Efficient and divergent synthesis of cyclophosphamide analogues from 2-arylamino-3-acetyl-5,6-dihydro-4H-pyrans

Article abstract of DOI:10.1039/b815416c

A facile and efficient one-pot synthesis of substituted cyclophosphamidic chlorides and their analogues has been developed from readily available enaminones, 2-arylamino-3-acetyl-5,6-dihydro-4H-pyrans. The Royal Society of Chemistry.

Full text of DOI:10.1039/b815416c

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Efficient and divergent synthesis of cyclophosphamide analogues
from 2-arylamino-3-acetyl-5,6-dihydro-4H-pyransw
Dexuan Xiang,a Peng Huang,b Kewei Wang,a Guangyuan Zhou,b Yongjiu Liangb
and Dewen Dong*ab
Received (in Cambridge, UK) 4th September 2008, Accepted 29th September 2008
First published as an Advance Article on the web 15th October 2008
DOI: 10.1039/b815416c
A facile and efficient one-pot synthesis of substituted cyclophos-
phamidic chlorides and their analogues has been developed from
readily available enaminones, 2-arylamino-3-acetyl-5,6-dihydro-
4H-pyrans.
Cyclophosphamide 1a was introduced in tumor therapy in 1958
and is until now the most important clinically used antitumor and
immunosupressive agent (Chart 1).1,2 It is becoming clear that
monooxidation of cyclophosphamide 1a to 4-hydroxycyclo-
phosphamide 1b is essentially responsible for the activation of
this agent by the drug-metabolizing enzymes of the liver.3
Cyclophosphamide analogues of particular clinical interest
include ifosfamide 1c and trofosfamide 1d.4 So far, numerous
structural modifications have been carried out in attempts to
improve the drug’s therapeutic index and elucidate their
mechanism of action. The notable approach for the synthesis
of cyclophosphamides was established by Takamizawa and co-
workers via the ozonolysis of O-3-butenylphosphorodiamidates.5
Other methods were reported by the reaction of phosphoramidic
dichlorides with 1,3-amino alcohols or 3-hydroxyamide.6
Chart 1
The substrates, 5,6-dihydro-4H-pyrans 2, were synthesized
from commercially available b-oxo amides and 1,3-dibromo-
ethane in the presence of K2CO3 in DMF in excellent yields
(up to 96%) according to our published procedure.7b With
substrates 2 in hand, we selected 2-phenylamino-3-acetyl-5,6-
dihydro-4H-pyran 2a as the model compound to examine its
behavior. Thus, the reaction of 2a with POCl3 (3.0 equiv.) was
first attempted in CH2Cl2 at room temperature. As monitored
by TLC, the reaction proceeded smoothly and furnished a
white solid after workup and subsequent purification by
column chromatography of the resulting mixture. The
product was characterized as a cyclophosphamidic chloride
(90% yield) on the basis of its spectral and analytical data
(Scheme 1). The structure of 3a was further confirmed by the
X-ray single-crystal analysis (Fig. 1).z
Recently, we reported the efficient synthesis of substituted
pyridin-2(1H)-ones via the Vilsmeier–Haack reactions of a variety
of b-oxo amide derivatives, 1-acyl and 1-carbamyl cyclopropanes,
5,6-dihydro-4H-pyrans, a-monosubstituted b-oxo amides and
a-unsubstituted b-oxo amides.7 Furthermore, we achieved one-
pot synthesis of fully substituted 1H-pyrazoles from the oximes of
1-acyl and 1-carbamyl cyclopropanes under Vilsmeier conditions
(POCl3/DMF).8 When DMF was replaced with CH2Cl2, the
same substrates, cyclopropyl oximes, afforded fully substituted
isoxazoles in high yields. The results suggested that POCl3, being
a reagent,9 showed different reaction behavior from the Vilsmeier
reagent, POCl3/DMF. Inspired by these results and in continua-
tion with our research interests regarding the development of new
approaches for the synthesis of highly valuable heterocycles, we
were interested in examining the reaction behavior of the readily
available enaminones toward POCl3 in CH2Cl2. As a result of
these studies, we provide a facile and efficient one-pot synthesis of
unsaturated cyclophosphamidic chlorides, a new ring system, and
their further synthetic transformations into cyclophosphamidic
amides and esters. In the present work, we wish to report our
results and the possible mechanism involved.
The optimization of the reaction conditions, including reaction
temperature and the ratio of POCl3 to 2a was then investigated. A
series of experiments revealed that 1.2 equiv. of POCl3 was
effective for the synthesis of 3a, and the yield of 3a reached
91% when the reaction of 2a with 1.2 equiv. of POCl3 was
performed in CH2Cl2 at room temperature for 40 min (Table 1,
entry 1). Under the optimal conditions, we carried out a series of
reactions of 2 aiming to determine its scope with respect to the
amide moiety. As shown in Table 1, the ring-opening/recycliza-
tion proved to be suitable for 2b–e bearing varied N-aryl groups,
affording the corresponding substituted cyclophosphamidic chlor-
ides 3b–e in very high yields (Table 1, entries 2–4). It is worth
mentioning that the cyclophosphamidic chlorides 3 are stable
when subjected to the aqueous workup process (duration: 1.0 h).
Therefore, we provided a simple and efficient one-pot
synthesis of substituted cyclophosphamidic chlorides. It was
assumed that the cyclophosphamidic chlorides 3 were formed
via tandem ring-opening mediated by POCl3 and an intra-
molecular cyclization as depicted in Scheme 2.6d,7b
a Department of Chemistry, Northeast Normal University, 130024
Changchun, China
b Changchun Institute of Applied Chemistry, Chinese Academy of
Sciences, 130022 Changchun, China.
E-mail: dongdw663@nenu.edu.cn; Fax: +86 431 8509 8635
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 689420. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b815416c
Scheme 1 Reaction of 2a with POCl3 in CH2Cl2.
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Next, we examined the reactions of 3a and alcohols with respect
to the synthesis of cyclophosphamidic esters. When 3a, methanol
(1.1 equiv.) and pyridine (1.2 equiv.) were subjected to CH2Cl2 at
room temperature for 1.0 h (monitored by TLC), the reaction
proceeded smoothly and furnished a white solid after workup and
purification by column chromatography of the resulting reaction
mixture. The product was characterized as a cyclophosphamidic
ester 5a-1 (90% yield) on the basis of its spectral and analytical
data (Table 3). In the same fashion, cyclophosphamidic esters
5a-2, 5a-3 and 5a-4 were obtained in excellent yields by reacting
3a with ethanol, phenol and benzyl alcohol, respectively (Table 3).
In fact, a one-pot synthesis of substituted cyclophosphami-
dic amides 4 from enaminones 2 was attempted. In a repre-
sentative experiment, 2a was treated with POCl3 (1.2 equiv.) in
CH2Cl2 at room temperature for 1.0 h, then triethyl amine
(4.0 equiv.) and ethyl amine (1.5 equiv.) were loaded in tandem
sequence under stirring. The reaction mixture was stirred for
further 1.0 h to afford 4a-1 in high yield (Scheme 3). Similarly,
a one-pot synthesis of substituted cyclophosphamidic ester
5a-1 from enaminone 2a was achieved by treatment of 2a with
POCl3 (1.2 equiv.) in CH2Cl2, followed by addition of pyridine
(4.0 equiv.) and methanol (1.2 equiv.).
Fig. 1 ORTEP drawing of 3a.
Table 1 Synthesis of cyclophosphamidic chlorides 3a
Entry
2
Ar
t/min
3
Yieldb (%)
1
2
3
4
5
2a
2b
2c
2d
2e
Ph
40
40
30
60
45
3a
3b
3c
3d
3e
91
89
92
87
90
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
In summary, a facile and efficient one-pot synthesis of
substituted cyclophosphamidic chlorides 3 has been developed
from readily available enaminones 2 in the presence of POCl3 in
a
Reagents and conditions: 2 (1.0 mmol), POCl3 (1.2 mmol), CH2Cl2, rt,
b
0.5–1.0 h. Isolated yield.
Table 2 Synthesis of cyclophosphamidic amides 4a
It is worth noting that the cyclophosphamidic chlorides 3
possess very rich functionality, such as a,b-unsaturated carbonyl
and chloropropyl groups, and in particular a phosphorus chloride
moiety, which may render them extremely versatile as valuable
synthetic scaffolds in the preparation of natural and synthetic
compounds with important biological and pharmacological acti-
vities. For example, the amidation product of 3 upon hydrogena-
tion may lead to the same core structure of cyclophosphamide 1.
Inspired by these, we next performed the reactions of cyclophos-
phamidic chlorides 3 with selected amines with the aim to
synthesize cyclophosphamidic amides. Thus, the reaction of 3a
and ethyl amine (aq, 1.1 equiv.) was conducted in the presence of
triethyl amine (1.2 equiv.) in CH2Cl2 at room temperature for
1.0 h. Workup and purification by column chromatography of the
resulting mixture furnished a product, which was characterized as
a cyclophosphamidic amide 4a-1 (92% yield) on the basis of its
spectral and analytical data (Table 2, entry 1). Under the
identical conditions, a range of cyclophosphamidic chlorides
3b–e containing different N-aryl groups were reacted with ethyl
amine, and the corresponding cyclophosphamidic amides 4 were
obtained in very high yields (Table 2, entries 2–5). The versatility
of the synthesis of cyclophosphamidic amides 4 was further
evaluated by reacting 3a with selected aliphatic and aromatic
amines, such as methylamine (aq), aniline and benzylamine
(Table 2, entries 6–8).
Entry
3
Ar
R
4
Yieldb (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3a
3a
3a
Ph
Et
Et
Et
Et
4a-1
4b-1
4c-1
4d-1
4e-1
4a-2
4a-3
4a-4
92
91
89
90
93
92
87
88
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
Ph
Et
Me
Ph
Bn
Ph
Ph
a
Reagents and conditions: 3 (1.0 mmol), RNH2 (1.1 mmol), Et3N
b
(1.2 mmol), CH2Cl2, rt, 1.0–1.5 h. Isolated yields.
Table 3 Synthesis of cyclophosphamidic esters 5aa
Entry
R
t/h
5a
Yield (%)b
1
2
3
4
Me
Et
Ph
Bn
1.0
1.5
1.5
1.0
5a-1
5a-2
5a-3
5a-4
90
93
94
92
a
Reagents and conditions: 3a (1.0 mmol), ROH (1.1 mmol), pyridine
b
(1.2 mmol), CH2Cl2, rt, 1.0–1.5 h. Isolated yields.
Scheme 2 Plausible mechanism for the synthesis of cyclophosphamidic
chlorides 3.
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24.4, 31.7, 36.7, 44.2, 111.9, 128.7, 128.9, 129.5, 134.5, 157.3, 165.0; IR
(KBr) 3221.8, 1675.3, 1455.6, 1392.9, 1257.3, 1121.9, 1073.0, 985.7,
695.6, 555.0 cmꢂ1; Anal. Calc. for C15H20ClN2O3P: C, 52.56; H, 5.88;
N, 8.17. Found: C, 52.42; H, 5.97; N, 8.23.
Typical procedure for the preparation of 5 from cyclophosphamidic
chlorides 3 (5a-1 as example): To a solution of 3a (333 mg, 1.0 mmol)
in CH2Cl2 (5 mL) at room temperature was added methanol (1.1 mmol)
and pyridine (1.2 mmol) in one portion. The mixture was stirred at room
temperature for 1.0 h. After the substrate 3a was consumed as indicated
by TLC, the mixture was then poured into saturated aqueous NaCl
(20 mL), which was extracted with dichloromethane (3 ꢁ 20 mL). The
combined organic phases were washed with water (3 ꢁ 20 mL), dried
over MgSO4, filtered and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, petroleum ether–diethyl
ether = 2 : 1) to give 5a-1 as a white solid (296 mg, 90%).
Scheme 3 One-pot synthesis of cyclophosphamidic amide (4a-1) and
ester (5a-1).
Selected data for 5a-1: White solid: mp 100–101 1C; 1H NMR (500 MHz,
CDCl3) d 1.94–1.98 (m, 2H), 2.27 (s, 3H), 2.51 (t, J = 7.5 Hz, 2H),
3.55–3.58 (m, 2H), 3.79 (d, J = 12 Hz, 3H), 7.32 (d, J = 7.5 Hz, 2H), 7.42
(d, J = 7.0 Hz, 1H), 7.46 (d, J = 7.0 Hz, 2H); 13C NMR (125 MHz,
CDCl3) d 18.9, 24.5, 31.6, 44.8, 56.0, 112.3, 129.2, 129.3, 129.4, 129.8,
133.2, 157.0, 164.1; Anal. Calc. for C14H17ClNO4P: C, 51.00; H, 5.20; N,
4.25. Found: C, 51.13; H, 5.28; N, 4.17.
CH2Cl2. As synthetic scaffolds, some of the newly synthesized
cyclophosphamidic chlorides were employed in the reactions with
selected amines and alcohols affording the corresponding cyclo-
phosphamidic amides 4 and esters 5, respectively, in high yields.
Moreover, one-pot synthesis of cyclophosphamidic amides 4 and
esters 5 from enaminones 2 has been achieved in high yields.
Associated with readily available starting materials, mild condi-
tions, high yields, and potential utility of the products, the one-pot
synthetic protocol for cyclophosphamide analogues is very attrac-
tive, in particular for library synthesis. The potential utilization
and extension of the scope of the methodology and the evaluation
of biological activity of the novel products are currently under
investigation in our laboratory.
1 For reviews, see: (a) G. Zon, Prog. Med. Chem., 1982, 19, 205–246;
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Notes and references
z Typical procedure for the synthesis of cyclophosphamidic chlorides 3
(3a as an example): To a solution of 2a (217 mg, 1.0 mmol) in CH2Cl2
(5 mL) at room temperature was added POCl3 (1.2 mmol) in one
portion. The mixture was stirred at room temperature for 40 minutes.
After substrate 2a was consumed as indicated by TLC, the mixture
was then poured into saturated aqueous NaCl (20 mL), which was
extracted with dichloromethane (3 ꢁ 20 mL). The combined organic
phases were washed with water (3ꢁ 20 mL), dried over MgSO4, filtered
and concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, petroleum ether–diethyl ether = 2 : 1) to
give 3a as a white solid (303 mg, 91%).
1
Selected data for 3a: White solid: mp 94–95 1C; H NMR (500 MHz,
CDCl3) d 1.94–2.02 (m, 2H), 2.33 (s, 3H), 2.52–2.65 (m, 2H), 3.54–3.61
(m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.46–7.51 (m, 3H); 13C NMR (125
MHz, CDCl3) d 18.8, 24.5, 31.5, 44.6, 114.4, 129.3, 129.6, 129.9, 131.9,
157.1, 163.1; IR (KBr) 1691.8, 1653.0, 1490.1, 1308.1, 1238.8, 1123.9,
1072.6, 945.0, 608.6, 543.5 cmꢂ1; Anal. Calc. for C13H14Cl2NO3P: C,
46.73; H, 4.22; N, 4.19. Found: C, 46.60; H, 4.28; N, 4.14. MS m/z
Calc.: 334.1; Found: 334.1 [M+].
Crystal data for 3a: C13H14Cl2NO3P, white crystal, M = 334.12,
monoclinic, P21/n, a = 9.560(3), b = 10.346(3), c = 15.722(5) A, b
= 104.543(5)1, V = 1505.2 (8) A3, Z = 4, T = 293(2), F000 = 688,
R1 = 0.0520, wR2 = 0.1501.
5 (a) A. Takamizawa, S. Matsumoto, T. Iwata, K. Katgiri,
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6 (a) T. Martinek, E. Forro, G. Gunther, R. Sillanpaa and F. Fulop,
´
¨ ¨
¨ ¨ ¨
Typical procedure for the preparation of 4 from cyclophosphamidic
chlorides 3 (4a-1 as example): To a solution of 3a (333 mg, 1.0 mmol)
in CH2Cl2 (5 mL) at room temperature was added ethylamine (aq,
1.1 mmol) and triethylamine (1.2 mmol) in one portion. The mixture was
stirred at room temperature for 1.0 h. After substrate 3a was consumed
as indicated by TLC, the mixture was then poured into saturated
aqueous NaCl (20 mL), which was extracted with dichloromethane
(3 ꢁ 20 mL). The combined organic phases were washed with water
(3 ꢁ 20 mL), dried over MgSO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (silica gel, petro-
leum ether–diethyl ether = 2 : 1) to give 4a-1 as a white solid
(315 mg, 92%).
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18, 1251–1253; (d) D. L. Hill, M. C. Kirk and R. F. Struck, J. Am.
Chem. Soc., 1970, 92, 3207–3208; (e) D. W. White, D. E. Gibbs and
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9 For POCl3-mediated heteroannulations, see: (a) C. Venkatesh,
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7, 2169–2172; (b) D. W. Gammon, R. Hunter and S. A. Wilson,
Tetrahedron, 2005, 61, 10683–10688.
Selected data for 4a-1: White solid: mp 125–126 1C; 1H NMR (500
MHz, CDCl3) d 0.97 (t, J = 7.0 Hz, 3H), 1.93–1.98 (m, 2H), 2.26
(s, 3H), 2.44–2.57 (m, 2H), 2.81–2.85 (m, 1H), 2.86–2.96 (m, 2H), 3.56
(t, J = 6.0 Hz 2H), 7.35 (d, J = 7.0 Hz, 2H), 7.39 (d, J = 7.0 Hz, 1H),
7.43 (d, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 16.7, 19.0,
ꢀc
This journal is The Royal Society of Chemistry 2008
6238 | Chem. Commun., 2008, 6236–6238