Concise synthesis of novel 2,6-diazaspiro[3.3]heptan-1-ones and their conversion into 2,6-diazaspiro[3.3]heptanes

Article abstract of DOI:10.1055/s-2007-986649

A concise synthesis, amenable to library production of 2,6-diazaspiro[3.3] heptan-1-ones and their subsequent conversion into 2,6-diazaspiro[3.3]heptanes is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-986649

LETTER
2587
Concise Synthesis of Novel 2,6-Diazaspiro[3.3]heptan-1-ones and Their
Conversion into 2,6-Diazaspiro[3.3]heptanes
Synthesis of
N
ovel 2,6
i
-Diaza
c
spiro[3.3]he
h
ptan-1-one
s
ael J. Stocks,* Daniel Hamza, Garry Pairaudeau, Jeffrey P. Stonehouse, Philip V. Thorne
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK
Fax +44(1509)645571; E-mail: mike.stocks@astrazeneca.com
Received 21 May 2007
O
O
Abstract: A concise synthesis, amenable to library production of
2,6-diazaspiro[3.3]heptan-1-ones and their subsequent conversion
into 2,6-diazaspiro[3.3]heptanes is reported.
1. SOCl2, 80 °C
Cl
Cl
Cl
Cl
HO
Cl
N
H
2. BnNH2,
CHCl3,
Et3N
Cl
Key words: ring closure, spiro compounds, combinatorial chemis-
try, lactams, heterocycles
40% NaOH
CH2Cl2, r.t.
The design and synthesis of novel, readily functionalised
low-molecular-weight fragments is of fundamental im-
portance in modern drug-discovery programs employing
rapid parallel-synthesis techniques.1
1. NaOEt
2. K2CO3,
toluene
O
O
N
N
OEt
Cl
Cl
Cl
4
3
The spirocyclic 2,6-diazaspiro[3.3]heptan-1-one ring sys-
tem 1 is an example of such a novel2 system and we report
here a practical synthesis of this chemically interesting
ring system amenable to either large-scale or plate-based
library chemistries. We also report on their subsequent
Scheme 2 Synthesis of 1-benzyl-3-chloromethyl-azetidine-3-
carboxylic acid ethyl ester
conversion
(Scheme 1).
into
2,6-diazaspiro[3.3]heptanes
2
4
LiOH, EtOH (aq), 1 equiv
O
R1
N
Ph
Ph
Ph
R1
N
N
N
N
CO2H
Cl
COCl
Cl
N
(COCl)2, CH2Cl2
N
R2
R2
1
2
7
5
6
Scheme 1 2,6-Diazaspiro[3.3]heptan-1-ones and their conversion
into 2,6-diazaspiro[3.3]heptanes
CO2H
OH
(obtained with 2 equiv of LiOH)
In 1991, Bartholomew and Stocks3 reported the synthesis
of 1-benzyl-3-chloromethyl-azetidine-3-carboxylic acid
ethyl ester 4 from the alkoxide-induced rearrangement of
a substituted azetidinone 3 (Scheme 2).
Scheme 3 Hydrolysis of ester 4 and preparation of acid chloride 7
Hydrolysis of 4 occurs readily through treatment with one
equivalent of lithium hydroxide in ethanol–water to afford
the stable crystalline substituted carboxylic acid 5 [n.b.
hydrolysis with 2 equivalents of lithium hydroxide at
60 °C affords the corresponding hydroxy-substituted
carboxylic acid 6 (Scheme 3)].4
conversion were obtained by treating 5 with oxalyl chlo-
ride in dichloromethane to afford the acid chloride 7
isolated as the stable crystalline hydrochloride salt.5 Pre-
mixing a suspension of 7 and the corresponding amine
(R1NH2) in dichloromethane at 5 °C, followed by the ad-
dition of triethylamine, afforded amides 8a–g in high
yield (Table 1).
The acid 5 will react with a series of amines or anilines in
the presence of a suitable coupling agent, such as HATU,
to generate the corresponding amides 8a–g in reasonable
yield. However, the optimal reaction conditions for this
Pleasingly, the conversion of amides 8a–g into their cor-
responding spirocyclic 2,6-diazaspiro[3.3]heptan-1-ones
1a–g occurred readily, optimum conditions being sodium
hydride in THF at room temperature (Scheme 4).6
SYNLETT 2007, No. 16, pp 2587–2589
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1
.1
0
.2
0
0
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Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986649; Art ID: D15407ST
© Georg Thieme Verlag Stuttgart · New York

2588
M. J. Stocks et al.
LETTER
Ph
Table 1 Generation of Amides 8a–g and 2,6-Diazaspiro[3.3]hep-
tan-1-ones 1a–g
O
N
Pd(OH)2, HCO2NH4,
EtOH, reflux, 4 h
HN
O
N
Entry Amine R1NH2
Step 1
Step 2
N
8a–g (yield, %a) 1a–g (yield, %a)
NH2
1a
9
1
8a (91)
1a (97)
1b (76)
Scheme 5 Hydrogenolysis of benzyl group
NH2
b
2
Table 2 Reduction of 2,6-Diazaspiro[3.3]heptan-1-one 1a
F
Ph
Ph
O
3
8c (96)
8d (48)
8e (50)
1c (82)
1d (66)
1e (67)
N
N
NH2
N
N
F
4
2a
1a
NH2
Entry Reagent
conditions
Conversion Comment
(%)a
O
5
1
2
3
4
5
LiAlH4, THF,
40 °C
0
1 equiv
NH2
Et
BH3·THF,
40 °C
0
Reversible complexation to
borane observed
6
7
NH2
8b
1f (46)c
1g (68)
N
Et
LiAlH4, AlCl3,
Et2O, 40 °C
38
58
78
1.5 equiv 55% recovered 1a
3 equiv 32% recovered 1a
5 equiv 15% recovered 1a
O
NH2
8g (58)
LiAlH4, AlCl3,
Et2O, 40 °C
a Yields refer to fully characterised and pure compounds.
b Combined yield, compounds 8b and 8d were used crude in subse-
quent cyclisation step.
LiAlH4, AlCl3,
Et2O, 40 °C
c Heating required at 70 °C for 3 h to effect cyclisation.
a Yields refer to fully characterised and pure compounds.
5 + R1NH2, HATU,
Et3N, CH2Cl2
7 + R1NH2, Et3N, CH2Cl2
Ph
To enable further elaboration,7 the benzyl group can be
readily removed. For example, 1a can be converted into 9
in 74% yield using transfer hydrogenation conditions
(Scheme 5).8
Ph
O
N
N
R1
R2
Cl
N
H
step 1
Cl
5 R2 = CO2H
7 R2 = COCl
In order to convert 1a into the corresponding 2,6-diaza-
spiro[3.3]heptane 2a,9 a series of reducing agents was
tested and the results are summarised in Table 2.
8a–g
step 2 NaH, THF
Ph
Surprisingly, 1a proved resistant to reduction with lithium
aluminium hydride and only unreacted starting material
was recovered after heating at 40 °C for 2 hours. Borane
in THF produced a highly crystalline and insoluble borane
complex10 and no evidence of reduction was observed.
The unreactive complex could be converted back into 1a
by heating in methanolic ammonia solution. Clean con-
version of 1a into 2a was observed by the reduction with
the LiAlH4/AlCl3 complex,11 although 5 equivalents of
the reagent were required for satisfactory conversion.12,13
O
N
N
R1
1a–g
Scheme 4 Synthesis of 2,6-diazaspiro[3.3]heptan-1-ones 1a–g
The following compounds 1a–g have been prepared as
representative examples to illustrate the applicability of
the reaction sequence through reaction with primary alkyl
amines as well as electron-rich, electron-poor, and steri-
cally hindered anilines (Table 1).
In summary, a concise synthesis of the chemically novel,
readily functionalised 2,6-diazaspiro[3.3]heptan-1-one
ring system has been reported as well as its conversion
into the substituted 2,6-diazaspiro[3.3]heptane ring sys-
tem. Work is continuing within our laboratory in this area
and we will report on further studies in the future.
Synlett 2007, No. 16, 2587–2589 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel 2,6-Diazaspiro[3.3]heptan-1-ones
2589
phenyl-2,6-diazaspiro[3.3]heptan-1-one (2.14 g) as a white
solid after recrystallisation from Et2O–i-hexane; mp 122–
123 °C. MS: m/z = 279.2 [M + H]+; 99.3% purity. Anal.
Calcd. for: C. 77.67; H, 6.52; N, 10.06. Found: C, 77.57; H,
6.55; N, 10.13. 1H NMR (400 MHz, CDCl3): d = 7.35–7.24
(m, 9 H), 7.10–7.06 (m, 1 H), 3.86 (s, 2 H), 3.66 (s, 2 H), 3.61
(d, J = 1.5 Hz, 4 H). 13C NMR (100 MHz, CDCl3): d = 165.8,
138.0, 137.4, 129.1, 128.5, 128.4, 127.2, 123.9, 116.3, 62.9,
58.2, 51.6, 50.3.
References and Notes
(1) For some recent applications of parallel synthesis in drug
design, see: (a) Habashita, H.; Kokubo, M.; Hamano, S.-I.;
Hamanaka, N.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa,
K.; Fukushima, D.; Maeda, K.; Mitsuya, H. J. Med. Chem.
2006, 49, 4140. (b) Edwards, P. J. IDrugs 2006, 9, 347.
(c) Lu, S.-F.; Chen, B.; Davey, D.; Dunning, L.; Jaroch, S.;
May, K.; Onuffer, J.; Phillips, G.; Subramanyam, B.; Tseng,
J.-L.; Wei, R. G.; Wei, M.; Ye, B. Bioorg. Med. Chem. Lett.
2007, 17, 1883.
(2) To the best of our knowledge the azetidine-derived
spirocyclic b-lactam (2,6-diazaspiro[3.3]heptan-1-one) ring
system has not previously been prepared in the chemical
literature. Proline-derived spirocyclic b-lactams are
represented in the chemical literature and are useful as b-turn
mimetics. For examples, see: (a) Macías, A.; Morán
Ramallal, A.; Alonso, E.; del Pozo, C.; González, J. J. Org.
Chem. 2006, 71, 7721. (b) Bittermann, H.; Gmeiner, P.
J. Org. Chem. 2006, 71, 97. (c) Khasanov, A. B.; Ramirez-
Weinhouse, M. M.; Webb, T. R.; Thiruvazhi, M. J. Org.
Chem. 2004, 69, 5766. (d) Alonso, E.; Lopez-Ortiz, F.; del
Pozo, C.; Peralta, E.; Macias, A.; Gonzalez, J. J. Org. Chem.
2001, 66, 6333. For recent syntheses of piperidine-derived
spirocyclic b-lactams, see: (e) Arnott, G.; Clayden, J.;
Hamilton, S. D. Org. Lett. 2006, 8, 5325. (f) Macias, A.;
Alonso, E.; del Pozo, C.; Gonzalez, J. Tetrahedron Lett.
2004, 45, 4657. (g) Clayden, J.; Hamilton, S. D.;
(7) The free azetidine 9 can be readily functionalised by reaction
with, for example: (a) acid chlorides to generate amides;
(b) aldehydes to generate N-substituted alkyl amines;
(c) isocyanates to generate ureas and (d) sulfonyl chlorides
to generate sulfonamides under standard reaction conditions.
(8) Analysis of 2-phenyl-2,6-diazaspiro[3.3]heptan-1-one (9):
mp 149–150 °C. GC-MS: m/z = 188 [M]+; 100% pure. Anal.
Calcd for: C, 70.19; H, 6.43; N, 14.79. Found: C, 70.05; H,
6.51; N, 14.79. 1H NMR (400 MHz, CDCl3): d = 7.35–7.30
(m, 4 H), 7.11–7.07 (m, 1 H), 4.27 (d, J = 9.6 Hz, 2 H), 3.86
(s, 2 H), 3.79 (d, J = 9.6 Hz, 2 H), 1.83 (s, 1 H). 13C NMR
(100.5 MHz, CDCl3): d = 166.1, 138.0, 129.1, 124.0, 116.3,
54.1, 51.7, 51.5.
(9) For a recent synthesis of this interesting ring system, see:
(a) Hillier, M. C.; Chen, C.-Y. J. Org. Chem. 2006, 71,
7885. (b) For an application of the use of 2,6-diaza-
spiro[3.3]heptanes in drug discovery, see: Engel, W.;
Eberlein, W.; Trummlitz, G.; Mihm, G.; Doods, H.; Mayer,
N.; De Jonge, A. EP 417631, 1991.
(10) For some examples of the reduction of b-lactams to
azetidines, see: (a) Brayer, J. L.; Alazard, J. P.; Thal, C.
Tetrahedron 1990, 46, 5187. (b) Ojima, I.; Zhao, M.;
Yamato, T.; Nakahashi, K.; Yamashita, M.; Abe, R. J. Org.
Chem. 1991, 56, 5263. (c) Yamashita, M.; Ojima, I. J. Am.
Chem. Soc. 1983, 105, 6339. (d) Ojima, I.; Yamato, T.;
Nakahashi, K. Tetrahedron Lett. 1985, 26, 2035.
(11) (a) Van Brabandt, W.; De Kimpe, N. Synlett 2006, 2039.
(b) Van Elburg, P. A.; Reinhoudt, D. N. Heterocycles 1987,
26, 437.
Mohammed, R. T. Org. Lett. 2005, 7, 3673.
(3) (a) Bartholomew, D.; Stocks, M. J. Tetrahedron Lett. 1991,
32, 4795. (b) Optimised experimental conditions for the
synthesis of 4 from the readily available precursor 3 are
given. To cold EtOH (250 mL) at 0–5 °C was added Na
metal (25.5 g, 1.5 equiv). The solution was allowed to warm
to r.t. and was stirred for 1 h. To the reaction mixture was
added a solution of compound 3 (190 g) in EtOH (100 mL)
and the reaction was stirred for 14 h at r.t. The reaction
mixture was slowly poured into ice-cold H2O and extracted
with PE (3 × 250 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated.
The crude reaction product (110 g) was dissolved in toluene
(800 mL) and K2CO3 (110 g, 2.2 equiv) added. The reaction
mixture was refluxed for 16 h, cooled, and filtered. The
residue was purified over silica gel eluting with 8% EtOAc
in isohexane to give 1-benzyl-3-chloromethylazetidine-3-
carboxylic acid ethyl ester (60 g) as pale yellow liquid. 1H
NMR (300 MHz, CDCl3): d = 7.37–7.22 (m, 5 H), 4.23 (q,
J = 7.1 Hz, 2 H), 4.05 (s, 2 H), 3.64 (s, 2 H), 3.43 (d, J = 8.5
Hz, 2 H), 3.31 (d, J = 8.5 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3 H).
(4) Hydrolysis of 4 was previously reported to afford 6; see ref.
3 for details.
(12) The high stoichiometry of the reduction makes this reaction
incompatable with library synthesis. However, a new
synthesis of 2,6-diazaspiro[3.3]heptanes, amenable to
library synthesis, will be communicated separately.
(13) Preparation of 2a
To a stirred solution of AlCl3 (0.20 g) in Et2O (3 mL) was
added LiAlH4 in Et2O (1 M, 1.49 mL) and the mixture stirred
at 40 °C for 15 min before being cooled to r.t. and 6-benzyl-
2-phenyl-2,6-diazaspiro[3.3]heptan-1-one (0.139 g) in THF
(1 mL) was added. The reaction was warmed to 40 °C for
1 h before being cooled to r.t. Then, H2O (0.2 mL), followed
by 15% NaOH solution (0.2 mL), and finally H2O (0.6 mL)
were added. The mixture was stirred for 15 min and filtered.
The solution was concentrated and the residue purified by
chromatography on silica gel eluting with 2–5% 0.7 N NH3
in MeOH in CH2Cl2 to afford 2-benzyl-6-phenyl-2,6-
diazaspiro[3.3]heptane (0.077 g) as an oil. MS: m/z = 265.17
[M + H]+. 1H NMR (400 MHz, CDCl3): d = 7.34–7.18 (m, 7
H), 6.73 (t, J = 7.5 Hz, 1 H), 6.44 (d, J = 7.0 Hz, 2 H), 3.94
(s, 4 H), 3.60 (s, 2 H), 3.40 (s, 4 H). 13C NMR (100 MHz,
CDCl3): d = 151.4, 137.7, 128.8, 128.4, 128.3, 127.1, 117.6,
111.5, 64.4, 63.5, 62.2, 34.7.
(5) Compound 7 can be stored under dry nitrogen for up to four
weeks.
(6) Preparation of 1a
To a stirred suspension of NaH (60% in mineral oil, 0.349 g)
in THF (30 mL) was added 1-benzyl-3-chloromethyl-
azetidine-3-carboxylic acid phenylamide (2.5 g) in THF
(15 mL) and the mixture stirred for 2 h at r.t. Then, H2O was
added and the mixture was extracted with EtOAc. The
organic phase was dried with anhyd MgSO4, filtered, and
concentrated. The residue was purified by flash column
chromatography eluting with EtOAc to give 6-benzyl-2-
Synlett 2007, No. 16, 2587–2589 © Thieme Stuttgart · New York