Rhodium-Catalyzed Oxidative Cycloaddition of N-tert-Butoxycarbonylhydrazones with Alkynes for the Synthesis of Functionalized Pyrroles via C(sp3)–H Bond Functionalization

Article abstract of DOI:10.1002/adsc.201600900

A rhodium(III)-catalyzed cycloaddition of N-tert-butoxycarbonylhydrazones with internal alkynes was developed. The reaction features a regioselective α-imino alkyl C(sp³)?H bond functionalization resulting in selective formation of highly functionalized NH-free pyrroles. Our studies showed that utilizing the N-tert-butoxycarbonyl (N-Boc) as the oxidizing directing group is critical for achieving the observed pyrrole formation versus the isoquinoline formation. To account for the pyrrole formation, we hypothesized that a prior tautomerization of the N-Boc-hydrazones to enamines should occur, followed by regioselective C(sp²)–H cleavage to form a putative five-membered rhodacycle. Subsequent coupling of the rhodacycle with the alkynes would afford the pyrrole products. (Figure presented.).

Full text of DOI:10.1002/adsc.201600900

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DOI: 10.1002/adsc.201600900
Rhodium-Catalyzed Oxidative Cycloaddition of N-tert-Butoxycar-
bonylhydrazones with Alkynes for the Synthesis of Functionalized
Pyrroles via C(sp3)–H Bond Functionalization
Chun-Ming Chan,a Zhongyuan Zhou,a and Wing-Yiu Yua,*
a
State Key Laboratory for Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Hung Hom, Kowloon, Hong Kong
Fax : (+852)-2364-9932; e-mail: wing-yiu.yu@polyu.edu.hk
Received: August 13, 2016; Revised: October 25, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600900.
Abstract: A rhodium(III)-catalyzed cycloaddition of hypothesized that a prior tautomerization of the N-
N-tert-butoxycarbonylhydrazones with internal al- Boc-hydrazones to enamines should occur, followed
kynes was developed. The reaction features a regiose- by regioselective C(sp2)–H cleavage to form a puta-
3
À
lective a-imino alkyl C(sp ) H bond functionaliza- tive five-membered rhodacycle. Subsequent coupling
tion resulting in selective formation of highly func- of the rhodacycle with the alkynes would afford the
tionalized NH-free pyrroles. Our studies showed that pyrrole products.
utilizing the N-tert-butoxycarbonyl (N-Boc) as the
oxidizing directing group is critical for achieving the
observed pyrrole formation versus the isoquinoline Keywords: alkynes; C–H activation; cycloaddition;
formation. To account for the pyrrole formation, we nitrogen heterocycles; rhodium
Introduction
analogous cycloaddition reactions based on ruthenium
catalysis. For other transition metal approaches,
Transition metal-catalyzed oxidative C H bond cyclo- Lohꢀs[8a] and Guanꢀs[8b] groups reported the Pd-cata-
addition reactions with alkynes[1,2] and carbenoids[3] lyzed pyrrole synthesis, whereas Zhang and co-work-
are attracting current attention for developing atom- ers also developed the related cobalt-catalyzed cyclo-
economical syntheses of medicinally valuable hetero- addition reaction.[9]
À
cycles. The versatility of the transition metal catalysis
approach is examplified by the recent advances in in- Rh-catalyzed regioselective C(sp ) H bond function-
Currently, extensive effort is directed to developing
3
À
doles and isoquinolines synthesis involving the alization for C–C and C–X (X=N, B, Si) bonds for-
Cp*RhIII-catalyzed oxidative C(sp2)–H cycloaddition mation.[10] However, examples for pyrrole synthesis
with N-oxyenamines as substrates.[1b,e] With the N–O by catalytic regioselective C(sp ) H bond functionali-
3
À
moieties as oxidizing directing groups, the cycloaddi- zation are sparse in the literature.[11] In 2010, Glorius
tions with alkynes and carbenoids can operate under and co-workers pioneered the Cp*Rh(III)-catalyzed
mild conditions without external oxidants and exhibit oxidative cycloaddition of enamides with alkynes
high regio- and chemoselectivity.[1–3]
to form pyrroles via C(sp ) H bond activation,
3
À
Pyrroles are privileged heterocyclic scaffolds pres- and a Cu(II) salt was employed as co-oxidant
ent in many pharmaceutical products and functional (Scheme 1b).[6b] In 2014, Zeng and co-workers report-
materials.[4] Analogous to the indoles and isoquino- ed the Pd-catalyzed C(sp ) H bond oxidative cycload-
3
À
À
lines synthesis, metal-catalyzed oxidative C H bond dition of N-(2-pyridyl)ketoimines with internal al-
cycloaddition for pyrroles synthesis has also received kynes to form N-(2-pyridyl)pyrroles.[11b] Later in 2015,
considerable interest.[5] In 2010, Fagnou[6a] and Glori- they also developed the Rh-catalyzed cyclization of
us[6b] first reported independently the N-acetylpyrrole a-imino C(sp ) H bonds with a-acyl diazocarbonyl
3
À
2
À
synthesis by [Cp*RhCl2]2-catalyzed C(sp ) H bond compounds to form the corresponding pyrroles
cycloaddition of N-acetylenamides with alkynes (Scheme 1c).[11a] In this report, we disclose the
(Scheme 1a). Later, the research groups of Wang,[7a] Cp*Rh(III)-catalyzed oxidative cycloaddition of N-
Ackermann[7b] and Liu[7c] successfully developed the Boc-hydrazones with internal alkynes to afford NH-
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Table 1. Optimization of the reaction conditions.[a]
Entry Solvent
Acid
Base
Yield [%][b]
(5.0 mL) (3.0 equiv.) (25 mol%) of 3aa
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
dioxane
toluene
DCE
AcOH
AcOH
AcOH
–
AcOH
PivOH
PhCO2H
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
CsOAc
CsOAc
–
70
<5
0
0
0
89
88
80
90
40
77
42
78
2[c]
3
4
CsOAc
CsOAc
CsOAc
CsOAc
NaOAc
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
5[d]
6
7
8
9
10
11
12
13
THF
[a]
Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), and
[Cp*RhCl2]2 (2.5 mol%) at 1208C for 16 h.
NMR yields.
Reaction was performed at 608C.
Reaction was performed without [Cp*RhCl2]2.
[b]
[c]
[d]
Scheme 1. Selected examples of pyrrole synthesis by metal-
catalyzed cycloaddition.
To further optimize the reaction, we first examined
the reaction temperature. Apparently, performing the
reaction at a lower temperature (e.g., 608C) led to
3aa formation in a trace quantity (Table 1, cf. entry 1
3
À
free pyrroles via regioselective a-imino C(sp ) H and 2). The presence of CsOAc, AcOH and
À
bond cycloaddition. This reaction features the N N [Cp*RhCl2]2 is essential, and the absence of any one
bond cleavage for effective product formation and component resulted in ineffective transformation (en-
catalyst turnovers without the need for external oxi- tries 3–5). Apart from AcOH, pivalic acid and benzo-
dants.
ic acid are equally effective for promoting the pyrrole
formation (entries 6 and 7). By examining several
acid-base
combinations,
employing
Na2CO3
Results and Discussion
(25 mol%) instead of CsOAc was found to give 3aa in
90% yield (entry 9). Common organic solvents other
To begin, we reacted 4-methylacetophenone N-Boc- than MeCN gave slightly lower product yields (en-
hydrazone (1a, 0.4 mmol) and diphenylacetylene (2a, tries 10–13).
0.2 mmol) with [Cp*RhCl2]2 (2.5 mol%), CsOAc
It is known that employing oxidizing directing
(25 mol%) and AcOH (3.0 equiv.) in MeCN (2.5 mL) groups is a favourable approach for designing transi-
À
at 1208C for 16 h, and pyrrole 3aa was obtained in tion metal-catalyzed C H bond cycloaddition reac-
68% yield. We were gratified to see that isoquinoline tions.[13] As shown by Hartwig,[14a] Fagnou[2r] and Glo-
4aa was formed in <10% yield (Supporting Informa- rius,[14b] the catalytic cross-coupling reactions of
tion, Table S3).[12] However, when the same protocol oximes and benzohydroxamic acids with alkynes af-
was applied to 4-bromoacetophenone N-Boc-hydra- forded indoles and isoquinolones, respectively, in ex-
zone 1f, no pyrrole or isoquinoline was obtained. cellent selectivity. It is generally accepted that cleav-
After several trials, we found that doubling the sol- age of the weak N–O s-bond facilitates the product
vent volume to 5 mL led to effective formation of pyr- formation (presumably via a sequence of oxidative ad-
role 3fa in 60% yield (Supporting Information, S6).[12] dition and reductive elimination) and catalyst turn-
overs. Recently, Glorius[2c] and co-workers reported
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Table 2. Effect of leaving groups (LG).[a,b]
Table 3. Scope of N-Boc-hydrazones.[a,b]
[a]
Reaction conditions:
1
(0.4 mmol), 2a (0.2 mmol),
[Cp*RhCl2]2 (2.5 mol%), Na2CO3 (25 mol%) and AcOH
(3.0 equiv.) in MeCN (5.0 mL) at 1208C for 16 h.
Isolated yields.
[b]
2
À
a catalytic oxidative C(sp ) H bond cycloaddition of
some Boc-protected hydrazines with alkynes to form
indoles, and the N N bond was found to be an effec-
À
tive oxidizing directing group. In this work, we have
examined a series of hydrazones bearing different ter-
minal leaving groups for the catalytic cycloaddition
with alkynes (Table 2). With N-Boc as a leaving
group, facile cycloaddition of 4-methylacetophenone
N-Boc-hydrazone 1a with diphenylacetylene 2a fur-
nished pyrrole 3aa in 90% yield with isoquinolines
4aa being formed in <5% yield. Importantly, the
analogous reactions with 4-methylacetophenone hy-
drazones bearing NHAc and OMe leaving groups
produced isoquinoline 4aa exclusively without any
pyrrole formation. Hydrazones with picolinamide and
NH2 leaving groups are ineffective substrates; neither
pyrroles nor isoquinolines were obtained.
[a]
Reaction conditions: 1 (0.4 mmol) and 2a (0.2 mmol),
[Cp*RhCl2]2 (2.5 mol%), Na2CO3 (25 mol%) and AcOH
(3.0 equiv.) in MeCN (5.0 mL) at 1208C for 16 h.
Isolated yields.
Reaction conditions: 1s (0.8 mmol) and 2a (0.2 mmol),
[Cp*RhCl2]2 (2.5 mol%), Na2CO3 (25 mol%) and AcOH
(3.0 equiv.) in MeCN (5.0 mL) at 1208C for 2 h.
[b]
[c]
With these optimized conditions in hand, reactions
of various para-substituted acetophenone N-Boc hy-
drazones with diphenylacetylene 2a were examined,
and the corresponding pyrroles 3aa–3ga were ob-
tained in 62–90% yields (Table 3). The molecular
structure of the pyrrole product 3ea has been con-
firmed by X-ray crystallography (Figure 1).[15] In these
cases, isoquinoline formation resulting from the ortho
2
À
C(sp ) H bond activation was insignificant (Support-
ing Information, Table S1).[12] For acetophenone N-
Figure 1. Molecular structure of 5-[4-(methylthio)phenyl]-
Boc-hydrazones bearing substituents located at other 2,3-diphenyl-1H-pyrrole (3ea).
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Table 4. Scope of alkynes.[a,b]
positions on the aryl ring, successful cycloadditions
were also achieved to give pyrroles 3ha–3oa in 42–
73% yields. As expected, the cycloaddition of a naph-
thyl-substituted acetophenone N-Boc hydrazone fur-
nished pyrrole 3pa in 72% yield.
3
À
For the Rh(III)-catalyzed C(sp ) H bond function-
alization, examples concerning the functionalization
3
[10]
À
of primary C(sp ) H bonds are well documented.
However, functionalizations of the analogous secon-
3
[16]
À
dary C(sp ) H bond are less common. In this work,
when an ethyl phenyl ketone-derived N-Boc-hydra-
zone was subjected to the Rh-catalyzed cycloaddition
reaction with diphenylacetylene, effective functionali-
3
À
zation of the secondary a-imino C(sp ) H bond was
achieved to give pyrrole 3qa in 75% yield. Nonethe-
less, the analogous reaction with the substrate bearing
an n-propyl imino substituent was sluggish; isoquino-
line 4va was obtained in 23% yield, with the desired
pyrrole 3va being formed in <5% yield.[12] An N-
Boc-hydrazone containing a seven-membered carbo-
cyclic ketone moiety was found to undergo effective
cycloaddition to produce the tricyclic pyrrole 3ra in
42% yield with <10% isoquinoline formation. Yet,
the analogous cycloaddition of the N-Boc-hydrazone
containing a six-membered carbocyclic ketone afford-
ed isoquinoline 4ua in 90% yield.[12] In this work,
[a]
Reaction conditions: 1a (0.4 mmol) and 2 (0.2 mmol),
[Cp*RhCl2]2 (2.5 mol%), Na2CO3 (25 mol%) and AcOH
(3.0 equiv.) in MeCN (5.0 mL) at 1208C for 16 h.
Isolated yields.
when an N-Boc-hydrazone derived from acetone was
3
[b]
À
employed as substrate, effective C(sp ) H bond cyclo-
[c]
NMR yield, isoquinoline 4af: 60% yield.
addition was achieved to give the a-methylpyrrole 3sa
in 32% yield.
With 4-methylacetophenone N-Boc-hydrazone 1a
as substrate, the alkyne scope has also been examined
(Table 4). The reaction with 1-phenyl-1-propyne 2b with an NHAc or OMe group resulted in exclusive
2
À
under the Rh-catalyzed conditions furnished pyrrole isoquinoline formation via the aryl C(sp ) H bond
3ab as a single regioisomer. Similar results were ob- functionalization. Presumably, successful pyrrole for-
tained for the analogous reactions with 1-phenyl-1- mation is associated with the N-Boc group to direct
3
À
butyne 2c, 1-phenyl-1-pentyne 2d and 1-phenyl-1- the C(sp ) H bond functionalization by the Rh(III)
hexyne 2e. When 4-octyne 2f was employed as the complex. To understand the observed selectivity for
3
À
coupling partner, isoquinoline 4af became a major the a-imino C(sp ) H bond functionalization, the cy-
product (60%), and the desired pyrrole 3af was cloaddition of the deuterated N-Boc-hydrazone 1t
formed in <20% yield. This finding implies that the with diphenylacetylene was performed under our op-
transition state for successful pyrrole formation timized conditions. The expected 3ta was obtained in
should be rather sensitive to steric factors. Having 90% yield without any loss of deuterium on the
such a hypothesis in mind, we anticipated that em- phenyl ring (Scheme 2a). This result implies that the
ploying a bulkier substituent such as a trimethylsilyl N-Boc group should play a key role in directing the
3
À
(TMS) group on the alkyne would hinder the pyrrole kinetically competitive C(sp ) H bond functionaliza-
formation. Interestingly, the reaction of phenylsilyl- tion.
A
Moreover, after subjecting 4-methylacetophenone
lpyrrole 3ag in 55% yield with a minor isoquinoline N-Boc-hydrazone 1a to the Rh(III)/AcOD/CD3CN
formation (<5%). Effective cycloadditions were also system at 1208C in the absence of diphenylacetylene
achieved with some substituted diphenylacetylenes, for 20 min, 50% deuterium incorporation was detect-
and pyrroles 3ah–3aj were obtained in 53–75% yields. ed at the a-imino methyl and the N-Boc groups
The catalytic pyrrole formation developed in this (Scheme 2b). This result may suggest that the imine-
3
À
work features the regioselective a-imino C(sp ) H enamine tautomerization could have been promoted
2
À
bond functionalization versus the aryl C(sp ) H bond by the Rh(III) catalyst coordinated to the N-Boc
functionalization (isoquinoline formation). As shown group.
earlier, replacing the N-Boc group of the substrate
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2
À
cleavage of the C(sp ) H bond to form rhodacycle A.
The complex A is presumably stabilized by the Boc
group.[18] After alkyne insertion, the 7-membered in-
termediate B would undergo the N-ligand shift to
give the 6-membered rhodacycle C.[19] Reductive
À
elimination via oxidative addition of the N N bond
to the Rh(III) should produce species D. Protonation
by acetic acid should furnish the desired pyrrole prod-
uct. An alternative route involving a Rh(V) nitrene
intermediate E by acylamino migration is also possi-
ble.[20] Subsequent carbon-migration to the nitrene
ligand on species E should produce species D.
Conclusions
In summary, we have developed a Rh(III)-catalyzed
oxidative cycloaddition of N-Boc-hydrazones with in-
ternal alkynes. Our study shows that the N-Boc group
is essential for the selective pyrrole formation. The re-
action provides a direct route to highly functionalized
3
À
pyrroles via direct C(sp ) H bond functionalization.
This reaction offers an expedient access to NH-free
pyrroles, which are key structural scaffolds of many
pharmaceutical products and functional materials.
Scheme 2. H/D exchange experiments.
A plausible reaction mechanism is depicted in
Scheme 3. The reaction should be initiated by the co-
ordination of the enamine isomer of the N-Boc-hy-
drazone 1 to the Rh(III) center,[17] followed by the
Scheme 3. Plausible reaction mechanism.
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the crude mixture was concentrated under reduced pressure.
Experimental Section
The solid remaining was then filtered and recrystallized with
a minimum amount of hot DCM. The desired product 1 was
used without further purification.
General
All the solvents and reagents were obtained from commer-
cial sources and used without purification unless stated oth-
erwise. All glasswares were dried overnight at 1508C prior
to use. All the Rh-catalyzed reactions were performed with-
out specific protection from air or moisture. Thin layer chro-
matography was performed on silica gel plates. Flash
column chromatography was performed on a silica gel
(Merck, 230–400 mesh) column. 1H and 13C NMR spectra
were recorded on a Bruker DPX-400 MHz spectrometer.
The chemical shift (d) values are given in ppm and are refer-
enced to residual solvent peaks; carbon multiplicities were
determined by DEPT-135 experiments. Coupling constants
(J) were reported in hertz (Hz). The NMR yield values
were determined with dibromomethane (6.98 mL) as internal
standard, which shows a singlet signal at dH =4.9 ppm in
CD2Cl2. Mass spectra and high resolution mass spectra (HR-
MS) were obtained on a VG MICROMASS Fison VG plat-
form, a Finnigan Model Mat 95 ST instrument, or a Brꢂker
APEX 47e FT-ICR mass spectrometer. X-ray crystallo-
graphic study was performed using a Bruker CCD area de-
tector diffractometer.
Typical Procedure for Preparation of 1s
A 100-mL round-bottom flask equipped with a magnetic
stirrer was charged with acetone (40 mL), acetic acid
(0.2 mL) and tert-butyl carbazate (5 g, 37.8 mmol). The mix-
ture was subjected to reflux for 1 h under a nitrogen atmos-
phere. The crude mixture was cooled and the resulting sus-
pension was filtered off. The filtrate was concentrated under
reduced pressure. The residue solid was then recrystallized
with a minimum amount of hot DCM. The desired product
1s was used without further purification. Compound 1s was
obtained as a white solid; yield: 6.37 g (98%); mp 103–
1
1048C. H NMR (400 MHz, CDCl3): d=1.39 (s, 9H), 1.73 (s,
3H), 1.90 (s, 3H), 7.58 (s, 1H); 13C NMR (100 MHz,
CDCl3): d=153.02 (C), 149.87 (C), 80.56 (C), 28.16 (CH3),
25.23 (CH3), 16.05 (CH3).
Acknowledgements
We thank The Hong Kong Research Grants Council
(PolyU5032/13P, C5023/14G) for financial support.
General Procedure for Rh(III)-Catalyzed Cyclo-
addition of N-Boc hydrazones with Alkynes for the
Synthesis of Pyrrole 3
References
A 10 mL-sealed tube equipped with a magnetic stirrer was
charged with [Rh(Cp*)Cl2]2 (3.2 mg, 2.5 mol%), Na2CO3
(5.3 mg, 25 mol%), N-Boc-hydrazone 1 (0.4 mmol) and
MeCN (5.0 mL). Alkyne 2 (0.2 mmol) and AcOH (34.3 mL,
0.6 mmol) were added sequentially. The mixture was then
stirred and heated at 1208C for 16 h. After cooling to room
temperature, the crude mixture was filtered through Celiteꢃ
and concentrated under reduced pressure. The residue was
then purified by flash column chromatography (hexanes/
ethyl acetate, 9:1, v/v) to give the desired product 3.
[1] Reviews on transition metal-catalyzed oxidative
C(sp2)–H annulations with alkynes, see: a) M. Gulꢄas,
J. L. MascareÇas, Angew. Chem. 2016, 128, 11164;
Angew. Chem. Int. Ed. 2016, 55, 11000; b) H. Huang,
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Ioffe, Chem. Rev. 2014, 114, 5426.
5-[4-(Methylthio)phenyl]-2,3-diphenyl-1H-pyrrole
(3ea)
[2] Selected examples of transition metal-catalyzed oxida-
tive C(sp2)–H annulations for indole synthesis, see:
a) B. Li, H. Xu, H. Wang, B. Wang, ACS Catal. 2016, 6,
3856; b) Q. Lu, S. Vꢅsquez-Cꢆspedes, T. Gensch, F.
Glorius, ACS Catal. 2016, 6, 2352; c) A. Lerchen, S.
Vꢅsquez-Cꢆspedes, F. Glorius, Angew. Chem. 2016, 128,
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Chen, Z. Lin, Organometallics 2015, 34, 309; e) G.
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Chem. Soc. 2008, 130, 16474; m) R. C. Larock, E. K.
Yum, M. D. Refvik, J. Org. Chem. 1998, 63, 7652;
n) R. C. Larock, E. K. Yum, J. Am. Chem. Soc. 1991,
was isolated as a pale yellow solid; yield: 50 mg (73%); mp
185–1868C; Rf =0.6 (hexanes/ethyl acetate 85:15, v/v). The
solid was redissolved in a minimum amount of DCM; diffu-
sion with hexane gave
a
pale yellow solid. 1H NMR
(400 MHz, CD2Cl2): d=2.55 (s, 3H), 6.72 (d, J=2.8 Hz,
1H), 7.23–7.27 (m, 1H), 7.30–7.45 (m, 11H), 7.54 (d, J=
8.4 Hz, 2H), 8.58 (s, 1H); 13C NMR (100 MHz, CD2Cl2): d=
136.68 (C), 136.42 (C), 133.05 (C), 131.74 (C), 129.28 (C),
129.10 (C), 128.68 (CH), 128.32 (CH), 127.50 (CH), 127.13
(CH), 126.99 (CH), 125.94 (CH), 125.74 (C), 124.09 (CH),
123.77 (C), 108.27 (CH), 15.72 (CH3); HR-MS (ESI): m/z=
341.1233, calcd. for C23H19NS+: 341.1223.
General Procedure for Preparation of N-Boc-
hydrazones 1
A 100-mL round-bottom flask equipped with a magnetic
stirrer was charged with aryl ketone 6 (5 mmol), acetic acid
(29 mL, 0.5 mmol) and EtOH (30.0 mL). The mixture was
stirred and heated under reflux for 15 min. Then tert-butyl
carbazate (0.990 g, 7.5 mmol) was added to the mixture and
subjected to reflux. Upon completion as indicated by TLC,
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113, 6689. For isoquinolines synthesis, see: o) S. Zhang,
D. Huang, G. Xu, S. Cao, R. Wang, S. Peng, J. Sun,
Org. Biomol. Chem. 2015, 13, 7920; p) P. C. Too, Y.-F.
Wang, S. Chiba, Org. Lett. 2010, 12, 5688. For pyridines
synthesis, see: q) P. C. Too, T. Noji, Y. J. Lim, X. Li, S.
Chiba, Synlett 2011, 19, 2789. For isoquinolones synthe-
sis, see: r) N. Guimond, C. Gouliaras, K. Fagnou, J.
Am. Chem. Soc. 2010, 132, 6908.
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FULL PAPERS
Rhodium-Catalyzed Oxidative Cycloaddition of N-tert-
Butoxycarbonylhydrazones with Alkynes for the Synthesis
of Functionalized Pyrroles via C(sp3)–H Bond
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Adv. Synth. Catal. 2016, 358, 1 – 9
Chun-Ming Chan, Zhongyuan Zhou, Wing-Yiu Yu*
Adv. Synth. Catal. 0000, 000, 0 – 0
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