A novel, microwave-assisted method for the synthesis of alicyclic-condensed 5H-1,4,6,7-tetrahydro-1,4-diazepin-5-ones

Article abstract of DOI:10.1016/j.tetlet.2008.05.034

An efficient, high-yielding method has been developed for the synthesis of cycloalkane-fused and phenyl-substituted 1,4-diazepin-5-ones from β-amino acids. The process involves the oxidative cleavage of a terminal olefin bond and an acid-catalyzed, microw

Full text of DOI:10.1016/j.tetlet.2008.05.034

Tetrahedron Letters 49 (2008) 4333–4335
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A novel, microwave-assisted method for the synthesis of
alicyclic-condensed 5H-1,4,6,7-tetrahydro-1,4-diazepin-5-ones
Árpád Balázs a, Erik Van der Eycken c, Ferenc Fülöp a,b,
*
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
b Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
c Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), K.U. Leuven, Celestijnenlaan 200F, B-3000 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, high-yielding method has been developed for the synthesis of cycloalkane-fused and phenyl-
substituted 1,4-diazepin-5-ones from b-amino acids. The process involves the oxidative cleavage of a
terminal olefin bond and an acid-catalyzed, microwave-assisted intramolecular condensation step.
Ó 2008 Published by Elsevier Ltd.
Received 15 April 2008
Revised 30 April 2008
Accepted 7 May 2008
Available online 11 May 2008
Keywords:
Microwave
b-Amino acid
Oxidative cleavage
1,4-Diazepin-5-one
Although the preparation and pharmaceutical properties of 1,4-
benzodiazepines have been well documented, less attention has
been paid to their saturated analogues. To the best of our knowledge,
there has been only one report on the synthesis of cycloalkane-
condensed 1,4-diazepinones.1 However, certain 1,4-diazepin-5-
ones exhibit significant biological properties, for example, as
lymphocyte function-associated antigen-1 inhibitors,2 anticonvul-
sants,3 HIV-1 reverse transcriptase inhibitors,4 pharmacophores
for structure–activity relationships,5 and most recently, c-turn-like
mimics.6
The reaction of cis-cyclohexane derivative 6 (R1 = Me) in the
presence of 10 mol % p-TsOH in dry CH2Cl2 in a MW reactor at
100 °C for only 5 min resulted in complete conversion to 1,4-diaze-
pin-5-one 9 in 90% yield.11 For cyclopentane derivative 7 (R1 = Me),
application of the same method gave compound 10 in 81% yield.
The method also proved adaptable for trans-cyclohexane deriva-
tive 14, providing 1,4-diazepin-5-one 15 in an excellent (88%)
yield. Broadening the scope of the transformation led to the syn-
thesis of the PMB-protected derivative 8 (n = 2, R1 = PMB), which
furnished diazepinone 11 in 83% yield.
We report here an efficient, microwave (MW)-assisted method
for the preparation of cis- and trans-cyclohexane- and cis-cyclopen-
tane-condensed 5H-1,4,6,7-tetrahydro-1,4-diazepin-5-ones.
Starting from racemic cis- and trans-2-aminocyclohexane-car-
boxylic acids 1 and 12 and cispentacin7 2, Cbz (benzyloxycarbonyl)
protection of the amino group followed by amidation with allyl-
methylamine or allyl(p-methoxy)benzylamine and subsequent
oxidative cleavage of the carbon–carbon double bond furnished
the corresponding formylmethyl carboxamides 6–8 and 14
(Scheme 1). An initial attempt, to perform the oxidative cleavage
in a one-pot fashion, according to a literature procedure,8 resulted
in a low yield of the desired carbonyl compound 6. However, the
stepwise procedure reported for carbohydrate derivatives by Shar-
ma and Nielsen9 resulted in compounds 6–8 and 14 in overall
yields of 71–79%.10
We next investigated the scope and limitations of the ring clo-
sure. 7-Phenyl-5H-1,4,6,7-tetrahydro-1,4-diazepin-5-one 18 was
formed in 83% yield from compound 17, itself synthesized from
( )-b-phenylalanine12 16 (Scheme 2) via the process established
for 1, 2 and 12 in Scheme 1.
Our efforts to apply this method to anthranilic acid derivatives
failed to yield the desired 1,4-benzodiazepin-5-ones. One possible
explanation is that decreasing the nucleophilicity of the aniline
nitrogen with a Cbz group inhibits nucleophilic attack on the
aldehyde moiety. However, for N-methyl- and N-benzylanthranil-
amides, a similar method involving the application of acetal
derivatives has been reported for the construction of 1,4-benzo-
diazepin-5-ones.13
In conclusion, b-amino acid-derived allylamides have been
transformed efficiently into the corresponding aldehydes by apply-
ing a dihydroxylation/reduction/oxidative cleavage sequence. The
formylmethyl derivatives obtained were cyclized to 1,4,6,7-tetra-
hydro-1,4-diazepin-5-ones in high yields in an acid-promoted
* Corresponding author. Tel.: +36 62 545 564; fax: +36 62 545 705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.05.034

4334
Árpád Balázs et al. / Tetrahedron Letters 49 (2008) 4333–4335
O
O
O
R1
O
R1
R1
O
N
N
N
i, ii
OH
NH2
1, 2
iii
n
n
n
iv
n
H
NH
NH
N
Cbz
Cbz
Cbz
3, 4, 5
6, 7, 8
9, 10, 11
O
O
O
Me
O
Me
Me
O
N
N
N
OH
NH2
i, ii
iii
iv
H
NH
NH
N
Cbz
Cbz
Cbz
12
13
14
15
1
2, 4, 7, 10
3, 4, 6, 7, 9, 10
R = Me :
n = 1 :
n = 2 : 1, 3, 5, 6, 8, 9, 11 R1 = PMB : 5, 8, 11
PMB = -methoxybenzyl
p
Scheme 1. Reagents and conditions: (i) CbzCl, NaOH, CH2Cl2, rt (81–90%); (ii) (COCl)2, CH2Cl2, rt, 4 h, then Et3N, R1-allylamine, CH2Cl2, rt, overnight (83–88%); (iii) (a)
RuCl3ÁnH2O, NaIO4, CH3CN/EtOAc/H2O, 0 °C, 5 min, (b) NaBH4, THF/H2O, rt, 20 min, (c) NaIO4, THF/H2O, 0–5 °C, 30 min (71–79% for the three steps); (iv) p-TsOH, CH2Cl2, MW,
100 °C, 5 min (81–90%).
O
O
O
Me
Me
O
N
N
OH
i, ii, iii
iv
H
NH
NH2
N
Cbz
Cbz
18
16
17
Scheme 2. Reagents and conditions: as in Scheme 1. Yields: (i) 83%, (ii) 79%, (iii) 63%, (iv) 83%.
11. General procedure for the preparation of 5H-1,4,6,7-tetrahydro-1,4-diazepin-5-
MW-assisted condensation reaction. The method proved not to be
restricted to cycloalkane-derived b-amino acids, and the nitrogens
can be orthogonally protected (R1 = PMB), which opens up the
possibility for further transformations.
ones 9–11, 15 and 18: A CEM Discover 10 ml MW vial was charged with
0.3 mmol of compounds 6–8, 14 or 17, 5.7 mg (10 mol %) of p-toluenesulfonic
acid and 2 ml of anhydrous dichloromethane, and was sealed with a Teflon cap.
The vial was irradiated at 100 °C (200 W) for 5 min, with a 1.5 min ramp time.
Next, the solvent was evaporated under reduced pressure and the residue was
purified by flash column chromatography on Merck silica gel (0.063–
0.200 mm); elution with 1:1 n-hexane/ethyl acetate gave the pure
compounds. Compound 9: white solid; yield 90%, mp 76–77 °C, 1H NMR
(400.13 MHz, CDCl3, d): 7.31–7.47 (m, 5H), 6.40 (br s, 1H), 5.05–5.28 (m, 3H),
4.37 (d, J 10.0 Hz, 1H), 3.08 (s, 3H), 2.94 (s, 1H), 2.34 (d, J 12.5, 1H), 1.85–2.06
(m, 2H), 1.68–1.83 (m, 2H), 1.27–1.60 (m, 3H). 13C NMR (100.61 MHz, CDCl3,
d): 171.9, 153.8, 136.2, 129.8, 129.2, 129.0, 128.8, 127.9, 114.3, 111.9, 68.6,
62.5, 43.9, 37.0, 36.6, 29.7, 25.8, 21.3. Anal. Calcd for C18H22N2O3: C, 68.77; H,
7.05; N, 8.91; O, 15.27. Found: C, 69.04; H, 6.92; N, 8.75; O, 15.44. Compound
10: colourless oil; yield 81%, 1H NMR (400.13 MHz, CDCl3, d): 7.31–7.39 (m,
5H), 6.31 (d, J 6.5 Hz, 1H), 5.41 (d, J 6.5 Hz, 1H), 5.13–5.25 (m, 2H), 4.65–4.72
(m, 1H), 2.99–3.10 (m, 4H), 2.19–2.29 (m, 2H), 1.57–1.95 (m, 4H). 13C NMR
(100.61 MHz, CDCl3, d): 173.3, 151.2, 136.6, 129.2, 129.1, 129.0, 128.8, 128.7,
119.8, 119.4, 69.4, 68.7, 48.6, 35.9, 29.8, 26.7, 22.4. Anal. Calcd for C17H20N2O3:
C, 67.98; H, 6.71; N, 9.33; O, 15.98. Found: C, 68.07; H, 6.82; N, 9.45; O, 15.74.
Compound 11: colourless oil; yield 83%, 1H NMR (400.13 MHz, CDCl3, d): 7.29–
7.39 (m, 5H), 7.19 (d, J 8.1 Hz, 2H), 6.84 (d, J 9.1 Hz, 2H), 6.39 (br s, 1H), 5.07–
5.24 (m, 3H), 4.74 (d, J 14.1 Hz, 1H), 4.56 (d, J 14.1 Hz, 1H), 4.37 (d, J 10.1 Hz,
1H), 3.78 (s, 3H), 2.96 (s, 1H), 2.38 (d, J 12.1 Hz, 1H), 1.89–2.05 (m, 2H), 1.77 (d,
J 14.1 Hz, 1H), 1.29–1.56 (m, 4H). 13C NMR (100.61 MHz, CDCl3, d): 171.9,
159.7, 136.5, 130.1, 130.0, 129.9, 129.8, 129.7, 129.6, 129.3, 129.2, 129.1, 129.0,
128.7, 114.7, 110.5, 68.8, 62.8, 55.9, 51.5, 44.3, 31.1, 30.0, 26.1, 21.7. Anal. Calcd
for C25H28N2O4: C, 71.41; H, 6.71; N, 6.66; O, 15.22. Found: C, 71.27; H, 6.90; N,
6.81; O, 15.37. Compound 15: white solid; yield 88%, mp 79–80 °C, 1H NMR
(400.13 MHz, CDCl3, d): 7.31–7.42 (5H, m), 6.39 (1H, br s), 5.15–5.25 (m, 2H),
5.10 (d, J 4.0 Hz, 1H), 4.36 (d, J 10.1 Hz, 1H), 3.08 (s,3H), 2.94 (br s, 1H), 2.34 (d, J
12.9 Hz, 1H), 1.86–2.02 (m, 2H), 1.71–1.83 (m, 1H), 1.22–1.61 (m, 4H). 13C NMR
(100.61 MHz, CDCl3, d): 171.4, 153.3, 135.9, 128.7, 128.6, 128.5, 128.3, 128.1,
113.8, 111.4, 68.2, 62.1, 43.5, 36.2, 30.3, 29.2, 25.4, 21.0. Anal. Calcd for
Acknowledgement
We are grateful to the Hungarian Research Foundation (OTKA
No. T049407) for financial support.
References and notes
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10. Representative analytical data for aldehyde 8: Colourless oil; yield 79%, 1H NMR
(400.13 MHz, CDCl3, d): 9.41 (s, 1H), 7.30–7.39 (m, 5H), 7.02–7.10 (m, 2H),
6.81–6.90 (m, 2H), 5.46 (d, J 7.6 Hz, 1H), 5.11 (s, 2H), 4.51 (q, J 15.7 Hz, 2H),
3.91 (d, J 4.9 Hz, 2H), 3.76–3.85 (m, 4H), 3.29 (d, J 4.1 Hz, 1H), 2.17–2.28 (m,
1H), 1.92–2.02 (m, 1H), 1.37–1.77 (m, 6H). 13C NMR (100.61 MHz, CDCl3, d):
197.2, 174.5, 159.5, 155.9, 136.6, 129.5, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7,
127.5, 114.5, 114.3, 66.5, 55.8, 55.4, 55.2, 49.5, 40.5, 29.3, 26.4, 22.7, 22.2. Anal.
Calcd for C25H30N2O5: C, 68.47; H, 6.90; N, 6.39; O, 18.24. Found: C, 68.29; H,
6.73; N, 6.50; O, 18.39.
C
18H22N2O3: C, 68.77; H, 7.05; N, 8.91; O, 15.27. Found: C, 68.93; H, 7.11; N,
9.02; O, 15.13. Compound 18: colourless oil; yield 83%, 1H NMR (DMSO-d6,
400.13 MHz, 319.3 K) 7.12–7.34 (m, 10H), 6.64 (d, J 8.5 Hz, 1H), 5.74–5.78 (m,

Árpád Balázs et al. / Tetrahedron Letters 49 (2008) 4333–4335
4335
1H), 5.39–5.46 (m, 1H), 5.12 (brs, 2H), 2.98–3.10 (m, 2H), 2.77 (s, 3H). 13C NMR
(100.61 MHz, CDCl3, d): 169.9, 152.6, 136.4, 129.5, 129.4, 129.3, 129.2, 129.1,
128.2, 128.1, 125.9, 125.8, 125.7, 115.8, 113.8, 68.9, 60.8, 59.8, 43.1, 35.6. Anal.
Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33; O, 14.27. Found: C, 71.23; H,
6.12; N, 8.26; O, 14.20.
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