Synthesis of 2-azaanthracenes via a sequential Sonogashira coupling/alkynyl imine-allenyl imine isomerization/aza-Diels-Alder/elimination-aromatization reaction

Article abstract of DOI:10.1021/ol1028207

An interesting sequential Sonogashira coupling/alkynyl imine-allenyl imine isomerization/aza-Diels-Alder/elimination-aromatization reaction, providing a facile synthesis of substituted 2-azaanthracenes from 1,6-diynes and imidoyl chlorides, is reported. T

Full text of DOI:10.1021/ol1028207

ORGANIC
LETTERS
2011
Vol. 13, No. 3
478-481
Synthesis of 2-Azaanthracenes via a
Sequential Sonogashira Coupling/
Alkynyl Imine-Allenyl Imine
Isomerization/Aza-Diels-Alder/
Elimination-Aromatization Reaction
Jian Cao, Xiongfa Yang, Xilin Hua, Yuan Deng, and Guoqiao Lai*
Key Laboratory of Organosilicon Chemistry and Material Technology of
Ministry of Education, Hangzhou Normal UniVersity, Wenyi Road 222,
Hangzhou 310012, People’s Republic of China
gqlai@hznu.edu.cn
Received November 20, 2010
ABSTRACT
An interesting sequential Sonogashira coupling/alkynyl imine-allenyl imine isomerization/aza-Diels-Alder/elimination-aromatization reaction,
providing a facile synthesis of substituted 2-azaanthracenes from 1,6-diynes and imidoyl chlorides, is reported. The easy procedure accessing
the products efficiently from readily available starting materials may imply a potential synthetic application.
Anthracenes and azaanthracenes are core structures employed
in a variety of practical applications, including potential
therapeutics,1 optical devices,2 and polymeric materials.3
Recently, Deiters et al. discovered that 2-azaanthracenes have
very unique fluorescent properties in contrast to regular
anthracenes.4 Although several synthetic routes to an-
thracenes have been reported,5 the method for the synthesis
of 2-azaanthracenes is still limited.4,6
Allenes have shown impressive synthetic potentials in organic
chemistry,7 and many novel reactions were well established in
the past decades.8 Mu¨ller et al. pioneered the Sonogashira
coupling/propargyl-allenyl isomerization reactions for the syn-
thesis of a variety of useful compounds including chalcones,
pyrazolines, pyrroles, fluorescent spirocycles, and some other
pharmaceutically interesting heterocycles.9 Several groups also
(4) Zou, Y.; Young, D. D.; Cruz-Montanez, A.; Deiters, A. Org. Let.
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C. V. Photochem. Photobiol. 2006, 82, 20. (c) Piao, W. H.; Wong, R.; Bai,
X. F.; Huang, J.; Campagnolo, D. I.; Dorr, R. T.; Vollmer, T. L.; Shi, F. D.
J. Immunol. 2007, 179, 7415. (d) Zhang, W.; Watanabe, K.; Wang, C. C. C.;
Tang, Y. J. Nat. Prod. 2006, 69, 1633–1636. (e) Zhang, W.; Burkhardt,
W. I.; Zhan, J.; Watanabe, K.; Boddy, C. N.; Tang, Y. J. Am. Chem. Soc.
2007, 129, 9304. (f) Pickens, L. B.; Kim, W.; Wang, P.; Zhou, H.; Watanabe,
K.; Gomi, S.; Tang, Y. J. Am. Chem. Soc. 2009, 131, 17677.
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Nakajima, K.; Shen, B. J.; Ohe, T.; Kanno, K. J. Org. Chem. 2006, 71,
7967. (d) Li, G.; Zhou, S.; Su, G.; Liu, Y.; Wang, P. G. J. Org. Chem.
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J. Org. Chem. 2008, 73, 3928. (b) Claessens, S.; Jacobs, J.; De Kimpe, N.
Synlett 2007, 741. (c) Krapcho, A. P.; Gilmor, T. P. J. Heterocycl. Chem.
1998, 35, 669.
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Chem.sEur. J. 2008, 14, 981. (b) Gimenez, R.; Pinol, M.; Serrano, J. L.
Chem. Mater. 2004, 16, 1377. (c) Kim, C. S.; Cho, Y. J.; Kwon, H. J.;
Kim, B. O.; Kim, S. M.; Yoon, S. S. Int. Patent WO 2010062107 , 2010.
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(b) Rameshbabu, K.; Kim, Y.; Kwon, T.; Yoo, J.; Kim, E. Tetrahedron
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10.1021/ol1028207  2011 American Chemical Society
Published on Web 12/23/2010

established a series of sequential reactions wherein an allene
intermediate, generated in situ, underwent subsequent processes
under mild conditions, providing an efficient synthesis of
structurally complex polycycles.10-12 In our continuous efforts
to explore mild and efficient methodologies for the synthesis
of heterocyclic compounds promoted by transition-metal
catalysts,13 we initially expected that reaction of diyne 1a
with imidoyl chloride 2a via Sonogashira coupling reaction
could afford the alkynyl imine 4a.14 To our delight, more
valuable 2-azaanthracene 3a was obtained rather than a
simple coupling product (Scheme 1). Herein, we wish to
Table 1. Optimization of the Reaction Conditions Base on the
Synthesis of 3a from 1a and 2aa
yield of
entry
solvent
base
Et3N
Et3N
Et3N
Et3N
Et3N
temp
time (h)
3a(%)
1
2
3
4
5
6
7
8
9
10
Et3N
THF
CH2Cl2
CH3CN
toluene
THF
THF
THF
THF
THF
rt
rt
rt
rt
rt
rt
rt
rt
10
10
10
10
10
10
10
10
7
62
74
51
57
43
0
Scheme 1
Et2NH
pyridine
0
b
K2CO3
35
64
70
Et3N
i-Pr2NEt
60 °C
rt
10
a Unless otherwise specified, the reaction was carried out using 1 (0.5
mmol), 2 (0.6 mmol), Pd(PPh3)2Cl2 (0.025 mmol), CuI (0.025 mmol), and
base (1 mL) in solvent (3 mL). b 1.5 mmol of K2CO3 were added.
report this convenient synthetic approach to substituted
2-azaanthracenes by utilizing a Pd-catalyzed tandem process
via an allene intermediate.
disfavored (entries 6, 7), indicating that the reaction was
sensitive to the type of base. When the reaction was run at 60
°C, the product 3a was obtained in lower yield (entry 9). Thus,
we chose the following reaction conditions as optimum for all
subsequent cyclizations: 0.5 mmol of 1, 0.6 mmol of 2, 0.025
mmol of Pd(PPh3)2Cl2, and 0.025 mmol of CuI in Et3N/THF
(v/v 1:3) were stirred at room temperature for 10 h.
With the optimized conditions in hand, the scope of this
Pd-catalyzed domino reaction was further investigated, and
the results are summarized in Table 2.
Our preliminary studies focused on the reaction of diyne 1a
with imidoyl chloride 2a in the presence of 5 mol % of
Pd(PPh3)2Cl2 and 5 mol % of CuI in Et3N at room temperature.
The 2-azaanthracene product 3a was isolated in 62% yield after
10 h (Table 1, entry 1). Further studies showed that a 1:3
combination of Et3N and THF as solvent was appropriate. Other
common solvents such as CH2Cl2, CH3CN, and toluene were
effective as well, although lower yields were obtained (entries
2-5). The effect of the base was also investigated. An inorganic
base, e.g., K2CO3 (entry 8), could also be applied to the reaction,
while secondary amine diethylamine and pyridine were totally
Table 2. Synthesis of 2-Azaanthracenes 3a
(8) (a) Ma, S. Chem. ReV. 2005, 105, 2829. (b) Ma, S. Acc. Chem. Res.
2003, 36, 701. (c) Ma, S. Acc. Chem. Res. 2009, 42, 1679. (d) Ma, S. Eur.
J. Org. Chem. 2004, 1175. (e) Ma, S. Aldrich. Acta. 2007, 40, 91. (f)
Marshall, J. A. Chem. ReV. 1996, 96, 31. (g) Yamamoto, Y.; Radhakrishnan,
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.
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12, 9081. (b) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3,
3297. (c) D’Souza, D. M.; Kiel, A.; Herten, D. P.; Mu¨ller, T. J. J.
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substrate
yield of
2
entry
1
R1
R2
R3
3 (%)
1
1a Ph
2a Ph
Ph
Ph
74 (3a)
77 (3b)
81 (3c)
79 (3d)
70 (3e)
83 (3f)
75 (3g)
52 (3h)
59 (3i)
Mu¨ller, T. J. J. Chem. Commun. 2006, 4096
.
2
3
4
5
1b 4-MeOC6H4 2a Ph
1c n-Hex 2b Ph
1d cyclopropyl 2b Ph
1a Ph 2b Ph
1d cyclopropyl 2c 4-MeC6H4
(10) (a) Shen, R.; Huang, X. Org. Lett. 2008, 10, 3283. (b) Shen, R.;
Huang, X.; Chen, L. AdV. Synth. Catal. 2008, 350, 2865. (c) Shen, R.; Zhu,
S.; Huang, X. J. Org. Chem. 2009, 74, 4118. (d) Huang, X.; Zhu, S.; Shen,
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AdV. Synth. Catal. 2009, 351, 2833. (f) Sha, F.; Huang, X. Angew. Chem.,
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
6
Int. Ed. 2009, 48, 3458
.
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2010, 75, 2706. (b) Zhou, H.; Xie, Y.; Ren, L.; Su, R. Org. Lett. 2010, 12,
356. (c) Zhou, H.; Xing, Y.; Yao, J.; Chen, J. Org. Lett. 2010, 12, 3674.
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7
8
9
1d cyclopropyl 2d 4-MeOC6H4 Ph
1d cyclopropyl 2e 2-ClC6H4 Ph
1d cyclopropyl 2f 3-NO2C6H4 Ph
10
1c n-Hex
2g Ph
2,4-Cl2C6H3 61 (3j)
vinyl 69 (3k)
2127. (e) Xu, G.; Chen, K.; Zhou, H. Tetrahedron Lett. 2010, 51, 6240
(12) Gao, G. L.; Niu, Y. N.; Yan, Z. Y.; Wang, H. L.; Wang, G. W.;
Shaukat, A.; Liang, Y. M. J. Org. Chem. 2010, 75, 1305
.
11
1c n-Hex
2h Ph
.
a Unless otherwise specified, the reaction was carried out using 1 (0.5
mmol), 2 (0.6 mmol), Pd(PPh3)2Cl2 (0.025 mmol), CuI (0. 025 mmol), and
Et3N (1 mL) in THF (3 mL) at room temperature for 10 h.
(13) (a) Cao, J.; Huang, X. Org. Lett. 2010, 12, 5048. (b) Cao, J.; Huang,
X. J. Comb. Chem. 2008, 10, 526. (c) Cao, J.; Huang, X. J. Comb. Chem.
2010, 12, 1.
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Org. Lett., Vol. 13, No. 3, 2011
479

The reactions proceeded smoothly to afford the corre-
sponding 2-azaanthracenes 3 in moderate to good yields.
Our preliminary results on these transformations showed
that the reaction was successful when the R1 group of
diynes 1 was an alkyl or aryl group (Table 2, entries 1-4).
The R2 and R3 group of imidoyl chlorides 2 can be a
substituted phenyl group with either an electron-donating
or electron-withdrawing group (entries 5-10). It should
be noted that the presence of a substituent on the ortho
position of aryl group R2 and R3 negatively affected the
reaction (entries 8, 10). Furthermore, the reaction was also
successful when R3 was vinyl (entry 11). The structures
of all these products were confirmed with the help of
spectral and analytical data, and the structure of 3e was
further established by X-ray diffraction analysis15 (Figure
1).
Scheme 3
1a and 2a under the standard conditions was stopped at 1 h,
and alkynyl imine 4a and 2-azaanthracene 3a were isolated
in 66% and 14% yields, respectively. Further investigation
demonstrated that the conversion from 4a to 3a required only
Et3N and no reaction occurred upon heating of 4a in the
absence of base.
Thus, based on the above results, we propose the following
plausible mechanism for this reaction (Scheme 4): (i) the
Scheme 4
Figure 1. ORTEP representation of 3e.
Interestingly, when R3 was an alkyl group the reaction
stopped at the alkynyl imine 4b, thus indicating the impor-
tance of the phenyl or vinyl group on the R3 position in the
subsequent cyclization reaction (Scheme 2).
Sonogashira coupling reaction of 1,6-diyne 1 and imidoyl
chloride 2 affords the intermediate alkynyl imine 4; (ii) the
intermediate 4, in which R3 is an aryl or vinyl group,
undergoes a base-assisted 1,5-hydride shift16 to form allene
intermediate A; (iii) that reaction is followed by an aza-
Diels-Alder reaction to form tricyclic intermediate B; (iv)
subsequently, elimination of a molecule of AcOH gives the
final product 2-azaanthracene 3.
Scheme 2
In conclusion, we have developed an interesting se-
quential reaction consisting of Pd-catalyzed coupling,
alkynyl imine-allenyl imine isomerization, aza-Diels-
Alder, and elimination-aromatization, leading to an ef-
ficient method to construct 2-azaanthracene derivatives.
The wide tolerance of various substituents in the substrates
and easy procedure to access the products efficiently from
readily available starting materials may imply a potential
synthetic application.
To have more insight into the reaction, we performed the
following reactions as shown in Scheme 3. The reaction of
(15) Crystal data for 3e: C32H23N, MW ) 421.51, Orthorhombic, space
j
group P1, final R indices [I > 2σ(I)], R1 ) 0.0383, wR2 ) 0.1008; R indices
(all data), R1 ) 0.0508, wR2 ) 0.1170; a ) 17.827(4) Å, b ) 11.746(2)
Å, c ) 11.045(2) Å, R ) 90°, ꢀ ) 90°, γ ) 90°, V ) 2312.8(8) Å3, T )
296(2) K, Z ) 4 reflections collected/unique 8505/3893 (Rint ) 0.0257),
number of observations [I > 2σ(I)] 3893, parameters: 299. Supplementary
crystallographic data have been deposited at the Cambridge Crystallographic
Data Centre, CCDC 800881.
(16) (a) Vadola, P. A.; Sames, D. J. Am. Chem. Soc. 2009, 131, 16525.
(b) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 13226. (c) Barluenga, J.; Fananas-Mastral, M.; Aznar, F.; Valdes, C.
Angew. Chem., Int. Ed. 2008, 47, 6594. (d) Mori, K.; Kawasaki, T.; Sueoka,
S.; Akiyama, T. Org. Lett. 2010, 12, 1732.
480
Org. Lett., Vol. 13, No. 3, 2011

Acknowledgment. This paper is dedicated to the memory
of Prof. Xian Huang (Zhejiang University). Financial
support was received from the National Natural Sci-
ence Foundation of China (20802014) and the Special
Funds for key innovation team of Zhejiang province
(2009R50016).
Supporting Information Available: Spectroscopic data
for 3a-k, 4a, and 4b. X-ray crystal data for 3e. Detailed
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1028207
Org. Lett., Vol. 13, No. 3, 2011
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