N-Tfa- and N-Fmoc-(α-aminoacyl)benzotriazoles as chiral C-acylating reagents under Friedel-Crafts reaction conditions

Article abstract of DOI:10.1021/jo050226q

Chiral N-Tfa- and N-Fmoc-protected (α-aminoacyl)benzotriazoles 1a-j undergo Friedel-Crafts-type reactions with indole, N-methylindole, pyrrole, N-methylpyrrole, and benzene in the presence of AlCl₃ in efficient two-step sequences leading to ena

Full text of DOI:10.1021/jo050226q

N-Tfa- and N-Fmoc-(r-aminoacyl)benzotriazoles as Chiral
C-Acylating Reagents under Friedel-Crafts Reaction Conditions
Alan R. Katritzky,* Rong Jiang, and Kazuyuki Suzuki
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received February 4, 2005
Chiral N-Tfa- and N-Fmoc-protected (R-aminoacyl)benzotriazoles 1a-j undergo Friedel-Crafts-
type reactions with indole, N-methylindole, pyrrole, N-methylpyrrole, and benzene in the presence
of AlCl3 in efficient two-step sequences leading to enantiomerically pure R-amino N-heterocyclic
ketones 2, 3, 5, 6, and 7 or diketone 4. In the absence of a reactive partner, Phe- and Trp-derivatives
1a, 1d undergo intramolecular cyclization to afford 12 and 13, again with retention of chirality.
Introduction
N-Acylbenzotriazoles, which are easily prepared from
carboxylic acids by (i) thionyl chloride and 1H-benzo-
triazole at 20 °C9a or (ii) BtSO2Me in the presence of
Et3N,9b are efficient C-acylating agents for heterocycles
such as indoles, pyrroles,10a furan, and thiophene10b under
Friedel-Craft conditions. Recently, we converted amino
acids into enantiomerically pure N-protected (aminoacyl)-
benotriazoles, which were then coupled with chiral
amines,11a amino acids, and peptides.11b-d We now report
the first syntheses of C-acylated indoles and pyrroles
utilizing N-(Tfa- and Fmoc-R-aminoacyl)benzotriazoles
under Friedel-Crafts conditions to obtain the corre-
Chiral N-protected R-amino ketones are useful precur-
sors to many biologically active compounds including
chiral R-amino alcohols,1 pharmaceutically important
chiral heterocycles,2,3 and diamines.1c,4 Preparations of
R-amino aliphatic ketones and R-amino aryl ketones have
been thoroughly investigated,5 but much less attention
has been directed toward the synthesis of R-aminoalkyl
heterocyclic ketones and to our knowledge, no general
method has been reported. Previous syntheses of chiral
R-amino ketones utilized N-protected R-amino acids,
esters, and amides (i) with organometallic reagents for
nucleophilic substitution6 or (ii) with AlCl3 for Friedel-
Crafts acylations.7 The methods using organometallic
reagents, though well-established, sometimes suffer from
drawbacks such as tedious purification6a and competition
between nucleophilic addition and nucleophilic substi-
tution.6b Moreover, N-protected R-amino acid chlorides
are often unstable and prone to racemization.8
(6) (a) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.;
Ricci, A.; Varchi, G. Synlett 1998, 1013. (b) Avenoza, A.; Busto, J. H.;
Peregrina, J. M. Tetrahedron 2002, 58, 10167. (c) De Luca, L.;
Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 1519. (d) Knudsen,
C. G.; Rapoport, H. J. Org. Chem. 1983, 48, 2260. (e) Zhou, Z. H.; Tang,
Y. L.; Li, K. Y.; Liu, B.; Tang, C. C. Heteroatom. Chem. 2003, 14, 603.
(f) Maurer, P. J.; Takahata, H.; Rapoport, H. J. Am. Chem. Soc. 1984,
106, 1095.
(7) (a) Buckley, T. F., III; Rapoport, H. J. Am. Chem. Soc. 1981,
103, 6157. (b) McClure, D. E., Arison, B. H.; Jones, J. H.; Baldwin, J.
J. J. Org. Chem. 1981, 46, 2431. (c) Nordlander, J. E.; Payne, M. J.;
Njoroge, F. G.; Balk, M. A.; Laikos, G. D.; Vishwanath, V. M. J. Org.
Chem. 1984, 49, 4107. (d) Nordlander, J. E.; Njoroge, F. G.; Payne, M.
J.; Warman, D. J. Org. Chem. 1985, 50, 3481. (e) Di Gioia, M. L.;
Leggio, A.; Liguori, A.; Napoli, A.; Siciliano, C.; Sindona, G. J. Org.
Chem. 2001, 66, 7002.
(8) Gross, M.; Meienhofer, J. The Peptides; Academic Press: New
York, 1979.
(9) (a) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795.
(b) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210.
(10) (a) Katritzky, A. R.; Suzuki, K.; Singh, S. K.; He, H.-Y. J. Org.
Chem. 2003, 68, 5720. (b) Katritzky, A. R.; Suzuki, K.; Singh, S. K.
Croat. Chem. Acta 2004, 77, 175.
(1) (a) Maurer, P. J.; Knudsen, C. G.; Palkowitz, A. D.; Rapoport,
H. J. Org. Chem. 1985, 50, 325. (b) Pace, R. D.; Kabalka, G. W. J.
Org. Chem. 1995, 60, 4838. (c) Reetz, M. T. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1531.
(2) (a) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825. (b)
Tandon, V. K.; Singh, K. A.; Awasthi, A. K.; Khanna, J. M.; Lal, B.;
Anand, N. Bioorg. Med. Chem. Lett. 2004, 14, 2867.
(3) Lee, K. W.; Hwang, S. Y.; Kim, C. R.; Nam, D. H.; Chang, J. H.;
Choi, S. C.; Choi, B. S.; Choi, H.; Lee, K. K.; So, B.; Cho, S. W.; Shin,
H. Org. Proc. Res. Dev. 2003, 7, 839.
(4) Tramontini, M. Synthesis 1982, 605.
(5) Florjancic, A. S.; Sheppard, G. S. Synthesis 2003, 1653 and
references therein.
10.1021/jo050226q CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/27/2005
J. Org. Chem. 2005, 70, 4993-5000
4993

Katritzky et al.
SCHEME 1. Preparation of N-Protected Aminoacylbenzotriazoles
sponding R-amino ketones with complete retention (>99%)
However, attempted C-acylation of pyrrole with Z-Ala-
Bt (1k) resulted in the loss of the Z group as indicated
by their crude NMR spectra and no desired product was
isolated.
of chirality.
Results and Discussion
Preparation of N-(Tfa- and Fmoc-r-aminoacyl)-
benzotriazoles. The amino group of L-alanine and
L-phenylalanine were protected with the N-trifluoroacetyl
(Tfa) group using ethyl trifluoroacetate in the presence
of Et3N in methanol to generate the N-Tfa-R-amino
acids.12 The resultant N-Tfa-protected amino acids were
treated with thionyl chloride and 4 equiv of benzotriazole
to give N-(Tfa-R-aminoacyl)benzotriazoles 1a and 1b
(Scheme 1). Racemic N-(Tfa-R-aminoacyl)benzotriazoles
1i and 1j were prepared similarly from DL-alanine and
DL-phenylalanine, respectively. N-(Fmoc-R-aminoacyl)-
benzotriazoles 1c-h were prepared by the above method
from commercially available N-Fmoc-L-phenylalanine,
L-tryptophan, and L-methionine.11d The Z-protected amino-
acylbenzotriazole 1k was prepared by a previously re-
ported method.11b
Friedel-Crafts Acylations of Pyrrole and N-
Methylpyrrole. Reactions of 1a-e in CH2Cl2 with 1.2
equiv of pyrrole in the presence of 3 equiv of anhydrous
AlCl3 under nitrogen at 20 °C for 3 h produced the
corresponding amino ketones 2a-e; reactions of 1a-e
with N-methylpyrrole under similar conditions also gave
the corresponding amino ketones 3a-e (Table 1). The
C-acylations occurred specifically at C-2, and no 3-acy-
lated products were observed.
Friedel-Crafts Acylations of Indole and N-Me-
thylindole. Utilizing the procedure developed above for
the acylation of pyrrole and N-methylpyrrole, C-acyla-
tions of indole to give 5a-e and of N-methylindole to give
6a-g were carried out in the presence of 3 equiv of AlCl3.
Most of the expected products were thus obtained in good
to moderate yields (Table 2). Exceptionally, the reaction
of Fmoc-Trp-Bt (1d) with indole failed to give expected
product 5d, and 1d decomposed under the reaction
conditions. However, N-TMS-indole readily reacted with
1d in the presence of TiCl4 or AlCl3 in 15 min to give the
product 5d in 87% and 41% isolated yields, respectively.
The TMS group was completely cleaved under these
reaction conditions.
Friedel-Crafts Acylations of Benzene. Most lit-
erature syntheses of chiral aryl R-amino ketones via
Friedel-Crafts type reactions involve N-protected R-ami-
no acid chlorides.7 However, the preservation of chirality
of R-amino acid chlorides was not always successful due
TABLE 1. C-Acylations of Pyrrole and N-Methylpyrrole
When compounds with an Fmoc group and bulky
aromatic side chains such as Fmoc-Phe-Bt (1c) and Fmoc-
Trp-Bt (1d) were used, the corresponding ketones were
obtained in lower yields than the ketones with aliphatic
side chains. For the reaction of 1d with N-methylpyrrole,
the 45% yield was not improved even when the reaction
time was extended to 24 h.
Furthermore, we extended this method to the prepara-
tion of the bis(acyl)-pyrrole 4 by using N-(Fmoc-amino-
diacyl)benzotriazole 1h (prepared from N-Fmoc-glutamic
acid) in 35% yield (Scheme 2). The yield of the amino-
diketone 4 was not as good as those from the mono-
acylation reactions, presumably due to the lack of solu-
bility of 1h in CH2Cl2. No mono-acylated compounds were
observed during the purification of 4 by column chroma-
tography.
amino ketone (yield. %)a
reactant
from pyrrole
from N-methylpyrrole
Tfa-Phe-Bt (1a)
Tfa-Ala-Bt (1b)
Fmoc-Phe-Bt (1c)
Fmoc-Trp-Bt (1d)
Fmoc-Met-Bt (1e)
2a (82)
2b (78)
2c (72)
2d (52)
2e (66)
3a (78)
3b (75)
3c (56)
3d (45)
3e (60)
a Isolated yield.
SCHEME 2. Preparation of Aminodiketone 4
(11) (a) Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.; Akhmedov,
N. G. Arkivoc 2002, 8, 134. (b) Katritzky, A. R.; Suzuki, K.; Singh, S.
K. Synthesis 2004, 2645. (c) Katritzky, A. R.; Angrish, P.; Suzuki, K.
Unpublished work. (d) Katritzky, A. R.; Angrish, P.; Hur, D.; Suzuki,
K. Synthesis 2005, 397.
(12) Curphey, T. J. J. Org. Chem. 1979, 44, 2805.
(13) Barrett, A. G. M. J. Org. Chem. 1984, 49, 4409.
4994 J. Org. Chem., Vol. 70, No. 13, 2005

(R-Aminoacyl)benzotriazoles as C-Acylating Reagents
TABLE 2. C-Acylations of Indole and N-Methylindole
1
yield. (Scheme 3) The H NMR and melting point of 7
matches the literature report.7c While our yield was
comparable to previous reports in the literature, the solid,
chirally stable benzotriazole derivatives are clearly more
convenient to handle than amino acid chlorides.
Configurational Analysis of Amino Ketones. Be-
cause one of the most important features of biologically
active amino ketones is associated with the presence of
the asymmetric R-carbon in their structures, total control
of chirality represents a major goal during the synthesis
of these amino ketones. To evaluate the chiral integrity
of these reactions, we examined the syntheses of amino
ketones 6a (L) and 6j (DL-mixture), prepared from N-
methylindole and Tfa-L-Phe-Bt (1a) and Tfa-DL-Phe-Bt
(1j), respectively as models. This study was accomplished
by chiral HPLC comparison of the two acylated products
of N-methylindole 6a and 6j starting from enantiomeri-
cally pure Tfa-L-phenylalanine and Tfa-DL-phenylalanine.
Two peaks equal in ratio appeared for 6j at 3.11 min
corresponding to L-isomer and at 6.59 min corresponding
to the D-isomer, whereas 6a gave only one peak appearing
at 3.11 min (solvent MeOH, flow rate 1.0 mL/min, UV
detection at 254 nm). Since all of the acylations were
carried out under the same conditions, the HPLC results
supported the conclusion that N-(Tfa- and Fmoc-R-
aminoacyl)benzotriazoles undergo Friedel-Crafts type
reactions with nitrogen heterocycles and benzene in the
presence of AlCl3 with full preservation (>99%) of the
configuration.
amino ketone (yield, %)a
reactant
from indole
from N-methylindole
Tfa-Phe-Bt (1a)
Tfa-Ala-Bt (1b)
5a (85)
5b (79)
5c (63)
5d (87)b,c
5e (83)
d
6a (62)
6b (75)
6c (40)
6d (45)
6e (90)
6f (85)
6g (75)
6j (64)
Fmoc-Phe-Bt (1c)
Fmoc-Trp-Bt (1d)
Fmoc-Met-Bt (1e)
Fmoc-L-Ala-Bt (1f)
Fmoc-D-Ala-Bt (1g)
Tfa-DL-Phe-Bt (1j)
d
d
a Isolated yield. b Reaction condition (N-TMS-indole 1.5 equiv,
TiCl4 2 equiv, CH2Cl2, 10 min, 20 °C). c Reaction with 1H-indole
gave no product. d Not attempted.
SCHEME 3. Acylation of Benzene
A NMR study utilizing diastereomers also supported
the preservation of configuration during the C-acylation.
Compound 9 was prepared by coupling of 1a with 8
obtained by the cleavage of the Fmoc group of 6f, which
to the instability of acid chlorides, which can react with
an amino protecting group to form oxazolinones.7a To
address this issue, we reacted Tfa-Ala-Bt (1b) with
benzene to give R-aminoalaninyl phenyl ketone 7 in 63%
SCHEME 4. Preparation of Diastereomers 9 and 11
J. Org. Chem, Vol. 70, No. 13, 2005 4995

Katritzky et al.
SCHEME 5. Intramolecular Cyclization of 1a and
1d
and 13 in 57% and 62% yield, respectively (Scheme 5).
The H NMR spectra of 12 and 13 showed the disap-
1
pearance of Bt signals in aromatic region, indicating the
loss of the benzotriazolyl group during the reaction. The
13C NMR spectrum of 12 showed a signal at 201.2 ppm
corresponding to the carbonyl group of the cyclized ketone
and the disappearance of the signal at 168.8 ppm
belonging to the carbonyl group at the R position of the
benzotriazolyl group in the starting material. Likewise,
the 13C NMR spectrum of 13 showed a signal for the
cyclized ketone at 191.3 ppm and the disappearance of
the signal of the R carbonyl group of the benzotriazolyl
group at 172.2 ppm. The cyclization also was confirmed
1
in H NMR spectrum by the observation of four protons
in the aromatic region of 12 due to the loss of one
aromatic proton from the starting material. Furthermore,
the splitting patterns of the two protons at the R position
to the phenyl ring of 1a and cyclized ketone 12 were
different. Regarding 1a, one of the two protons appeared
at 3.37 ppm (dd, J ) 13.8, 7.2 Hz) and the other one at
3.59 ppm (dd, J ) 13.8, 5.1 Hz). In the 1H NMR spectrum
of 12, one proton was observed at 3.05 ppm (dd, J ) 16.8,
5.7 Hz) and the other at 3.89 ppm (dd, J ) 16.8, 5.1 Hz).
The difference of chemical shifts of the two protons (0.84
ppm) in 12 was much larger than that of the two protons
(0.22 ppm) in 1a, which can be rationalized by the
formation of a five-membered ring system.
was generated from the acylation of Fmoc-L-Ala-Bt (1f)
with N-methylindole. A similar process was used to
prepare the other diastereomer 11. (Scheme 4) The
methyl group of the alanine moiety in a diastereomer 9
(L-Phe-L-Ala) displays a single doublet at 1.51 ppm,
whereas 11 (L-Phe-D-Ala) exhibited a single doublet at
1.39 ppm. No trace was found of methyl peaks charac-
teristic of 11 in the 1H NMR spectrum of 9 and also
nothing of 9 in the NMR of 11.
Configurational Analysis of Intramolecular Cy-
clization. A NMR study utilizing diastereomers was
carried out to examine the preservation of configuration
in products 12 and 13 from the intramolecular cycliza-
tions of 1a and 1d. Tricyclic amine 14 was obtained by
the cleavage of 13 using morpholine. The coupling of
amine 14 with Tfa-DL-Ala-Bt (1i) gave as expected a
mixture of the four stereoisomers 15 (two pairs of
diastereomers). The coupling of amine 14 with Tfa-L-Ala-
Bt (1b) did not give diastereomers 16 exclusively, but
Intramolecular Cyclization of 1a and 1d. The
lower yields of R-amino ketones 2d (52%), 3c (41%), and
6d (45%) obtained from aromatic side chains containing
aminoacylbenzotriazoles 1c and 1d (as compared to those
from aminoacylbenzotriazoles 1a,b,e containing alphatic
side chains) suggested a competing intramolecular acy-
lation reaction of the aromatic side chains in 1a and 1d.
We reacted the two compounds 1a and 1d under the
conditions used for the preparation of 5 and 6 but in the
absence of indole and generated the cyclized products 12
SCHEME 6. Preparation of Diastereomers 15, 16, and 17
SCHEME 7. Mechanism of Racemization
4996 J. Org. Chem., Vol. 70, No. 13, 2005

(R-Aminoacyl)benzotriazoles as C-Acylating Reagents
1
DMF); H NMR (DMSO-d6) δ 3.20 (dd, J ) 13.8, 8.1 Hz, 1H),
another enantiomer 17 was obtained as a result of
racemization (Scheme 6). There were two doublets ob-
served in the NMR spectrum of 15 corresponding to the
methyl group of the alanine moiety from Tfa-DL-Ala-Bt
(1i), which was the same with the methyl group of the
alanine moiety in the mixture of 16 and 17 at 1.49 and
1.51 ppm. This result suggested that racemization occurr-
ed during the preparation of the diastereomers. Since
compound 13 has OPR value ([R]23D ) -4.3) and no race-
mization was observed for the coupling of amine 8 and
Tfa-L-Phe-Bt (1a), it is reasonable to conclude that the
racemization probably took place in the stage of the cleav-
age of Fmoc group (from 13 to 14) as a result of the acidic
proton at the R position to the carbonyl group of the
cyclopentenone, which can be easily deprotonated to form
an enol. (Scheme 7)
3.47 (dd, J ) 13.8, 4.5 Hz, 1H), 4.15 (t, J ) 7.2 Hz, 1H), 4.29-
4.42 (m, 2H), 5.86 (d, J ) 7.4 Hz, 1H), 6.06-6.11 (m, 1H),
7.12-7.27 (m, 8H), 7.34 (t, J ) 7.5 Hz, 2H), 7.44-7.54 (m, 3H),
7.60 (t, J ) 7.5 Hz, 1H), 7.70 (d, J ) 7.2 Hz, 1H), 8.10 (d, J )
8.1 Hz, 1H), 8.19 (d, J ) 7.8 Hz, 1H); 13C NMR (DMSO-d6) δ
25.7, 38.9, 55.8, 68.0, 114.4, 120.0, 120.4, 125.1, 126.6, 127.1,
127.4, 127.8, 128.8, 129.4, 130.9, 131.1, 135.3, 141.3, 143.7,
146.1, 155.8, 171.0. Anal. Calcd for C30H24N4O3: C, 73.75; H,
4.95; N, 11.47. Found: C, 73.53; H, 5.07; N, 11.24.
9H-Fluoren-9-ylmethyl N-[(1S)-2-(1H-1,2,3-benzotria-
zol-1-yl)-1-methyl-2-oxoethyl]carbamate (Fmoc-L-Ala-Bt,
1f): colorless microcrystals; yield, 85%; mp 160-161 °C; [R]23
D
1
) -96.8 (c 1.6, DMF); H NMR (DMSO-d6) δ 1.59 (d, J ) 7.2
Hz, 3H), 4.27 (t, J ) 6.6 Hz, 1H), 4.38 (d, J ) 6.9 Hz, 2H),
5.45 (quintet, J ) 6.9 Hz, 1H), 7.34-7.47 (m, 4H), 7.65 (t, J )
7.8 Hz, 1H), 7.75 (d, J ) 2.4 Hz, 1H), 7.77 (d, J ) 2.7 Hz, 1H),
7.82 (t, J ) 7.5 Hz, 1H), 7.92 (d, J ) 7.2 Hz, 2H), 8.25-8.37
(m, 3H); 13C NMR (DMSO-d6) δ 16.8, 46.6, 50.1, 65.9, 114.0,
120.1, 120.2, 125.2, 126.7, 127.1, 127.7, 130.6, 131.1, 140.8,
143.7, 145.3, 156.1, 172.5. Anal. Calcd for C24H20N4O3: C,
69.89; H, 4.89; N, 13.58. Found: C, 69.48; H, 4.94; N, 13.41.
9H-Fluoren-9-ylmethyl N-[(1R)-2-(1H-1,2,3-benzotria-
zol-1-yl)-1-methyl-2-oxoethyl]carbamate (Fmoc-D-Ala-Bt,
Conclusion
The syntheses of N-Tfa- and N-Fmoc-R-amino ketones
containing N-heterocycles and benzene using N-(Tfa- and
Fmoc-R-aminoacyl)benzotriazoles under the Friedel-
Crafts conditions have been achieved in moderate to high
yield. Full preservation (>99%) of chirality has been sug-
gested by HPLC. This new method for the preparation
of novel enantiomerically pure R-amino ketones contain-
ing heterocyclic moieties offers a facile access to potential-
ly valuable biological and pharmacological compounds.
1g): colorless microcrystals; yield, 85%; mp 161 °C; [R]23
)
D
+95.6 (c 1.6, DMF). 1H NMR and 13C NMR are the same with
Fmoc-L-Ala-Bt (1f).
9H-Fluoren-9-ylmethyl N-[(1S)-4-benzotriazol-1-yl-1-
(benzotriazol-1-yl-carbonyl)-4-oxobutyl]
carbamate-
(Fmoc-Glu-Di-Bt, 1h): colorless flakes; yield, 63%; mp 166-
167 °C; [R]23 ) -19.7 (c 1.6, DMF); 1H NMR (DMSO-d6) δ
D
2.40-2.64 (m, 2H), 3.71 (t, J ) 6.6 Hz, 2H), 4.23 (t, J ) 6.9
Hz, 1H), 4.34 (d, J ) 6.9 Hz, 2H), 5.67-5.73 (m, 1H), 7.32 (t,
J ) 7.2 Hz, 2H), 7.40 (t, J ) 7.2 Hz, 2H), 7.58-7.90 (m, 8H),
8.16 (d, J ) 8.1 Hz, 1H), 8.24-8.28 (m, 3H), 8.46 (d, J ) 6.6
Hz, 1H); 13C NMR (DMSO-d6) δ 24.9, 31.4, 46.6, 53.5, 65.9,
113.9, 114.0, 120.0, 120.1, 120.2, 125.2, 126.4, 126.8, 127.1,
127.6, 130.5, 130.7 (2C), 131.1, 140.7, 143.7, 145.3, 145.4,
156.2, 171.3, 171.5. Anal. Calcd for C30H24N4O3: C, 67.24; H,
4.41; N, 17.15. Found: C, 67.09; H, 4.23; N, 17.12.
N-[(1R,S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-methyl-2-ox-
oethyl]-2,2,2-trifluoroacetamide (Tfa-DL-Ala-Bt, 1i): color-
less needles; yield, 80%; mp 110-112 °C. 1H NMR and 13C
NMR are the same as for Fmoc-L-Phe-Bt (1b).
Experimental Section
General Procedure for the Preparation of N-Protect-
ed (Aminoacyl)benzotriazoles (1a-l). Thionyl chloride (10
mmol, 0.73 mL) was added to the 1H-benzotriazole (40 mmol,
4.76 g) dissolved in anhydrous THF (30 mL), and the solution
was heated at 40 °C for 30 min. After cooling to 0 °C, a solution
of N-protected amino acid (10 mmol) in anhydrous THF was
added, and the mixture was stirred at 20 °C for 2 h. The white
precipitate was filtered off, and the filtrate was concentrated
and diluted with dichloromethane followed by washing with
saturated sodium carbonate (50 mL×3) and water (50 mL) and
drying with anhydrous MgSO4. Evaporation of the solvent gave
products 1a-l in 63-83% yields, which were recrystallized
from CHCl3/hexanes for CHN analysis. Compounds 1d, 1e, and
1k have been previously reported and fully characterized.11b,d
N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-benzyl-2-oxoet-
hyl]-2,2,2-trifluoroacetamide (Tfa-L-Phe-Bt, 1a): colorless
N-[(1R,S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-benzyl-2-oxo-
ethyl]-2,2,2-trifluoroacetamide (Tfa-DL-Phe-Bt, 1j): color-
less needles; yield, 89%; mp 132-133 °C. 1H NMR and 13C
NMR are the same as for Fmoc-L-Phe-Bt (1a).
General Procedure for the Acylations of Nitrogen
Heterocycles. AlCl3 (0.4 g, 3 mmol) was added to the mixture
of nitrogen heterocycle (2.4 mmol) and 1 (2 mmol) dissolved
in anhydrous CH2Cl2 (20 mL) at 0 °C. After removing the ice-
bath, the reaction mixture was stirred at room temperature
for 3 h and then quenched by MeOH (1 mL). Removal of
CH2Cl2 under reduced pressure gave the crude product, which
was purified by column chromatography (EtOAc/hexanes )
4:1) to give the desired products 2, 3, 5, 6, and 7 in 40-90%
yields, which were further recrystallized from CHCl3/hexane
for CHN analysis.
needles; yield, 83%; mp 136-137 °C; [R]23 ) +49.7 (c 1.6,
D
1
CHCl3); H NMR (CDCl3) δ 3.37 (dd, J ) 14.4, 7.2 Hz, 1H),
3.59 (dd, J ) 14.1, 5.1 Hz, 1H), 6.31 (dd, J ) 12.9, 7.5 Hz,
1H), 7.04-7.09 (m, 3H), 7.26-7.29 (m, 3H), 7.60 (t, J ) 8.1
Hz, 1H), 7.73 (t, J ) 8.1 Hz, 1H), 8.19 (d, J ) 7.3 Hz, 1H),
8.22 (d, J ) 7.4 Hz, 2H); 13C NMR (CDCl3) δ 38.5, 54.2, 114.7,
115.5 (q, J ) 288.0 Hz), 120.6, 127.0, 127.9, 128.9, 129.1, 130.8,
131.2, 133.8, 146.1, 156.7 (q, J ) 38.4 Hz), 168.8. Anal. Calcd
for C17H13F3N4O2: C, 56.36; H, 3.62; N, 15.46. Found C, 56.55;
H, 3.53; N, 15.34.
N-[(1S)-1-Benzyl-2-oxo-2-(1H-pyrrol-3-yl)ethyl]-2,2,2-
trifluoroacetamide (2a): white needles; yield, 82%; mp 171-
172 °C; [R]23D ) +44.3 (c 1.6, CHCl3); 1H NMR (CDCl3) δ 3.18
(dd, J ) 13.5, 5.1 Hz, 1H), 3.35 (dd, J ) 13.5, 5.1 Hz, 1H),
5.47 (q, J ) 7.5 Hz, 1H), 6.33-6.36 (m, 1H), 6.97-7.01 (m,
3H), 7.13 (s, 1H), 7.23-7.25 (m, 4H), 9.40 (br s, 1H); 13C NMR
(CDCl3) δ 39.8, 55.2, 111.8, 115.7 (q, J ) 287.8 Hz), 118.4,
126.7, 127.4, 128.5, 128.9, 129.4, 134.7, 156.4 (q, J ) 37.8 Hz),
184.8. Anal. Calcd for C15H13F3N2O2: C, 58.07; H, 4.22; N, 9.03.
Found: C, 57.85; H, 4.16; N, 8.84.
N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-methyl-2-oxo-
ethyl]-2,2,2-trifluoroacetamide (Tfa-L-Ala-Bt, 1b): color-
less needles; yield, 76%; mp 115-116 °C; [R]23 ) -106.4 (c
D
1.6, CHCl3); 1H NMR (CDCl3) δ 1.82 (d, J ) 7.2 Hz, 3H), 6.04
(quintet, J ) 7.5 Hz, 1H), 7.29 (d, J ) 5.4 Hz, 1H), 7.58 (t, J
) 7.2 Hz, 1H), 7.73 (t, J ) 7.5 Hz, 1H), 8.17 (d, J ) 7.8 Hz,
1H), 8.25 (d, J ) 8.1 Hz, 1H); 13C NMR (CDCl3) δ 19.1, 49.8,
114.4, 115.8 (q, J ) 285.7 Hz), 120.8, 127.2, 131.2, 131.4, 146.3,
156.9 (q, J ) 38.2 Hz), 170.5. Anal. Calcd for C11H9F3N4O2:
C, 46.16; H, 3.17; N, 19.57. Found: C, 46.33; H, 3.05; N, 19.27.
9H-Fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-benzotria-
zol-1-yl-2-oxoethyl] carbamate (Fmoc-L-Phe-Bt, 1c): color-
less flakes; yield, 83%; mp 136-137 °C; [R]23D ) +35.6 (c 1.6,
2,2,2-Trifluoro-N-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-
yl)ethyl]acetamide (2b): colorless needles; yield, 78%;. mp
1
142-143 °C; [R]23 ) -2.0 (c 1.6, CHCl3); H NMR (CDCl3) δ
D
J. Org. Chem, Vol. 70, No. 13, 2005 4997

Katritzky et al.
1.57 (d, J ) 6.9 Hz, 3H), 5.28 (quintet, J ) 6.9 Hz, 1H), 6.38
(quintet, J ) 1.8 Hz, 1H), 7.07 (s, 1H), 7.16 (s, 1H), 7.58 (br s,
1H), 9.80 (br s, 1H); 13C NMR (CDCl3) δ 20.6, 50.8, 112.0, 115.9
(q, J ) 285.2 Hz), 118.5, 127.0, 128.4, 156.7 (q, J ) 37.6 Hz),
186.5. Anal. Calcd for C9H9F3N2O2: C, 46.16; H, 3.87; N, 11.96.
Found: C, 46.39; H, 3.77; N, 11.80.
5.31(q, J ) 6.3 Hz, 1H), 5.68 (d, J ) 8.4 Hz, 1H), 6.15 (q, J )
2.7 Hz, 1H), 6.87 (s, 1H), 7.03-7.05 (m, 3H), 7.21-7.23 (m,
3H), 7.30 (t, J ) 7.5 Hz, 2H), 7.40 (t, J ) 7.2 Hz, 2H), 7.57 (t,
J ) 6.6 Hz, 2H), 7.76 (d, J ) 7.2 Hz, 2H); 13C NMR (DMSO-
d6) δ 37.7, 40.5, 47.2, 56.7, 66.9, 108.8, 120.0, 120.5, 125.2,
125.3, 126.9, 127.1, 127.7, 128.3, 129.5, 132.3, 136.3, 141.3,
144.0, 155.6, 187.5. Anal. Calcd for C29H26N2O3: C, 77.31; H,
5.82; N, 6.22. Found: C, 76.93; H, 5.76; N, 6.21.
9H-Fluoren-9-ylmethyl-N-[(1S)-1-(1H-indol-3-ylmethyl)-
2-oxo-2-(1-methyl-1H-pyrrol-2-yl)ethyl]carbamate (3d):
gray microcrystals; yield, 45%; mp 154-155 °C; [R]23D ) +35.6
(c 1.6, DMF); 1H NMR (DMSO-d6) δ 3.28 (dd, J ) 14.1, 5.1
Hz, 1H), 3.41 (dd, J ) 14.7, 6.6 Hz, 1H), 3.56 (s, 3H), 4.20 (t,
J ) 7.2 Hz, 1H), 4.29-4.42 (m, 2H), 5.25 (q, J ) 6.3 Hz, 1H),
5.84 (d, J ) 8.1 Hz, 1H), 6.54 (d, J ) 2.1 Hz, 1H), 6.60 (s, 1H),
6.86 (d, J ) 1.8 Hz, 1H), 7.05-7.10 (m, 2H), 7.15 (t, J ) 7.5
Hz, 1H), 7.29 (t, J ) 7.8 Hz, 3H), 7.39 (t, J ) 7.5 Hz, 2H), 7.56
(t, J ) 7.5 Hz, 3H), 7.75 (d, J ) 7.5 Hz, 2H), 8.00 (s, 1H); 13C
NMR (DMSO-d6) δ 30.1, 36.8, 47.4, 57.0, 67.1, 109.9, 111.2,
119.1, 119.8, 120.1 (2C), 122.2, 123.1, 123.9, 125.4, 125.5,
127.3, 127.8 (2C), 128.0, 136.2, 141.5, 144.2, 156.1, 193.0;
HRMS calcd for C31H27N3O3 (M + H)+ 490.2125, found
490.2151.
9H-Fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-oxo-2-(1H-
pyrrol-2-yl)ethyl]carbamate (2c): colorless needles; yield,
1
72%; mp 186-187 °C; [R]23 ) +16.7 (c 1.6, DMF); H NMR
D
(DMSO-d6) δ 3.09 (dd, J ) 13.8, 6.0 Hz, 1H), 3.26 (dd, J )
13.5, 6.0 Hz, 1H), 4.19 (t, J ) 6.9 Hz, 1H), 4.29 (t, J ) 6.9 Hz,
1H), 4.44 (dd, J ) 10.2, 7.2 Hz, 1H), 5.29 (dd, J ) 14.1, 6.6
Hz, 1H), 5.69 (d, J ) 8.4 Hz, 1H), 6.29 (d, J ) 3.3 Hz, 1H),
6.99 (s, 1H), 7.05 (d, J ) 2.4 Hz, 2H), 7.20 (d, J ) 6.3 Hz, 3H),
7.29 (t, J ) 7.5 Hz, 2H), 7.39 (t, J ) 7.2 Hz, 2H), 7.56 (t, J )
4.5 Hz, 2H), 7.76 (d, J ) 7.5 Hz, 2H), 9.60 (br s, 1H); 13C NMR
(DMSO-d6) δ 40.4., 47.4, 56.6, 67.1, 111.6, 118.0, 120.2, 125.4,
126.1, 127.1, 127.2, 127.9, 128.6, 129.7, 136.2, 141.5, 144.0,
144.1, 155.8, 187.2. Anal. Calcd for C28H24N2O3: C, 77.04; H,
5.54; N, 6.42. Found: C, 76.79; H, 5.70; N, 6.29.
9H-Fluoren-9-ylmethyl-N-[(1S)-1-(1H-indol-3-ylmethyl)-
2-oxo-2-(1H-pyrrol-2-yl)ethyl] carbamate (2d): white plates;
1
yield, 52%; mp 196-197 °C; [R]23 ) +32.5 (c 1.6, DMF); H
D
NMR (DMSO-d6) δ 3.04 (dd, J ) 14.7, 9.3 Hz, 1H), 3.22 (dd, J
) 14.7, 5.1 Hz, 1H), 4.18-4.21 (m, 3H), 4.97-5.04 (m, 1H),
6.21-6.23 (m, 1H), 6.99 (t, J ) 7.2 Hz, 1H), 7.04-7.09 (m, 2H),
7.13 (s, 1H), 7.19 (d, J ) 2.1 Hz, 1H), 7.25-7.43 (m, 5H), 7.57
(d, J ) 7.8 Hz, 1H), 7.67 (d, J ) 6.6 Hz, 2H), 7.87 (d, J ) 7.5
Hz, 2H), 7.92 (s, 1H), 10.85 (s, 1H), 11.90 (s, 1H); 13C NMR
(DMSO-d6) δ 27.7, 46.6, 56.4, 65.7, 110.0, 110.2, 111.4, 116.8,
118.1, 118.4, 120.1, 120.9, 123.8, 125.3, 126.1, 127.0, 127.2,
127.6, 129.9, 136.1, 140.7, 143.8, 155.7, 188.2. Anal. Calcd for
C30H25N3O3: C, 75.77; H, 5.30; N, 8.84. Found: C, 75.55; H,
5.18; N, 8.76.
9H-Fluoren-9-ylmethyl N-[(1S)-3-(methylsulfanyl)-1-
(1H-pyrrol-2-ylcarbonyl) propyl]carbamate (2e): colorless
plates; yield, 66%; mp 163-164 °C; [R]23D ) -5.9 (c 1.6, DMF);
1H NMR (DMSO-d6) δ 1.92-2.01 (m, 1H), 2.06 (s, 3H), 2.14-
2.26 (m, 1H), 2.51-2.60 (m, 2H), 4.21 (t, J ) 6.9 Hz, 1H), 4.35-
4.56 (m, 2H), 5.21 (dd, J ) 9.3, 8.1 Hz, 1H), 5.83 (d, J ) 8.4
Hz, 1H), 6.32 (d, J ) 3.3 Hz, 1H), 7.08 (s, 1H), 7.12 (s, 1H),
7.28 (t, J ) 7.2 Hz, 2H), 7.38 (t, J ) 7.8 Hz, 2H), 7.59 (d, J )
7.2 Hz, 2H), 7.75 (d, J ) 7.8 Hz, 2H), 9.80 (br s, 1H); 13C NMR
(DMSO-d6) δ 15.6, 30.2, 34.2, 47.2, 54.6, 67.0, 111.5, 118.2,
120.0, 125.1, 126.3, 127.1, 127.7, 129.4, 141.3, 143.9, 156.1,
187.7. Anal. Calcd for C24H24N2O3S: C, 68.55; H, 5.75; N, 6.66.
Found: C, 68.26; H, 5.85; N, 6.74.
N-[(1S)-1-Benzyl-2-(1-methyl-1H-pyrrol-2-yl)-2-oxoethyl]-
2,2,2-trifluoroacetamide (3a): colorless needles; yield, 78%;
mp 109-110 °C; [R]23D ) +43.6 (c 1.6, CHCl3); 1H NMR (CDCl3)
δ 3.17 (dd, J ) 13.8, 4.8 Hz, 1H), 3.31 (dd, J ) 13.8, 6.6 Hz,
1H), 3.68 (s, 3H), 5.32 (dd, J ) 12.6, 6.0 Hz, 1H), 6.62 (d, J )
1.5 Hz, 2H), 7.00-7.03 (m, 2H), 7.19-7.26 (m, 4H), 7.36 (br s,
1H); 13C NMR (CDCl3) δ 36.8, 39.3, 56.4, 109.9, 115.9 (q, J )
287.3 Hz), 122.3, 124.3, 127.3, 128.3, 128.5, 129.7, 135.4, 156.5
(q, J ) 37.2 Hz), 190.1. Anal. Calcd for C16H15F3N2O2: C, 59.26;
H, 4.66; N, 8.64. Found: C, 59.17; H, 4.62; N, 8.47.
9H-Fluoren-9-ylmethyl N-[(1S)-1-[(1-methyl-1H-pyrrol-
2-yl)carbonyl]-3-(methylsulfanyl)propyl]carbamate (3e):
light yellow needles; yield, 60%; mp 109-110 °C; [R]23D ) -17.3
1
(c 1.6, DMF); H NMR (DMSO-d6) δ 1.86-2.00 (m, 1H), 2.06
(s, 3H), 2.14-2.25 (m, 1H), 2.44-2.63 (m, 2H), 3.66 (s, 3H),
4.21 (t, J ) 6.3 Hz, 1H), 4.37 (d, J ) 6.9 Hz, 2H), 5.07-5.13
(m, 1H), 5.84 (d, J ) 8.4 Hz, 1H), 6.59 (t, J ) 2.4 Hz, 1H),
6.65 (s, 1H), 7.26-7.32 (m, 2H), 7.38 (t, J ) 6.0 Hz, 3H), 7.60
(d, J ) 7.2 Hz, 2H), 7.75 (d, J ) 7.5 Hz, 2H); 13C NMR (DMSO-
d6) δ 15.7, 30.3, 34.2, 36.9, 47.3, 55.6, 67.0, 110.0, 120.1, 122.8,
124.1, 125.3, 127.2, 127.8, 128.0, 141.4, 143.9, 156.2, 192.7.
Anal. Calcd for C25H26N2O3S: C, 69.10; H, 6.03; N, 6.45.
Found: C, 69.11; H, 5.98; N, 6.46.
9H-Fluoren-9-ylmethyl N-[(1S)-4-oxo-4-(1H-pyrrol-2-
yl)-1-(1H-pyrrol-2-ylcarbonyl)butyl]carbamate (4): light
violet microcrystals; yield, 35%; mp 140-141 °C; [R]23D ) +12.2
(c 1.6, DMF); 1H NMR (DMSO-d6) δ 1.80-1.92 (m, 1H), 2.09-
2.20 (m, 1H), 2.80-3.03 (m, 2H), 4.22-4.27 (m, 3H), 4.83
(quintet, J ) 7.5 Hz, 1H), 6.20 (d, J ) 17.1 Hz, 2H), 6.94 (s,
1H), 7.10 (d, J ) 16.8 Hz, 2H), 7.29 (s, 1H), 7.34 (t, J ) 7.5
Hz, 2H), 7.41 (t, J ) 7.2 Hz, 2H), 7.73 (t, J ) 6.9 Hz, 2H), 7.82
(d, J ) 8.1 Hz, 1H), 7.89 (d, J ) 7.5 Hz, 2H), 11.86 (d, J ) 9.6
Hz, 2H); 13C NMR (DMSO-d6) δ 27.2, 33.8, 46.6, 55.4, 65.6,
109.7, 109.9, 116.3, 116.9, 120.1, 125.3, 125.9, 127.1, 127.6,
129.6, 131.5, 140.7, 143.7, 143.9, 156.1, 188.4, 188.8. Anal.
Calcd for C28H25N3O4: C, 71.93; H, 5.39; N, 8.99. Found: C,
72.11; H, 5.41; N, 8.91.
N-[(1S)-1-Benzyl-2-(1H-indol-3-yl)-2-oxoethyl]-2,2,2-tri-
fluoroacetamide (5a): gray needles; yield, 85%; mp 198-
199 °C; [R]23D ) +22.0 (c 1.6, CHCl3); 1H NMR (CDCl3) δ 3.22
(dd, J ) 13.5, 5.1 Hz, 1H), 3.31 (dd, J ) 13.5, 6.3 Hz, 1H),
5.47 (dd, J ) 12.9, 7.2 Hz, 1H), 7.05 (t, J ) 3.6 Hz, 2H), 7.20-
7.22 (m, 3H), 7.33-7.44 (m, 3H), 7.55 (d, J ) 7.2 Hz, 1H), 7.64
(d, J ) 3.0 Hz, 1H), 8.33-8.35 (m, 1H), 8.83 (br s, 1H); 13C
NMR (CDCl3) δ 39.8, 56.4, 111.7, 115.2, 115.7 (q, J ) 285.8
Hz), 122.2, 123.5, 124.5, 125.3, 127.3, 128.5, 129.5, 132.5,
135.2, 136.2, 156.6 (q, J ) 37.0 Hz), 190.1. Anal. Calcd for
C13H11F3N2O2: C, 63.33; H, 4.20; N, 7.77. Found: C, 62.98; H,
4.08; N, 7.75.
2,2,2-Trifluoro-N-[(1S)-1-methyl-2-(1-methyl-1H-pyrrol-
2-yl)-2-oxoethyl]-acetamide (3b): colorless needles; yield,
1
75%; mp 120-121 °C; [R]23 ) -7.4 (c 1.6, CHCl3); H NMR
D
(CDCl3) δ 1.53 (d, J ) 7.2 Hz, 3H), 3.73 (s, 3H), 5.13 (quintet,
J ) 6.3 Hz, 1H), 6.61-6.60 (m, 2H), 7.40 (t, J ) 1.8 Hz, 1H),
7.73 (br s, 1H); 13C NMR (CDCl3) δ 19.9, 36.7, 51.4, 109.7, 115.7
(q, J ) 286.4 Hz), 121.2, 124.1, 127.8, 156.2 (q, J ) 37.0 Hz),
191.3. Anal. Calcd for C10H11F3N2O2: C, 48.39; H, 4.47; N,
11.29. Found: C, 48.70; H, 4.38; N, 11.15.
2,2,2-Trifluoro-N-[(1S)-2-(1H-indol-3-yl)-1-methyl-2-oxo-
ethyl]acetamide (5b): colorless microcrystals; yield, 79%; mp
1
189-190 °C; [R]23 ) -7.0 (c 1.6, CHCl3); H NMR (CDCl3) δ
D
1.61 (d, J ) 6.9 Hz, 3H), 5.31 (quintet, J ) 6.9 Hz, 1H), 7.23
(br s, 1H), 7.33-7.45 (m, 2H), 7.44-7.48 (m, 1H), 7.97 (d, J )
3.3 Hz, 1H), 8.35 (t, J ) 5.4 Hz, 1H), 8.89 (br s, 1H); 13C NMR
(CDCl3) δ 20.4, 51.5, 111.7, 114.2, 115.7 (q, J ) 286.4 Hz),
122.3, 123.5, 124.5, 125.5, 132.0, 136.4, 156.5 (q, J ) 37.6 Hz),
191.5. Anal. Calcd for C13H11F3N2O2: C, 54.93; H, 3.90; N, 9.86.
Found: C, 54.98; H, 3.91; N, 9.85.
9H-Fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-(1-methyl-
1H-pyrrol-2-yl)-2-oxoethyl]carbamate (3c): colorless needles;
yield, 56%; mp 172-173 °C; [R]23 ) +9.9 (c 1.6, DMF); 1H
D
NMR (DMSO-d6) δ 3.05 (dd, J ) 13.8, 6.3 Hz, 1H), 3.25 (dd, J
) 13.8, 5.7 Hz, 1H), 3.89 (s, 3H), 4.20 (t, J ) 7.2 Hz, 1H), 4.29
(dd, J ) 10.5, 7.5 Hz, 1H), 4.43 (dd, J ) 10.2, 7.2 Hz, 1H),
4998 J. Org. Chem., Vol. 70, No. 13, 2005

(R-Aminoacyl)benzotriazoles as C-Acylating Reagents
9H-Fluoren-9-ylmethyl-N-[(1S)-1-benzyl-2-oxo-2-(1H-
indol-3-yl)ethyl]carbamate (5c): yellow flakes; yield, 63%;
mp 101-102 °C; [R]23D ) -18.3 (c 1.6, DMF); 1H NMR (DMSO-
d6) δ 3.08 (dd, J ) 13.8, 6.0 Hz, 1H), 3.23 (dd, J ) 13.8, 6.3
Hz, 1H), 4.11-4.17 (m, 1H), 4.24-4.30 (m, 1H), 4.38-4.44 (m,
1H), 5.25 (dd, J ) 14.7, 6.3 Hz 1H), 6.00 (d, J ) 7.1 Hz, 1H),
7.06-7.39 (m, 14 H), 7.52 (t, J ) 7.2 Hz, 2H), 7.73 (d, J ) 7.2
Hz, 1H), 8.34 (d, J ) 8.4 Hz, 1H), 9.30 (br s, 1H); 13C NMR
(DMSO-d6) δ 40.3, 47.3, 57.8, 67.3, 119.3, 115.6, 120.1, 122.3,
123.2, 124.2, 125.3, 125.7, 127.0, 127.3, 127.9, 128.6, 129.7,
132.8, 136.5, 136.6, 141.4, 143.9, 156.2, 192.8. Anal. Calcd for
C32H26N2O3: C, 78.99; H, 5.39; N, 5.76. Found: C, 78.78; H,
5.65; N, 6.20.
9H-Fluoren-9-ylmethyl-N-[(1S)-2-(1H-indol-3-yl)-1-(1H-
indol-3-ylmethyl)-2-oxoethyl]carbamate (5d): To a solu-
tion of Fmoc-Trp-Bt (1d) (1.06 g, 2 mmol) and N-TMS-indole13
(0.58 g, 3 mmol) in CH2Cl2 (30 mL) was added TiCl4 (1 M
CH2Cl2 solution) (4 mL, 4 mmol) was added quickly at 0 °C.
The reaction mixture was stirred for 15 min at the temperature
and quenched with MeOH (2 mL). The solution was directly
subjected to column chromatography (EtOAc/hexanes ) 1:2)
to give the desired product 5d in 0.9 g (87%), which was further
recrystallized in CHCl3/hexanes to provide brown microcrys-
tals: yield, 87%; mp 194-195 °C; [R]23D ) +28.3 (c 1.6, DMF);
1H NMR (DMSO-d6) δ 3.12 (dd, J ) 14.6, 8.7 Hz, 1H), 3.29
(dd, J ) 14.7, 5.5 Hz, 1H), 4.20 (s, 3H), 5.16 (dd, J ) 14.0, 8.2
Hz, 1H), 7.00 (t, J ) 7.4 Hz, 1H), 7.07 (t, J ) 7.0 Hz, 1H),
7.21-7.51 (m, 9H), 7.62-7.68 (m, 3H), 7.86 (d, J ) 7.4 Hz,
2H), 7.96 (d, J ) 8.3 Hz, 1H), 8.24-8.33 (m, 2H), 10.8 (s, 1H),
12.0 (s, 1H); 13C NMR (DMSO-d6) δ 21.7, 46.6, 56.9, 65.7, 110.4,
111.3, 112.2, 114.4, 118.3, 120.0, 120.8, 121.4, 121.9, 123.0,
123.7, 125.3, 125.8, 127.0, 127.3, 127.6, 133.8, 136.1, 136.5,
140.6, 143.8, 155.8, 193.7. Anal. Calcd for C34H27N3O3: C,
77.70; H, 5.18; N, 7.99. Found: C, 77.47; H, 5.28; N, 7.90.
9H-Fluoren-9-ylmethyl N-[(1S)-1-(1H-indol-3-ylcarbo-
nyl)-3-(methylsulfanyl)-propyl]carbamate (5e): colorless
plates; yield, 83%; mp 128-129 °C; [R]23D ) -51.2 (c 1.6, DMF);
1H NMR (DMSO-d6) δ 1.90-2.01 (m, 2H), 2.05 (s, 3H), 2.54-
2.62 (m, 2H), 4.20-4.30 (m, 3H), 4.96-5.03 (m, 1H), 7.22-
7.28 (m, 2H), 7.30 (t, J ) 7.5 Hz, 2H), 7.40 (td, J ) 6.9, 2.1
Hz, 2H), 7.50-7.52 (m, 1H), 7.23 (t, J ) 6.9 Hz, 2H), 7.85 (s,
1H), 7.89 (d, J ) 7.5 Hz, 2H), 8.22 (d, J ) 6.6 Hz, 1H), 8.42 (d,
J ) 3.0 Hz, 1H), 12.05 (s, 1H); 13C NMR (DMSO-d6) δ 14.6,
30.1, 31.9, 46.7, 55.7, 65.6, 112.2, 113.9, 120.1, 121.3, 121.9,
123.0, 125.3, 125.7, 127.0, 127.6, 133.8, 136.5, 140.7, 143.8,
156.0, 193.6 Anal. Calcd for C28H26N2O3S: C, 71.46; H, 5.57;
N, 5.95. Found: C, 71.16; H, 5.89; N, 5.55.
N-[(1S)-1-Benzyl-2-(1-methyl-1H-indol-3-yl)-2-oxoethyl]-
2,2,2-trifluoroacetamide (6a): colorless needles; yield, 62%;
mp 176-177 °C; [R]23D ) +32.9 (c 1.6, CHCl3); 1H NMR (CDCl3)
δ 3.24 (d, J ) 2.1 Hz, 1H), 3.26 (d, J ) 3.3 Hz, 1H), 3.75 (s,
3H), 5.43 (q, J ) 6.3 Hz, 1H), 7.07-7.10 (m, 2H), 7.19-7.22
(m, 3H), 7.34-7.38 (m, 3H), 7.51 (s, 1H), 7.62 (d, J ) 7.5 Hz,
1H), 8.32-8.35 (m, 1H); 13C NMR (CDCl3) δ 33.5, 39.8, 56.4,
109.9, 115.4 (q, J ) 285.7 Hz), 113.4, 122.3, 123.3, 124.0, 126.2,
127.1, 128.4, 129.6, 135.6., 136.9, 137.5, 156.5 (q, J ) 37.0 Hz),
189.5. Anal. Calcd for C20H17F3N2O2: C, 64.17; H, 4.58; N, 7.48.
Found: C, 64.36; H, 4.41; N, 7.46.
) 13.8, 7.2 Hz, 1H), 3.74 (s, 3H), 4.20 (t, J ) 7.2 Hz, 1H), 4.30
(dd, J ) 10.2, 7.2 Hz, 1H), 4.42 (dd, J ) 10.2, 7.2 Hz, 1H),
5.25 (dd, J ) 14.4, 6.9 Hz, 1H), 5.97 (d, J ) 8.4 Hz, 1H), 7.11-
7.44 (m, 12 H), 7.53 (s, 1H), 7.57 (t, J ) 5.1 Hz, 2H), 7.75 (d,
J ) 7.2 Hz, 1H), 8.37-8.39 (m, 1H); 13C NMR (DMSO-d6) δ
33.6, 40.5, 47.2, 57.7, 67.0, 109.8, 114.2, 120.0, 120.9, 122.6,
123.1, 123.8, 125.2, 125.3, 126.7, 127.1, 127.7, 128.3, 129.7,
136.8, 137.5, 141.3, 143.9, 155.8, 191.9. Anal. Calcd for
C33H28N2O3: C, 79.18; H, 5.64; N, 5.60. Found: C, 78.98; H,
5.81; N, 5.79.
9H-Fluoren-9-ylmethyl-N-[(1S)-1-(1H-indol-3-ylmethyl)-
2-oxo-2-(1-methyl-1H-indol-2-yl)ethyl]carbamate (6d): col-
orless microcrystals; yield, 45%; mp 191-192 °C; [R]23
)
D
+32.9 (c 1.6, DMF); 1H NMR (DMSO-d6) δ 3.11 (dd, J ) 14.7,
9.0 Hz, 1H), 3.27 (dd, J ) 14.4, 5.4 Hz, 1H), 3.83 (s, 3H), 4.18-
4.23 (m, 3H), 5.13 (dd, J ) 14.1, 8.4 Hz, 1H), 6.99 (t, J ) 7.2
Hz, 1H), 7.07 (t, J ) 7.2 Hz, 1H), 7.21-7.42 (m, 8H), 7.54 (d,
J ) 7.2 Hz, 1H), 7.66 (t, J ) 6.6 Hz, 3H), 7.86-7.92 (m, 3H),
8.26 (d, J ) 7.2 Hz, 1H), 8.32 (s, 1H), 10.84 (s, 1H); 13C NMR
(DMSO-d6) δ 27.8, 33.2, 46.6, 57.0, 65.7, 110.4, 110.6, 111.3,
113.2, 118.3, 120.0, 120.8, 121.5, 122.2, 123.0, 123.6. 125.3
(2C), 126.2, 127.0, 127.3, 127.6, 136.0, 137.2, 137.4, 140.6,
143.8, 155.8, 193.3. Anal. Calcd for C35H29N3O3: C, 77.90; H,
5.42; N, 7.79. Found: C, 77.70; H, 5.48; N, 7.61.
9H-Fluoren-9-ylmethyl N-[(1S)-1-[(1-methyl-1H-indol-
3-yl)carbonyl]-3-(methylsulfanyl)propyl] carbamate (6e):
colorless microcrystals; yield, 90%; mp 140-141 °C; [R]23
)
D
-41.5 (c 1.6, DMF); 1H NMR (DMSO-d6) δ 1.95-2.05 (m, 1H),
2.08 (s, 3H), 2.19-2.29 (m, 1H), 2.49-2.69 (m, 2H), 3.85 (s,
3H), 4.22 (t, J ) 7.2 Hz, 1H), 4.34-4.44 (m, 2H), 5.27 (dd, J )
10.2, 8.1 Hz, 1H), 5.94 (d, J ) 6.9 Hz, 1H), 7.30 (t, J ) 7.8 Hz,
2H), 7.34-7.41 (m, 5H), 7.59 (t, J ) 7.2 Hz, 2H), 7.75 (d, J )
7.2 Hz, 2H), 8.00 (s, 1H), 8.39 (d, J ) 6.0 Hz, 1H); 13C NMR
(DMSO-d6) δ 15.8, 30.5, 34.0, 34.3, 47.4, 55.3, 61.2, 110.1,
114.0, 120.2, 122.7, 123.3, 124.1, 125.3, 126.7, 127.2, 127.9,
136.9, 137.8, 141.5, 144.0, 156.4, 192.6. Anal. Calcd for
C29H28N2O3S: C, 71.87; H, 5.82; N, 5.78. Found: C, 71.48; H,
5.76; N, 6.31.
9H-Fluoren-9-ylmethyl N-[(1S)-1-methyl-2-(1-methyl-
1H-indol-3-yl)-2-oxo-ethyl]carbamate (6f): colorless needles;
1
mp 144-145 °C; yield, 85%; [R]23 ) -60.1 (c 1.6, DMF); H
D
NMR (DMSO-d6) δ 1.52 (d, J ) 6.9 Hz, 3H), 3.85 (s, 3H), 4.23
(t, J ) 7.2 Hz, 1H), 4.38 (d, J ) 7.2 Hz, 2H), 5.10 (quintet, J
) 7.2 Hz, 1H), 6.00 (d, J ) 4.8 Hz, 1H), 7.27-7.42 (m, 7H),
7.61 (d, J ) 7.2 Hz, 2H), 7.60 (d, J ) 7.5 Hz, 2H), 7.86 (s, 1H),
8.34-8.39 (m, 1H); 13C NMR (DMSO-d6) δ 21.1, 33.9, 47.4,
52.4, 67.1, 110.0, 113.5, 120.2, 122.7, 123.3, 124.0, 125.4, 126.7,
127.3, 127.9, 136.3, 137.8, 141.5, 144.1, 155.9, 193.5. Anal.
Calcd for C27H24N2O3: C, 76.40; H, 5.70; N, 6.60. Found: C,
76.52; H, 5.71; N, 6.61.
N-[(1R,S)-1-Benzyl-2-(1-methyl-1H-indol-3-yl)-2-oxo-
ethyl]-2,2,2-trifluoroacetamide (6j): colorless needles; yield,
64%; mp 170-172 °C; 1H NMR and 13C NMR are the same as
for N-[(1S)-1-benzyl-2-(1-methyl-1H-indol-3-yl)-2-oxoethyl]-
2,2,2-trifluoroacetamide (6a).
Procedure for C-Acylations of Benzene. AlCl3 (0.4 g, 3
mmol) was added to 1d (2 mmol) dissolved in benzene (20 mL)
at 0 °C. After removing the ice-bath, the reaction mixture was
stirred at room temperature for 3 h and then quenched by
MeOH (1 mL). Removal of solvent under reduced pressure gave
the crude product, which was directly purified by column
chromatography (EtOAc/hexane ) 1:10) to give product 7 in
63% yield.
N-[(1S)-1-Benzyl-2-oxo-2-phenylethyl]-2,2,2-trifluoro-
acetamide (7): colorless needles; mp 64-65 °C (lit.7c mp 62-
63 °C); yield, 63%; 1H NMR (CDCl3) δ 1.57 (d, J ) 7.2 Hz,
3H), 5.13 (quintet, J ) 7.2 Hz, 1H), 6.70 (br s, 1H), 7.29-7.40
(m, 5H); 13C NMR (CDCl3) δ 21.2, 50.0, 116.0 (q, J ) 287.3
Hz), 126.4, 128.3, 129.2, 141.1, 156.6 (q, J ) 37.0 Hz), 195.1.
Procedure for Preparation of Amines 8, 10, and 14 by
Cleavage of Fmoc Protecting Group. Carbamate 6f or 6g
(0.42 g, 1 mmol) was dissolved in morpholine (10 mL, 10
2,2,2-Trifluoro-N-[(1S)-1-methyl-2-(1-methyl-1H-indol-
3-yl)-2-oxoethyl] acetamide (6b): colorless needles; yield,
1
75%; mp 161-162 °C; [R]23 ) -84.2 (c 1.6, CHCl3); H NMR
D
(CDCl3) δ 1.60 (d, J ) 6.9 Hz, 3H), 3.90 (s, 3H), 5.29 (quintet,
J ) 6.9 Hz, 1H), 7.35-7.40 (m, 3H), 7.77 (d, J ) 5.4 Hz, 1H),
7.88 (s, 1H), 8.30-8.34 (m, 1H); 13C NMR (CDCl3) δ 20.7, 34.1,
51.6, 110.3, 112.7, 116.0 (q, J ) 287.8 Hz), 122.6, 123.6, 124.3,
126.5, 136.5, 137.9, 156.7 (q, J ) 37.8 Hz), 191.1. Anal. Calcd
for C14H13F3N2O2: C, 56.38; H, 4.39; N, 9.39. Found: C, 56.44;
H, 4.33; N, 9.31.
9H-Fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-(1-methyl-
1H-indol-3-yl)-2-oxoethyl] carbamate (6c): colorless needles;
1
yield, 40%; mp 153-154 °C; [R]23 ) +13.1 (c 1.6, DMF); H
D
NMR (DMSO-d6) δ 3.16 (dd, J ) 13.5, 5.7 Hz, 1H), 3.23 (dd, J
J. Org. Chem, Vol. 70, No. 13, 2005 4999

Katritzky et al.
mmol). After 30 min of stirring, 300 mL of water was added.
After the mixture was extracted with hexane until the TLC
showed the disappearance of the first spot, indicating the
elimination of 9-methylene-9H-fluorene, the water phase was
further extracted with EtOAc. Then the EtOAc organic phase
was dried with MgSO4, and the evaporation of solvent gave
crude product (2S)-2-amino-1-(1-methyl-1H-indol-3-yl)-1-pro-
panone (8) [or (2R)-2-amino-1-(1-methyl-1H-indol-3-yl)-1-pro-
panone (10) from 6g] in 75% yield (75% from 10 as well), which
can be used for the next step without further purification. The
cleavage of 9H-fluoren-9-ylmethyl N-[(2S)-3-oxo-1,2,3,4-tet-
rahydrocyclopenta[b]indol-2-yl]carbamate (13) following the
same procedure gave racemic 2-amino-1,2-dihydrocyclopenta-
[b]indol-3(4H)-one (14) in 71% yield. We used these three
compounds as crude staring materials for the next coupling
reaction without purification. Therefore, we do not provide
their characterization.
the ice-bath, the reaction mixture was stirred at room tem-
perature for 3 h and then quenched by MeOH (1 mL). Removal
of solvent under reduced pressure gave the crude product,
which was purified by column chromatography (EtOAc/hex-
anes ) 6:1) to give the intramolecular acylated products 12
(13 from 1d). They were further recrystallized from CHCl3/
hexanes for CHN analysis.
2,2,2-Trifluoro-N-[(2S)-1-oxo-2,3-dihydro-1H-inden-2-
yl]acetamide (12): white flakes; yield, 57%; mp 207-208 °C;
1
[R]23 ) -3.2 (c 1.6, DMF); H NMR (DMSO-d6) δ 3.05 (dd, J
D
) 16.8, 5.4 Hz, 1H), 3.55 (dd, J ) 16.8, 8.4 Hz, 1H), 4.61-4.68
(m, 1H), 7.45 (t, J ) 7.5 Hz, 1H), 7.59 (d, J ) 7.5 Hz, 1H),
7.69-7.76 (m, 2H), 9.96 (d, J ) 7.8 Hz, 1H); 13C NMR (DMSO-
d6) 32.1, 54.6, 115.8 (q, J ) 286.9 Hz), 123.5, 126.8, 127.8,
134.6, 135.6, 151.4, 156.3 (q, J ) 36.5 Hz), 201.2. Anal. Calcd
for C11H8F3NO2: C, 54.33; H, 3.32; N, 5.76. Found: C, 54.31;
H, 3.24; N, 5.70.
Procedure for the Preparation of Diastereomers 9
and 11. Amine 8 (or 10) 0.21 g (1 mmol) was stirred with Tfa-
L-Phe-Bt (1a) (0.36 g, 1 mmol) in CH2Cl2 (20 mL) at 20 °C for
1 h. Evaporation of solvent gave crude product, which can be
purified by column chromatography (EtOAc/hexane ) 1:6).
(2S)-N-[(1S)-1-Methyl-2-(1-methyl-1H-indol-3-yl)-2-oxo-
ethyl]-3-phenyl-2-[(2,2,2-trifluoroacetyl) amino]propana-
9H-Fluoren-9-ylmethyl N-[(2S)-3-oxo-1,2,3,4-tetrahy-
drocyclopenta[b]indol-2-yl]carbamate (13): white flakes;
yield, 62%; 235 °C (dec.); [R]23D ) -39.0 (c 1.6, DMF); 1H NMR
(DMSO-d6) δ 2.88 (dd, J ) 16.2, 3.0 Hz, 1H), 3.51 (dd, J )
16.2, 6.9 Hz, 1H), 4.24-4.38 (m, 3H), 4.53 (quintet, J ) 6.9
Hz, 1H), 7.14 (t, J ) 7.5 Hz, 1H), 7.33-7.48 (m, 6H), 7.72 (d,
J ) 7.5 Hz, 4H), 7.90-8.01 (m, 2H), 11.76 (s, 1H); 13C NMR
(DMSO-d6) δ 28.1, 46.7, 59.6, 65.6, 113.6, 120.1, 121.4, 122.8,
127.8, 125.9, 126.9, 127.1, 127.6, 136.6, 140.7, 140.9, 143.4,
143.8, 155.9, 191.3. Anal. Calcd for C26H20N2O3: C, 76.45; H,
4.94; N, 6.86. Found: C, 76.24; H, 4.88; N, 6.72.
Procedure for the Preparation of Diastereomers 15
(16 and 17). Amine 14 (0.17 g, 1 mmol) was stirred with Tfa-
DL-Ala-Bt (1i) or Tfa-L-Ala-Bt (1b) (0.28 g, 1 mmol) in CH2Cl2
(20 mL) at 20 °C for 1 h. Evaporation of solvent gave the
corresponding crude product which can be purified by column
chromatography (EtOAc/hexanes ) 1:3).
N-(1-Oxo-1,2,3,8-tetrahydrocyclopenta[a]inden-2-yl)-2-
[(2,2,2-trifluoroacetyl)amino] propanamide (15): white
plates; yield, 52%; mp 257-258 °C; 1H NMR (DMSO-d6)
(diastereomeric mixture) δ 1.49 (d, J ) 7.0 Hz, 3H), 1.50 (d, J
) 7.0 Hz, 3H), 2.93-3.03 (m, 2H), 3.12 (br s, 2H), 3.57-3.66
(m, 2H), 4.58-4.79 (m, 2H), 4.76-4.92 (m, 2H), 7.16 (t, J )
6.9 Hz, 2H), 7.38 (t, J ) 7.5 Hz, 2H), 7.73 (d, J ) 8.1 Hz, 2H),
8.01-8.08 (m, 2H), 8.58 (br s, 2H), 10.8 (s, 2H); 13C NMR
(DMSO-d6) (diastereomeric mixture) δ17.4, 17.5, 28.4, 28.5,
49.3 (2C), 59.0, 59.3, 113.6, 116.2 (q, J ) 285.2 Hz), 120.5,
120.6, 121.5, 123.5, 127.2 (2C), 136.8, 136.9, 143.9(2C), 156.4
(q, J ) 40.0 Hz), 170.9, 190.0, 190.1; HRMS calcd for
C17H15F3N2O3 (M + 2H)+ 354.1191, found 354.1185.
mide (9): colorless needles; mp 212-214 °C; yield, 80%; [R]23
D
) -12.1 (c 1.6, DMF); 1H NMR (CDCl3) δ 1.50 (d, J ) 6.9 Hz,
3H), 3.14 (d, J ) 6.9 Hz, 2H), 3.87 (s, 3H), 5.01 (q, J ) 7.2 Hz,
1H), 5.37 (quintet, J ) 7.2 Hz, 1H), 7.15 (s, 5H), 7.33-7.40
(m, 3H), 7.49 (d, J ) 6.9 Hz, 1H), 8.04 (s, 1H), 8.34-8.37 (m,
1H); 13C NMR (CDCl3) δ 21.0, 33.6, 38.8, 51.0, 54.7, 109.9,
112.9, 115.8 (q, J ) 285.7 Hz), 122.5, 123.2, 123.9, 126.5, 127.3,
128.6, 129.2, 135.3, 136.9, 137.7, 156.7 (q, J ) 37.6 Hz), 168.8,
192.4. Anal. Calcd for C23H22F3N3O3: C, 62.02; H, 4.98; N, 9.43.
Found: C, 61.95; H, 4.91; N, 9.34.
(2S)-N-[(1R)-1-Methyl-2-(1-methyl-1H-indol-3-yl)-2-oxo-
ethyl]-3-phenyl-2-[(2,2,2-trifluoroacetyl) amino]propana-
mide (11): colorless needles; mp 212-214 °C; yield, 80%; [R]23
D
) -14.0; 1H NMR (CDCl3) δ 1.39 (d, J ) 6.6 Hz, 3H), 3.24 (d,
J ) 7.2 Hz, 2H), 3.75 (s, 3H), 5.24 (q, J ) 7.2 Hz, 1H), 5.38
(quintet, J ) 7.2 Hz, 1H), 7.01 (t, J ) 7.2 Hz, 1H), 7.22-7.34
(m, 8H), 7.86 (d, J ) 6.9 Hz, 1H), 7.95 (s, 1H), 8.32-8.34 (m,
1H); 13C NMR (CDCl3) δ 20.7, 33.6, 39.6, 51.5, 54.7, 110.1,
112.9, 115.8 (q, J ) 285.7 Hz), 122.5, 123.2, 123.9, 126.7, 127.2,
128.8, 129.3, 136.0, 137.8, 156.7 (q, J ) 37.6, Hz), 169.4, 192.9.
Anal. Calcd for C23H22F3N3O3: C, 62.02; H, 4.98; N, 9.43.
Found: C, 61.95; H, 4.91; N, 9.34.
Procedure for the Intramolecular Acylations of 1a
and 1d. AlCl3 (0.4 g, 3 mmol) was added to 1a (or 1d) (2 mmol)
dissolved in anhydrous CH2Cl2 (20 mL) at 0 °C. After removing
JO050226Q
5000 J. Org. Chem., Vol. 70, No. 13, 2005