reagent for the
synthesis of esters and amides, nor the anhydride intermediate,
nor the use of diphosphorus tetraiodide (P2I4),21 as a mild
coupling agent, resulted in acylation. Even the original attach-
ment method developed by Patchornik,13 which involves heating
a mixture of 5-bromo-7-nitroindoline and N-protected-R-amino
acids with thionyl chloride in toluene at 40-70 °C for several
hours, failed for DniH (2), obviously due to the presence of
two strong electron-withdrawing groups on the aromatic part.
To circumvent that problem, our next approach was to prepare
N-protected-R-amino acyl-5,7-dinitroindolines 3a-z via an
indirect acylation. Again, neither the formation of N-(protected-
R-amino acyl)benzotriazoles, developed by Katritzky22 as
acylating agents to create peptide bonds, nor the synthesis of
N-(protected-R-amino acyl)indolines, were able to form the
corresponding N-protected-R-amino acyl-5,7-dinitroindolines
3a-z.
To avoid having a very poor nucleophile for the acylation, a
new strategy was envisioned. The goal was to prepare a
phenylethylamine derivative such as 4-7, which could be easily
acylated with different N-protected-R-amino acids 1a-z, due
to the nucleophilic and sterically undemanding primary amine.
AftersubsequentcyclizationbyintramolecularBuchwald-Hartwig
amide N-arylation,23 N-protected-R-amino acyl-5,7-dinitroin-
dolines 3a-z could be obtained (Scheme 2).
(17) Helgen, C.; Bochet, C. G. J. Org. Chem. 2003, 68, 2483–2486.
(18) Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert, M. Acc. Chem.
Res. 1996, 29, 268–274.
(19) Que´le´ver, G.; Burlet, S.; Garino, C.; Pietrancosta, N.; Laras, Y.; Kraus,
J.-L. J. Comb. Chem. 2004, 6, 695–698.
(20) Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579–
4582.
(21) Suzuki, H.; Tsuji, J.; Hiroi, Y.; Sato, N.; Osuka, A. Chem. Lett. 1983,
449–452.
The photolabile protecting group R,R-dimethyl-3,5-dimethox-
ybenzyloxycarbonyl (Ddz),27 available for the amine function
and initially developed for peptide applications, was also tested
in this two-step sequence (Table 2). All N-Ddz-R-amino acids
1o-z gave good to excellent yields (66-91%) in the coupling
reaction (step 1). With regards to the intramolecular amine
arylation (step 2), the yields were essentially similar (69-88%),
(22) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 11, 1656–1665.
4520 J. Org. Chem. Vol. 74, No. 12, 2009

Synthesis of PhotoactiVable Amino Acid DeriVatiVes
SCHEME 2. Alternative Pathway for the Synthesis of N-Protected-r-Amino Acyl-5,7-dinitroindolines
SCHEME 3. Synthesis of Phenol 15
SCHEME 4. Unsuccessful Synthesis of Phenylethylamine Derivatives 4-7
SCHEME 5. Successful Preparation of Amine Hydrochloride 20
except for the threonine derivative 1x (entry 10) where the yield
was moderate (40%). Extending the reaction time to 9 h led
only to a slight increase of the yield (to 52%), probably because
of the surrounding steric bulk.
II. Preparation of N-Protected-r-Amino Acid Amides
by Photochemical Acylation. With these building blocks in
hand, we checked their reactivity in the photoacylation reaction,
using phenethylamine (21). Thus, N-protected-R-amino acyl-
J. Org. Chem. Vol. 74, No. 12, 2009 4521

De´bieux and Bochet
SCHEME 6. Synthesis of N-Protected-r-Amino Acyl-5,7-dinitroindolines 3a-z from 2-(2-Bromo-3,5-dinitrophenyl)ethanamine
Hydrochloride (20)
TABLE 1. Preparation of N-Boc, Cbz, and Fmoc-r-Amino
TABLE 3. Preparation of N-Protected-r-Amino Acid Amides
Acyl-5,7-dinitroindolines
entry
reactant
R1
yielda (%)
yielda c yieldb c
,
,
amino
acid
1
2
3
Boc-L-Phe-Dni, 3e
Cbz-L-Ser(tBu)-Dni, 3g
Ddz-L-Leu-Dni, 3r
PhCH2
(CH3)3COCH2
(CH3)2CHCH2
80
77
92
entry
product
(%) of 9 (%) of 3
1
2
3
4
5
6
7
8
9
Cbz-L-Leu-OH, 1a
Cbz-L-Ala-OH, 1b
Fmoc-L-Ala-OH, 1c
Cbz-L-Pro-OH, 1d
Boc-L-Phe-OH, 1e
Boc-L-Ser-OH, 1f
Cbz-L-Leu-Dni, 3a
Cbz-L-Ala-Dni, 3b
Fmoc-L-Ala-Dni, 3c
Cbz-L-Pro-Dni, 3d
Boc-L-Phe-Dni, 3e
Boc-L-Ser-Dni, 3f
86
94
92
94d
90
78
95
94
97
82
92
97
85
95
94
84
0
a Isolated yield.
88d
81
0
SCHEME 7. Photochemical Amidation with
N-Protected-r-Amino Acyl-5,7-dinitroindolines
Cbz-L-Ser(tBu)-OH, 1g Cbz-L-Ser(tBu)-Dni, 3g
91
84
80
0
0
0
Boc-L-Val-OH, 1h
Boc-L-Met-OH, 1i
Boc-L-Val-Dni, 3h
Boc-L-Met-Dni, 3i
Fmoc-L-Met-Dni 3j
10 Fmoc-L-Met-OH 1j
11 Boc-L-Cys(Bzl)-OH, 1k Boc-L-Cys(Bzl)-Dni, 3k
12 Boc-L-Cys(Acm)-OH, 1l Boc-L-Cys(Acm)-OH, 3l
13 Boc-L-Tyr(tBu)-OH, 1m Boc-L-Tyr(tBu)-Dni, 3m
82
80
14 Boc-L-Trp-OH, 1n
Boc-L-Trp-Dni, 3n
an attractive facet to our strategy of chromatic orthogonality.28
The experiments were carried out in quartz test tubes, using a
LED-based photoreactor (Lumos 43), emphasizing the simplicity
of this reaction.
a General conditions: amino acid (1.26 mmol), IBCF (1.20 mmol),
NMM (1.20 mmol), CH2Cl2 (10 mL), -20 °C, 1 h; 20 (1.20 mmol),
Et3N (1.20 mmol), DMF (5 mL), room temperature, 4 h. b General
conditions: intermediate 9a-n (1 mmol), Pd(dba)2 (5 mol %), Me-Phos
(5 mol %), K2CO3 (2 equiv), Tol/MeCN ) 3:1 (20 mL), MW, 100 °C,
2 h. c Isolated yield. d Rotamers.
III. Verification of the Stereochemical Integrity of the
Amino Acids. To determine whether our conditions caused
racemization of the amino acids during the two-step procedure
and the photochemical reaction, we synthesized two diastere-
oisomers Ddz-L-Ala-L-Phe-OtBu and Ddz-D-Ala-L-Phe-OtBu
from commercially available and enantiomerically pure Ddz-
L-Ala-OH (1p) and Ddz-D-Ala-OH (1q), respectively. For the
photochemical reaction, Ddz-L-Ala-Dni (3p) and Ddz-D-Ala-
Dni (3q) were separately irradiated at 385 nm with L-
phenylalanine tert-butyl ester hydrochloride (L-Phe-OtBu·HCl)
in the presence of 1 equiv of Et3N to furnish the two
TABLE 2. Preparation of N-Ddz-r-Amino Acyl-5,7-dinitroindolines
yielda c yieldb c
,
,
entry
amino acid
Product
(%) of 9 (%) of 3
1
2
3
4
5
6
7
8
9
Ddz-L-Gly-OH, 1o
Ddz-L-Ala-OH, 1p
Ddz-D-Ala-OH, 1q
Ddz-L-Leu-OH, 1r
Ddz-L-Phe-OH, 1s
Ddz-L-Trp-OH, 1t
Ddz-L-Pro-OH, 1u
Ddz-L-Gly-Dni, 3o
Ddz-L-Ala-Dni, 3p
Ddz-D-Ala-Dni, 3q
Ddz-L-Leu-Dni, 3r
Ddz-L-Phe-Dni, 3s
Ddz-L-Trp-Dni, 3t
Ddz-L-Pro-Dni, 3u
77
94
91
92
91
87
77d
80
83
66
76
78
88
88
69
77
81d
72
Ddz-L-Tyr(tBu)-OH, 1v Ddz-L-Tyr(tBu)-Dni, 3v
Ddz-L-Ser(tBu)-OH, 1w Ddz-L-Ser(tBu)-Dni, 3w
80
1
corresponding diastereoisomers, which were analyzed by H
10 Ddz-L-Thr(tBu)-OH, 1x Ddz-L-Thr(tBu)-Dni, 3x
40, 52e
77
11 Ddz-L-Asp(OtBu)-OH, 1y Ddz-L-Asp(OtBu)-Dni, 3y 85
12 Ddz-L-Glu(OtBu)-OH, 1z Ddz-L-Glu(OtBu)-Dni, 3z
85
NMR before and after column chromatographic purification. It
showed no detectable racemization (i.e., <5%). The methyl
signal in the L-Ala- and the one in the D-Ala-diastereoisomer
were well distinguishable by their different chemical shifts. In
each spectrum, the absence of two separate doublets for the
methyl protons corresponding to the LL- and DL-diastereoiso-
mers indicated that these reactions occurred with complete
retention of chirality. The absence of racemization further
confirms the absence of a ketene intermediate, in line with our
previously reported mechanism.29
75
a General conditions: amino acid (1.26 mmol), IBCF (1.20 mmol),
NMM (1.20 mmol), CH2Cl2 (10 mL), -20 °C, 1 h; 20 (1.20 mmol),
Et3N (1.20 mmol), DMF (5 mL), room temperature, 4 h. b General
conditions: intermediate 9o-z (1 mmol), Pd(dba)2 (5 mol %), Me-Phos
(5 mol %), K2CO3 (2 equiv), Tol/MeCN ) 3:1 (20 mL), MW, 100 °C,
2 h. c Isolated yield. d Rotamers. e After 9 h of reaction.
5,7-dinitroindolines 3e,g,r were irradiated at 385 nm with 1
equiv of amine 21 in acetonitrile for 16 h, affording the
corresponding amides 22e,g,r in good yields (77-92%) (Table
3 and Scheme 7). The Boc, Cbz, and Ddz amine protecting
groups are compatible with these reaction conditions. It is
interesting to note that the Ddz photolabile protecting group is
stable at this operating wavelength (385 nm), i.e., it does not
affect the yield of photoamidation (entry 3). This result adds
(24) (a) Bonnaterre, F.; Bois-Chaussy, M.; Zhu, J. Org. Lett. 2006, 8, 4351–
4354.
(25) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421–7428.
(26) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043–6048.
(27) (a) Cameron, J. F.; Fre´chet, J. M. J. J. Org. Chem. 1990, 55, 5919–
5922. (b) Birr, C.; Lochinger, W.; Stahnke, G.; Lang, P. Liebigs Ann. Chem.
1972, 763, 162–172.
(28) (a) Blanc, A.; Bochet, C. G. J. Org. Chem. 2002, 67, 5567–5577. (b)
Bochet, C. G. Angew. Chem., Int. Ed. 2001, 40, 2071–2073.
(29) Cohen, A. D.; Helgen, C.; Bochet, C. G.; Toscano, J. P. Org. Lett. 2005,
7, 2845–2848.
(23) For reviews, see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald,
S. L. Acc. Chem. Res. 1998, 31, 805–818. (b) Hartwig, J. F. Angew. Chem., Int.
Ed. 1998, 37, 2046–2067.
4522 J. Org. Chem. Vol. 74, No. 12, 2009

Synthesis of PhotoactiVable Amino Acid DeriVatiVes
(C), 138.0, 135.7, 131.9, 130.1, 120.7-111.2 (CF3), 120.0, 38.1,
29.1. IR (neat) 3284, 3267, 3238, 3204, 3101, 1692, 1604, 1546,
1523, 1456, 1429, 1335, 1294, 1256, 1200, 1173, 1085, 701. HR-
MS 346.0257 (C10H8F3N3O6 + Na+ calcd 346.0257).
Conclusion
We have described a methodology for the preparation of
N-protected-R-amino acyl-5,7-dinitroindolines 3a-x, and their
utilization for photochemical acylation to synthesize N-protected-
R-amino acid amides 22e,g,r under neutral conditions. The mild
conditions, the simplicity, the operational ease, and the retention
of the chirality offer advantages over conventional coupling
techniques, and they could make this methodology a method
of choice for the preparation of N-protected-R-amino acid
amides and peptides by photochemical acylation, thus avoiding
the use of coupling reagents. It is, however, clear that this
strategy remains appropriate for applications where scales
remain modest and costs of building blocks are not crucial (i.e.,
for automated microscale synthesis).
N-(2-Bromo-3,5-dinitrophenethyl)-2,2,2-trifluoroacetamide (16).
Under argon, a solution of N-(2-hydroxy-3,5-dinitrophenethyl)-
2,2,2-trifluoroacetamide (15) (0.220 g, 0.68 mmol), PBr3 (104 µL,
1.088 mmol), and DMF (0.4 mL, 5.187 mmol) in toluene (5 mL)
was stirred at 110 °C during 1 h. After addition of water and EtOAc,
the product was extracted with EtOAc (3 × 20 mL) and the
combined organic layers were washed with water (2 × 10 mL)
and brine (10 mL), and then dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. Purification by flash
column chromatography [SiO2, hexane/EtOAc (1:1)] provided the
desired product as a yellowish solid (234 mg, 89%). Mp 155-156
1
°C. H NMR (360 MHz, DMSO-d6) δ 9.53 (br, 1H), 8.81 (d, J )
2.2 Hz, 1H), 8.42 (d, J ) 2.3 Hz, 1H), 3.55 (m, 2H), 3.20 (t, J )
6.6 Hz, 2H); 13C NMR (125.0 MHz, DMSO-d6) δ 156.8-156.0
(C(O)CF3), 151.3, 146.4, 143.2, 127.5, 122.0, 119.2-112.3 (CF3),
118.0.0, 38.2, 34.7. IR (neat) 3298, 3087, 1696, 1558, 1537, 1460,
1348, 1211, 1174, 734. HR-MS 407.9421 (C10H7BrF3N3O5 + Na+
calcd 407.9413).
Experimental Section
Preparation of 2-(2-Bromo-3,5-dinitrophenyl)ethanamine Hy-
drochloride (20). N-(2-Methoxyphenethyl)-2,2,2-trifluoroacetamide
(13). Under argon, to a stirred solution of 2-methoxyphenetylamine
(4.84 mL, 32.4 mmol) in dry CH2Cl2 (60 mL) was added
trifluoroacetic anhydride (6.82 mL, 48.6 mmol) dropwise at around
5 °C, over a period of 15 min, with vigorous stirring. After the
reaction mixture was stirred at RT for 1.75 h, water (60 mL) and
CH2Cl2 (60 mL) were added. The organic layer was washed with
water, separated, dried over MgSO4, and evaporated to give a
colorless solid (7.745 g, 97%). Mp 67-68 °C. 1H NMR (360 MHz,
CDCl3) δ 7.26 (t, J ) 8.0 Hz, 1H), 7.20-7.13 (2H), 6.93 (m, 2H),
3.86 (s, 3H), 3.56 (m, 2H), 2.92 (t, J ) 6.4 Hz, 2H); 13C NMR
(90.55 MHz, CDCl3) δ 157.7-156.5 (C(O)CF3), 157.1 (C), 130.7,
128.4, 126.5, 121.1, 120.6-111.1 (CF3), 110.4, 55.1, 41.0, 29.2.
IR (neat) 3308, 3109, 2997, 1698, 1601, 1563, 1495, 1468, 1440,
1246, 1201, 1180, 1123, 1033, 757. HR-MS 270.0713
(C11H12F3NO2 + Na+ calcd 270.0712).
N-(2-Methoxy-3,5-dinitrophenethyl)-2,2,2-trifluoroacetamide (14).
A solution of N-(2-methoxyphenethyl)-2,2,2-trifluoroacetamide (13)
(2.472 g, 10 mmol) in 1,2-dichloroethane (10 mL) was added
dropwise over a period of 20 min, with agitation and cooling using
an ice bath, to a mixture of fuming nitric acid (100%) (2.49 mL,
60 mmol) and sulfuric acid (96%; 5.28 mL, 95 mmol) in
1,2-dichloroethane (20 mL), keeping the temperature of the solution
below 5 °C. The solution was stirred at 0 to 5 °C during 1 h and
then quenched on ice. The product was extracted with CH2Cl2,
washed with water, with saturated aq NaHCO3, then with water to
neutrality, and finally with brine. The organic layer was dried with
anhydrous MgSO4 and filtered, and then the solvents were
evaporated under reduced pressure to give the desired product as a
yellowish solid (3.135 g, 93%). Mp 97-99 °C. 1H NMR (360 MHz,
DMSO-d6) δ 9.50 (m, 1H), 8.67 (d, J ) 2.7 Hz, 1H), 8.43 (d, J )
2.7 Hz, 1H), 3.93 (s, 3H), 3.50 (m, 2H), 3.02 (t, J ) 6.8 Hz, 2H);
13C NMR (90.55 MHz, DMSO-d6) δ 157.0-155.8 (C(O)CF3),
156.2 (C), 142.9, 142.0, 136.6, 129.7, 120.6-111.1 (CF3), 119.8,
63.6, 62.7, 28.8. IR (neat) 3298, 1700, 1534, 1345, 1209, 1181,
983. HR-MS 360.0410 (C11H10F3N3O6 + Na+ calcd 360.0414).
N-(2-Hydroxy-3,5-dinitrophenethyl)-2,2,2-trifluoroacetamide (15).
Under argon, N-(2-methoxy-3,5-dinitrophenethyl)-2,2,2-trifluoro-
acetamide (14) (1.180 g, 3.5 mmol) and LiCl (454 mg, 10.5 mmol)
were heated in boiling DMF (10 mL) during 2 h. The solvent was
then evaporated under reduced pressure and 1 M aq HCl was added
to the resulting mixture. The product was extracted with EtOAc
and washed 3 times with water and with brine. The organic layer
was dried with anhydrous MgSO4 and filtered, and then the solvents
were evaporated under reduced pressure to give the desired product
as a yellow solid (1.059 g, 94%). Mp 133-136 °C. 1H NMR (360
MHz, DMSO-d6) δ 9.48 (br, 1H), 8.63 (d, J ) 2.7 Hz, 1H), 8.27
(d, J ) 2.3 Hz, 1H), 3.49 (m, 2H), 2.67 (t, J ) 6.6 Hz, 2H); 13C
NMR (90.55 MHz, DMSO-d6) δ 157.0-155.8 (C(O)CF3), 156.1
2-(2-(2,2,2-Trifluoroacetamido)ethyl)-4,6-dinitrophenyl Trifluo-
romethanesulfonate (17). Under argon, a solution of N-(2-hydroxy-
3,5-dinitrophenethyl)-2,2,2-trifluoroacetamide (15) (0.323 g, 1.0
mmol) in anhydrous CH2Cl2 (10 mL) was treated with Et3N (0.364
mL, 2.6 mmol), and the resulting solution was cooled in an ice-salt
bath and treated dropwise with trifluoromethanesulfonic anhydride
(0.219 mL, 1.6 mmol). After that, the mixture was stirred at room
temperature for 2 h, 0.5 N HCl (10 mL) was added in one portion,
and the mixture was stirred for 30 min. The aqueous layer was
separated and extracted with CH2Cl2 (2 × 20 mL). The combined
organic layers were washed with saturated NaHCO3, water, and
brine, then dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography [SiO2, CH2Cl2 then EtOAc/hexane (1:1)] providing
the desired product as a yellow solid (296 mg, 65%). 1H NMR (360
MHz, CDCl3) δ 8.82 (d, J ) 2.7 Hz, 1H), 8.55 (d, J ) 2.7 Hz,
1H), 6.56 (br, 1H), 3.78 (m, 2H), 3.27 (t, J ) 6.8 Hz, 2H); 13C
NMR (125.0 MHz, CDCl3) δ 158.4-157.5 (C(O)CF3), 146.4,
143.6, 142.4, 137.4, 130.2, 121.0, 119.7 (CF3), 117.2 (CF3), 39.3,
30.4.
N-(2-Iodo-3,5-dinitrophenethyl)-2,2,2-trifluoroacetamide (18). A
solution of 2-(2-(2,2,2-trifluoroacetamido)ethyl)-4,6-dinitrophenyl
trifluoromethanesulfonate (17) (114 mg, 0.25 mmol) and NaI (0.129,
0.85 mmol) in EtOAc (5 mL) was heated under reflux for 2 h.
After cooling to room temperature, the reaction mixture was washed
with saturated Na2S2O3 and brine, then dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography [SiO2, CH2Cl2 then
EtOAc/hexane (1:1)] providing the desired product as a yellow solid
1
(99 mg, 92%). H NMR (360 MHz, DMSO-d6) δ 9.54 (m, 1H),
8.63 (d, J ) 2.3 Hz, 1H), 8.28 (d, J ) 2.3 Hz, 1H), 3.53 (t, J ) 6.4
Hz, 2H), 3.22 (t, J ) 6.8 Hz, 2H); 13C NMR (125.0 MHz, DMSO-
d6) δ 156.8-155.9 (C(O)CF3), 156.0, 147.2, 147.0, 125.7,
119.2-112.4 (CF3), 116.7, 102.7, 39.3, 38.5. HR-MS 455.9275
(C10H7F3IN3O5 + Na+ calcd 455.9275).
tert-Butyl 2-Bromo-3,5-dinitrophenethylcarbamate (19). A solu-
tion of N-(2-bromo-3,5-dinitrophenethyl)-2,2,2-trifluoroacetamide
(16) (1.0 g, 2.59 mmol) and DMAP (97 mg, 0.777 mmol) in
anhydrous MeCN (20 mL) was stirred at room temperature under
argon. A solution of di-tert-butyl dicarbonate (0.750 g, 3.367 mmol)
in anhydrous MeCN (5 mL) was added dropwise and the reaction
mixture was stirred at room temperature for 15 h. The solvent was
removed in vacuo and the product was purified by flash column
chromatography [SiO2, gradient hHexane/EtOAc (4:1) to hexane/
EtOAc (3:1)] to provide the desired product as a yellowish solid
1
(667 mg, 66%). Mp 137 °C. H NMR (360 MHz, CDCl3) δ 8.40
(d, J ) 2.7 Hz, 1H), 8.28 (d, J ) 2.7 Hz, 1H), 4.68 (br, 1H), 3.47
J. Org. Chem. Vol. 74, No. 12, 2009 4523

De´bieux and Bochet
(m, 2H), 3.22 (t, J ) 6.8 Hz, 2H), 1.41 (s, 9H); 13C NMR (90.55
MHz, CDCl3) δ 155.9, 151.5, 146.5, 144.5, 127.5, 123.1, 118.2,
80.1, 39.6, 37.4, 28.4 (3 × C). IR (neat) 3343, 1685, 1543, 1439,
1363, 1344, 1302, 1274, 1253, 1163, 1037, 734, 647. HR-MS
412.0117 (C13H16BrN3O6 + Na+ calcd 412.0115).
MeCN (5 mL) were then added through the septum. The sealed
vial was then subjected to microwave heating (100 °C) for 2 h.
After the reaction mixture was cooled to room temperature, the
catalyst and salt were removed by filtration through a short pad of
Celite and washed with EtOAc (50 mL). The filtrate was concen-
trated to dryness and purified by flash column chromatography to
provide the desired product.
2-(2-Bromo-3,5-dinitrophenyl)ethanamine Hydrochloride (20).
Under argon, tert-butyl 2-bromo-3,5-dinitrophenethylcarbamate (19)
(340 mg, 0.87 mmol) was treated with HCl (1.25 M in EtOH, 20.9
mL, 26.1 mmol) then the mixture was stirred at room temperature
for 16 h. A colorless precipitate was formed during the reaction
and then the solvent was evaporated under reduced pressure. The
resulting solid was washed with EtOAc and filtrated to give the
desired product as a yellowish solid (258 mg, 91%). Mp 246-250
Benzyl (S)-4-Methyl-1-(5,7-dinitroindolin-1-yl)-1-oxopentan-2-
ylcarbamate (3a). Purification was by flash column chromatography
[SiO2, hexane/EtOAc (1:1)] to give a yellow solid (429 mg, 94%).
1
Mp 69 °C. H NMR (360 MHz, CDCl3) δ 8.58 (s, 1H), 8.27 (s,
1H), 7.35-7.27 (5H), 5.35 (d, J ) 8.7 Hz, 1H), 5.06 (dd, J )
19.5, 12.2 Hz, 2H), 4.86 (td, J ) 10.0, 3.6 Hz, 1H), 4.69 (q, J )
7.7 Hz, 1H), 4.33 (q, J ) 10.0 Hz, 1H), 3.51 (m, 1H), 3.30 (m,
1H), 1.83 (m, 1H), 1.63 (t, J ) 7.3 Hz, 2H), 1.01 (t, J ) 6.6 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 172.8, 156.6, 143.9, 139.9,
139.4, 138.8, 136.1, 128.7 (2 × C), 128.4, 128.0 (2 × C), 123.4,
119.9, 67.3, 52.1, 50.4, 41.4, 28.9, 24.7, 23.3, 22.0. IR (neat) 3405,
3326, 2961, 1699, 1609, 1545, 1466, 1441, 1396, 1373, 1341, 1282,
1256, 1217, 1047, 737. HR-MS 479.1534 (C22H24N4O7 + Na+ calcd
479.1537).
1
°C dec. H NMR (360 MHz, D2O) δ 8.67 (d, J ) 2.3 Hz, 1H),
8.50 (d, J ) 2.3 Hz, 1H), 3.42-3.32 (4H); 13C NMR (90.55 MHz,
D2O) δ 151.3, 146.9, 141.8, 128.4, 123.6, 119.9, 38.4, 34.1. IR
(KBr pastille) 3416, 3082, 2923, 1608, 1584, 1543, 1480, 1348,
1309, 1043, 738. HR-MS 289.9779 (C8H8BrN3O4 + H+ calcd
289.9771).
General Procedure for the Preparation of 9a-z. Under argon,
a solution of N-protected-R-amino acids (1a-z) (1.26 mmol) and
N-methylmorpholine (135 µL, 1.20 mmol) in anhydrous DCM (10
mL) at -20 °C was treated with isobutylchloroformate (159 µL,
1.20 mmol). After 1 h, a solution of 2-(2-bromo-3,5-dinitrophe-
nyl)ethanamine hydrochloride (20) (392 mg, 1.20 mmol) in
anhydrous DMF (5 mL) was added dropwise and then, after 5 min
of stirring, Et3N (168 µL, 1.20 mmol) was added dropwise to the
solution. The reaction mixture was warmed to room temperature,
stirred for 4 h, and quenched with saturated NaHCO3 solution. The
mixture was diluted with CH2Cl2 and the organic layer was washed
with 1 M aq HCl, saturated aq NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography providing
the desired product.
Benzyl (S)-1-(2-Bromo-3,5-dinitrophenethylcarbamoyl)-3-me-
thylbutylcarbamate (9a). Purification was by flash column chro-
matography [SiO2, hexane/EtOAc (1:1)] to give a slightly yellow
solid (555 mg, 86%). 1H NMR (360 MHz, CDCl3) δ 8.36 (d, J )
2.3 Hz, 1H), 8.24 (d, J ) 1.8 Hz, 1H), 7.37-7.29 (5H), 6.43 (br,
1H), 5.12-5.01 (3H), 4.07 (m, 1H), 3.58 (m, 2H), 3.19 (m, 2H),
1.65-1.55 (2H), 1.47 (m, 1H), 0.90 (t, J ) 5.7 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 172.9, 156.5, 151.5, 146.6, 144.1, 136.1, 128.7
(2xC), 128.5, 128.2 (2 × C), 127.6, 122.9, 118.3, 67.4, 53.7, 40.9,
38.5, 36.7, 24.8, 23.0, 22.0. IR (neat) 3315, 2957, 1693, 1652, 1542,
1348, 1265, 1232, 736. HR-MS 559.0800 (C22H25BrN4O7 + Na+
calcd 559.0799).
Typical Procedure for the Preparation of N-Protected-r-
Amino Acid Amides 22e,g,r by Photochemical Acylation. All
experiments were performed in anhydrous acetonitrile (dried by
passing it, under an argon atmosphere, through a Grubbs purification
system).30 A mixture of N-protected-R-amino acyl-5,7-dinitroin-
dolines (3e,g,r) (0.10 mmol) and phenethylamine (0.10 mmol, 1
equiv) in dry MeCN (2 mL) was irradiated at 385 nm in a quartz
tube for 16 h, under an argon atmosphere, with vigorous stirring.
The mixture was filtered, concentrated to dryness, and purified by
flash column chromatography to provide the desired product.
tert-Butyl (S)-1-(Phenethylcarbamoyl)-2-phenylethylcarbamate
(22e). Purification was by flash column chromatography [SiO2,
hexane/EtOAc (3:2)] to give a yellow solid (29.5 mg, 80%). Mp
128-131 °C. 1H NMR (360 MHz, CDCl3) δ 7.32-7.18 (8H), 7.03
(d, J ) 6.3 Hz, 2H), 5.69 (br, 1H), 5.02 (br, 1H), 4.24 (m, 1H),
3.41 (m, 2H), 3.03 (m, 2H), 2.64 (m, 2H), 1.39 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 171.1, 155.4, 138.7, 136.9, 129.5 (4 × C),
128.8 (4 × C), 127.1, 126.7, 80.3, 56.2, 40.7, 38.9, 35.7, 28.4 (3
× C). IR (neat) 3308, 3021, 2968, 2923, 1680, 1647, 1520, 1442,
1359, 1289, 1240, 1161, 739, 691. HR-MS 391.1991 (C22H28N2O3
+ Na+ calcd 391.1992).
Acknowledgment. We thank the Swiss National Science
Foundation for their generous support (grant 620-066063).
Supporting Information Available: Procedures for preparing
3b-z, 9b-z, and 22g,r and spectral data for 3a-z, 9a-z,
13-20, and 22e,g,r. This material is available free of charge
via the Internet at http://pubs.acs.org.
General Procedure for the Preparation of N-Protected-r-
Amino Acyl-5,7-dinitroindolines 3a,b, 3d,e, 3g-i, and 3m-z. A
flame-dried vial was charged with intermediates 9a,b, 9d,e, 9g-i,
and 9m-z (1 mmol), MePhos (0.05 mmol, 5 mol %), K2CO3 (2
mmol), and Pd(dba)2 (0.05 mmol, 5 mol %). The vial was capped,
evacuated, and backfilled with argon; this evacuation/backfill
sequence was repeated two additional times. Anhydrous and
deoxygenated (argon bubbling for 10 min) toluene (15 mL) and
JO900442P
(30) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518–1520.
4524 J. Org. Chem. Vol. 74, No. 12, 2009