Multicomponent approach to unique 1,4-diazepine-2-amines

Article abstract of DOI:10.1016/j.tetlet.2009.03.141

Isocyanide-based multicomponent reaction (IMCR) of 1,3-diaminopropane with carbonyl compounds has been developed as an efficient strategy for the synthesis of 1,4-diazepine-2-amines. Br?nsted and Lewis acids are able to promote the reaction, and TMSCl has

Full text of DOI:10.1016/j.tetlet.2009.03.141

Tetrahedron Letters 50 (2009) 2854–2856
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Tetrahedron Letters
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Multicomponent approach to unique 1,4-diazepine-2-amines
a
b
a
a
Volodymyr Kysil a, , Alexander Khvat , Sergey Tsirulnikov , Sergey Tkachenko , Alexandre Ivachtchenko
*
a ChemDiv, Inc., 6605 Nancy Ridge Dr., San Diego, CA 92121, USA
b Chemical Diversity Research Institute, Khimki, Moscow Reg. 114401, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Isocyanide-based multicomponent reaction (IMCR) of 1,3-diaminopropane with carbonyl compounds has
been developed as an efficient strategy for the synthesis of 1,4-diazepine-2-amines. Brønsted and Lewis
acids are able to promote the reaction, and TMSCl has been found to be the most efficient among them.
The IMCR is applicable to a variety of carbonyl compounds and isocyanides.
Received 20 February 2009
Revised 17 March 2009
Accepted 18 March 2009
Available online 25 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanide-based multicomponent reaction
(IMCR)
1,4-Diazepine-2-amine
1,4-Diazepine ring synthesis
Trimethylchlorosilane (TMSCl)
Spiro-compounds
1,4-Diazepines are of considerable importance due to their wide
spectrum of biological activity. For instance, substituted 1,4-diaze-
pines have been reported as dipeptidyl peptidase IV inhibitors for
treatment of type 2 diabetes1, gelatinase type A (MMP-2) and type
B (MMP-9) and collagenase 3 (MMP-13) inhibitors (potentially
antiarthritic and oncolytic drugs),2 HDM2 antagonists,3 caspase
inhibitors,4 LFA-1/ICAM-1 interaction inhibitors (antipsoriatics),5
chymase inhibitors (agents for treatment of atopic dermatitis),6
integrin alphaLbeta2 (LFA-1) antagonists,7 5-HT2C agonists,8 mel-
anocortin MC1 and MC4 receptor agonists.9 In addition, the nu-
cleus of highly functionalized 1,4-diazepine is a key structural
fragment of recently isolated Streptomyces sp. II novel lipo-nucleo-
side antibiotics caprazamycins.10 Moreover, according to Prous Sci-
ence Integrity data,11 several functionalized 1,4-diazepines are
currently being developed in phase II clinical studies for treatment
of several conditions: overactive bladder or urge urinary inconti-
nence,12 schizophrenia, obesity,13 nausea and vomiting.14 There-
fore, 1,4-diazepines are an attractive synthetic target. Although
many synthetic routes for 1,4-diazepine ring construction have
been developed, novel flexible strategies for the synthesis of di-
verse hitherto unknown 1,4-diazepines should benefit both syn-
thetic heterocyclic and medicinal chemistry.
ecules.15 At the same time, only a few examples of the IMCR-based
approaches for the synthesis of 1,4-diazepines have been
reported.16
We have recently reported an unprecedented IMCR of ethylene-
diamine(s) with carbonyl compounds which leads to highly substi-
tuted pyrazine-2-amines.17 We assumed that this IMCR could be
broadened to the synthesis of 1,4-diazepine-2-amines if 1,3-dia-
mines are involved as starting diamines. The present Letter
describes such extension as a part of scope evaluation of the men-
tioned IMCR. It should be noted, that while IMCRs of 1,2-diazanu-
cleophiles including primary amines are under extensive
elaboration for the last few years,18,19 only one example of
seven-membered ring formation employing 5-(2-pyrrolidi-
nyl)methyl-1H-tetrazole as a 1,3-diazanucleophile has been repor-
ted18d to date.
In our initial experiments, we evaluated conditions and po-
tential promoters for the IMCR performance on a model reaction
of 1,3-diaminopropane 1, cylohexanone 2, and tert-butyl isocya-
nide 3a (Scheme 1). Notably, acidic catalysis is usually required
H
During the past decade, isocyanide-based multicomponent
reactions (IMCRs) gained significant interest within the scientific
community as an efficient, convenient, time-saving, and atom-eco-
nomical approach to a variety of drug-like small heterocyclic mol-
N
NH2
+
CN R1
3
+
O
NH2
NH
R1
N
4
1
2
HCl
* Corresponding author. Tel.: +1 858 794 4860; fax: +1 858 794 4931.
E-mail addresses: vkysil@chemdiv.com, vkysil@sbcglobal.net (V. Kysil).
Scheme 1. IMCR of 1,3-diaminopropane with cyclohexanone and various
isocyanides.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.141

V. Kysil et al. / Tetrahedron Letters 50 (2009) 2854–2856
2855
Table 1
R1
N
R1
Synthesis of 1,4-diazepine-2-amines by the IMCR of 1,3-diaminopropane and
carbonyl compounds
R2
R2
H
N
R1
R2
NH2
NH2
O
NH
+
Entry Carbonyl compound
Isocyanide
Product
Yield
(%)
NH2
7
6
5
1
A+
A+
1
2
3
4
5
6
7
8
Cyclohexanone 2
Cyclohexanone 2
Cyclohexanone 2
Cyclohexanone 2
tert-Butyl
4a R = t-Bu
4b R = cyclo-C5
4c R = Bn
63
81
79
91
72
62
64
59
isocyanide 3a
Cyclopentyl
isocyanide 3b
Benzyl
isocyanide 3c
4-Chlorobenzyl 4d R = 4-ClC6H4CH2
isocyanide 3d
Cyclohexyl
isocyanide 3e
Cyclohexyl
isocyanide 3e
Cyclohexyl
isocyanide 3e
Cyclohexyl
R1
R1
A
R2
NH
R2
HN+
N+
A+ - Bronsted or
Lewis acid
A
9
NH2
8
N+
C
R3
Tetrahydro-4H-
thiopyran-4-one 13a
N-Boc-piperidone-4 13b
15a X = S
R3
HN
R3
R1
15b X = N-Boc
16a R = 4-MeOC6H4
R3
N+
C
R1
R2
R2
NH
N
4-Methoxybenzaldehyde
14a
1-Methyl-pyrrole-2-
carbaldehyde 14b
- LA
NH2
R1
NH
N
HN
11
R2
A
16b R = 1-
Methylpyrrol-2-yl
N
isocyanide 3e
10
12
Scheme 2. Proposed mechanistic scenario of the IMCR of 1,3-diaminopropane with
carbonyl compounds.
and allowed isolation of target material employing chromatogra-
phy-free simple work-up and purification procedures.22
We further evaluated a small set of additional isocyanides 3b–d
in the IMCR of cyclohexanone and 1,3-diaminopropane under our
discovered conditions (Scheme 1). In addition, two more ketones
(namely tetrahydro-4H-thiopyran-4-one 13a and N-Boc-piperi-
done-4 13b) and two aldehydes (p-methoxybenzaldehyde 14a
and 1-methyl-pyrrole-2-carbaldehyde 14b) were allowed to react
with 1,3-diaminopropane and cyclohexyl isocyanide with the hope
of expanding the scope of this reaction (Scheme 3). We were
pleased to find that all these reactions proceeded cleanly, provid-
ing target 1,4-diazepine-2-amines 4, 15, and 16 in good yields
(Table 1, entries 1–8).
for successful IMCRs. In the case of the most popular Passerini
and Ugi IMCRs, carboxylic acid, which is one of the components
of these reactions, plays the role of activating agent due to pro-
tonation of C@O or C@N bonds consequently for further reaction
with isocyanide. Otherwise, Brønsted or Lewis acid activation is
necessary, and the success of such reactions dramatically de-
pends on the right choice of acid.19 Therefore, the following
set of potential acidic promoters was selected on the basis of
previously reported acid-catalyzed reactions of carbonyl and azo-
methine compounds with various
p-C-nucleophiles including
isocyanides: HCl, TsOH,18e,g Sc(OTf)2, Yb(OTf)3,18a TMSCl, TBSOTf,
and TMSOTf.17,20
Spectral data for the synthesized compounds were found to be
in a good agreement with proposed structures of 1,4-diazepine-2-
amine monohydrochlorides.23
According to LC–MS- (including UV- and ELSD-) monitoring of
reaction mixtures, all evaluated additives demonstrated reactiv-
ity in the investigated MCR to a certain extent. However, forma-
tion of target product 4a was accompanied by several high
molecular weight by-products when these additives were used
in catalytic amounts. This might be explained on the basis of a
postulated mechanism of the IMCR (Scheme 2).
The mechanism entails condensation of starting carbonyl
compound 5 and diamine 1 providing azomethine 6 or cyclic
aminal 7 whose activation with acid A+ provides intermediates
8 and 9 that are able to react with isocyanide 3 to form cation
10. Intramolecular attack in the cation 10 assures diazepine ring
closure with the formation of imine 11 or its amino-tautomer
12. Alternatively, highly reactive cation 10 can be trapped by
any nucleophile existing in the reaction mixture including start-
ing isocyanide21 or available amines that should lead to high
molecular weight by-products. As a result of several additional
experiments, we found that these side reactions could be mini-
mized when TMSCl was used in equimolar ratio. This improved
the reaction outcome in yield and purity of target compound
In conclusion, we have reported a novel strategy for the
1,4-diazepine ring construction based on MCR of 1,3-propanedi-
amine, carbonyl compounds, and isocyanides, which allows the
synthesis of hitherto unknown highly substituted 1,4-diaze-
pine-2-amines including spiro-heterocycles. While scope of the
IMCR is still under evaluation, it appears to be general with
regard to carbonyl and isocyanide components. Further scope
evaluation of the IMCR with respect to a variety of 1,3-diamines,
carbonyl compounds, and isocyanides as well as applications of
the IMCR are now under investigation in our laboratories.
Acknowledgment
The authors thank Dr. Frederick Lakner for critical reading and
correction of this Letter.
References and notes
1. (a) Biftu, T.; Feng, D.; Qian, X.; Liang, G. B.; Kieczykowski, G.; Eiermann, G.; He,
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H
X
N
H
N
X
Ar
O
Ar-CHO
14
NC
13
NH2
+
NH
N
NH
N
HCl
NH2
HCl
1
3a
16
15
3. Raboisson, P.; Marugán, J. J.; Schubert, C.; Koblish, H. K.; Lu, T.; Zhao, S.; Player,
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Scheme 3. IMCR of 1,3-diaminopropane with cyclohexyl isocyanide and various
carbonyl compounds.

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V. Kysil et al. / Tetrahedron Letters 50 (2009) 2854–2856
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Tobisu, M.; Ito, S.; Kitajima, A.; Chatani, N. Org. Lett. 2008, 10, 5223–5225; (b)
Tobisu, M.; Kitajima, A.; Yoshioka, S.; Hyodo, I.; Oshita, M.; Chatani, N. J. Am.
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Oshita, M.; Tobisu, M.; Ishii, Y.; Murai, S. J. Am. Chem. Soc. 2003, 125, 7812–
7813; (h) Bez, G.; Zhao, C-G. Org. Lett. 2003, 5, 4991–4993; (i) Xia, Q.; Ganem, B.
Synthesis 2002, 14, 1969–1972; (j) Kozikowski, A. P.; Park, P. U. J. Org. Chem.
1984, 49, 1674–1676.
22. General procedure for the MCR of 1,3-diaminopropane, carbonyl compounds, and
isocyanides. A mixture of carbonyl compound (0.5 mmol), 1,3-diaminopropane
(0.5 mmol), and methanol (1 mL) was stirred in a 10 mL capped tube for 3 h at
9. Szewczyk,J.R.;Speake,J.D.;Sammond,D.M.;Sherrill,R.G.WO2005118573,2005.
10. Igarashi, M.; Takahashi, Y.; Shitara, T.; Nakamura, H.; Naganawa, H.; Miyake, T.;
Akamatsu, Y. J. Antibiot. 2005, 58, 327–337.
45–50 °C. Solutions of TMSCl (500
lL of 1 M, 0.5 mmol) in acetonitrile and
11. http://integrity.prous.com/integrity/servlet/xmlxsl.
isocyanide (500 L of 1 M, 0.5 mmol) in methanol were added into the reaction
l
12. (a) Dvorak, C. A.; Fisher, L. E.; Green, K. L.; Stabler, R. S.; Maag, H.; Prince, A.;
Repke, D. B.; Harris, R. N. III WO 2001090081, 2001.; (b) Cefalu, J. S.; Harris, R.;
Maag, H.; Nunn, P. A.; Ford, A.; Hedge, S.; Wyllie, M. G. J. Urol. 2007, 177. Abst. 424.
13. Ramamoorthy, S. P. WO 2003091250, 2003.
14. (a) Harada, H.; Morie, T.; Kato, S. Chem. Pharm. Bull. 1998, 46, 1160–1164; (b)
Yoshida, N. J. Pharmacol. Exp. Ther. 1992, 260, 1159–1165; (c) Yoshida, N.;
Omoya, H.; Kato, S.; Ito, T. Eur. J. Pharmacol. 1992, 216, 435–440.
mixture, which was stirred at 50–60 °C for 4 h and then at 40–50 °C until
completion of the reaction (based on LC–MS/ELSD-monitoring; reactions
usually required stirring for 20–24 h). Volatiles were evaporated under
reduced pressure and the residue was treated with dry EtOAc, kept in an
ultrasonic bath until completion of precipitate formation, then centrifuged.
Precipitate was washed twice with EtOAc, acetonitrile, and Et2O with
centrifugation each time, and dried under reduced pressure. The procedure
usually provided pure monohydrochlorides of target materials.
15. For recent reviews covering IMCRs and their applications see: (a) Dömling, A.
Chem. Rev. 2006, 106, 17–89; (b) Akritopoulou-Zanze, I.; Djuric, S. W.
Heterocycles 2007, 73, 125–147; (c) Akritopoulou-Zanze, I. Curr. Opinion
Chem. Biol. 2008, 12, 324–331; (d) Hulme, C. In Multicomponent Reactions;
Zhu, J., Bienayme, H., Eds.; Wiley-VCH, Verlag GmbH & Co.KgaA: Weinheim,
2005; pp 311–341; (e) Hulme, C.; Gore, V. Current Med. Chem. 2003, 10, 51–80;
(f) Doemling, A. In Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-
VCH, Verlag GmbH & Co.KgaA: Weinheim, 2005; pp 76–94; (g) Marcaccini, S.;
Torroba, T. In Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH,
Verlag GmbH & Co.KgaA: Weinheim, 2005; pp 33–75; (h) Zhu, J. Eur. J. Org.
Chem 2003, 1133–1144; (i) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.;
Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899–907;
(j) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (k) Ganem, B.
Acc. Chem. Res. 2009, 42, 463–472.
16. For examples of 1,4-diazepines synthesis employing IMCR based strategies see:
(a) Banfi, L.; Basso, A.; Guanti, G.; Kielland, N.; Repetto, C.; Riva, R. J. Org. Chem.
2007, 72, 2151–2160; (b) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-
Rad, J. J. Org. Chem. 2008, 73, 3925–3927; (c) Zychilinski, A. V.; Ugi, I.
Heterocycles 1998, 49, 29–32; (d) Rossen, K.; Sager, J.; DiMichele, L. M.
Tetrahedron Lett. 1997, 38, 3183–3186.
23. Data for the representative examples of synthesized compounds:
N-(tert-Butyl)-7,11-diazaspiro[5.6]dodec-11-en-12-amine hydrochloride 4a. 1H
NMR (400 MHz, DMSO-d6): d (ppm) 8.06 (br t, J = 4.5 Hz, 1H); 7.41 (br s;
1H); 3.75–3.79 (m, 2H); 2.82 (br t, J = 6.0 Hz, 1H); 2.72–2.80 (m, 2H); 1.81–
1.91 (m, 2H); 1.67–1.76 (m, 4H); 1.29–1.64 (m, 6H); 1.40 (s, 9H). 13C NMR
(100 MHz, DMSO-d6):
d (ppm) 172.9; 61.7; 54.1; 42.5; 32.3; 29.9; 28.4;
28.3; 24.1; 21.0. HRMS (ESI–TOF): calcd for C14H27N3 (M+H+) 238.2278,
found 238.2285.
N-Benzyl-7,11-diazaspiro[5.6]dodec-11-en-12-amine hydrochloride 4c. 1H NMR
(400 MHz, DMSO-d6): d (ppm) 9.41 (br t, J = 5.7 Hz, 1H); 9.06 (br t, 1H);
7.24–7.38 (m, 5H); 4.56 (d, J = 5.7 Hz, 2H); 3.50–3.57 (m, 2H); 2.87 (br t,
J = 6.1 Hz, 1H); 2.76–2.83 (m, 2H); 1.40–1.92 (m, 11H); 1.21–1.33 (m, 1H).
13C NMR (100 MHz, DMSO-d6): d (ppm) 173.9; 136.2; 128.9; 127.9; 127.5;
61.1; 44.8; 41.9; 32.8; 30.0; 24.6; 20.9. HRMS (ESI–TOF): calcd for C17H25N3
(M+H+) 272.2121, found 272.2125.
N-Cyclohexyl-3-thia-7,11-diazaspiro[5.6]dodec-11-en-12-amine
hydrochloride
15a. 1H NMR (400 MHz, DMSO-d6): d (ppm) 9.22 (br s, 1H); 8.22 (br d,
J = 8.0 Hz, 1H); 3.70–3.75 (m, 1H); 3.55–3.63 (m, 2H); 2.97–3.08 (m, 3H);
2.74–2.82 (m, 2H); 2.25–2.34 (m, 2H); 2.07–2.17 (m, 2H); 1.96–2.04 (m,
2H); 1.52–1.79 (m, 7H); 1.23–1.41 (m, 4H); 0.98–1.11 (m, 1H). 13C NMR
(100 MHz, DMSO-d6): d (ppm) 171.3; 60.5; 51.7; 41.1; 38.9; 33.2; 31.3; 29.7;
25.2; 24.8; 22.3. HRMS (ESI-TOF): calcd for C15H27N3S (M+H+) 282.1998,
found 282.1995.
17. Kysil, V.; Tkachenko, S.; Khvat, A.; Williams, C.; Tsirulnikov, S.; Churakova, M.;
Ivachtchenko, A. Tetrahedron Lett. 2007, 48, 6239–6244.
18. Besides our report,17 see also: (a) Keung, W.; Bakir, F.; Patron, A. P.; Rogers, D.;
Priest, Ch. D.; Darmohusodo, V. Tetrahedron Lett. 2004, 45, 733–737; (b)
Carballares, S.; Espinosa, J. F. Org. Lett. 2005, 7, 2329–2331; (c) Illgen, K.;
Nerdinger, S.; Behnke, D.; Friedrich, C. Org. Lett. 2005, 7, 2517–2518; (d)
tert-Butyl 12-(cyclohexylamino)-3,7,11-triazaspiro-[5.6]dodec-11-ene-3-carbox-
ylate hydrochloride 15b. 1H NMR (400 MHz, DMSO-d6): d (ppm) 9.24 (br m,
1H); 8.01 (br d, J = 7.8 Hz, 1H); 3.64–3.85 (m, 3H); 3.57–3.63 (m, 2H); 2.88–
3.10 (m, 3H); 2.75–2.85 (m, 2H); 1.50–1.94 (m, 11H); 1.37 (s, 9H); 1.18–1.36
(m, 4H); 0.98–1.11 (m, 1H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 171.1;
154.2; 79.2; 59.4; 51.8; 41.6; 32.1; 31.3; 29.9; 28.6; 25.2; 24.8. HRMS (ESI–
TOF): calcd for C20H36N4O2 (M+H+) 365.2911, found 365.2913.
N-Cyclohexyl-2-(1-methyl-1H-pyrrol-2-yl)-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-
amine hydrochloride 16b. 1H NMR (400 MHz, DMSO-d6): d (ppm) 9.58 (br s,
1H); 9.31 (br d, J = 6.3 Hz, 1H); 6.78–6.80 (m, 1H); 5.93–5.96 (m, 1H); 5.83–
5.85 (m, 1H); 5.30 (d, J = 2.5 Hz, 1H); 3.64–3.78 (m, 1H); 3.60 (s, 3H); 3.42–
3.58 (m, 2H); 3.23–3.31 (m, 1H); 2.77–2.87 (m, 1H); 2.32–2.43 (m, 1H);
1.79–1.89 (m, 2H); 1.47–1.73 (m, 5H); 1.24–1.38 (m, 3H); 1.04–1.17 (m,
2H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 167.5; 124.7; 124.6; 109.3;
106.9; 57.4; 51.1; 44.2; 43.3; 34.5; 31.5; 31.2; 30.6; 25.2; 24.5; 24.4. HRMS
(ESI–TOF): calcd for C16H26N4 (M+H+) 275.2230, found 275.2231.
ˇ
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