Bronsted acid-mediated reactions of aldehydes with 2-vinylaniline and biphenyl-2-amine

Article abstract of DOI:10.1016/j.tetlet.2014.02.090

Herein we report simple Bronsted acid-mediated reactions of aldehydes with 2-vinylaniline and biphenyl-2-amine. Ultimately, the useful nitrogen-containing heterocycle derivatives are obtained. The electronic properties of the substituents on the aldehydes and 2-vinylaniline were investigated. It was found that molecules with both electron-donating and -withdrawing substituents were perfectly suitable substrates for this transformation, and the expected products were obtained in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.02.090

Tetrahedron Letters 55 (2014) 2280–2282
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bronsted acid-mediated reactions of aldehydes with 2-vinylaniline
and biphenyl-2-amine
⇑
Xu Zhang , Xuefeng Xu, Lintao Yu, Qiang Zhao
School of Chemistry and Pharmacy Engineering, Nanyang Normal University, Nanyang 473061, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report simple Bronsted acid-mediated reactions of aldehydes with 2-vinylaniline and biphe-
nyl-2-amine. Ultimately, the useful nitrogen-containing heterocycle derivatives are obtained. The
electronic properties of the substituents on the aldehydes and 2-vinylaniline were investigated. It was
found that molecules with both electron-donating and -withdrawing substituents were perfectly suitable
substrates for this transformation, and the expected products were obtained in moderate to excellent
yields.
Received 13 December 2013
Revised 14 February 2014
Accepted 24 February 2014
Available online 3 March 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
HOTf-catalyzed
Heterocycle derivatives
Aldehydes
Electronic properties
Rearrangement
Introduction
offers promises to perform enantioselective additions and to toler-
ate labile functional groups. However, it also limits large-scale
Recognizing the industrial value of nitrogen-containing hetero-
cyclic compounds,1 chemists continue to devise novel methods for
their synthesis.2 The preparative chemistry of nitrogen-containing
heterocyclic compounds is illustrative, where traditional routes for
azine ring fusion typically involve intramolecular cyclizations of
highly functionalized substrates at elevated temperatures under
strongly acidic reaction conditions.3 More recently, metal-cata-
lyzed approaches have begun to address some of these issues, as
exemplified by the Larock isoquinoline synthesis that couples
o-iodoaldimines and alkynes in the presence of a palladium
catalyst.4 Our interest in hydroarylation of 2-vinylaniline and
biphenyl-2-amine derivatives are a powerful method for the for-
mation of synthetically versatile quinoline and phenanthridine
derivatives. However, such hydroarylations are commonly carried
out in highly acidic media and the substrate scope can be limited.
Nucleophilic addition of protected amines to unsaturated carbon–
carbon bonds provides one of the simplest methods to construct
valuable synthetic building blocks. Continuous efforts have been
made in this field with various methods developed, particularly,
in the past decade. Most of these methods use expensive and often
toxic metal catalysts, including palladium,5,6 rhodium,7 ruthe-
nium,8 tin(IV) chloride,9 main group metals,10 and most recently,
platinum and gold.11 The employment of metal-based catalysts
applications of these reactions and often generates heavy metal
impurities in the product. Direct use of simple Bronsted acids un-
der relatively mild conditions may overcome these shortcomings.
Up to date, the acids catalyzing such reaction also have some
shortcomings. For example, the CF3COOH-catalyzed hydroaryla-
tion of cinnamic acids is limited to electron-rich substrates.12 Thus,
we are interested in developing methods for the hydroarylation of
electron-deficient reaction. Various Bronsted acids have been
found to catalyze hydroamination, hydrophosphonylation, aziri-
dination, and transfer-hydrogenation of imines.13 Even though
Bronsted acid mediated olefin hydration was known over 50 years
ago, other acid-catalyzed additions to simple olefins have been
studied to a less extent.14 Direct addition of nitrogen, oxygen,
and sulfur nucleophiles to a, b-unsaturated ketones catalyzed by
Bronsted acid was reported recently.15 Hartwig and co-workers re-
ported an intramolecular hydroamination of olefins catalyzed by
Bronsted acids in 2002.16 Bergman also described an acid-cata-
lyzed hydroamination of activated alkenes with anilines.17 Herein,
we report a simple, efficient nucleophilic intermolecular addition
of imine to unactivated olefins catalyzed by trifluoromethanesulfo-
nic acid (HOTf, triflic acid).18 Our modified reaction conditions can
tolerate some substrates that were previously regarded as
incompatible with strong Bronsted acids. Although many interest-
ing developments in this field have been reported, the substrate
availability, cost, stoichiometric amount of additives, and
functional group tolerance are limitations of the current methods
⇑
Corresponding author. Tel.: +86 377 6772 7395.
E-mail address: zhangxuedu@126.com (X. Zhang).
http://dx.doi.org/10.1016/j.tetlet.2014.02.090
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

X. Zhang et al. / Tetrahedron Letters 55 (2014) 2280–2282
2281
With this set of conditions in hand, the scope of quinoline for-
mation was demonstrated with a variety of substituted 2-vinylan-
ilines, as shown in Table 2, the reaction provides the desired
quinolines regardless of the electron-donating or -withdrawing
character of the 2-vinylaniline substituents. Additionally, aromatic
aldehydes with either an electron-donating or -withdrawing char-
acter were able to give good yields between 48 and 90% (Table 2).
The broad scope of quinoline formation was demonstrated by
using aldehydes with a variety of substituents, such as para-
substituents (–Me, –OMe, –F, and –NO2), which all could afford
good yields, as shown in Table 2. But the electronic properties of
the substituents on the 2-vinylaniline exert certain influence on
the yields. Lower yields were generally observed for substrates
with electron-withdrawing substituents as compared with those
with electron-donating substituents. Then, we elucidated the
scope of aldehydes that are applicable for this reaction. In general,
aldehydes bearing methoxy, methyl, and nitro groups at the para
position afforded the desired quinoline products, regardless of
the electron-donating or -withdrawing character of the aldehyde
substituents, the electronic properties of the substituents on the
aldehydes are relatively small.
Scheme 1. Bronsted acid-mediated reactions of aldehydes with 2-vinylaniline and
biphenyl-2-amine.
Table 1
Optimization of reaction conditionsa
Entry
Catalyst
Solvent
Temp (°C)
Yieldb (%)
Next, when the 2-vinylaniline was replaced by biphenyl-2-
amine at the same reaction conditions, the desired products were
obtained in satisfactory yields. However, the reaction time needs
extending the reaction time to 24 h and raising the temperature
to 80 °C. Again by extending the reaction time or raising the
temperature of the reaction, no significant effect on the reaction
was observed. To show the synthetic utility of this method, a
variety of aldehydes were subjected to the optimized conditions.
In this reaction, the substituents on the aldehydes were further
investigated, and it was found that aldehydes with both electron-
withdrawing and electron-donating substituents were compatible,
1
2
3
4
5
6
7
8
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
CF3COOH
HCl
Toluene
Toluene
THF
MeOH
CCl4
H2O
DMF
DMSO
Toluene
Toluene
Toluene
RT
40
40
40
40
40
40
40
40
40
40
23
82
46c
52
NR
NR
67
72
9
10
11
63
NRc
NR
H2SO4
a
All reactions were carried out by employing amine (1.0 mmol), aldehyde
(1.0 mmol), and HOTf (5.0 mmol %).
b
Yields after column chromatographic purification with silica gel.
NR represents ‘the reaction does not occur’.
c
Table 2
Examples of quinoline derivative synthesisa
for nitrogen-containing heterocycle derivatives’ synthesis.
A
simple and novel method for synthesizing nitrogen-containing
heterocycle derivatives is highly desirable and has practical
applications.
Herein we wish to report Bronsted acid-mediated reactions of
aldehydes with 2-vinylaniline and biphenyl-2-amine (Scheme 1).
The starting materials are readily available from commercial ven-
dors, and synthetically useful nitrogen-containing heterocycle
derivatives were prepared in excellent yields. This strategy is effi-
cient in building complex structures from simple starting materials
in an environmentally benign fashion.
We initially performed the reaction of the 2-vinylaniline
(1.0 mmol) and benzaldehyde (1.0 mmol) in the presence of HOTf
(5.0 mmol %) in toluene under atmospheric conditions. We were
pleased to find that the reaction in toluene at room temperature
for 10 h afforded the desired product with a yield of 23% (Table 1,
entry 1). Importantly, when the temperature was raised to 40 °C,
the yield was increased to 82% for 10 h (Table 1, entry 2). Solvent
optimization revealed that other solvents (CCl4 and H2O) are
non-operative and no products could be isolated (Table 1, entries
5 and 6). Other solvents (THF, MeOH, DMF, and DMSO) are not very
good (Table 1, entries 3, 4, 7, and 8). When the catalyst was re-
placed by CF3COOH, the yield of product was dropped to 63% for
10 h, suggesting that CF3COOH also has catalytic activity, but the
yield is lower than the HOTf catalyst, the reason may be related
to its acidity of the catalyst. No reactions occurred (Table 1, entries
8 and 9) when the catalyst was changed to other acids such as HCl
and H2SO4, emphasizing the important role played by the counter-
ion. Following these general conditions, we then examined the
scope of this reaction, and the results are summarized in Table 2.
a
All reactions were carried out by employing amine (1.0 mmol), aldehyde
(1.0 mmol), and HOTf (5.0 mmol %), yields after column chromatographic
purification with silica gel.

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X. Zhang et al. / Tetrahedron Letters 55 (2014) 2280–2282
Table 3
Acknowledgements
Examples of phenanthridine derivative synthesisa
X.Z. acknowledges support from the Science Foundation of
Nanyang Normal University (ZX2013030).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
090.
References and notes
1. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4,
2337.
2. Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644.
3. (a) Xu, X.; Guo, S.; Dang, Q.; Chen, J.; Bai, X. J. Comb. Chem. 2007, 9, 773; (b)
Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.;
Yamazaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org. Chem. 2000, 65, 9143.
4. (a) Hwang, S.; Lee, Y.; Lee, P. H.; Shin, S. Tetrahedron Lett. 2009, 50, 2305; (b)
Gao, H.; Zhang, J. Adv. Synth. Catal. 2009, 351, 85; (c) Fischer, D.; Tomeba, H.;
Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 4764;
(d) Konno, T.; Chae, J.; Miyabe, T.; Ishihara, T. J. Org. Chem. 2005, 70, 10172; (e)
Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179.
5. (a) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042; (b) Roesch,
K. R.; Larock, R. C. Org. Lett. 1999, 1, 553. J. Org. Chem. 1998, 63, 5306.
6. (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546; (b)
Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14286; (c)
Utsunomiya, M.; Kawatsura, M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2003, 42,
5865; (d) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123,
2907; (e) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2003, 42, 2892.
a
All reactions were carried out by employing amine (1.0 mmol), aldehyde
(1.0 mmol), and HOTf (5.0 mmol %); Yields after column chromatographic purifi-
cation with silica gel.
7. (a) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 6042; (b) Ahmed, M.;
Seayad, A. M.; Jackstell, R.; Beller, M. Angew. Chem., Int. Ed. 2003, 42, 5615; (c)
Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 5608.
8. (a) Oe, Y.; Ohta, T.; Ito, Y. Chem. Commun. 2004, 1620; (b) Takaya, J.; Hartwig, J.
F. J. Am. Chem. Soc. 2005, 127, 5756; (c) Utsunomiya, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2004, 126, 2702.
Scheme 2. Postulated mechanism.
9. (a) Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004, 43, 5542; (b)
Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959; (c)
Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584; (d) Hong, S.;
Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768.
10. Crimmin, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem. Soc. 2005, 127, 2042.
11. (a) Bender, C. F.; Widenhoefer, R. J. Am. Chem. Soc. 2005, 127, 1070; (b) Qian, H.;
Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536; (c) Karshtedt, D.;
Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2005, 127, 12640; (d) Yang, C.-G.; He, C.
J. Am. Chem. Soc. 2005, 127, 6966; (e) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem.
Soc. 2006, 128, 1798; (f) Brouwer, C.; He, C. Angew. Chem., Int. Ed. 2006, 45,
1744; (g) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747.
12. (a) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356; (b) Rowland, G.
B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am.
Chem. Soc. 2005, 127, 15696; (c) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org.
Lett. 2005, 7, 2583; (d) Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126,
1612; (e) Magnus, R.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett.
2005, 7, 3781.
furnishing the respective phenanthridine derivatives (Table 3). But
the electronic property of the substituents on the amine influence
on the yields is very obvious (Table 3, 3t, 3w, and 3x). Additionally,
when the ortho-substituted aldehydes are used, the yield de-
creased significantly (Table 3, 3w and 3x).
In light of these experiments we propose a tentative mechanism
for HOTf-catalyzed nitrogen-containing heterocycle derivatives’
synthesis using 2-vinylaniline/biphenyl-2-amine aldehydes,
(Scheme 2). Firstly, the amine and the aldehyde were easily
condensed to yield the imine product, followed by the attack of
the double bond to the protonated imine, and rearrangement
occurred, which was followed by deprotonation and oxidation to
yield the final product.
13. Modena, G.; Rivetti, F.; Scorrano, G.; Tonellato, U. J. Am. Chem. Soc. 1977, 99,
3392.
14. Wang, B.; Gu, Y.; Yang, L.; Suo, J.; Kenichi, O. Catal. Lett. 2004, 96, 71.
15. Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5, 2141.
In conclusion, we have developed
a
HOTf-catalyzed
nitrogen-containing heterocycle derivatives’ synthesis using
2-vinylaniline/biphenyl-2-amine and aldehydes, readily available
from commercial vendors, to give synthetically useful structures
efficiently. The use of a single catalytic system to mediate chemical
transformations in a synthetic operation is important for the devel-
opment of new atom-economic strategies. We found that this
strategy is efficient in building complex structures from simple
starting materials in an environmentally benign fashion.
16. Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471.
17. Anderson, L. L.; Arnold, J.; Bergman, G. J. Am. Chem. Soc. 2005, 127, 14542.
18. Zhang, X.; Xu, X.; Yu, L.; Zhao, Q. Asian J. Org. Chem. 2014. http://dx.doi.org/
10.1002/201300212.