Facile installation of a hydroxyalkyl group into hydroxyanthraquinones and aminoanthraquinones through the modified Marschalk reaction

Article abstract of DOI:10.1002/ejoc.201300891

1,4-Dihydroxyanthraquinones are widely featured in numerous natural products and drugs. It is important to be able to functionalize the 1,4-dihydroxyanthraquinone skeleton through a simple yet efficient transformation, which could be potentially useful for the drug discovery process. We describe herein a simple and efficient method to derivatize 1,4-dihydroxyanthraquinone by using a modified Marschalk reaction. This method provides a clear advantage over traditional approaches, which often require the protection and deprotection of the OH groups. We also demonstrate the applicability of this reaction to other hydroxyanthraquinones and aminoanthraquinones. We describe herein a simple method for the derivatization of 1,4-dihydroxyanthraquinone through a modified Marschalk reaction. This method provides a clear advantage over traditional approaches, which often require the protection and deprotection of the OH groups. We have also demonstrated that this reaction is applicable to other anthraquinones. Copyright

Full text of DOI:10.1002/ejoc.201300891

FULL PAPER
DOI: 10.1002/ejoc.201300891
Facile Installation of a Hydroxyalkyl Group into Hydroxyanthraquinones and
Aminoanthraquinones through the Modified Marschalk Reaction
Li-Ming Zhao,*[a] Feng-Yan Ma,[a] Hai-Shan Jin,[a] Jiao Ma,[a] Huan Wang,[a] and
Chuan-Zhao Fu[a]
Keywords: Synthetic methods / Medicinal chemistry / Antitumor agents / Quinones / Aldehydes
1,4-Dihydroxyanthraquinones are widely featured in numer-
ous natural products and drugs. It is important to be able to
functionalize the 1,4-dihydroxyanthraquinone skeleton
through a simple yet efficient transformation, which could be
potentially useful for the drug discovery process. We describe
herein a simple and efficient method to derivatize 1,4-di-
hydroxyanthraquinone by using a modified Marschalk reac-
tion. This method provides a clear advantage over traditional
approaches, which often require the protection and deprotec-
tion of the OH groups. We also demonstrate the applicability
of this reaction to other hydroxyanthraquinones and amino-
anthraquinones.
Introduction
Over the past 40 years, anthracycline antibiotics such as
doxorubicin and daunomycin have frequently been used
clinically for the treatment of different human cancers.[1]
The 1,4-dihydroxyanthraquinone skeleton is one feature
that these effective drugs typically share (see Figure 1).
However, the elimination of the OCH3 group at the 4-posi-
tion of the structure of these drugs usually results in an
enhancement of activity.[2] Consequently, 1,4-dihydroxy-
anthraquinone has received considerable attention for em-
ployment as a building block and has been extensively in-
vestigated for the synthesis of other possible antitumor
agents to develop improved drugs. A successful example of
this is mitoxantrone, which was developed to decrease the
cardiotoxicity that is associated with doxorubicin.[3]
However, because of the hydroxy functional groups in
the anthraquinone ring system, the traditional strategy for
the effective elaboration of antitumor anthraquinones
based on the 1,4-dihydroxyanthraquinone skeleton requires
the protection of the hydroxy groups prior to modification,
which will inevitably lead to protection and deprotection
procedures.[4] The in situ reduction to 9,10-dihydro-
anthracene is necessary to activate the compound, as a
Vilsmeier reaction with a classical anthraquinone is never
possible. For example, Ahn and co-workers reported on the
synthesis of 2-substituted-1,4-dihydroxyanthraquinone de-
rivatives along with their antitumor activity.[5] The intro-
duction of a 2-hydroxyalkyl group into the anthraquinone
Figure 1. Structures of anthracyclines.
skeleton requires five steps, as the methylation and demeth-
ylation steps are unavoidable (see Figure 2). Therefore, a
simple and efficient method to derivatize 1,4-dihydroxy-
anthraquinone that avoids tedious protection–deprotection
sequences and increases molecular complexity in an eco-
nomical fashion would be highly desirable.
The Marschalk reaction, which involves the direct alkyl-
ation of 1-hydroxyanthraquinone in the presence of an alde-
hyde and sodium dithionite under basic conditions, has
emerged as a powerful means to derivatize and function-
alize certain highly deactivated anthraquinones.[6] In the
original Marschalk reaction, 2-alkylated anthraquinones
were formed as a result of further reduction. Nonetheless,
from a practical point of view, the introduction of a hy-
droxyalkyl group into the anthraquinone skeleton is more
[a] School of Chemistry and Chemical Engineering, and Jiangsu
Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Jiangsu Normal University,
Xuzhou 221116, Jiangsu, China
E-mail: lmzhao@jsnu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300891.
Eur. J. Org. Chem. 2013, 7193–7199
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L.-M. Zhao, F.-Y. Ma, H.-S. Jin, J. Ma, H. Wang, C.-Z. Fu
FULL PAPER
Figure 2. Example of the traditional strategy for the elaboration of 1,4-dihydroxyanthraquinone (CAN = cerium ammonium nitrate).
attractive because the hydroxyalkyl group is one of most Using ethanol as the solvent gave a similar result, but a
versatile functional groups in organic synthesis and is slightly higher product yield was obtained (see Table 1, En-
widely used for functional group transformations. Surpris- try 2). Switching the solvent to methanol and prolonging
ingly, the installation of such a versatile group to the hy- the reaction time provided a high conversion of starting ma-
droxyanthraquinones has not been extensively and system- terial with a good 63% yield of 3a, however, the 2-alkylated
atically investigated, despite the fact that the original Mar- product 4a was also formed in 11% yield (see Table 1, En-
schalk procedure has been modified from time to time try 3). By decreasing the temperature from 0 to –10 °C and
(mainly to focus on formaldehyde).[7] Recently, our group the time from 5 to 3 h, the generation of 2-alkylated prod-
disclosed the convenient functionalization of 6,8-O-di- uct 4a was suppressed to afford 3a in 57% yield (see
methyl-emodin to introduce a hydroxymethyl group into the Table 1, Entry 4). Changing the temperature to 0 °C but
hydroxyanthraquinone natural product emodin.[8] On the maintaining the same reaction time led to an improvement
basis of the success of this approach, we designed and syn- of the reaction (see Table 1, Entry 5). The conversion of 1
thesized a series of emodin derivatives to screen their anti- was poor when the reaction time was further decreased to
tumor activity.[9] Inspired by these results, we envisioned 1 h (see Table 1, Entry 6). Attempts to use fewer equivalents
that it may be feasible to apply the modified Marschalk of the sodium dithionite and NaOH led to a dramatic drop
reaction to derivatize 1,4-dihydroxyanthraquinone in a sim-
ple manner. Herein, we report a highly practical one-step
procedure to introduce a hydroxyalkyl group into 1,4-di-
Table 1. Optimization of reaction conditions.
hydroxyanthraquinone to lead to 2-hydroxyalkyl-1,4-di-
hydroxyanthraquinones, which can be subsequently derivat-
ized and functionalized.
Results and Discussion
Ideally, the hydroxyalkylation of 1,4-dihydroxyanthra-
quinone should result in substitution at only the 2-position.
However, we noted that in the hydroxymethylation of 1,4-
dihydroxyanthraquinone as reported by Mitscher et al., dis-
ubstitution occurred when formaldehyde was used as the
aldehyde source, and the reaction afforded 3-methyl-2-hy-
droxymethyl-1,4-dihydroxyanthraquinone as an impurity,
which was difficult to isolate.[7a] Therefore, benzaldehyde
was initially chosen as the model substrate to investigate
the hydroxyalkylation with 1,4-dihydroxyanthrquinone, as
it might avoid an overreaction at the 3-position as a result
of the steric hindrance from the aromatic ring (see Table 1).
As anticipated, using benzaldehyde as the substrate and
conducting the reaction in water under nitrogen at 0 °C for
3 h afforded the desired 2-hydroxyalkylated product 3a
along with the recovered starting material 1 without the
formation of the 3-substituted product (see Table 1, En-
Entry Solvent
T
[°C]
Ratio[a]
t
[h]
% 3a[b] % 4a[b] % Recovery
of 1[b]
1
2
3
4
5
6
7
8
9
H2O
EtOH
0
0
0
–10
0
0
0
0
0
1:4:6:2
1:4:6:2
1:4:6:2
1:4:6:2
1:4:6:2
1:4:6:2
1:4:6:1
1:4:2:2
1:2:6:2
3
3
5
3
3
1
3
3
3
13
37
63
57
77
39
17
10
72
trace
trace
11
trace
trace
trace
trace
trace
16
78
46
12
37
7
49
66
62
trace
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
try 1). However, the yield of the desired product 3a was low. [a] Ratio is 1/benzaldehyde/NaOH/Na2S2O4. [b] Isolated yield.
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Anthracycline Antitumor Agent Synthesis
in the yield of 3a (see Table 1, Entries 7 and 8). Decreasing from the substituent on the phenyl ring was extensively in-
the amount of benzaldehyde to 2 equiv. had no significant vestigated. Both electron-withdrawing and -donating
influence on the yield of 3a, but alkylated product 4a was groups were studied by varying their functionality, number,
formed (see Table 1, Entry 9), which resulted in the diffi- and location on the phenyl ring. Generally, the aromatic
culties in the purification of 2-hydroxyalkylated product 3a. aldehydes with electron-withdrawing substituents were
This led us to employ 4 equiv. of the aldehyde as the opti- more reactive than those with electron-donating ones and,
mal amount for our methodology, although the additional thus, gave higher yields. The benzaldehydes that contained
benzaldehyde resulted in the recovery of small amounts of electron-withdrawing substituents on the phenyl ring read-
starting material 1 (see Table 1, Entry 5). Finally, the opti- ily underwent reaction with 1 to give the corresponding
mal conditions were eventually identified as 1 (1 mmol), products 3i–3n in excellent yields. For instance, 4-fluoro-
4 equiv. of aldehyde, 6 equiv. of NaOH, and 2 equiv. of benzaldehyde (2k) gave hydroxyalkylation product 3k with
Na2S2O4 in methanol under nitrogen at 0 °C.
the highest yield (95%; see Table 2, Entry 10). The desired
With these conditions identified, we then assessed the product 3m was obtained in 91% yield from 4-bromobenz-
scope of the reaction with respect to 1,4-dihydroxyanthra- aldehyde (2m; see Table 2, Entry 12), and terephthal-
quinone 1 and various aldehydes (see Table 2). As shown in aldehyde (2n) gave product 3n in 89% yield (see Table 2,
Table 2, the hydroxyalkylation reaction proceeded smoothly Entry 13). The position of the electron-withdrawing substit-
with a wide range of aldehydes. In general, aliphatic alde- uents on the phenyl ring of the benzaldehydes had no obvi-
hydes were less effective than aromatic aldehydes (see ous influence on the yield. Almost the same yields were
Table 2, Entries 1–7 vs. 8–21). In addition to acetaldehyde obtained when 2-fluorobenzaldehyde (2i), 3-fluorobenz-
(2c), the unbranched aliphatic aldehydes propionaldehyde aldehyde (2j), and 4-fluorobenzaldehyde (2k) were used as
(2d) and butyraldehyde (2e) provided the desired products the reactant (see Table 2, Entries 8–10). Conversely, the po-
3d and 3e, respectively, in good yields (see Table 2, Entries 3 sition of the electron-donating groups on the phenyl ring
and 4). The α-branched aldehydes isobutyraldehyde (2f) had a significant influence on the reaction. If benzaldehyde
and cyclopropanecarbaldehyde (2g) were less reactive and had a strong electron-donating substituent at the meta posi-
gave the products in low yield (see Table 2, Entries 5 and tion, the hydroxyalkylation became easier (see Table 2, En-
6). The β-branched aldehyde isovaleraldehyde (2h) gave rise try 17). An ortho- or para-substituted benzaldehyde with a
to an acceptable yield (see Table 2, Entry 7). As for aro- strong electron-donating group resulted in a decrease in the
matic aldehydes, the influence of the electronic properties reaction yield (see Table 2, Entries 16 and 18). The number
Table 2. Scope of the modified Marschalk reaction with different aldehydes.
Entry
Aldehyde
R
Product
% Yield[a]
1
2
3
4
5
6
7
8
formaldehyde (2b)
H
methyl
ethyl
propyl
isopropyl
cyclopropyl
isobutyl
2-FC6H4
3-FC6H4
3b
3c
3d
3e
3f
3g
3h
3i
44
48
75
61
30
37
47
93
92
95
90
91
89
50
62
42
85
32
56
73
69
acetaldehyde (2c)
propionaldehyde (2d)
butyraldehyde (2e)
isobutyraldehyde (2f)
cyclopropanecarbaldehyde (2g)
isovaleraldehyde (2h)
2-fluorobenzaldehyde (2i)
3-fluorobenzaldehyde (2j)
4-fluorobenzaldehyde (2k)
4-chlorobenzaldehyde (2l)
4-bromobenzaldehyde (2m)
terephthalaldehyde (2n)
5-bromo-2-hydroxybenzaldehyde (2o)
4-methylbenzaldehyde (2p)
2-methoxybenzaldehyde (2q)
3-methoxybenzaldehyde (2r)
4-methoxybenzaldehyde (2s)
3,4-dimethylbenzaldehyde (2t)
2-furaldehyde (2u)
9
3j
3k
3l
10
11
12
13
14
15
16
17
18
19
20
21
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CHOC6H4
5-Br-2-OHC6H3
4-CH3C6H4
2-CH3OC6H4
3-CH3OC6H4
4-CH3OC6H4
3,4-(CH3)2C6H3
2-furyl
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
2-thenaldehyde (2v)
2-thienyl
[a] Isolated yield.
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FULL PAPER
of substituents on the phenyl ring of the benzaldehyde did anthraquinone (see Table 3, Entries 3–5). In view of these
affect the reaction yield slightly. For example, 4-methyl- findings, this strategy could serve as a general approach to
benzaldehyde (2p) provided the product in 62% yield (see synthesize hydroxyalkylanthraquinones, which are useful
Table 2, Entry 15), whereas the yield from 3,4-dimethyl- handles for further elaboration to prepare more complex
benzaldehyde (2t) was slightly lower at 56% yield (see anthraquinones that exhibit antitumor activity.
Table 2, Entry 19). In addition to the benzaldehydes, the
The satisfactory results of this method to provide the hy-
heteroaryl aldehydes 2-furaldehyde (2u) and 2-thenaldehyde droxyalkylated product rather than the alkylated one, which
(2v) were also compatible under the reaction conditions to is produced by the traditional Marschalk reaction, can be
give 3u and 3v in 73 and 69% yield, respectively (see rationalized by the suppression of the retro-Michael reac-
Table 2, Entries 20 and 21). The structure of product 3l was tion, which results in the irreversible elimination of benzylic
further confirmed by X-ray diffraction analysis (see the hydroxy group to afford the alkylated product.[11] The Mar-
Supporting Information).[10]
schalk reaction can be viewed as a base-catalyzed aldol con-
To further explore the scope of the reaction, we investi- densation that is preceeded by the reduction of the anthra-
gated the hydroxyalkylation of anthraquinones 5a–5c, and quinone by treatment with dithionite to give its correspond-
the results are provided in Table 3. As shown, the anthra- ing anthrahydroquinone. Aldols that contain one or more
quinones that contained electron-donating substituents phenyl groups α or β to the hydroxy group spontaneously
proved to be excellent substrates for this transformation. dehydrate at room temperature to form an α,β-unsaturated
For example, 1-hydroxy-4-methoxyanthraquinone (5a) was carbonyl with an extended conjugated π system. Then,
more reactive because of the presence of the electron-donat- anthraquinones such as 3a, which is the enol tautomer of
ing methoxy group and afforded the product in good yield an aldol, undergo a base-catalyzed dehydration (i.e., a retro-
(see Table 3, Entry 1). Not only electron-rich anthra- Michael reaction) at room temperature to form an unsatu-
quinone 5a but also the lesser electron-rich anthraquinone rated carbonyl that is reduced by dithionite to give the an-
5b was well tolerated in this reaction, although the yield thrahydroquinone of 4a. The significance of this work is
from 5b was not high (see Table 3, Entry 2). Remarkably, that the dehydration of 3a at 0 °C is quite slow, which al-
the reaction was also successfully applied to an amino- lows 3a to be isolated in good yield. As shown in Scheme 1,
anthraquinone is converted in the first step into its leuco
form A in the presence of NaOH and Na2S2O4. Next, the
Table 3. Reaction of aldehyde with various anthraquinones.
condensation of A with the aldehyde affords adduct B,
which further isomerizes to afford the hydroxyalkyated an-
thrahydroquinone anion C. Finally, a rapid oxidation and
low reaction temperature suppress the removal of the
hydroxy group. Therefore, the desired hydroxyalkylated
product D is generated.
The data in Table 2 show that the yields of aldolization
Entry
5
R1
R2
R3
R
Product % Yield[a]
with electron-poor aldehydes were higher than those with
electron-rich aldehydes, implying that the reactivity of the
aldolization increases as the aldehydes become more elec-
trophilic. This phenomenon highlights the mechanistic con-
sideration for the base-catalyzed aldol condensation. On the
other hand, the high yield of 6a in Table 3 compared with
1
2
3
4
5
5a OH CH3OH
C6H5 (2a)
6a
6b
6c
6d
6e
85
31
51
47
45
5b OH
5c NH2
5c NH2
5c NH2
H
H
H
H
OH C6H5 (2a)
H
H
H
C6H5 (2a)
4-BrC6H4 (2m)
3-CH3OC6H4 (2r)
[a] Isolated yield.
Scheme 1. Proposed reaction mechanism.
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Anthracycline Antitumor Agent Synthesis
1
3c: M.p. 133–134 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.16
6b–6e also can be explained by the proposed mechanism.
The yield of 6a is high because the anion of the anthrahy-
droquinone of 5a is quite nucleophilic because of the two
electron-donating substituents on the ring.
(s, 1 H), 12.68 (s, 1 H), 8.16–8.4 (m, 2 H), 7.91–7.88 (m, 2 H), 7.41–
7.40 (m, 1 H), 5.48 (d, J = 4.4 Hz, 1 H), 5.02–4.99 (m 1 H), 1.35
(d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
186.9, 186.0, 157.0, 154.1, 149.2, 135.0, 134.9, 132.9, 132.8, 126.6,
126.5, 124.3, 112.0, 111.1, 62.7, 23.6 ppm. HRMS (ESI): calcd. for
C16H12O5Na [M + Na]+ 307.0582; found 307.0577.
Conclusions
1
3d: M.p. 158–159 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.20
(s, 1 H), 12.71 (s, 1 H), 8.18–8.15 (m, 2 H), 7.93–7.91 (m, 2 H),
7.41 (s, 2 H), 5.47 (d, J = 5.2 Hz, 1 H), 4.89–4.85 (m, 1 H), 1.86–
1.76 (m, 1 H), 1.59–1.49 (m 1 H), 0.95 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 186.6, 185.7, 156.7, 154.2,
148.0, 134.8, 134.7, 132.6, 132.5, 126.4, 126.3, 124.9, 111.6, 110.9,
67.2, 29.5, 9.8 ppm. HRMS (ESI): calcd. for C17H14O5Na [M +
Na]+ 321.0739; found 321.0734.
In summary, we have successfully developed a facile
hydroxyalkylation reaction of 1,4-dihydroxyanthraquinone
in a simple manner. The introduction of a hydroxyalkyl
group into hydroxyanthraquinone does not require protec-
tion and deprotection procedures. We have also demon-
strated that this reaction is applicable to other hydroxy-
anthraquinones and aminoanthraquinones. In addition, the
high efficiency, broad substrate scope, mild conditions, and
simple operation make this methodology quite practical
and attractive for the synthetic community. Applications of
this methodology are in progress in our laboratory.
1
3e: M.p. 129–130 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.23
(s, 1 H), 12.74 (s, 1 H), 8.22–8.20 (m, 2 H), 7.97–7.93 (m, 2 H),
7.43 (s, 1 H), 5.46 (d, J = 5.2 Hz, 1 H), 4.96–4.92 (m, 1 H), 1.75–
1.67 (m, 1 H), 1.55–1.39 (m, 3 H), 0.91 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 186.8, 185.9, 156.8, 154.1,
148.5, 134.9, 134.8, 132.8, 132.7, 126.5, 126.4, 124.8, 111.8, 111.1,
65.8, 39.0, 18.4, 13.8 ppm. HRMS (ESI): calcd. for C18H16O5Na
[M + Na]+ 335.0895; found 335.0889.
Experimental Section
1
3f: M.p. 175–176 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.29
(s, 1 H), 12.76 (s, 1 H), 8.26–8.23 (m, 2 H), 7.99–7.95 (m, 2 H),
7.41 (s, 1 H), 5.42 (d, J = 4.8 Hz, 1 H), 4.82 (t, J = 4.4 Hz, 1 H),
2.06–1.97 (m, 1 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.78 (t, J = 6.8 Hz,
3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 187.1, 186.1,
156.6, 154.4, 147.4, 135.0, 134.9, 132.9, 132.9, 126.6, 126.5, 125.8,
112.0, 1113, 70.1, 32.7, 19.7, 16.0 ppm. HRMS (ESI): calcd. for
C18H16O5Na [M + Na]+ 335.0895; found 335.0900.
General Methods: All aldehydes were commercially available. Li-
quid aldehydes were freshly distilled prior to use, and solid alde-
hydes were used as purchased without further purification. Other
reagents were used as purchased without further purification. The
1H and 13C NMR spectroscopic data were recorded at 400 and
100 MHz in CDCl3, and the chemical shifts (δ) are reported in ppm
relative to TMS as the internal standard. Multiplicities are indi-
cated as s (singlet), d (doublet), t (triplet), q (quartet), br. s (broad
singlet), m (multiplet), and the coupling constants (J) are reported
in Hertz (Hz). High resolution mass spectra were recorded using
electrospray ionization.
1
3g: M.p. 156–157 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.26
(s, 1 H), 12.73 (s, 1 H), 8.23–8.19 (m, 2 H), 7.96–7.93 (m, 2 H),
7.44 (s, 1 H), 5.48 (d, J = 5.2 Hz, 1 H), 4.70 (t, J = 5.2 Hz, 1 H),
1.23–1.15 (m, 1 H), 0.57–0.51 (m, 1 H), 0.45–0.33 (m, 3 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 186.7, 185.8, 156.8, 154.4,
147.7, 134.8, 134.7, 132.6, 126.4, 126.3, 125.1, 111.9, 111.1, 66.5,
17.2, 1.7, 1.6 ppm. HRMS (ESI): calcd. for C18H14O5Na
[M + Na]+ 333.0739; found 333.0739.
Representative Procedure for the Synthesis of 3 and 6: To a 0 °C
solution of anthraquinone (1 mmol) in MeOH (20 mL) and aque-
ous NaOH (1 n, 6 mL) was added a solution of Na2S2O4 (0.35 g,
2 mmol) in water (2 mL) under N2. After 10 min, the aldehyde
(4.0 mmol) was added by syringe. The reaction mixture was stirred
for 3 h at 0 °C. The solution was poured into cold water (10 mL)
that contained 30% H2O2 (2 mL), and the mixture was stirred for
10 min. The mixture was acidified by the addition of HCl (3 n solu-
tion, 2 mL), and the resulting mixture was extracted with CH2Cl2,
dried, and concentrated. The residue was purified by flash column
chromatography (CH2Cl2) to afford 3 or 6 as an orange solid.
1
3h: M.p. 165–166 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.18
(s, 1 H), 12.70 (s, 1 H), 8.20–8.09 (m, 2 H), 7.96–7.84 (m, 2 H),
7.41 (s, 1 H), 5.42 (d, J = 5.2 Hz, 1 H), 5.01–4.90 (m, 1 H), 1.97–
1.83 (m, 1 H), 1.51–1.37 (m, 1 H), 0.99 (d, J = 6.4 Hz, 3 H), 0.92
(d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
186.7, 185.7, 156.9, 154.1, 149.1, 134.9, 134.7, 132.6, 132.6, 126.4,
126.3, 124.6, 111.6, 110.8, 64.5, 46.2, 24.5, 23.6, 21.6 ppm. HRMS
(ESI): calcd. for C19H18O5Na [M + Na]+ 349.1052; found 349.1053.
1
3a: M.p. 217–218 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.19
1
(s, 1 H), 12.75 (s, 1 H), 8.25–8.20 (m, 2 H), 7.96–7.91 (m, 2 H),
7.65 (s, 1 H), 7.44 (d, J = 7.2 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 2 H),
7.27–7.23 (m, 1 H), 6.23 (d, J = 4.4 Hz, 1 H), 6.03 (d, J = 4.4 Hz,
1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 187.1, 186.2,
156.7, 154.0, 146.6, 142.9, 135.1, 134.9, 132.9, 132.9, 128.2, 127.4,
126.9, 126.6, 126.6, 124.7, 112.4, 111.6, 68.2 ppm. HRMS (ESI):
calcd. for C21H14O5Na [M + Na]+ 369.0739; found 369.0728.
3i: M.p. 211–212 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.07
(s, 1 H), 12.75 (s, 1 H), 8.25–8.18 (m, 2 H), 7.97–7.91 (m, 2 H),
7.63 (s, 1 H), 7.36–7.28 (m, 2 H), 7.21–7.13 (m, 2 H), 6.32 (d, J =
4.8 Hz, 1 H), 6.25 (d, J = 4.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 187.1, 186.3, 156.5, 154.1, 144.9, 135.1, 134.9,
133.0, 132.9, 129.6 (d, J = 10.7 Hz), 129.1 (d, J = 2.0 Hz), 126.7,
126.6, 125.5, 124.3 (d, J = 3.6 Hz), 115.4 (d, J = 21.6 Hz), 112.3,
111.8, 62.5 ppm. HRMS (ESI): calcd. for C21H13FO5Na
[M + Na]+ 387.0645; found 387.0643.
1
3b: M.p. 208–209 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.09
(s, 1 H), 12.81 (s, 1 H), 8.29–8.24 (m, 2 H), 8.02–7.97 (m, 2 H),
1
7.42 (s, 1 H), 5.60 (t, J = 5.6 MHz, 1 H), 4.66 (d, J = 5.6 MHz, 2 3j: M.p. 198–200 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.15
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 186.9, 186.1,
157.0, 154.2, 144.7, 135.1, 134.9, 133.0, 132.8, 126.6, 126.6, 124.5,
111.7, 110.9, 57.5 ppm. HRMS (ESI): calcd. for C15H10O5Na [M
+ Na]+ 293.0426; found 293.0426.
(s, 1 H), 12.67 (s, 1 H), 8.22–8.10 (m, 2 H), 7.94–7.84 (m, 2 H),
7.61 (s, 1 H), 7.41–7.35 (m, 1 H), 7.29–7.23 (m, 2 H), 7.11–7.06 (m,
1 H), 6.36 (d, J = 4.4 Hz, 1 H), 6.04 (d, J = 4.0 Hz, 1 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 187.0, 186.1, 162.0 (d, J =
Eur. J. Org. Chem. 2013, 7193–7199
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L.-M. Zhao, F.-Y. Ma, H.-S. Jin, J. Ma, H. Wang, C.-Z. Fu
FULL PAPER
241.3 Hz), 156.7, 153.8, 145.9, 145.9, 145.8, 135.0, 134.9, 132.8,
132.8, 130.1 (d, J = 8.6 Hz), 126.6, 126.5, 124.9, 122.8 (d, J =
3.0 Hz), 114.1 (d, J = 20.6 Hz), 113.4 (d, J = 2.0 Hz), 112.4, 111.7,
67.5 (d, J = 2.0 Hz) ppm. HRMS (ESI): calcd. for C21H13FO5Na
[M + Na]+ 387.0645; found 387.0635.
126.5, 125.9, 120.1, 112.0, 111.4, 111.2, 62.7, 55.5 ppm. HRMS
(ESI): calcd. for C22H16O6Na [M + Na]+ 399.0845; found 399.0845.
1
3r: M.p. 142–143 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.19
(s, 1 H), 12.71 (s, 1 H), 8.20–8.18 (m, 2 H), 7.93–7.90 (m, 2 H),
7.61 (s, 1 H), 7.24 (t, J = 8.4 Hz, 1 H), 7.01–7.00 (m, 2 H), 6.83–
6.81 (m, 1 H), 6.20 (d, J = 4.8 Hz, 1 H), 6.01 (d, J = 4.4 Hz, 1 H),
1
3k: M.p. 230–231 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.12
(s, 1 H), 12.69 (s, 1 H), 8.23–8.10 (m, 2 H), 7.96–7.83 (m, 2 H), 3.74 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 187.0,
7.62 (s, 1 H), 7.46 (dd, J = 8.4, 6.4 Hz, 2 H), 7.15 (t, J = 9.0 Hz, 2
H), 6.27 (d, J = 4.0 Hz, 1 H), 6.00 (d, J = 4.0 Hz, 1 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 186.9, 186.0, 161.4 (d, J =
242.5 Hz), 156.7, 153.9, 146.3, 139.1, 135.0, 134.8, 132.8, 132.7,
129.0, 128.9, 126.5, 126.5, 124.9 (d, J = 21.0 Hz), 111.9 (d, J =
75.1 Hz), 67.6 ppm. HRMS (ESI): calcd. for C21H13FO5Na [M +
Na]+ 387.0645; found 387.0640.
186.1, 159.1, 156.7, 154.0, 146.5, 144.6, 135.0, 134.9, 132.9, 132.8,
129.3, 126.6, 126.5, 124.9, 119.0, 112.6, 112.5, 112.4, 111.6, 67.9,
55.0 ppm. HRMS (ESI): calcd. for C22H16O6Na [M + Na]+
399.0845; found 399.0841.
1
3s: M.p. 191–192 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.16
(s, 1 H), 12.75 (s, 1 H), 8.19–8.18 (m, 2 H), 7.92–7.88 (m, 2 H),
7.63 (s, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H),
1
3l: M.p. 193–195 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.15 6.10 (d, J = 4.4 Hz, 1 H), 5.96 (d, J = 4.0 Hz, 1 H), 3.71 (s, 3
(s, 1 H), 12.71 (s, 1 H), 8.23–8.17 (m, 2 H), 7.94–7.90 (m, 2 H), H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 186.8, 185.9,
7.63 (s, 1 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H),
158.5, 156.8, 154.1, 147.0, 134.9, 134.8, 132.8, 132.7, 128.2, 126.5,
6.33 (d, J = 4.4 Hz, 1 H), 6.01 (d, J = 4.4 Hz, 1 H) ppm. 13C NMR 126.4, 124.5, 113.5, 112.1, 111.3, 67.8, 55.0 ppm. HRMS (ESI):
(100 MHz, [D6]DMSO): δ = 187.1, 186.2, 156.9, 153.8, 146.0,
141.9, 135.1, 134.9, 132.8, 131.9, 128.8, 128.2, 126.6, 126.6, 124.7,
112.5, 111.7, 67.6 ppm. HRMS (ESI): calcd. for C21H13ClO5Na [M
+ Na]+ 403.0349; found 403.0343.
calcd. for C22H16O6Na [M + Na]+ 399.0845; found 399.0837.
1
3t: M.p. 138–139 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.12
(s, 1 H), 12.71 (s, 1 H), 8.16–8.07 (m, 2 H), 7.89–7.79 (m, 2 H),
7.60 (s, 1 H), 7.18 (s, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 7.07 (d, J =
3m: M.p. 205–206 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 13.16 8.0 Hz, 1 H), 6.09 (d, J = 4.4 Hz, 1 H), 5.93 (d, J = 4.0 Hz, 1 H),
(s, 1 H), 12.71 (s, 1 H), 8.24–8.17 (m, 2 H), 7.95–7.90 (m, 2 H), 2.19 (s, 3 H), 2.16 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
7.62 (s, 1 H), 7.52 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H),
δ = 186.7, 185.9, 156.8, 154.1, 146.9, 140.3, 135.8, 135.2, 134.8,
6.33 (d, J = 4.4 Hz, 1 H), 5.99 (d, J = 4.0 Hz, 1 H) ppm. 13C NMR 134.7, 132.7, 132.6 129.2, 128.0, 126.4, 126.3, 124.7, 124.4, 112.0,
(100 MHz, [D6]DMSO): δ = 187.0, 186.2, 156.7, 153.8, 145.9,
142.3, 135.1, 134.9, 132.9, 132.8, 131.1, 129.1, 126.6, 126.5, 124.7,
120.5, 112.4, 111.7, 67.6 ppm. HRMS (ESI): calcd. for
C21H13BrO5Na [M + Na]+ 446.9844; found 446.9844.
111.2, 68.1, 19.4, 19.0 ppm. HRMS (ESI): calcd. for C23H18O5Na
[M + Na]+ 397.1052; found 397.1040.
1
3u: M.p. 174–176 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.09
(s, 1 H), 12.69 (s, 1 H), 8.21–8.18 (m, 2 H), 7.94–7.91 (m, 2 H),
7.61 (s, 1 H), 6.40–6.39 (m, 1 H), 6.31 (d, J = 5.6 Hz, 1 H), 6.22
(d, J = 3.2 Hz, 1 H), 6.03 (d, J = 5.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 186.9, 186.2, 156.5, 154.6, 154.1,
1
3n: M.p. 202–203 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.14
(s, 1 H), 12.67 (s, 1 H), 9.97 (s, 1 H), 8.15 (d, J = 4.0 Hz, 2 H),
7.88 (d, J = 6.8 Hz, 4 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.63 (s, 1 H),
6.45 (d, J = 3.6 Hz, 1 H), 6.10 (d, J = 3.2 Hz, 1 H) ppm. 13C NMR 143.3, 142.5, 135.0, 134.9, 132.8, 132.8, 126.6, 126.5, 125.6, 112.3,
(100 MHz, [D6]DMSO): δ = 192.7, 186.8, 185.9, 156.7, 153.8,
149.5, 145.4, 135.4, 134.9, 134.8, 132.7, 132.6, 129.5, 127.6, 126.5,
126.4, 124.9, 112.3, 111.6, 68.0 ppm. HRMS (ESI): calcd. for
C22H14O6Na [M + Na]+ 397.0688; found 397.0683.
111.9, 110.4, 107.3, 61.9 ppm. HRMS (ESI): calcd. for
C19H12O6Na [M + Na]+ 359.0532; found 359.0533.
1
3v: M.p. 164–166 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.17
(s, 1 H), 12.69 (s, 1 H), 8.22–8.19 (m, 2 H), 7.94–7.89 (m, 2 H),
7.59 (s, 1 H), 7.44–7.43 (m, 1 H), 7.02 (d, J = 3.2 Hz, 1 H), 6.97–
6.94 (m, 1 H), 6.53 (d, J = 4.4 Hz, 1 H), 6.28 (d, J = 4.8 Hz, 1
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 187.0, 186.2,
156.6, 153.8, 147.0, 145.7, 135.1, 134.9, 132.9, 132.8, 126.6, 126.5,
125.3, 124.7, 124.5, 112.5, 111.8, 63.9 ppm. HRMS (ESI): calcd.
for C19H12O5SNa [M + Na]+ 375.0303; found 375.0292.
1
3o: M.p. 176–178 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.19
(s, 1 H), 12.75 (s, 1 H), 9.90 (s, 1 H), 8.25–8.22 (m, 2 H), 7.98–7.93
(m, 2 H), 7.38 (s, 1 H), 7.28–7.24 (m, 2 H), 6.79 (d, J = 8.8 Hz, 1
H), 6.26 (d, J = 5.6 Hz, 1 H), 6.02 (d, J = 5.6 Hz, 1 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 187.1, 186.2, 156.4, 154.8,
154.0, 145.5, 135.0, 134.9, 133.0, 132.9, 131.4, 131.0, 130.0, 126.7,
126.6, 125.8, 117.5, 112.3, 111.7, 109.8, 62.8 ppm. HRMS (ESI):
calcd. for C21H13BrO6Na [M + Na]+ 462.9793; found 462.9794.
1
6a: M.p. 178–180 °C. H NMR (400 MHz, [D6]DMSO): δ = 12.27
(s, 1 H), 8.13 (d, J = 7.2 Hz, 1 H), 8.07 (d, J = 7.6 Hz, 1 H), 7.93
(s, 1 H), 7.87–7.80 (m, 2 H), 7.46 (d, J = 7.6 Hz, 2 H), 7.33 (t, J =
1
3p: M.p. 173–174 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.15
(s, 1 H), 12.74 (s, 1 H), 8.18–8.17 (m, 2 H), 7.90–7.87 (m, 2 H), 7.4 Hz, 2 H), 7.24 (t, J = 7.2 Hz, 1 H), 6.23 (d, J = 4.4 Hz, 1 H),
7.62 (s, 1 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H),
6.15 (d, J = 4.4 Hz, 1 H), 5.97 (d, J = 4.8 Hz, 1 H), 2.25 (s, 3
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 186.9, 186.0,
156.8, 154.0, 146.8, 139.9, 136.5, 135.0, 134.8, 132.8, 132.7, 128.7,
126.9, 126.5, 126.4, 124.6, 112.2, 111.4, 68.0, 20.7 ppm. HRMS
(ESI): calcd. for C22H16O5Na [M + Na]+ 383.0895; found 383.0899.
6.06 (d, J = 4.0 Hz, 1 H), 3.97 (s, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 188.9, 179.9, 153.9, 153.2, 143.3, 143.0, 135.0,
134.5, 133.4, 131.7, 129.2, 128.5, 128.1, 127.2, 127.0, 126.5, 125.9,
120.5, 117.0, 115.0, 68.4, 56.6 ppm. HRMS (ESI): calcd. for
C22H16O5Na [M + Na]+ 383.0895; found 383.0887.
1
6b: M.p. 187–189 °C. H NMR (400 MHz, [D6]DMSO): δ = 12.10
1
3q: M.p. 220–221 °C. H NMR (400 MHz, [D6]DMSO): δ = 13.15
(br. s, 2 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.81–7.77 (m, 2 H), 7.70 (d,
(s, 1 H), 12.75 (s, 1 H), 8.26–8.17 (m, 2 H), 7.97–7.89 (m, 2 H), J = 7.2 Hz, 1 H), 7.43 (d, J = 7.6 Hz, 2 H), 7.37–7.30 (m, 3 H),
7.42 (s, 1 H), 7.28 (t, J = 7.6 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.25–7.21 (m, 1 H), 6.15 (br. s, 1 H), 6.09 (s, 1 H) ppm. 13C NMR
7.02 (d, J = 8.4 Hz, 1 H), 6.91 (t, J = 7.2 Hz, 1 H), 6.35 (d, J =
4.8 Hz, 1 H), 5.89 (d, J = 5.2 Hz, 1 H), 3.80 (s, 3 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 186.9, 186.1, 156.6, 156.5,
154.8, 146.4, 134.9, 134.8, 132.9, 132.8, 130.5, 128.8, 127.5, 126.6,
(100 MHz, [D6]DMSO): δ = 193.0, 181.7, 161.8, 158.4, 144.2,
141.6, 138.0, 134.4, 133.9, 132.3, 128.6, 127.6, 127.1, 124.8, 119.8,
119.7, 116.5, 115.9, 68.3 ppm. HRMS (ESI): calcd. for
C21H14O5Na [M + Na]+ 369.0739; found 369.0736.
7198
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Eur. J. Org. Chem. 2013, 7193–7199

Anthracycline Antitumor Agent Synthesis
1
6c: M.p. 157–158 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.19
(d, J = 7.6 Hz, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.90–7.81 (m, 2 H),
7.69 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.43 (d, J =
7.6 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 2 H), 7.25 (t, J = 7.2 Hz, 1 H),
6.41 (d, J = 4.4 Hz, 1 H), 5.97 (d, J = 4.0 Hz, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 184.3, 182.5, 149.5, 142.3, 136.6,
134.4, 134.2, 133.3, 133.1, 132.7, 132.4, 127.9, 127.0, 126.3, 126.3,
126.0, 115.2, 112.3, 71.5 ppm. HRMS (ESI): calcd. for
C21H15NO3Na [M + Na]+ 352.0950; found 352.0951.
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1
6d: M.p. 205–206 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.20
(d, J = 7.6 Hz, 1 H), 8.13 (d, J = 7.6 Hz, 1 H), 7.89–7.84 (m, 2 H),
7.70 (d, J = 7.6 Hz, 1 H), 7.54–7.49 (m, 3 H), 7.38 (d, J = 8.4 Hz,
2 H), 6.49 (d, J = 4.4 Hz, 1 H), 5.97 (d, J = 4.0 Hz, 1 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 184.4, 182.6, 149.5, 141.9,
136.3, 134.5, 133.5, 133.2, 132.8, 132.4, 130.9, 128.7, 126.5, 126.2,
120.3, 115.4, 112.4, 70.7 ppm. HRMS (ESI): calcd. for
C21H14BrNO3Na [M + Na]+ 430.0055; found 430.0050.
1
6e: M.p. 169–171 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.20
(d, J = 7.6 Hz, 1 H), 8.13 (d, J = 7.6 Hz, 1 H), 7.90–7.81 (m, 2 H),
7.67 (d, J = 7.6 Hz, 1 H), 7.49 (d, J = 7.2 Hz, 1 H), 7.24 (t, J =
7.6 Hz, 1 H), 7.05 (s, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 6.84–6.82 (m,
1 H), 6.39 (d, J = 4.0 Hz, 1 H), 5.94 (d, J = 7.2 Hz, 1 H), 3.74 (s,
3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 184.4, 182.7,
159.1, 149.6, 144.1, 136.7, 134.5, 134.4, 133.5, 133.2, 132.7, 132.5,
129.2, 126.5, 126.2, 118.7, 115.4, 112.5, 112.3, 112.3, 71.3,
55.0 ppm. HRMS (ESI): calcd. for C22H17NO4Na [M + Na]+
382.1055; found 382.1054.
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Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of compounds 3a–3v and
6a–6e as well as X-ray crystal structure of compound 3l.
Acknowledgments
[10] CCDC-942479 (for 3l) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
The authors are thankful for financial support from the Natural
Science Foundation of Jiangsu Province (BK2012576), the Major
Program of Natural Science Foundation (12KJA150005), the Pri-
ority Academic Program Development of Jiangsu Higher Educa-
tion Institutions, and the Innovation Training Program for the Ji-
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Received: June 18, 2013
Published Online: September 19, 2013
Eur. J. Org. Chem. 2013, 7193–7199
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7199