Multicomponent synthesis of pentyl-sulfonyl amidines via diazoalkane

Article abstract of DOI:10.1055/s-0031-1290667

A series of pentyl-sulfonyl amidines was obtained using a multicomponent synthesis process. The rearrangement of unstable tosylazide-cyclopentanonenamine cycloadducts yielded a diazoalkane intermediate. This primary, unstable reaction product showed good reactivity with certain acid compounds in order to form the corresponding derivatives. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290667

LETTER
▌1523
lMetteur lticomponent Synthesis of Pentyl-Sulfonyl Amidines via Diazoalkane
Synthesis of Pentyl-Sulfonyl Amidines
Alessandro Contini, Emanuela Erba,* Sara Pellegrino
DISMAB-Sez. di Chimica Organica ‘Alessandro Marchesini’, Via G. Venezian, 21, 20133 Milano, Italy
Fax +39(02)50314476; E-mail: emanuela.erba@unimi.it
Received: 28.02.2012; Accepted after revision: 28.03.2012
R3
R1
R1
R3
R4
Abstract: A series of pentyl-sulfonyl amidines was obtained using
a multicomponent synthesis process. The rearrangement of unstable
tosylazide–cyclopentanonenamine cycloadducts yielded a diazoal-
kane intermediate. This primary, unstable reaction product showed
good reactivity with certain acid compounds in order to form the
corresponding derivatives.
N
O
N
R2
R4
R2
H
TsN3
R2
R1
Key words: sulfonyl amidines, multicomponent reaction, diazo-
alkane, amino acids, antiresorptive agent
N
N
N
R3
N
R4
Ts
Amidines are versatile starting materials used in several
synthetic contexts, mainly in the preparation of heterocy-
clic compounds.1 In addition, amidines are prominent
structural motifs found in numerous bioactive natural
products,2 which serve as important pharmacophores,
synthetic intermediates, and efficient coordinating li-
gands.3 In this study we proposed a simple, rapid, and in-
expensive process for the synthesis of tosylamidines
linked to a reactive moiety through a four-methylene alkyl
chain. Similar structures have shown potent antiresorptive
activities in vitro, and structure–activity relationship stud-
ies were also recently performed.4
– N2
R2
R1
R3
N
Ts
N
R4
Scheme 1
products was obtained, which was shown to be of no syn-
thetic use. Surprisingly, when we performed the multi-
component reaction starting from cyclopentanone,
tosylazide, and proline methyl ester hydrochloride in the
presence of triethylamine we separated a single main
product in good yields. Analytical data of the obtained
compound indicated that tosyl and proline residues were
intact. Moreover, 13C NMR showed the presence of an
amidine carbon (δC = 165.6 ppm) close to a quaternary
carbon ester (δC = 171.0 ppm). A TOCSY experiment
showed the presence of a four-methylene carbon open
chain, which was connected to the amidine moiety (δH =
2.89 and 3.03 ppm; δC = 30.7 ppm) on one side, while the
terminal methylene on the other side was connected to a
heteroatom (δH = 3.62 ppm; δC = 43.6 ppm). The exact
mass of 400.1220 correlated with the chemical formula
C18H25ClN2O4S, which allowed us to assign product 1 to
the formula depicted in Figure 1.
Several years ago, our group reported a simple and versa-
tile multicomponent reaction which offered a straightfor-
ward method for the creation of amidines via heterocyclic
transformation.5 The multicomponent reaction protocol
used in the current study follows this general procedure.
At room temperature, a primary or secondary amine was
added to a solution containing a carbonyl compound (al-
dehyde or ketone) in an inert solvent in the presence of a
moderate amount of molecular sieves. After 15–30 min-
utes, an equivalent amount of azide was added, and the re-
action was followed using TLC analysis. The use of
tosylazide resulted in the isolation of products corre-
sponding to tosylamidines (Scheme 1).
The proposed mechanism involves the azide cycloaddi-
tion of enamine, resulting in the formation of 4,5-dihydro-
triazole, which, by nitrogen loss and transposition of the
substituent from the 5- to 4-position, provides the desired
amidines. Different behaviours were observed in some
cases, and it is thought that the nature of the starting car-
bonyl reactant governs the outcome of the reaction.5,6
H
CO2Me
N
Cl
N
SO2
The use of cyclopentanone under these reaction condi-
tions was previously considered, but a complex mixture of
Me
1
SYNLETT 2012, 23, 1523–1525
Advanced online publication: 25.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Figure 1
DOI: 10.1055/s-0031-1290667; Art ID: ST-2012-D0175-L
© Georg Thieme Verlag Stuttgart · New York

1524
A. Contini et al.
LETTER
The assigned structure was compared with similar prod-
ucts that have been recently reported,7 and the analytical
data were found to be in agreement with the suggested hy-
pothesis. It can therefore be assumed that the formation of
product 1 derives from the initial breaking of the N2–N3
bond in the unstable dihydrotriazole, followed by amidine
bond formation and the contemporary breaking of the
C3a–C6a bond (Scheme 2).
Table 1 Synthesis of Compounds 2
R1
R1
toluene
R1
O
HN
R1
N
TsN3
HR2
R2
6a
N
O
3a
N
NH2
N
MeO
N
Ts
N
S
N
O
N
O
MeO2C
N
N
R1
S
Me
O
R1
O
A
Entry
R1NR1
R2
Yield (%)a
Me
1
2
3
4
5
6
7
1a
2a
2b
2c
2d
2e
2f
proline
proline
proline
proline
proline
proline
morpholine
Cl
PhCO2
MeCO2
70
65
72
62
65
35
68
N
N
O
N
MeO2C
N
S
Me
MeC6H4SO3
BocNHCHMeCO2
O2NC6H4O
PhCO2
O
B
Scheme 2
The resultant diazoalkane A, which is stabilised by the di-
azirine form B,8 reacts with HCl derived from triethyl-
amine hydrochloride. This is, in turn, formed in the
reaction between proline methyl ester hydrochloride and
triethylamine. With the aim to remove the HCl source, we
first performed the reaction by using equal volumes of
proline methyl ester hydrochloride and sodium methoxide
in a toluene solution. The solution of proline methyl ester
was used in the routine synthetic protocol. When the TLC
control showed a loss of tosylazide, we added a reactive
acid, which was able to react with the diazoalkane, into
the same reaction mixture. In the reaction scheme, the ad-
dition of benzoic acid resulted in the formation of ester 2a
(Table 1, entry 2)in good yields.
a Related to chromatographically pure products, structures deter-
mined by 1H and 13C NMR spectroscopy.
1). This prove that amino acids, opportunely protected,
are able to react with the diazolcane intermediate A. As a
consequence the pentylamidine moiety could be inserted
into depsipeptide chains.10
In conclusion, readily available starting materials have
been used in one-pot reactions to obtain a series of new 5-
substituted pentylamidines, using a rapid and inexpensive
method. This synthetic protocol is really versatile, as it
was demonstrated that it could be extended to several re-
agents, and the derivatives obtained can undergo many
other transformations.
The one-pot method here described was then applied to
other acid reagents, such as acetic acid, 4-toluensolfonic
acid, N-Boc-alanine, and 4-nitrofenol, and the corre-
sponding products 2b–e (Table 1, entries 3–6) were ob-
tained in good yields.9 With the aim to further generalise
this synthetic protocol, proline was replaced with morpho-
line, which is a plain secondary amine, and when the to-
sylazide cycloaddition reaction was complete, benzoic
acid was added. As expected the obtained derivative 2f
(Table 1, entry 7) contained morpholine in the amidine
portion.
References and Notes
(1) (a) Clerici, F.; Gelmi, M. L.; Rossi, L. M. Synthesis 1987,
1025. (b) Battistini, M.; Erba, E.; Pocar, D. Synthesis 1992,
1206. (c) Pocar, D.; Roversi, E.; Trimarco, P.; Valgattarri,
G. Liebigs Ann. 1995, 487. (d) Erba, E.; Pocar, D.; Trimarco,
P. J. Chem. Soc., Perkin Trans. 1 1998, 3535. (e) Beccalli, E.
M.; Contini, A.; Trimarco, P. Eur. J. Org. Chem. 2003, 3976.
(2) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203.
(3) (a) Body, G. V. In The Chemistry of Amidine and Imidates;
Vol. 2, Chap. 8; Patai, S.; Rappoport, Z., Eds.; Wiley: New
York, 1991. (b) Barker, J.; Kilner, M. Coord. Chem. Rev.
1994, 133, 219.
(4) Lee, M. Y.; Kim, M. H.; Kim, J.; Kim, S. H.; Kim, B. T.;
Jeong, I. H.; Chang, S.; Chang, S. Y. Bioorg. Med. Chem.
Lett. 2010, 20, 541.
(5) (a) Cassani, F.; Celentano, G.; Erba, E.; Pocar, D. Synthesis
2004, 1041. (b) Fusco, R.; Bianchetti, G.; Pocar, D.; Ugo, R.
This preliminary results show that this method can be ap-
plied to a large number of reagents. Furthermore, the
products obtained in this preliminary survey are liable to
further transformations, for example: the tosylate 2c can
undergo substitution reactions with nucleophiles. A par-
ticularly interesting result is described in entry 5 (Table
Synlett 2012, 23, 1523–1525
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chem. Ber. 1963, 802.
(6) Contini, A.; Erba, E.; Trimarco, P. ARKIVOC 2008, (xii),
136.
Synthesis of Pentyl-Sulfonyl Amidines
1525
(1.9 g, 62%); [α] –78.2 (c 1, CHCl3). 1H NMR (200 MHz,
CDCl3): δ = 1.70–2.26 (m, 8 H, 4 CH2), 2.37 and 2.44 (2 s,
6 H, 2 CH3Ph), 2.91–2.99 (m, 2 H, CH2), 3.45 (s, 3 H,
CH3O), 3.46–3.74 (m, 2 H, CH2), 4.02–4.08 (m, 2 H, CH2O),
4.43–4.49 (m, 1 H, CH), 7.21 (d, J = 8.16 Hz, 2 H, ArH),
7.35 (d, J = 8.10 Hz, 2 H, ArH), 7.71 (d, J = 8.16 Hz, 2 H,
ArH), 7.78 (d, J = 8.10 Hz, 2 H, ArH). 13C NMR (50 MHz,
CDCl3): δ = 21.6 (CH3), 21.8 (CH3), 22.5 (CH2), 24.8 (CH2),
28.9 (CH2), 29.3 (CH2), 31.7 (CH2), 48.2 (CH2), 52.2 (CH3),
61.1 (CH), 70.0 (CH2), 126.3 (CH), 128.1 (CH), 129.3 (CH),
130.2 (CH), 133.1 (C), 141.3 (C), 142.1 (C), 145.1 (C),
166.4 (C), 171.9 (C). ESI-HRMS: m/z calcd for
(7) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 2038.
(8) Liu, M. T. H. Chem. Soc. Rev. 1982, 127.
(9) General Procedure for the Preparation of Amidine 2a–e
The proline methyl ester hydrochloride (1 g, 0.006 mol) was
suspended in toluene (20 mL), and an equivalent amount of
NaOMe (6 mL of 1 M solution) was added. After 30 min the
solvent was concentrated to 10 mL under vacuum, and 5 g of
molecular sieves were added. To the stirred mixture were
added at first cyclopentanone (0.5 g, 0.006 mol) and after 15
min tosylazide (0.92 g, 0.006 mol). The reaction was
monitored with TLC (EtOAc–hexane = 1:1), and after 15
min the tosylazide was completely disappeared. The suitable
reactant was added (0.012 mol), and the stirring was
continued for 1 h. Then the mixture was filtered, and toluene
was removed under vacuum. The crude was dissolved in
CH2Cl2, washed with H2O (10 mL), dried with Na2SO4,
filtered, and the filtrate concentrated in vacuo. The crude
was purified by silica gel chromatography (EtOAc–hexane =
1:1) affording the pure amidines 1a,b and 2a–e
C25H37N2O7S2: 536.1650; found: 536.1651.
Methyl 1-{5-[(2-{[(tert-Butoxy)carbonyl]amino}-
propanoyl)oxy]-1-(tosylimino)pentyl}pyrrolidine-2-
carboxylate (2d)
Colorless oil (2.1, 65%); [α]D –2.29 (c 1, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 1.39–144 (m, 12 H, 4 CH3), 1.85–
2.29 (m, 8 H, 4 CH2), 2.37 (s, 3 H, CH3Ph), 2.82–3.21 (m, 2
H, CH2), 3.45 (s, 3 H, CH3O), 3.46–3.75 (m, 2 H, CH2),
4.05–4.25 (m, 3 H, CH and CH2), 4.43–4.49 (m, 1 H, CH),
5.08–5.15 (m, 1 H, NH), 7.22 (d, J = 8.18 Hz, 2 H, ArH),
8.73 (d, J = 8.18 Hz, 2 H, ArH). 13C NMR (50 MHz, CDCl3):
δ = 18.8 (CH3), 21.6 (CH3), 23.0 (CH2), 24.8 (CH2), 28.5
(CH3), 29.3 (CH2), 32.0 (CH2), 48.1 (CH2), 49.5 (CH3), 52.2
(CH3), 61.1 (CH), 64.6 (CH2), 79.9 (C), 126.4 (CH), 129.1
(CH), 141.3 (C), 142.1 (C), 155.4 (C), 166.6 (C), 172.0 (C),
173.6 (C). ESI-HRMS: m/z calcd for C26H39N3O8S:
553.2457; found: 553.2458.
Methyl 1-[5-Chloro-1(tosylimino)pentyl]pyrrolidine-2-
carboxylate (1)
Colorless oil (1.68 g, 70%); [α]D –79.8 (c 1, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.92–2.08 (m, 6 H, 3 CH2),
2.09–2.19 and 2.20–2.28 (2 m, 2 H, CH2), 2.40 (s, 3 H,
CH3Ph), 2.85–2.92 and 2.99–3.08 (2 m, 2 H, CH2), 3.49 (s,
3 H, OCH3), 3.58–3.64 (m, 2 H, CH2Cl), 3.61–3.68 and
3.73–3.80 (2 m, 2 H, CH2N), 4.49–4.54 (m, 1 H, CH),
7.25(d, J = 8.20 Hz, 2 H, ArH), 7.77 (d, J = 8.20 Hz, 2 H,
ArH). 13C NMR (75 MHz, CDCl3): δ = 21.6 (CH3), 23.6
(CH2), 24.8 (CH2), 29.3 (CH2), 31.6 (CH2), 32.3 (CH2), 44.5
(CH2), 48.1 (CH2), 52.2 (CH3), 61.1 (CH), 126.3 (CH), 129.3
(CH), 141.3 (C), 142.1 (C), 166.6 (C), 172.0 (C). ESI-
HRMS: m/z calcd for C18H25ClN2O4S: 400.1223; found:
400.1220.
Methyl 1-[5(4-Nitrophenyloxy)-1-(tosylimino)pentyl]-
pyrrolidine-2-carboxylate (2e)
Colorless oil (1.0g, 35%); [α]D –99.5 (c 1, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 1.82–2.23 (m, 8 H, 4 CH2), 2.37 (s,
3 H, CH3Ph), 2.87–3.12 (m, 2 H, CH2), 3.45 (s, 3 H, CH3),
3.54–3.73 (m, 2 H, CH2), 4.05–4.21 (m, 2 H, CH2), 4.45–
4.51 (m, 1 H, CH), 6.94 (d, J = 8.16 Hz, 2 H, ArH), 7.20 (d,
J = 8.06 Hz, 2 H, ArH), 7.73 (d, J = 8.06 Hz, 2 H, ArH), 8.19
(d, J = 8.16 Hz, 2 H, ArH). 13C NMR (50 MHz, CDCl3): δ =
21.6 (CH3), 23.2 (CH2), 24.8 (CH2), 29.0 (CH2), 29.3 (CH2),
32.1 (CH2), 48.1 (CH2), 52.2 (CH3), 61.1 (CH), 68.3 (CH2),
114.7 (CH2), 126.1 (CH), 126.35 (CH), 129.2 (CH), 129.3
(CH), 141.3 (C), 141.7 (C), 142.1 (C), 164.2 (C), 166.5 (C),
172.0 (C). ESI-HRMS: m/z calcd for C24H29N3O7S:
503.1726; found: 503.1724.
Methyl 1-[5-(Benzoyloxy)-1-(tosylimino)pentyl]-
pyrrolidine-2-carboxylate (2a)
Colorless oil (1.8g, 65%); [α]D –67.8 (c 1, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 1.82–2.25 (m, 6 H, 3 CH2), 2.37 (s,
3 H, CH3Ph), 2.87–3.13 (m, 2 H, CH2), 3.45 (s, 3 H, OCH3),
3.50–3.75 (m, 3 H, CH2), 4.34–4.401 (m, 2 H, OCH2), 4.42–
4.51 (m, 1 H, CH), 7.20 (d, J = 8.20 Hz, 2 H, ArH), 7.30–
7.60 (m, 3 H, ArH), 7.73–7.85 (m, 2 H, ArH), 8.00 (d,
J =8.20 Hz, 2 H, ArH). 13C NMR (50 MHz, CDCl3): δ = 21.6
(CH3), 23.2 (CH2), 24.8 (CH2), 28.9 (CH2), 29.3 (CH2), 32.1
(CH2), 48.1 (CH2), 52.2 (CH3), 61.1 (CH), 64.4 (CH2), 126.4
(CH), 128.6 (CH), 129.1 (CH), 129.8 (CH), 130.5 (C), 133.1
(CH), 141.4 (C), 142.0 (C), 166.7 (C), 172.0 (C). ESI-
HRMS: m/z calcd for C25H30N2O6S: 486.1824; found:
486.1822.
5-Morpholino-5-(tosylimino)pentyl Benzoate (2f)
Morpholine (0.2 g, 0.0023 mol) and cyclopentanone (0.19 g,
0.0023 mol) were dissolved in CH2Cl2 (10 mL), and 2 g of
molecular sieves were added. The mixture was stirred for 30
min, and tosylazide (0.35 g, 0.0023 mol) was added. After 15
min benzoic acid (0.56 g, 0.0046 mol) was added, and the
stirring was continued for 1 h. Then the mixture was filtered,
washed with H2O (10 mL), dried with Na2SO4, filtered, and
the filtrate was concentrated in vacuo. The crude was
purified by silica gel chromatography (EtOAc–hexane =
1:1) affording the pure 2f. Colorless oil (0.68g, 68%). 1H
NMR (200 MHz, CDCl3): δ = 1.64–2.01 (4 H, m, 2 CH2),
2.38 (3 H, s, CH3Ph), 2.97–3.10 (2 H, m, CH2), 3.42–3.78 (8
H, m, 4 CH2-morpholine), 4.25–4.39 (2 H, m, CH2O), 7.23
(2 H, d, J = 8.20 Hz, ArH), 7.42–7.61 (3 H, m, ArH), 7.90 (2
1-[5-Acetyloxy-1-(tosylimino)pentyl]pyrrolidine-2-
carboxylate (2b)
Colorless oil (1.8g, 72%); [α]D –80.9 (c 1, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 1.78–2.24 (m, 8 H, 4 CH2), 2.05 (s,
3 H, CH3CO), 2.38 (s, 3 H, CH3), 2.89–3.18 (m, 2 H, CH2),
3.46 (s, 3 H, CH3O), 3.53–3.76 (m, 2 H, CH2), 4.07–5.18 (m,
2 H, CH3O), 4.46–4.52 (m, 1 H, CH), 7.22 (d, J =8.20 Hz, 2
H, ArH), 7.74 (d, J = 8.20 Hz, 2 H, ArH). 13C NMR (50MHz,
CDCl3): δ = 21.2 (CH3), 21.6 (CH3), 23.2 (CH2), 24.8 (CH2),
28.8 (CH2), 29.3 (CH2), 32.1 (CH2), 48.1 (CH2), 52.3 (CH3),
61.1 (CH), 63.9 (CH2), 126.4 (CH), 129.1 (CH), 141.3 (C),
142.1 (C), 166.7 (C), 172.0 (C). ESI-HRMS: m/z calcd for
C20H28N2O6S: 424.1668; found: 424.1666.
H, d, J = 8.15 Hz, ArH), 8.02 (2 H, d, J = 8.20 Hz, ArH). 13
C
NMR (50 MHz, CDCl3): δ = 21.6 (CH3), 23.8 (CH2), 28.9
(CH2), 30.3 (CH2), 45.0 (CH2), 46.8 (CH2), 64.1 (CH2), 66.5
(CH2), 66.7 (CH2), 126.4 (CH), 128.7 (CH), 129.4 (CH),
129.7 (CH), 130.4 (C), 133.3 (CH), 141.4 (C), 142.3 (C),
166.7 (C), 167.4 (C). ESI-HRMS: m/z calcd for
C23H28N2O5S: 444.1718; found: 444.1719.
Methyl 1-[1-(Tosylimino)-5-(tosyloxy)pentyl]-
pyrrolidine-2-carboxylate (2c)
This reaction was performed in cyclohexane. Colorless oil
(10) Pilari, T.; Tron, G. C.; Masson, G.; Zhu, J. Org. Lett. 2007,
5275.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1523–1525

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