Masked 3-aminoindan-1-ones by a palladium-catalyzed three-component annulation reaction

Article abstract of DOI:10.1021/jo048187q

(Chemical Equation Presented) A new palladium(0)-catalyzed three-component reaction involving a set of salicylic aldehyde triflates, ethylene glycol vinyl ether, and various secondary nucleophilic amines has been developed. Through systematic optimization

Full text of DOI:10.1021/jo048187q

Masked 3-Aminoindan-1-ones by a Palladium-Catalyzed
Three-Component Annulation Reaction
Anna Arefalk, Mats Larhed, and Anders Hallberg*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC,
Box-574, SE-751 23 Uppsala, Sweden
anders.hallberg@farmkemi.uu.se
Received October 14, 2004
A new palladium(0)-catalyzed three-component reaction involving a set of salicylic aldehyde triflates,
ethylene glycol vinyl ether, and various secondary nucleophilic amines has been developed. Through
systematic optimization experiments using multivariate design, the conditions effecting robust and
convenient one-pot generation of protected 3-aminoindan-1-ones were identified. A reaction route
involving an initial internal Heck arylation of the hydroxyalkyl vinyl ether, iminium ion formation,
and subsequent tandem cyclization is invoked to explain the selective formation of the isolated
tertiary 3-aminoindan acetals. Hydrogenolysis of orthogonally blocked 3-aminoindan-1-ones
delivered primary or secondary amines after 10-20 min of microwave heating.
Introduction
substituted 3-aminoindan-1-ones and the corresponding
glycol acetales since modeling suggested that these
groups might be well accommodated in the S2 site of the
protease. Previously, the preparation of 3-aminoindan-
1-one was accomplished in a multistep procedure from
benzaldehyde where an intramolecular Friedel-Crafts
acylation of 3-amino-3-phenylpropanoic acid was a key
reaction.7,8 The corresponding N-substituted 3-amino-
indan-1-ones were prepared via a five-step protocol
involving R-bromination of 1-indanone, acetalization,
dehydrobromination, removal of the protection group, and
subsequent conjugate addition with various amines.
Multicomponent reactions have attracted increasing
interest due to the significant preparative advantages
over stepwise procedures.9 We herein report a palladium-
catalyzed three-component annulation reaction that de-
livers masked 3-aminoindan-1-ones in moderate to good
yields. This noncarbonylative reaction sequence has the
potential to smoothly provide a plethora of varied indan
Indanones constitute an important class of compounds,
and as a consequence thereof, several methods for their
preparation have been developed. For instance, Larock
has reported palladium-catalyzed carbonylative annula-
tion reactions that frequently deliver very high yields of
indanones from o-iodostyrenes.1 Furthermore, Negishi
observed N,N-diethylaminoindan-1-one as a byproduct in
palladium-catalyzed carbonylative cyclizations starting
from o-iodostyrenes when triethylamine was employed
as the base.1,2
The indan skeleton is found in the P2 position in many
potent aspartic protease inhibitors,3 in particular encom-
passing an N-acylated 1-amino-2-hydroxyindan as in the
HIV-inhibitor indinavir.4 It was previously revealed by
Lyle et al. that additional substituents at the 3-position
of the bicyclic ring system were also well tolerated by
the HIV-1 enzyme.5 In our medicinal chemistry program,6
we desired a method for chemoselective generation of
(5) Lyle, T. A.; Wiscount, C. M.; Guare, J. P.; Thompson, W. J.;
Anderson, P. S.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W.
A.; Quintero, J. C.; Dixon, R. A. F.; Sigal, I. S.; Huff, J. R. J. Med.
Chem. 1991, 34, 1228-1230.
(6) Alterman, M.; Andersson, H. O.; Garg, N.; Ahlsen, G.; Lo¨vgren,
S.; Classon, B.; Danielson, U. H.; Kvarnstro¨m, I.; Vrang, L.; Unge, T.;
Samuelsson, B.; Hallberg, A. J. Med. Chem. 1999, 42, 3835-3844.
(7) Dallemagne, P.; Rault, S.; Pilo, J. C.; Foloppe, M. P.; Robba, M.
Tetrahedron Lett. 1991, 32, 6327-6328.
(8) Kinbara, K.; Katsumata, Y.; Saigo, K. Chem. Lett. 2002, 266-
267.
(9) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471-1499.
(1) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804-
4807.
(2) Negishi, E.-i.; Coperet, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour,
J. M. J. Am. Chem. Soc. 1996, 118, 5904-5918.
(3) Ersmark, K.; Feierberg, I.; Bjelic, S.; Hamelink, E.; Hackett, F.;
Blackman, M. J.; Hulten, J.; Samuelsson, B.; Qvist, J.; Hallberg, A. J.
Med. Chem. 2004, 47, 110-122.
(4) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel,
S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.
Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096-4100.
10.1021/jo048187q CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/05/2005
938
J. Org. Chem. 2005, 70, 938-942

Masked 3-Aminoindan-1-ones
TABLE 1. Optimization Studya
phosphino)propane), 1:2), Bu2NH, and PMP (1,2,2,6,6-
pentamethylpiperidine), as outlined in Table 1 and
Figure 1. To be able to compare the outcome of the
reactions, naphthalene was added as internal standard.
The reaction mixtures were analyzed with GC-MS, and
the peak area ratio between product 4a and naphthalene
was used as the productivity response.
exp
no.
[Pd]
(µmol)
DPPP
(µmol)
3a
(mmol)
PMP
respb
(%)
(mmol)
1
2
1
5
1
5
1
5
1
5
3
3
3
2
10
2
10
2
10
2
10
6
6
6
0.10
0.10
0.20
0.20
0.10
0.10
0.20
0.20
0.15
0.15
0.15
0.10
0.10
0.10
0.10
0.30
0.30
0.30
0.30
0.20
0.20
0.20
60
201
49
144
93
244
57
174
129
119
130
3
4
5
6
7
8
9
10
11
a Constant in all experiments: aryl triflate (1a) (0.10 mmol),
vinyl ether (2) (0.30 mmol), 80 °C, 4 h (4.0 mg of naphthalene as
internal standard). b Response ) GC-MS peak area of 4a/peak
area of naphthalene × 100.
All three varied factors were found to be of significance
for the preparative outcome. The amount of palladium-
phosphine catalyst had a big influence on the reaction
rate, but in control experiments we could demonstrate
that it did not have any effect on the yield if the reaction
was heated at 80 °C for a longer time. However, the
amount of PMP must be kept high, perhaps to facilitate
the Pd(0) regeneration in the catalytic cycle and/or to
suppress protonation of the reacting amines 3a-g. The
outcome of the reaction was also found to be favorable if
the amount of the amine 3a was lower than the amount
of aryl triflate 1a. There may be two primary reasons
for this: First, nucleophilic amines are known to coor-
dinate to palladium(II), consequently disturbing the
catalytic cycle and making the Heck reaction less effective
at high concentrations.11,12 Second, if the amount of
secondary amine in the reaction is too high the iminium
ion 5 (Scheme 1) reacts further to form the corresponding
FIGURE 1. Scaled and centered coefficients (PLS, two
components), R2 ) 0.997, Q2 ) 0.649, conf lev ) 0.95.
structures that are not easily accessible by other syn-
thetic methods and that should serve as useful building
blocks in medicinal chemistry.
SCHEME 1. Proposed Reaction Pathway for the
Formation of 4
Results and Discussion
The primary aim of this study was to develop a general
method for a one-pot reaction providing an entry to
protected 3-aminoindan-1-one derivates (4) (eq 1). Sali-
cylic aldehyde triflates (1), ethylene glycol vinyl ether (2),
and various amines (3) constituted the reactants. Prefer-
ably this new method should be suitable for both the
synthesis of primary, secondary, and tertiary amines.
Unfortunately, initial attempts made with primary
amines, e.g., butylamine, benzylamine, and valine methyl
ester, were not successful despite manipulations of reac-
tion temperatures as well as the relative amounts of
reactants. Thus, we decided to focus our research efforts
on secondary amines as starting materials with the
ambition to employ benzylic derivatives as potential
precursors for primary and secondary 3-aminoindanones.
A model annulation reaction with aryl triflate 1a and
secondary amine 3a (eq 1) was selected. The reaction
optimization was performed using a full factorial design10
with different concentrations of three reaction variables,
the catalytic system (Pd(OAc)2/DPPP (1,3-bis(diphenyl-
aminal in an intermolecular process. If the aminal is
formed no ring closure will occur. As demonstrated in
Figure 1, it is more important to keep the concentration
of the secondary amine low than to keep the amount of
palladium catalyst high since the correlated cross-term
between the catalyst and 3a was found to be negative.
After further experimental studies, a maximum limit of
3.0 equiv of PMP and 0.75 equiv of secondary amine (3)
(10) Box, G. E. P.; Hunter, W. G.; Hunter, J. S. Statistics for
experimenters. An introduction to design, data analysis, and model
building; John Wiley & Sons: New York, 1978.
(11) Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. J. Org. Chem.
2001, 66, 544-549.
(12) Seligson, A. L.; Trogler, W. C. J. Am. Chem. Soc. 1991, 113,
2520-2527.
J. Org. Chem, Vol. 70, No. 3, 2005 939

Arefalk et al.
TABLE 2. One-Pot Synthesis of Protected
3-Aminoindan-1-ones (4)
relative to the aryl triflate (1) was selected both to keep
the amount of expensive reactants low and to accomplish
an efficient workup procedure. The amount of catalyst
was adjusted to 2.0 mol % securing that the reactions
were completed overnight.
To evaluate the selected conditions a set of salicylic
triflates and secondary amines were identified. Thus, a
mixture of the salicylic triflate 1 (2.0 mmol), the second-
ary amine 3 (1.5 mmol), the vinyl ether 2 (6.0 mmol),
palladium acetate/DPPP (0.040/0.080 mmol), PMP (6.0
mmol), and acetonitrile was heated overnight at 80 °C
(eq 1). The results of the preparative reactions are
outlined in Table 2.
The effect of increasing sterical hindrance was studied
with a selection of five different aliphatic secondary
amines (3a-e). Interestingly, all products were obtained
in good, comparable yields except 4d wherein the highly
hindered diisopropylamine (3d) was used as nucleophilic
amine (entry 4). In this particular case, a considerable
amount of the protected 3-hydroxy-indan-1-one was
formed as a byproduct. Having a conformationally re-
strained tertiary carbon in the R-position in one of the
N-alkyl groups, as in 3e, turned out to slightly improve
the yield (compare entries 1 and 5).
To investigate if the reaction was compatible with
somewhat more electron-poor amines, two benzylic amines
(3f,g) were examined. Our purpose when choosing ben-
zylic amines was to explore whether benzylic amines
could serve as equivalents for both primary amines and
ammonia. Rewardingly, the annulation reaction worked
as smoothly with benzylic amines as with aliphatic
(entries 6 and 7).
We have previously reported that DPPP-controlled
internal Heck reaction does not work with highly electron-
withdrawing substituents on the salicylic aldehyde.13,14
We therefore decided to include only electron-donating
substituents in this study. Hence, the methoxy-substi-
tuted aryl triflates 1b,c were reacted with the amine 3f.
The outcome was that compound 4h was formed in
slightly lower yield (51%) and 4i, with the methoxy group
para to the formyl group, in slightly higher yield (71%)
than the corresponding parent compound 4f. The dis-
appointing yield of 4h was a direct consequence of
competing formation of 3-hydroxyindan-1-one acetal.
We suggest that 4 is formed by the reaction pathway
presented in Scheme 1. The Heck arylation of vinyl ethers
with aryl triflates and bidentate ligands is proposed to
proceed via charged aryl palladium species.15-17 Thus, the
insertion process is electronically controlled leading to
R-arylation of the electron-rich olefin 2. During the
reaction, the free aldehyde 1 and the corresponding
iminium ion are in equilibrium. Since the iminium ion
is very electron-deficient, thereby deactivating the system
for internal vinylation,14 the aldehyde form is probably
more prone to undergo DPPP-controlled Heck coupling.
(13) Bengtson, A.; Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67,
5854-5856.
(14) Larhed, M.; Andersson, C. M.; Hallberg, A. Tetrahedron 1994,
50, 285-304.
(15) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-
3066.
(16) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(17) Larhed, M.; Hallberg, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; John Wiley &
Sons: New York, 2002; Vol. 1, pp 1133-1178.
a All products were obtained as racemic mixtures.
940 J. Org. Chem., Vol. 70, No. 3, 2005

Masked 3-Aminoindan-1-ones
Once the iminium ion is formed on a vinylated substrate
the ring closure is very fast.18 With the methoxy group
located in the para position to the formyl group (1c) the
vinylated aldehyde is stabilized by resonance. The ring
closure to the desired product 4i via the iminium ion of
type 5 is therefore a cleaner process, compared to that of
the corresponding reaction with triflate 1b where a
substantial amount of 3-hydroxyindan-1-one acetal is
generated after attack on the more activated aldehyde
function (entries 8 and 9, Table 2). The cyclization of the
charged intermediate 5 is believed to occur after initial
activation of the vinyl ether by an intramolecular acetal-
ization. Thus, the hydroxy function acts as a nucleophilic
neighboring group in the annulation process.
primary amine 9 employing microwave-assisted hydro-
genolysis (eq 4).
As in the case of the previously reported one-pot
synthesis of blocked 3-hydroxyindanones,13 no mono-
cyclized 2-aryl-2-methyl-1,3-dioxolane was detected even
though the ethylene glycol vinyl ether has been success-
fully used previously for preparation of ketals of aceto-
phenones from aryl triflates lacking an electrophilic
group in the ortho position.19-21
To examine whether benzylamines could serve as
equivalents for primary amines and ammonia, pure
compounds 4f,g were treated with Pd/C and ammonium-
formiate to remove the benzyl groups. After 10 min of
controlled microwave heating, compound 4f was selec-
tively cleaved into the desired secondary amine 6 (eq 2).
Indeed, the benzylic C-N bond was cleaved rather than
the benzylic indan C-N bond.
Conclusions
In conclusion, we have developed a novel one-pot
method for the preparation of protected 3-aminoindan-
1-ones from salicylic aldehyde triflates, ethylene glycol
vinyl ether, and nucleophilic amines. Both primary,
secondary, and tertiary amino products were produced
and isolated in useful yields. The reaction sequence
reported denotes a new type of palladium-catalyzed
three-component annulation, which relies on a regio-
selective Heck arylation and subsequent intramolecular
nucleophilic attack by the ethylene glycol vinyl ether. The
protocol is expected to be useful in high-throughput
synthesis of a range of 3-aminoindan derivatives.
Experimental Section
General Methods. The aryl triflates were prepared ac-
cording to a fast microwave procedure.23 All other chemicals
used were commercially available.
General Procedure for the Synthesis of N,N-Disub-
stituted 3-Amino-1,1-(ethylenedioxy)indans (Table 2).
The aryl triflate (2.0 mmol) was dissolved in MeCN (14 mL)
in a reaction tube. Ethylene glycol vinyl ether (6.0 mmol, 540
µL), PMP (6.0 mmol, 1100 µL), Pd(OAc)2 (40 µmol, 400 µL of
1 M stock solution in MeCN), DPPP (80 µmol, 400 µL of 1 M
stock solution in MeCN), and the secondary amine (1.5 mmol)
were added. The tube was flushed with N2 and sealed with a
screw cap. The reaction mixture was stirred at 80 °C for 18 h.
After evaporation of the solvent the crude product was purified
on basic Al2O3. The sample was applied to the column with a
small volume of EtOAc and eluted with EtOAc, isohexane (1:
4). The remaining PMP was removed in a vacuum (10 mbar,
70 °C).
3-(N,N-Dibutylamino)-1,1-(ethylenedioxy)indan (4a).
The title compound was obtained in 64% yield (296 mg) as dark
red, thick oil: 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J ) 7.3,
6H), 1.20-1.30 (m, 2H), 1.30-1.39 (m, 2H), 1.40-1.49 (m, 4H),
2.19 (dd, J ) 7.6, 13.4, 1H), 2.27-2.33 (m, 2H), 2.34 (dd, J )
7.1, 13.4, 1H), 2.37-2.44 (m, 2H), (4.02-4.24 (m, 4H), 4.56
(dd, J ) 7.1, 7.6, 1H), 7.29-7.31 (m, 1H), 7.34-7.38 (m, 2H),
7.40-7.42 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 20.6,
31.1, 37.0, 50.5, 62.1, 64.8, 65.9, 115.1, 122.9, 125.1, 128.0,
129.8, 141.7, 145.7. Anal. Calcd for C19H29NO2: C, 75.2; H,
9.6; N, 4.6. Found: C, 75.0; H, 9.4; N, 4.6.
On the contrary, with the tertiary amine 4g, carrying
two benzyl groups, the indan C-N bond was cleaved
preferentially, releasing dibenzylamine and carbonyl
protected 1-indanon. Therefore, in the search for a more
suitable ammonia equivalent we decided to revisit the
use of primary amines. The sterically hindered and
electron-poor R-phenylbenzylamine (7) was identified as
a potential ammonia synthon. This compound was thought
to coordinate weaker to palladium(II) than the previously
studied aliphatic primary amines, at the same time as
the corresponding imine should act as a reactive electro-
phile in the subsequent annulation.22 Keeping the reac-
tion conditions identical to those used for the secondary
amines except for raising the temperature to 90 °C
(sealed vessel), the desired N-protected product 8 was
obtained in fair yield (eq 3). The diphenylmethyl protect-
ing group could then be selectively cleaved into the
(18) In case of sluggish amines, the intermediate vinyl-substituted
salicylic aldehyde triflate was detected by LC/MS.
(19) McClelland, R. A.; Watada, B.; Lew, C. S. Q. J. Chem. Soc.,
Perkin Trans. 2 1993, 1723-1727.
(20) Larhed, M.; Hallberg, A. J. Org. Chem. 1997, 62, 7858-7862.
(21) Vallin, K. S. A.; Larhed, M.; Johansson, K.; Hallberg, A. J. Org.
Chem. 2000, 65, 4537-4542.
(22) Primary amines coordinate harder to palladium(II) than sec-
ondary amines, thereby retarding the catalytic cycle in the Heck
reaction; see ref 12.
3-(N-Ethylamino)-1,1-(ethylenedioxy)indan (6). Com-
pound 4f (124 mg, 0.40 mmol), Pd/C (10%) (43 mg, 40 µmol),
ammonium formiate (250 mg, 4.0 mmol), and 4 mL of MeOH
(23) Bengtson, A.; Hallberg, A.; Larhed, M. Org. Lett. 2002, 4, 1231-
1233.
J. Org. Chem, Vol. 70, No. 3, 2005 941

Arefalk et al.
were mixed in a 5 mL process vial. The vial was sealed, and
the reaction mixture was heated with microwaves to 100 °C
for 10 min. After filtration, the solvent was removed in a
vacuum and the crude product was extracted between EtOAc
and 10% K2CO3(aq). The organic phase was dried with
K2CO3(s) and evaporated to afford the title compound in 72%
yield (63 mg) as yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.15
(t, J ) 7.1, 3H), 1.73 (bs, 1H), 2.12 (dd, J ) 4.9, 13.5, 1H),
2.62 (dd, J ) 7.0, 13.5, 1H), 2.69-2.81 (m, 2H), 4.05-4.22 (m,
4H), 4.28 (dd, J ) 4.9, 7.0, 1H), 7.27-7.41 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 15.6, 41.6, 45.5, 58.9, 65.3, 65.6, 115.2,
123.2, 124.8, 128.4, 129.8, 141.9, 145.3. Anal. Calcd for C13H17-
NO2: C, 71.2; H, 7.8; N, 6.4. Found: C, 71.0; H, 7.9; N, 6.2.
1,1-(Ethylenedioxy)-3-(R-phenylbenzylamino)indan (8).
The aryl triflate (340 µL, 2.0 mmol) was dissolved in MeCN
(14.0 mL) in a reaction tube. Ethylene glycol vinyl ether (6.0
mmol, 540 µL), PMP (6.0 mmol, 1100 µL), Pd(OAc)2 (40 µmol,
400 µL of 1 M stock solution in MeCN), DPPP (80 µmol, 400
µL of 1 M stock solution in MeCN), and C,C-diphenylmethyl-
amine (260 µL, 1.5 mmol) were added. The tube was flushed
with N2 and sealed with a screw cap. The reaction mixture
was stirred at 90 °C for 18 h. After evaporation of the solvent,
the crude product was purified on basic Al2O3. The sample was
applied to the column with a small volume of EtOAc and eluted
with EtOAc/isohexane (1:4). The product was further purified
by recrystallization from MeOH. The title compound was
obtained in 48% yield (260 mg) as pale orange crystals: 1H
NMR (400 MHz, CDCl3) δ 1.81 (dd, J ) 1.9, 11.3, 1H), 2.13
(dd, J ) 5.3, 13.3, 1H), 2.65 (dd, J ) 6.8, 13.3, 1H), 4.01-4.23
(m, 5H), 5.06-5.09 (m, 1H), 7.18-7.23 (m, 2H), 7.28-7.36 (m,
6H), 7.38-7.42 (m, 1H), 7.45-7.48 (m, 2H), 7.52-7.56 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 46.1, 56.7, 65.1, 65.4, 65.5, 115.2,
123.0, 124.9, 127.17, 127.19, 127.4, 127.5, 128.3, 128.62,
128.63, 129.8, 141.6, 143.7, 144.5, 145.9. Anal. Calcd for C24H23-
NO2: C, 80.6; H, 6.5; N, 3.9. Found: C, 80.5; H, 6.6; N, 4.0.
3-Amino-1,1-(ethylenedioxy)indan (9). Compound 8 (143
mg, 0.40 mmol), Pd/C (10%) (43 mg, 40 µmol), ammonium
formiate (250 mg, 4.0 mmol), and 4 mL of MeOH were mixed
in a 5 mL process vial. The vial was sealed, and the reaction
mixture was heated with microwaves to 100 °C for 20 min.
After filtration, the solvent was removed in a vacuum and the
crude product was extracted between MeCN, hexane, and an
aqueous phase consisting of equal parts of brine and 10%
K2CO3 (aq). The phases were separated, and the hexane phase
was extracted three more times with MeCN. The combined
MeCN phases were evaporated to afford the title compound
in 64% yield (49 mg) as white crystals: 1H NMR (400 MHz,
CD3OD) δ 1.95 (dd, J ) 6.5, 13.4, 1H), 2.64 (dd, J ) 7.1, 13.4,
1H), 4.00-4.20 (m, 4H), 4.28 (dd, J ) 6.5, 7.1, 1H), 7.28-7.46
(m, 4H); 13C NMR (100 MHz, CD3OD) δ 48.6, 53.4, 65.9, 66.6,
115.8, 124.1, 124.9, 129.0, 131.0, 142.7, 148.2. Anal. Calcd for
C11H13NO2‚1/2H2O: C, 67.0; H, 7.0; N, 7.1. Found: C, 67.2; H,
6.9; N, 6.9.
Acknowledgment. We acknowledge financial sup-
port from the Swedish Research Council and from Knut
and Alice Wallenberg’s Foundation. We also thank
Biotage AB for providing us with the SmithSyntheziser.
Supporting Information Available: Experimental pro-
cedures and analytical data of all prepared compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048187Q
942 J. Org. Chem., Vol. 70, No. 3, 2005