Copper-catalyzed intramolecular C-N bond formation: A straightforward synthesis of benzimidazole derivatives in water

Article abstract of DOI:10.1021/jo1021426

A straightforward, efficient, and more sustainable copper-catalyzed method has been developed for intramolecular N-arylation providing the benzimidazole ring system. With Cu₂O (5 mol %) as the catalyst, DMEDA (10 mol %) as the ligand, and K₂CO₃ as the base, this protocol was applied to synthesize a small library of benzimidazoles in high yields. Remarkably, the reaction was exclusively carried out in water, rendering the methodology highly valuable from both environmental and economical points of view.

Full text of DOI:10.1021/jo1021426

pubs.acs.org/joc
attention. The classical method for the synthesis of benzimi-
Copper-Catalyzed Intramolecular C-N Bond
Formation: A Straightforward Synthesis of
Benzimidazole Derivatives in Water
dazoles is via the condensation of benzene-1,2-diamines with
either carboxylic acid derivatives under strong acid/high tem-
perature conditions or aldehydes under oxidative conditions.3
Although these transformations are widely used in the pre-
paration of benzimidazoles, there remain many drawbacks
to overcome such as the use of highly toxic reagents, strong
acids and, in some cases, harsh reaction conditions.3
Jinsong Peng,* Min Ye, Cuijuan Zong, Fangyun Hu,
Lingtong Feng, Xiaoyan Wang, Yufeng Wang, and
Chunxia Chen*
Given the importance of these heterocycles in drug synth-
esis, the design and development of more milder, novel, and
sustainable processes for the assembly of the benzimidazole
ring system is imperative. One of the methods employed for
the synthesis of nitrogen heterocycles is the transition-metal-
catalyzed carbon-nitrogen cross-coupling reaction.4
Although significant progress in the palladium-5 and nick-
el-catalyzed6 C-N bond formation have been made under
mild conditions, the high cost of palladium and the required
especially designed ligands, as well as the high toxicity of
nickel catalysts, led to a need to explore the use of inexpen-
sive and more sustainable metals for such coupling reactions.
Therefore, the development of an environmentally benign
and cheaper copper-7 or iron-mediated8 catalysis for car-
bon-carbon or carbon-heteroatom cross-coupling reac-
tions has become an important goal. Additionally, organic
reactions in water have recently attracted much attention
because water is the most economical, safest, and environ-
mentally friendly medium.9
Department of Chemistry and Chemical Engineering,
College of Science, Northeast Forestry University,
Harbin, 150040, P. R. China
*jspeng1998@163.com; ccx1759@163.com
Received October 28, 2010
A straightforward, efficient, and more sustainable copper-
catalyzed method has been developed for intramolecular
N-arylation providing the benzimidazole ring system.
With Cu2O (5 mol %) as the catalyst, DMEDA (10 mol %)
as the ligand, and K2CO3 as the base, this protocol was
applied to synthesize a small library of benzimidazoles
in high yields. Remarkably, the reaction was exclusively
carried out in water, rendering the methodology highly
valuable from both environmental and economical points
of view.
The transition-metal-catalyzed C-N cross-coupling
methodologies for the synthesis of benzimidazole derivatives
(4) For examples: (a) Zou, B. L.; Yuan, Q. L.; Ma, D. W. Angew. Chem.
2007, 119, 2652. Angew. Chem., Int. Ed. 2007, 46, 2598. (b) Zheng, N.;
Anderson, K. W.; Huang, X. H.; Nguyen, H. N.; Buchwald, S. L. Angew.
Chem. 2007, 119, 7653. (g) Angew. Chem., Int. Ed. 2007, 46, 7509. (c) Willis,
M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int. Ed. 2005, 44, 403.
ꢀ
ꢀ
(d) Barluenga, J.; Jimenez-Aquino, A.; Aznar, F.; Valdes, C. J. Am. Chem. Soc.
2009, 131, 4031. (e) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3767.
(5) For reviews on Pd-catalyzed aminations of aryl halides, see: (a) Muci,
A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 133. (b) Zapf, A.; Beller,
M.; Riermeier, T. H. Transition Metals for Organic Synthesis; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, p 231.
Benzimidazoles are frequently found in a diverse array of
compounds, including biologically and therapeutically active
agents or natural products1 and functional materials.2 There-
fore, the construction of these heterocycles has received much
(6) Selected examples: (a) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 6054. (b) Bricout, H.; Carpentier, J.-F.; Mortreux, A. Tetrahedron
1998, 54, 1073. (c) Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002,
67, 3029and references therein. (d) Omar-Amrani, R.; Thomas, A.; Brenner,
E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311. (e) Matsubara, K.; Ueno,
K.; Koga, Y.; Hara, K. J. Org. Chem. 2007, 72, 5069. (f) Chen, C.; Yang,
L.-M. J. Org. Chem. 2007, 72, 6324.
(7) For recent reviews on copper-catalyzed cross couplings, see: (a) Klapars,
A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727.
(b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (c) Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (d) Beletskaya, I. P.; Cheprakov,
A. V. Coord. Chem. Rev. 2004, 248, 2337. (e) Ma, D.; Cai, Q. Acc. Chem. Res.
2008, 41, 1450. (f) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054. (g) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954 and
references cited therein.
(1) (a) Baudy, R. B.; Fletcher, H., III; Yardley, J. P.; Zaleska, M. M.;
Bramlett, D. R.; Tasse, R. P.; Kowal, D. M.; Katz, A. H.; Moyer, J. A.;
Abou-Gharbia, M. J. Med. Chem. 2001, 44, 1516. (b) Boiami, M.; Gonzalez,
M. Mini-Rev. Med. Chem. 2005, 5, 409. (c) Kataoka, M.; Tatsuta, M.;
Yasoshima, K.; Yura, T.; Urbahns, K.; Kiba, A.; Yamamoto, N.; Gupta,
J. B.; Hashimoto, K. Bioorg. Med. Chem. Lett. 2005, 15, 805. (d) Ragno, G.;
Risoli, A.; Ioele, G.; De Luca, M. Chem. Pharm. Bull. 2006, 54, 802. (e) Sabat,
M.; Vanrens, J. C. L. M. J.; Brugel, T. A.; Maier, J.; Golebiowski, A.; De, B.;
Easwaran, V.; Hsieh, L. C.; Walter, R. L.; Mekel, M. J.; Evdokimov, A.;
Janusz, M. J. Bioorg. Med. Chem. Lett. 2006, 16, 5973. (f) Figueiras, A.;
Sarraguc-a, J. M. G.; Carvalho, R. A.; Pais, A. A. C. C.; Veiga, F. J. B. Pharm.
Res. 2007, 24, 377.
(8) For reviews, see: (a) Bolm, C.; Legros, J.; Paih, J. L.; Zani, L. Chem.
€
Rev. 2004, 104, 6217. (b) Furstner, A.; Martin, R. Chem. Lett. 2005, 624.
(c) Sherry, B. D.; Furstner, A.Acc. Chem. Res. 2008, 41, 1500. (d) Plietker, B. Iron
€
(2) (a) Asensio, J. A.; Gomez-Romero, P. Fuel Cells 2005, 5, 336.
(b) Schwartz, G.; Fehse, K.; Pfeiffer, M.; Walzer, K.; Leo, K. Appl. Phys.
Lett. 2006, 89, 083509.
(3) (a) Grimmett, M. R. Imidazole and Benzimidazole Synthesis, Best
Synthetic Methods; Meth-Cohn, O., Ed.; Academic: London, 1997. (b) Yang,
D.; Fokas, D.; Yu, J.; Li, L.; Baldino, C. M. Synthesis 2005, 47 and references
therein. (c) Ebenezer, W. J.; Hutchings, M.; Jones, K.; Lambert, D. A.; Watt,
I. Tetrahedron Lett. 2007, 48, 1641.
Catalysis in Organic Chemistry: Reactions and Applications; Wiley-VCH:
ꢁ
Weinheim, 2008; p 147. (e) Czaplik, W. M.; Mayer, M.; Cvengros, J.;
von Wangelin, A. J. ChemSusChem 2009, 2, 396 and references therein.
(9) (a) Organic Synthesis in Water; Grieca, P. A., Ed.; Blackie A & P:
€
London, 1998. (b) Lindstrom, U. M. Chem. Rev. 2002, 102, 2741. (c) Kobayahi,
S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (d) Li, C.-J. Chem. Rev. 2005, 105,
3095. (e) Blackmond, D. G.; Armstrong, A.; Coomber, V.; Wells, A. Angew.
Chem. 2007, 119, 3872. Angew. Chem., Int. Ed. 2007, 46, 3798.
716 J. Org. Chem. 2011, 76, 716–719
Published on Web 12/22/2010
DOI: 10.1021/jo1021426
r
2010 American Chemical Society

Peng et al.
JOCNote
TABLE 1. Optimization of Copper-Catalyzed Intramolecular C-N
Cross-Coupling of Benzamidine 1a in Watera
entry catalyst ligand
1c
base
K2CO3
temp (°C) time (h) yieldb (%)
100
100
100
100
100
100
100
110
100
100
100
100
100
100
100
100
30
30
30
30
30
30
24
24
30
30
30
30
30
30
30
30
19
22
83
81
65
67
2c
3
L2 K2CO3
K2CO3
Cu2O
CuI
4d
5d
6d
7
8
9
10
11
12
13
14
15
16
L1 K2CO3
L1 K2CO3
L1 K2CO3
L1 K2CO3
L1 K2CO3
L1 K2CO3
L2 K2CO3
L3 K2CO3
L4 K2CO3
L5 K2CO3
L2 Cs2CO3
L2 NEt3
CuBr
CuCl
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
FIGURE 1. Selected ligands used in copper-catalyzed intramolecular
N-arylation of 1a in water.
84 (71)e
86
91
a practical, cheap, and efficient copper-catalyzed intramolecular
N-arylation of (o-haloaryl)amidines to afford synthetically
valuable benzimidazole derivatives with environmentally
benign water as the solvent.16
98(88)f
82
94
91
94
94
91
N-(2-Iodophenyl)benzamidine (1a) derived from the addi-
tion of 2-iodobenzenamine to benzonitrile was selected as
a model substrate for a copper-catalyzed intramolecular
N-arylation reaction in aqueous media. After an initial screen
of various copper catalysts (5 mol %), we found that the use
of Cu2O gave the best yield (84%) with potassium carbonate
as the base in water at 100 °C (entries 4-7, Table 1). To
optimize other reaction conditions, we then examined dif-
ferent ligands, bases, reaction time and temperature using
5 mol % of Cu2O as the catalyst. Some results from that study
are summarized in Table 1. At first, the blank experiment
(without the copper catalyst) of 1a was examined in water
at 100 °C for 30 h, we were surprised to find that 1a showed
very low conversion into the corresponding benzimidazole
(ca. 20%) and mainly the formation of decomposition products
(ca. 70%) (entries 1 and 2, Table 1). The use of Cu2O as the
catalyst could efficiently promote this transformation giving
83% yield; more importantly, it could suppress the formation
of undesired decomposition products, confirming that these
results attributed predominantly to the copper-catalyzed aryla-
tion reaction (entries 1-3, Table 1). Compared to the ligand-
free cross-coupling reaction, the use of 10 mol % of L-proline
slightly shortened the reaction time (24 h vs 30 h, entries 3 and 7,
Table 1). We then carried out a set of experiments to reveal the
crucial role of the reaction temperature (entries 7-9, Table 1).
Although at higher temperature, the transformation gave
comparable yield to the reaction at 100 °C (86% vs 84%,
entries 7 and 8, Table 1). In order to increase the yield of 2a,
we then investigated the effect of various bidentate ligands
(L-proline, DMEDA, 1,10-phenanthroline, 8-hydroxyquino-
line-5-sulfonic acid and TMHD, Figure 1) on the reaction
(entries 9-13, Table 1). Cu2O(DMEDA) was found to be a
very effective catalyst for this cross-coupling reaction with
the best yield (entry 10, Table 1). Finally, other bases such as
L2 K3PO4 3H2O
3
aReaction conditions: 1.0 equiv of 1a (1.0 mmol), 2.0 equiv of base,
5 mol % of Cu2O, 10 mol % of ligand, water (1.5 mL). bYield of isolated
product after chromatography. cDecomposition product of 1a was also
d
isolated from the reaction mixture in ca. 70% yield. 10 mol % of the
catalyst was used. e3 mol % of Cu2O and 6 mol % of ligand were used.
f80 °C for 48 h.
have also been reported. For example, Brain10 reported the
first palladium-catalyzed N-arylation of (o-bromophenyl)-
amidines to give benzimidazoles intoluene. Batey11 demonstrated
an intramolecular aryl guanidinylation to form biologically
relevant 2-aminobenzimidazoles using both palladium and
copper catalysts in DME. Palladium- or copper-catalyzed
cascade aryl amination/condensation processes of o-halo-
acetanilides have been developed for the synthesis of 1,2-disub-
stituted benzimidazoles in t-BuOH or DMSO by Ma4a and
Buchwald,4b respectively. Buchwald12 also pioneered studies
to construct a benzimidazole core structure through an
efficient copperII-catalyzed C-H functionalization/C-N
bond-forming approach in DMSO. Shortly afterward, Yang
and Shi13 developed a straightforward method for the synthe-
sis of benzimidazoles via PdII-catalyzed C-H activation
with Cu(OAc)2/O2 as a co-oxidant in NMP. More recently,
the regiospecific reaction of 1,2-dihaloarenes with N-substituted
amidines or guanidines was conducted in NMP to synthesize
benzimidazoles with low to moderate yields under the high-
temperature conditions.14 Nevertheless, the aforementioned
method15 implied the use of toxic and hazardous organic
solvents and, in some cases, the requirement of additives, high
temperature or excess oxidative reagents. Herein, we report
(10) (a) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893.
(b) Brain, C. T.; Brunton, S. A. J. Org. Chem. 2003, 68, 6814.
(11) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(12) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932.
(13) Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen, J.-H.; Yang, Z.;
Cs2CO3, Et3N, and K3PO4 3H2O were examined; K2CO3
3
provided better results (entries 10, 14-16, Table 1).
Shi, Z.-J. Chem. Eur. J. 2009, 15, 7292.
;
(14) (a) Deng, X.; Mani, N. S. Eur. J. Org. Chem. 2010, 680. (b) Deng, X.;
McAllister, H.; Mani, N. S. J. Org. Chem. 2009, 74, 5742.
(16) Selected examples on copper-catalyzed intermolecular aminations of
aryl halides in neatly aqueous media, see: (a) Lu, Z.; Twieg, R. J. Tetrahedron
Lett. 2005, 46, 2997. (b) Wang, F.; Fu, H.; Jiang, Y.; Zhao, Y. Green Chem.
(15) Other recent examples, see: (a) Lv, X.; Bao, W. J. Org. Chem. 2009,
74, 5618. (b) Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.;
Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (c) Kumar, S.; Ila, H.;
Junjappa, H. J. Org. Chem. 2009, 74, 7046.
2008, 10, 452. (c) Wang, Y.; Wu, Z.; Wang, L.; Li, Z.; Zhou, X. Chem. Eur.
;
J. 2009, 15, 8971. (d) Liang, L.; Li, Z.; Zhou, X. Org. Lett. 2009, 11, 3294.
(e) Li, X.; Yang, D.; Jiang, Y.; Fu, H. Green Chem. 2010, 12, 1097.
J. Org. Chem. Vol. 76, No. 2, 2011 717

Peng et al.
JOCNote
TABLE 2. Copper-Catalyzed Synthesis of Benzimidazole Derivativesa
aReaction conditions: 1.0 equiv of N-(2-haloaryl)benzamidine (1.0 mmol), 2.0 equiv of K2CO3, 5mol%ofCu2O, 10 mol % of DMEDA, water (1.5 mL), 100
°C, 30 h. bYield of isolated product after chromatography; the values in parentheses are isolated yields of the corresponding decomposition products. cTwo
tautomers were observed in 60:1 ratios by GC. dTwo tautomers were observed in 100:1 ratios by GC. eTwo tautomers were observed in 1:5 ratios by GC.
With the optimized reaction conditions in hand, we then
explored the scope and generality of the present process
(Table 2). As shown in Table 2, this method is efficient for
the synthesis of a number of benzimidazoles 2 in good to
excellent yields. The nature of the ortho-substituted halogen
on the aniline moiety was very important to the reaction
outcome. (o-Iodoaryl)amidines or (o-bromoaryl) amidines
can smoothly be converted to the desired products in high to
718 J. Org. Chem. Vol. 76, No. 2, 2011

Peng et al.
JOCNote
SCHEME 1. Proposed Mechanism for the Intramolecular
N-Arylation of Amidines Using a Copper Catalyst
occurred through a coordination of the imine function group
of amidine to the Cu(I) center followed by an intramolecular
oxidative addition of aryl halide 1 to Cu(I), affording an
intermediate complex 3. The resulting complex 3 reacted
with base to form Cu-N bond and afforded an intermediate
complex 4, which preceded the formation of the coupling
product 2 and regeneration of the catalytic copper species
(path A, Scheme 1).7g However, an alternative pathway via
nucleophilic substitution in the first step19 then followed by
oxidative addition could not be completely ruled out (path B).
In summary, we have successfully developed a straight-
forward, efficient, and more sustainable copper-catalyzed
method for intramolecular N-arylation providing the benzi-
midazole ring system, a valuable framework with interesting
therapeutic properties. The present protocol uses Cu2O in
combination with a simple diamine derivative (DMEDA) as
the catalyst under mild reaction conditions; furthermore, the
use of a water as the solvent will render the methodology de-
scribed herein economically and environmentally advantageous
and of remarkable practical value for industrial applications.
excellent yields, however, the use of aryl chlorides to effect
such transformations afforded inferior results than their iodo
or bromo analogues. No desired products were obtained for
all the selected o-chloro-substituted substrates in Table 2
(with the exception of entry 9) that probably attributed to
their poorer tendency to undergo oxidative addition to
transition metal complexes (entries 3, 6, and 12, Table 2).
For aryl iodides or bromides, a variety of substituents on the
benzonitrile moiety, such as Me, OMe, Cl, Br, or CN, can be
used. It is worth noting that C-Br or C-Cl compatible with
reaction conditions are particularly appealing, since these
substituents offer great opportunity for further synthetic
manipulations (entries 13, 14, 16, 17, 19, and 21, Table 2).
The steric hindrance of ortho substituents on the nitrile
moiety seemed not to hamper the reaction, and the benzimi-
dazoles could be obtained in excellent yields (entries 7, 8, 13,
and 14, Table 2). In addition, 2-alkylbenzimidazoles can also
be obtained in good yields (entries 20, 22, and 25, Table 2).
Regarding the aniline moiety, several functional groups
including halogens and electron-donating (Me and OMe,
entries 18 and 24) or electron-withdrawing (NO2, entry 20)
substituents were tolerated well; the electronic nature of the
aromatic motifs did not seem to affect the efficiency of this
transformation. It is important to note that for the use of
p-methyl or chloro substrates, two tautomers were observed
in above 50:1 ratios by GC that may arise from the migration
of CdN group (entries 18 and 19, Table 2).17 Interestingly,
when p-nitro substrate was used, only one tautomer was
isolated in excellent yield (entry 20, Table 2). In comparison,
two tautomers of the product were isolated in 1:5 ratios when
the MeO group was introduced into the para position of the
N-aryl ring of the amidine (entry 24, Table 2). The tauto-
meric ratios were probably dependent on the electronic effect
of substituents on the aniline moiety.18 The desired products
2n and 2o from N0-phenylated alkyl or aryl amidine sub-
strates could also be obtained in moderate to good yields
(entries 25 and 26, Table 2).
Experimental Section
General Procedures for Copper-Catalyzed Intramolecular C-N
Bond-Forming Reaction of (o-Halophenyl)benzamidine. A 10 mL
Schlenk tube equipped with a magnetic stirring bar was charged
with (o-haloaryl)benzamidine substrates (1.0 mmol, 1.0 equiv),
Cu2O (0.05 mmol, 7.2 mg), DMEDA (0.1 mmol, 8.8 mg), and
K2CO3 (276 mg, 2.0 mmol, 2.0 equiv), and then 1.5 mL of H2O
was added via syringe at room temperature. The tube was sealed
and put into a preheated oil bath at 100 °C for 30 h. The reaction
mixture was cooled to room temperature, quenched with water
(3 mL), and diluted with ethyl acetate (5 mL). The layers were
separated, and the aqueous layer was extracted with (2ꢀ5 mL)
ethyl acetate. The combined organic extracts were dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo.
The crude product was then purified by flash chromatography
on silica gel (H), eluting with 5-10% ethyl acetate/petroleum ether.
Product Characterization of Representative Examples. 2-Phenyl-
1H-benzo[d]imidazole (2a): 1H NMR (DMSO-d6, 400 MHz) δ 12.92
(s, 0.19H), 8.20 (d, 2H, J = 7.6 Hz), 7.68 (d, 1H, J = 6.8 Hz),
7.58-7.48 (m, 4H), 7.23 (d, 2H, J=6.8 Hz). 13C NMR (DMSO-d6,
100 MHz) δ 151.6, 144.2, 135.3, 130.6, 130.3, 129.4, 126.9, 123.0,
122.2, 119.3, 111.8; HRMS-ESI (m/z) [M þ Na]þ calcd for C13H10-
N2Na 217.0742, found 217.0745.
2-(4-Bromophenyl)-1H-benzo[d]imidazole (2g): 1H NMR
(DMSO-d6, 400 MHz) δ 13.01 (s, 0.17H), 8.14 (d, 2H, J=8.8 Hz),
7.78 (d, 2H, J=8.8 Hz), 7.69 (d, 1H, J=7.6 Hz), 7.56 (d, 1H, J=
7.2 Hz), 7.26-7.22 (m, 2H). 13C NMR (DMSO-d6, 100 MHz) δ
150.6, 144.2, 135.5, 132.5, 129.8, 128.8, 123.7, 123.3, 122.4, 119.4,
111.9; HRMS-ESI (m/z) [M þ Na]þ calcd for C13H9BrN2Na
294.9847, found 294.9845.
Acknowledgment. We are grateful to the funds supported
by the Fundamental Research Funds for the Central Uni-
versities (DL10BB07, DL09BB34) and by a Grant-in-Aid for
Young Teachers from Northeast Forestry University.
A proposed reaction mechanism of the intramolecular
C-N bond formation of amidines to benzimidazole derivatives
was shown in Scheme 1. This transformation presumably
Supporting Information Available: Experimental procedures
and spectral data for the compounds. This material is available
free of charge via the Internet http://pubs.acs.org.
(17) 5-Substituted benzoimidazoles were confirmed as major tautomers
by NMR and GC experiment with the standard samples.
(19) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4120.
ꢀ ꢀ
(18) Lazar, L.; Fulop, F. Eur. J. Org. Chem. 2003, 3025.
€ €
J. Org. Chem. Vol. 76, No. 2, 2011 719