A Sc(OTf)3-catalyzed cascade reaction of o-aminoacetophenone with methanamine: Construction of dibenzo[b,h][1,6]naphthyridine derivatives

Article abstract of DOI:10.1039/c4ob02220c

An unexpected Sc(OTf)₃-catalyzed and air-mediated cascade reaction of o-aminoacetophenones with methanamines was discovered as an efficient synthetic approach to a novel class of fluorescent fused-four-ring dibenzo[b,h][1,6]naphthyridine derivatives. Two possible mechanisms of the reaction were proposed. The photophysical properties of the dibenzo[b,h][1,6]naphthyridine 1a were initially considered. This journal is

Full text of DOI:10.1039/c4ob02220c

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
A Sc(OTf)3-catalyzed cascade reaction of
o-aminoacetophenone with methanamine:
construction of dibenzo[b,h][1,6]naphthyridine
derivatives†
Cite this: Org. Biomol. Chem., 2015,
13, 2122
Dan Mao,‡ Jun Tang,‡ Wenbo Wang, Xin Liu, Shengying Wu, Jianjun Yu and
Limin Wang*
Received 19th October 2014,
Accepted 3rd December 2014
An unexpected Sc(OTf)3-catalyzed and air-mediated cascade reaction of o-aminoacetophenones with
methanamines was discovered as an efficient synthetic approach to a novel class of fluorescent fused-
four-ring dibenzo[b,h][1,6]naphthyridine derivatives. Two possible mechanisms of the reaction were pro-
posed. The photophysical properties of the dibenzo[b,h][1,6]naphthyridine 1a were initially considered.
DOI: 10.1039/c4ob02220c
www.rsc.org/obc
Introduction
A cascade reaction,1 in which the reactive intermediate from
one step directly undergoes further transformations, is very
important in organic synthesis, because such sequential pro-
cesses can not only rapidly build up complex molecules, but
also efficiently enhance the chemo-, regio-, and diastereo-
selectivity for the overall transformation. It is one of the most
practiced methods for the preparation of complex heterocyclic
compounds from commercially available starting materials.2
The naphthyridine moiety is an important building block
in various natural products. It has exhibited a broad range
of biological activities, medical applications and also fluore-
scence activities. For example, 1,6-naphthyridine was reported
to be a promising scaffold with drug-like properties;3 1,8-
naphthyridine derivatives were found as a new class of
chemotherapeutic agents4 and also showed anti-aggressive
and potent anti-inflammatory activities;5 a naphthyridine carbox-
amide provided evidence for discordant resistance between
mechanistically identical inhibitors of HIV-1 integrase.6 Fur-
thermore, fluorescent naphthyridine derivatives can be used
as luminescence materials in molecular recognition7 and
fluorescence detection.8 However, except for a few reports,9 in
which naphthyridine derivatives were synthesized through
Scheme 1 An unexpected cascade reaction catalyzed by Sc(OTf)3.
one-pot multicomponent processes, multi-step synthesis pro-
cedures were required in most cases.3–8
Rare earth metal Lewis acids have been widely utilized in
the past few decades.10 Our group has paid special attention to
multicomponent condensation reactions (MCR) catalyzed by
rare earth metal Lewis acids as well.11 Herein, we report an
Sc(OTf)3-catalyzed unexpected cascade reaction of o-aminoace-
tophenones with methanamines (Scheme 1). In this reaction,
two CvC bonds, one C–C bond and one C–N bond were
formed with high selectivity to generate a novel series of fluore-
scent fused-four-ring naphthyridine derivatives. Besides, an
air-mediated C–H activation occurred in the reaction, which
was rarely reported before.12
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China
University of Science and Technology, 130 Meilong Road, Shanghai 200237,
P. R. China. E-mail: wanglimin@ecust.edu.cn; Fax: +86-21-64253881
†Electronic supplementary information (ESI) available: Copies of NMR spectral
data and crystallographic information in CIF format for compounds 1a. CCDC
Results and discussion
Recently, Wang and co-workers13 reported efficient methods of
796953. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4ob02220c
‡These authors contributed equally to this work.
synthesizing 2-phenylquinazolines (Scheme 2). However, the
2122 | Org. Biomol. Chem., 2015, 13, 2122–2128
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 2 The previous reported reactions of 2-aminobenzoketones
with benzylic amines.
Fig. 1 The molecular structure of compound 1a.
Table 1 The optimization of the cascade reactiona
bearing
(Fig. 1).
a novel fused-four-ring structure was generated
Further investigations into the reaction were performed.
Besides the product 1a, another compound 4a was isolated as
the main byproduct in most cases. Their yields are presented
in Table 1. The reaction could be promoted by a variety of
Lewis acids with different efficiencies (Table 1, entries 2–8).
However, none of them was better than Sc(OTf)3 which
achieved the best result giving the desired product 1a in 72%
yield. Then the optimal loading of Sc(OTf)3 was revealed to be
5 mol% (Table 1, entries 8–10). The best reaction temperature
was 90 °C (Table 1, entries 9, 11–12). When toluene was
employed as the solvent, the reaction could undergo slightly
more smoothly giving 1a in 75% yield (Table 1, entry 13). The
use of other solvents, such as dioxane, 1,2-dichloroethane
(DCE) or more starting materials 3a, 2a did not improve the
yield (Table 1, entries 14–18). It is worth mentioning that
when the reaction was conducted in ethanol, neither 1a nor
the byproduct 4a was obtained in high yield, which may be
caused by the ligand effect that ethanol competed with ben-
zylamine to coordinate to Sc(OTf)3. Considering the economi-
cal viability and environmental benefit, in most cases, the
reaction was still performed under solvent-free conditions for
further investigation.
The substrate scope of the cascade reaction of o-amino-
acetophenones with methanamines was then explored under
the optimal conditions. The isolated yields of the corres-
ponding products 1a–p are exhibited in Table 2. The reactions
of all substituted benzylamines with o-aminoacetophenone
gave the corresponding products in good yields (Table 2,
entries 1–8). Heteroaromatic methanamines were suitable sub-
strates for this reaction as well (Table 2, entries 9 and 10).
Notably, aliphatic amines could also react with o-aminoaceto-
phenone affording the corresponding products, though the
yields were relatively low (Table 2, entries 11–13). Furthermore,
substituted o-aminoacetophenones were explored. 1-(2-Amino-
5-bromophenyl)ethanone could also react with methanamines
giving the corresponding products in moderate yields (Table 2,
entries 14–16). Unfortunately, o-aminoacetophenones bearing
electron-donating substituents reacting with benzylamine gave
messy mixtures (Table 2, entries 17 and 18).
Yield of
Yield of
Entry
Cat.
x
Solvent
1a b (%)
4a c (%)
1
2
3
4
5
6
7
8
None
AlCl3
FeCl3
AgOTf
—
10
10
10
10
10
10
10
5
2
5
5
5
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Toluene
Dioxane
DCE
Ethanol
2a
0
12
4
0
Trace
Trace
30
24
Trace
23
28
20
17
15
22
16
20
30
18
Trace
25
7
Bi(OTf)3
Pd(OAc)2
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
18
Trace
24
72
70
56
43
33
75
52
28
14
Trace
68
9
10
11d
12e
13
14
15
16f
17g
18h
5
5
5
5
5
3a
a The reactions of o-aminoacetophenone 3a (1.25 mmol) with
benzylamine 2a (0.5 mmol) with 2 mL solvent or no solvent were
carried out for 12 h at 90 °C. b Isolated yields based on 2a. c Isolated
yields based on 3a. d The reaction was performed at 65 °C. e The
reaction was performed at 110 °C. f The reaction was performed at
reflux. g Excess amount of benzylamine 2a was used as the solvent.
h Excess amount of o-aminoacetophenone 3a was used as the solvent.
desired product 4-methyl-2-phenylquinazoline could not be
obtained when R (Scheme 2) was the methyl group. A very
recent report on similar work by Han and coworkers14 also did
not cover such a case. This inspired our research on why the
methyl group was an exception.
Initially, o-aminoacetophenone (3a) and benzylamine (2a)
were chosen as model substrates. In the absence of a catalyst,
no product was detected (Table 1, entry 1). Then the reaction
was performed in the presence of 10 mol% Sc(OTf)3, an
unknown compound with strong fluorescence was isolated as
the main product. A crystal15 with green fluorescence was
obtained from the evaporation of the solution of the product
in CH2Cl2–CH3OH (1/2) through solvent diffusion. X-ray crystal
structure analysis revealed that a naphthyridine derivative 1a
The mechanism of the cascade reaction was further dis-
cussed. Initially, the main byproduct 2-(4-methylquinolin-2-yl)-
aniline 4a was suspected to be a key intermediate of the reac-
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 2122–2128 | 2123

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 2 The scope of the cascade reactiona
Then intermediate b was oxidized to d by oxygen in air via
the radical reaction. To support this hypothesis, a typical
radical scavenger tetramethylpiperidine N-oxide (TEMPO) was
added to the reaction of o-aminoacetophenone with benzyl-
amine under the optimal conditions, and no trace of the
desired product 1a could be obtained (Scheme 5a). Then, the
template reaction was carried out under an oxygen and argon
atmosphere, respectively. Trace product 1a was found under
argon atmosphere (Scheme 5b), which clearly revealed that the
oxygen plays an important role in the reaction. In the case of
pure oxygen, 4-methyl-2-phenylquinazoline 5a was isolated as
the main product (Scheme 5c), which should have been
afforded via the transformation reported by the previous litera-
ture (Scheme 2), and only 22% yield of the desired product 1a
was obtained, revealing that there was a competition between
aldol condensation (a to b) and oxidation (a to i). This method
can be an alternative synthetic method of compound 5.19
However, when the reaction was carried out in air, oxidation
(b to d) took place only after the aldol condensation (a to b)
completed.
Product Yield of
1a–p
Entry R1
R2
1a–p b (%)
1
2
3
4
H
H
H
H
Ph
1a
1b
1c
1d
1e
1f
1g
1h
1i
70
78
80
72
76
76
80
82
61
81
35
42
55
45
50
68
—
—
4-CH3C6H4
4-tBuC6H4
4-ClC6H4
4-FC6H4
5
H
6
7
H
H
3-FC6H4
2-FC6H4
8
9
H
H
3,4-F,F-C6H3
Pyridin-2-yl
10
11c
12
13d
14d
15d
16d
17e
18e
H
H
H
H
5-Br
5-Br
5-Br
5-Methyl-thiophen-2-yl 1j
CH3
C3H7
C15H31
Ph
4-ClC6H4
3,4-F,F-C6H3
1k
1l
1m
1n
1o
1p
—
—
Once intermediate d was formed, paths A and B were in
competition. The reaction went to path A to afford the main
byproduct 4. When the reaction went to path B, a supposed
spiro intermediate f was generated, and the spiro was then
broken down to generate intermediate g, which emitted NH3
and gave the final product 1.
4,5-OMe,OMe Ph
4,5-(OCH2O) Ph
a Reaction conditions: o-aminoacetophenones
3
(1.25 mmol),
methanamines 2 (0.5 mmol). b Isolated yields based on 2. c Aqueous
solution of ethylamine was used. d Toluene was used as the solvent.
e The starting materials were converted to a complex mixture.
However, there might be another mechanism (Scheme 6).17
In the presence of Sc(OTf)3, o-aminoacetophenone 3 reacted
with aldehyde, which was formed from the corresponding
methanamine via oxidation, to afford 2,3-dihydroquinolin-4
(1H)-ones 7.20 7 further reacted with 3 to give the product 1.
To verify this mechanism, two control experiments were
conducted (Scheme 7). First, the benzaldehyde was detected by
HPLC in a mixture of benzylamine and Sc(OTf)3 after heating
in air for 2 h. Then several aldehydes were chosen to react with
o-aminoacetophenone 3a. In the cases of benzaldehyde and
4-chlorobenzaldehyde, 1a and 1d were detected as trace pro-
ducts in complex mixtures, respectively. However, in the cases
of 4-methylbenzaldehyde and butyraldehyde, the corres-
ponding product 1b or 1l was not detected.
Though the second proposed mechanism (Scheme 6) was
more concise, several problems existed. First, the reaction of
methanamines with o-aminoacetophenones giving imines
should undergo more smoothly than the transformation of
methanamines to aldehydes. Second, only several aldehydes
could react with o-aminoacetophenone giving the products in
very low yields went against with the substrate scope study that
almost all the methanamines were suitable substrates for the
cascade reaction. On the other hand, the result that a trace of
product 1a was detected under an argon atmosphere was
inconsistent with the first proposed mechanism (Scheme 4) as
well. Thus, we speculated that both the pathways were possible
processes to form the products.
Scheme 3 Compound 4a reacted with benzylamine or benzaldehyde.
tion. Thus the reaction of compound 4a with benzylamine was
conducted in the presence of Sc(OTf)3 at 90 °C. However, the
desired product 1a was not observed. In addition, the isolated
4a could not react with benzaldehyde via cross-dehydrogena-
tive coupling (CDC)16 under the same conditions (Scheme 3).
On the basis of our results and previous related reports, a
proposed mechanism is depicted in Scheme 4.17 Firstly, imine
or enamine a was formed through the condensation of 2 and
3. Then, a reacted with o-aminoacetophenone 3 through the
intermolecular aldol reaction, which led to intermediate b by
dehydration. This reaction underwent smoothly in the pres-
ence of Sc(OTf)3,18 which could be a very efficient catalyst for
aldol condensation. It is worth noting that trace product 1a
was detected when benzylamine was used as the solvent, and
the product was afforded in 68% yield when o-aminoacetophe-
none was used as the solvent (Table 1, entries 17 and 18). It
could be explained that an excess amount of benzylamine led
to much less o-aminoacetophenone to react with imine a.
Due to the intermolecular hydrogen bond (N1–H–N2, can be
seen from supplementary crystallographic data†), the com-
pound 1a was stable and was not further oxidized in the
2124 | Org. Biomol. Chem., 2015, 13, 2122–2128
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 4 The proposed mechanism of the cascade reaction (some easy steps and the role of Sc(OTf)3 were omitted for clarity).
ultraviolet spectra and fluorescence spectra in solvents with
different polarities. The absorption spectra of 1a was less
dependent on the solvent polarity (Fig. 2), while the emission
spectra shifted dramatically to longer wavelengths with the
solvent polarity increased from hexane (fluorescence
maximum λem = 428 nm) to methanol (λem = 525 nm) (Fig. 3b),
and 1a exhibited amazing fluorescence color variations in
various solvents under illumination with 365 nm light: dark
blue to yellow (Fig. 3a). The high sensitivity of the emission
spectra of 1a to solvent may be due to a charge shift away from
the amino group in the excited state, towards the electron
acceptor: the quinoline group. This led to a large dipole
moment in the excited state, which interacted with the
polar solvent molecules to reduce the energy of the excited
state, resulting in emission at lower energies and longer
wavelengths.
Scheme 5 Several control experiments.
Conclusions
In conclusion, we have reported an unexpected and efficient
synthesis of a novel class of fluorescent heterocyclic com-
pounds with naphthyridine moieties, using the Sc(OTf)3-
catalyzed cascade reaction of o-aminoacetophenones with
methanamines. Efforts were made to research the mechanism
of the cascade reaction and two possible mechanisms were
proposed. The fluorescence properties of the novel fused-four-
ring heterocyclic compound 1a were initially disclosed. The
cascade reaction. But in the presence of an excess amount of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the isolated
compound 1a could be converted to the highly conjugated
compound 6a in quantitative yield (Scheme 8).
It was observed that the products, dibenzo[b,h][1,6]-
naphthyridine derivatives 1, showed strong fluorescence, thus
we further investigated the photophysical properties of 1a by
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 2122–2128 | 2125

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 6 Another possible mechanism of the cascade reaction (some easy steps were omitted for clarity).
Scheme 7 Control experiments for the cascade reaction.
Fig. 3 Fluorescence photographs (a) and fluorescence emission
spectra (excitation wavelength, λex = 383 nm) (b) of 1a in different sol-
vents. H, hexane; T, toluene; E, ethyl acetate; D, dimethylformamide; M,
methanol.
fluorescence emission spectra of 1a exhibited a prominent
solvatofluorochromism with the increase of solvent polarity,
which may result in potential application in molecular recog-
nition and fluorescence detection.
Scheme 8 Compound 1a oxidized by DDQ.
Experimental section
General information
1H NMR and 13C NMR spectra were recorded at 400 MHz and
100 MHz, respectively using tetramethylsilane as an internal
reference. Chemical shifts (δ) and coupling constants (J) were
expressed in parts per million and hertz, respectively. Melting
points were uncorrected. Samples for IR were prepared as a
thin film on a KBr plate. High resolution mass spectra (HRMS)
were recorded on a Micromass GCT with the electron ioniza-
tion (EI) resource. All reagents were obtained from commercial
sources and used without further purification.
Fig. 2 Normalized absorption spectra of 1a in hexane and methanol.
2126 | Org. Biomol. Chem., 2015, 13, 2122–2128
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
General procedure for synthesis of 1a–p
W. Xu, P. G. Pearson, W. A. Schleif, R. Cortese, E. Emini,
V. Summa, M. K. Holloway and S. D. Young, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 11233–11238.
6 G. Roma, M. D. Braccio, G. Grossi, F. Mattioli and M. Ghia,
Eur. J. Med. Chem., 2000, 35, 1021–1035.
7 (a) T. Peng, T. Murase, Y. Goto, A. Kobori and K. Nakatani,
Bioorg. Med. Chem. Lett., 2005, 15, 259–262; (b) W. B. Lu,
L. H. Zhang, X. S. Ye, J. C. Su and Z. X. Yu, Tetrahedron,
2006, 62, 1806–1816.
To a mixture of o-aminoacetophenones (1.25 mmol) and
methanamines (0.5 mmol) was added Sc(OTf)3 (5 mol%). After
stirring at 90 °C under an air atmosphere for 12 h, the mixture
was extracted with CH2Cl2 and H2O. The organic layer was
dried with Na2SO4, and then concentrated in vacuo. The pro-
ducts 1a–p were obtained by column chromatography on silica
gel with 5–10% ethyl acetate in petroleum ether as the eluent.
8 (a) Y. Zhou, Y. Xiao and X. H. Qian, Tetrahedron Lett., 2008,
49, 3380–3384; (b) M.-M. Yu, Z.-X. Li, L.-H. Wei, D.-H. Wei
and M.-S. Tang, Org. Lett., 2008, 10, 5115–5118;
(c) H. Satake, S. Nishizawa and N. Teramae, Anal. Sci., 2006,
22, 195–197; (d) K. Ghosh, T. Sen and R. Fröhlich, Tetrahe-
dron Lett., 2007, 48, 2935–2938; (e) T. Chen, A. J. Tong and
Y. M. Zhou, Spectrochim. Acta, Part A, 2007, 66, 586–589.
9 (a) K. Godula and D. Sames, Science, 2006, 312, 67–72;
(b) F. Collet, R. H. Dodd and P. Dauban, Chem. Commun.,
2009, 5061–5074; (c) P. R. Schreiner and A. Fokin, Chem.
Rec., 2004, 3, 247–257.
10 For selected examples, see: (a) S. Kobayashi and
K. Manabe, Acc. Chem. Res., 2002, 35, 209–217;
(b) M. Curini, F. Epifano, S. Genovese, M. C. Marcotullio
and O. Rosati, Org. Lett., 2005, 7, 1331–1333;
(c) M. M. A. R. Moustafa and B. L. Pagenkopf, Org. Lett.,
2010, 12, 4736–4738; (d) D. S. Huang, X. Q. Liu, L. J. Li,
Y. D. Cai, W. G. Liu and Y. Shi, J. Am. Chem. Soc., 2013, 135,
8101–8104.
Acknowledgements
This research was financially supported by the National Nature
Science Foundation of China (21272069, 20672035) and the
Fundamental Research Funds for the Central Universities and
Key Laboratory of Organofluorine Chemistry, Shanghai Insti-
tute of Organic Chemistry, Chinese Academy of Sciences.
Notes and references
1 (a) D. Enders, C. Grondal and M. R. M. Hüttl, Angew.
Chem., Int. Ed., 2007, 46, 1570–1581; (b) D. Enders,
M. R. M. Hüttl, C. Grondal and G. Raabe, Nature, 2006,
441, 861–863; (c) Y. Lu, X. Du, X. Jia and Y. Liu, Adv. Synth.
Catal., 2009, 351, 1517–1522; (d) Y. Lee, S. W. Seo and
S.-G. Kim, Adv. Synth. Catal., 2011, 353, 2671–2675.
2 (a) R. Martín, M. R. Rivero and S. L. Buchwald, Angew.
Chem., Int. Ed., 2006, 45, 7079–7082; (b) S. A. Raw and 11 For selected examples, see: (a) J. Tang, L. M. Wang, D. Mao,
R. J. K. Taylor, J. Am. Chem. Soc., 2004, 126, 12260–12261;
(c) J. B. Xiang, L. Y. Zheng, F. Chen, Q. Dang and X. Bai,
Org. Lett., 2007, 9, 765–767.
W. B. Wang, L. Zhang, S. Y. Wu and Y. S. Xie, Tetrahedron,
2011, 67, 8465–8469; (b) L. M. Wang, J. J. Liu, H. Tian,
C. T. Qian and J. Sun, Adv. Synth. Catal., 2005, 347, 689–
694; (c) J. Tang, L. M. Wang, S. Y. Wu and D. Mao, Synlett,
2011, 2913–2928; (d) J. Q. Liu, Q. Shen, J. J. Yu, M. Y. Zhu,
J. W. Han and L. M. Wang, Eur. J. Org. Chem., 2012, 6933–
6939; (e) L. M. Wang, J. Sheng, H. Tian, J. W. Han, Z. Y. Fan
and C. T. Qian, Synthesis, 2004, 3060–3064; (f) L. M. Wang,
J. J. Xia, H. Tian, F. Qin, C. T. Qian and J. Sun, Synthesis,
2003, 1241–1247; (g) D. Mao, J. Tang, W. B. Wang, S. Y. Wu,
X. Liu, J. J. Yu and L. M. Wang, J. Org. Chem., 2013, 78,
12848–12854.
3 (a) L. F. Zeng, Y. Wang, R. Kazemi, S. L. Xu, Z. L. Xu,
T. W. Sanchez, L. M. Yang, B. Debnath, S. Odde, H. Xie,
Y. T. Zheng, J. Ding, N. Neamati and Y. Q. Long, J. Med.
Chem., 2012, 55, 9492–9509; (b) A. M. Thompson,
C. J. C. Connolly, J. M. Hamby, S. Boushelle, B. G. Hartl,
A. M. Amar, A. J. Kraker, D. L. Driscoll, R. W. Steinkampf,
S. J. Patmore, P. W. Vincent, B. J. Roberts, W. L. Elliott,
W. Klohs, W. R. Leopold, H. D. H. Showalter and
W. A. Denny, J. Med. Chem., 2000, 43, 4200–4211;
(c) F. Pierre, P. C. Chua, S. E. O’Brien, A. Siddiqui-Jain, 12 (a) O. G. Schramm, N. Dediu, T. Oeser and T. J. J. Müller,
P. Bourbon, M. Haddach, J. Michaux, J. Nagasawa,
M. K. Schwaebe, E. Stefan, A. Vialettes, J. P. Whitten,
T. K. Chen, L. Darjania, R. Stansfield, K. Anderes,
J. Org. Chem., 2006, 71, 3494–3500; (b) H. Wu, W. Lin,
Y. Wan, H.-Q. Xin, D.-Q. Shi, Y.-H. Shi, R. Yuan, R.-C. Bo
and W. Yin, J. Comb. Chem., 2010, 12, 31–34.
J. Bliesath, D. Drygin, C. Ho, M. Omori, C. Proffitt, 13 (a) J. T. Zhang, D. P. Zhu, C. M. Yu, C. F. Wan and
N. Streiner, K. Trent, W. G. Rice and D. M. Ryckman,
J. Med. Chem., 2011, 54, 635–654.
4 G. Y. Lesher, E. J. Froelich, M. D. Gruett, J. H. Bailey and
R. P. Brundage, J. Med. Chem., 1962, 5, 1063–1065.
5 D. J. Hazuda, N. J. Anthony, R. P. Gomez, S. M. Jolly,
Z. Y. Wang, Org. Lett., 2010, 12, 2841–2843; (b) J. T. Zhang,
C. M. Yu, S. J. Wang, C. F. Wan and Z. Y. Wang, Chem.
Commun., 2010, 46, 5244–5246.
14 B. Han, C. Wang, R. F. Han, W. Yu, X. Y. Duan, R. Fang and
X. L. Yang, Chem. Commun., 2011, 47, 7818–7820.
J. S. Wai, L. H. Zhuang, T. E. Fisher, M. Embrey, Jr., 15 CCDC 796953 contains the supplementary crystallographic
J. P. Guare, M. S. Egbertson, J. P. Vacca, J. R. Huff, data.
P. J. Felock, M. V. Witmer, K. A. Stillmock, R. Danovich, 16 C. J. Li, Acc. Chem. Res., 2009, 42, 335–344.
J. Grobler, M. D. Miller, A. S. Espeseth, L. X. Jin, 17 When R1 = H, R2 = phenyl, the masses of the intermediates
I.-W. Chen, J. H. Lin, K. Kassahun, J. D. Ellis, B. K. Wong,
and products could be detected by atmospheric solids
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 2122–2128 | 2127

View Article Online
Paper
Organic & Biomolecular Chemistry
analysis probe (ASAP). See ESI† for details. About ASAP, see: 19 Y. Ohta, Y. Tokimizu, S. Oishi, N. Fujii and H. Ohno, Org.
(a) C. N. McEwen, R. G. McKay and B. S. Larsen, Anal. Chem., Lett., 2010, 12, 3963–3965.
2005, 77, 7826–7831; (b) C. McEwen and S. Gutteridge, J. Am. 20 (a) S. Chandrasekhar, K. Vijeender and C. Sridhar, Tetra-
Soc. Mass Spectrom., 2007, 18, 1274–1278.
18 S. Kobayashi, M. Sugiura, H. Kitagawa and W. W.-L. Lam,
Chem. Rev., 2002, 102, 2227–2302.
hedron Lett., 2007, 48, 4935–4937; (b) M. Muthukrishnan,
M. Mujahid, V. Punitharasu and D. A. Dnyneshwar, Synth.
Commun., 2010, 40, 1391–1398.
2128 | Org. Biomol. Chem., 2015, 13, 2122–2128
This journal is © The Royal Society of Chemistry 2015