New methods for the preparation of aryl 2-iminoimidazolidines

Article abstract of DOI:10.1016/j.tetlet.2012.06.042

A divergent strategy for the synthesis of 1-aryl- and 2-aryl-2- iminoimidazolidines is presented. Cyclization of N-Boc-N′-aryl-N″- (2-hydroxyethyl)guanidines in the presence of methanesulfonyl chloride and triethylamine or sodium hydride at 0 °C affords the corresponding 2-iminoimidazolidines in good yields.

Full text of DOI:10.1016/j.tetlet.2012.06.042

Tetrahedron Letters 53 (2012) 4532–4535
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Tetrahedron Letters
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New methods for the preparation of aryl 2-iminoimidazolidines
⇑
Daniel H. O’Donovan, Isabel Rozas
School of Chemistry, University of Dublin, Trinity College Dublin, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A divergent strategy for the synthesis of 1-aryl- and 2-aryl-2-iminoimidazolidines is presented. Cycliza-
tion of N-Boc-N0-aryl-N00-(2-hydroxyethyl)guanidines in the presence of methanesulfonyl chloride and
triethylamine or sodium hydride at 0 °C affords the corresponding 2-iminoimidazolidines in good yields.
Ó 2012 Published by Elsevier Ltd.
Received 12 April 2012
Revised 28 May 2012
Accepted 8 June 2012
Available online 15 June 2012
Keywords:
2-Iminoimidazolidines
1-Aryl-2-iminoimidazolidines
2-Aryl-2-iminoimidazolidines
Cyclization
During a recent series of biological studies, our group became
interested in aryl 2-iminoimidazolidines as DNA minor groove
binders for the potential treatment of cancer,1 and as ligands of
In the present work, we have expanded this procedure to the
synthesis of 4-substituted-2-iminoimidazolidines through the use
of 4-substituted imidazolidine-2-thiones 3, which were prepared
by two different procedures. Thus, 4-methylimidazolidin-2-thione
a-adrenergic receptors for the treatment of central nervous system
disorders.2 The aryl 2-iminoimidazolidine motif is often employed
as an analogue of the guanidine functional group with increased
steric bulk and hydrophobicity, and is found in several clinical
adrenergic drugs including brimonidine (antiglaucoma) and cloni-
dine (antihypertensive/anaesthetic). This heterocycle is also found
in numerous natural products including the neurotoxic sodium
channel blocker saxitoxin3 and the closely-related analogues
gonyautoxin4 and zetekitotoxin AB.5
Several approaches to the synthesis of aryl 2-iminoimidazoli-
dines have been reported, including a two-step method for simple
unsubstituted compounds previously reported by our group.6 Sev-
eral other methods7,8 construct the 2-iminoimidazolidine hetero-
cycle via the reaction of a 1,2-diamine with an imine bearing two
suitable leaving groups, or with cyanogen bromide.9 Although this
approach is often used for the preparation of optically active
derivatives,10 the introduction of the requisite functionality on
(3a) was prepared via the 2-thiohydantoin derivative 1 of L-alanine
following Scheme 1 (i),11 while 4-(2-furyl)imidazolidin-2-thione
(3b) was ultimately synthesized from 2-furfural according to liter-
ature procedures [see Scheme 1 (ii)].12
Compounds 3a and 3b were bis-Boc protected under standard
conditions to afford the corresponding protected imidazolidin-2-
thiones 4 (see Scheme in Table 1). In the presence of HgCl2 and
Et3N, these substrates reacted readily with several aromatic
amines to afford the expected N,N0-bis-Boc protected 2-iminoimi-
dazolidines 5 in good yields, which were deprotected using 4 M
HCl/1,4-dioxane to produce the desired 2-aryliminoimidazolidine
hydrochloride salts 6.
We initially hoped to incorporate the chirality of the parent
amino acid, L-alanine into the final 2-iminoimidazolidine 6 as per
Scheme 1 (i). However, preparation of the (S)-Mosher’s acid deriv-
ative of 3a revealed that epimerization had occurred during the
reaction sequence and, therefore, the product 2-iminoimidazoli-
dines were racemic (see Supplementary data). Moreover, the prep-
aration of the requisite imidazolidine-2-thiones 3 remains an
impediment to the expedient synthesis of the desired compounds
6. Thus, we examined an alternative approach via the cyclization of
(2-hydroxyethyl)guanidines 9. The requisite guanidine was pre-
pared by the reaction of N-Boc-N0-phenylthiourea (7) and 2-substi-
tuted-2-aminoethanol derivatives 8a–c using our standard
guanidylation procedure (Scheme 2).13
the 1,2-diamine and imine components often necessitates
a
lengthy sequence of five or more synthetic steps from commercial
starting materials.
We have previously described the preparation of unsubstituted
aryl 2-iminoimidazolidines by the reaction of N,N0-bis-Boc pro-
tected imidazolidine-2-thione with an aromatic amine in the pres-
ence of HgCl2 and a mild base.6
Many 2-aminoethanol derivatives 8 are available in high optical
purity from commercial sources; alternatively, these compounds
may be prepared via reduction of the corresponding amino acid
⇑
Corresponding author. Tel.: +353 1 896 3731; fax: +353 1 671 2826.
E-mail address: rozasi@tcd.ie (I. Rozas).
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.06.042

D. H. O’Donovan, I. Rozas / Tetrahedron Letters 53 (2012) 4532–4535
4533
S
S
HO
NH2
Ac
b,c
a
HN
O
N
HN
NH
(i)
O
1
3a
H
d,e
NO2
f,g
O
O
S
O
O
N
(ii)
HN OMe
NH
2
3b
Scheme 1. Reagents and conditions: Preparation of imidazolidin-2-thiones 3a (i) and 3b (ii). (a) KNCS, Ac2O, 75 °C, 1 h, 68%, (b) 4 M aq. HCl,
l
W 150 °C, 5 min, 99%, (c)
Me2S.BH3, THF, 60 °C, 3.5 h, 53%, (d) 1. MeNO2, NaOH, 2. HCl, MeOH/H2O, 0 °C to rt, 0.5 h, 65%, (e) MeONH2.HCl, NaHCO3, THF/H2O, rt, 16 h, 88%. (f) Zn/AcOH, 55 °C, 2 h, 78%.
(g) 1,10-thiocarbonyldiimidazole, Et3N, CH2Cl2, rt, 1 h, 44%.
Table 1
Preparation of 2-aryliminoimidazolidines 6 from imidazolidine-2-thiones 3
R3
N
R2
Boc
N
H
N
S
S
N
b,c
a
R1
R1
R1
NBoc
NR4
NH
3a R1 = Me
4
5 R3 = R4 = Boc
3b R1 = 2-Furyl
6 R3 = .HCl, R4 = H
Entry
Product
R1
R2
4-EtO
4-N(CH3)2
3,4-(CH2)4
4-EtO
Yield (%) (5)
Yield (%) (6)
Overall yield (%)
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
2-Furyl
62
72
74
65
78
88
70
58
60
76
71
73
43
42
44
49
55
64
2-Furyl
2-Furyl
CH3
CH3
CH3
4-N(CH3)2
3,4-(CH2)4
(a) NaH, Boc2O, THF, 0 °C to rt, 3 h, 81% (3a), 84% (3b). (b) R2PhNH2, HgCl2, Et3N, CH2Cl2, 0 °C to rt, 16 h, 62–88%. (c) 4 M HCl/1,4-dioxane, CH2Cl2, 55 °C, 3.5 h, 58–76%.
NHBoc
S
NBoc R
HgCl2, Et3N
NH2
HO
OH
+
N
H
N
H
N
H
CH2Cl2
0 °C to rt, 16 h
R
7
8
9a, R = H, 94%
9b, R = Me, 83%
9c, R = Ph, 90%
Scheme 2. Preparation of N-(2-hydroxyethyl)-N0-arylguanidines 9.
with lithium aluminium hydride.14 Exposure of 9 to MsCl in the
presence of Et3N at 0 °C led to the complete consumption of start-
ing material within 0.5 h and the formation of two isomeric 2-imi-
noimidazolidine products, presumably via an unobserved O-
mesylate intermediate. The two products could be readily sepa-
rated using strongly basic chromatography (see Supplementary
data). Using Et3N as the base, 2-aryliminoimidazolidine product
10 was typically obtained as the major isomer, while the minor
product corresponded to the 1-aryl-2-iminoimidazolidine isomer
11. This assignment was confirmed by deprotection of the Boc
groups using 4 M HCl in 1,4-dioxane followed by a comparison of
their characterization data with values previously reported in the
literature (Table 2, compounds 12a and 13a).
counterintuitive result can be explained by closely examining the
lowest energy conformation of the starting material 9a. For elec-
tronic reasons, the preferred tautomer of 9a places the C@N double
bond in conjugation with the electron-withdrawing Boc substitu-
ent.15 This tautomer allows the formation of a strong intramolecu-
lar hydrogen bond (IMHB) between the Boc carbonyl oxygen O1
and the NH proton at N1, which is made slightly acidic by the
adjoining phenyl group. This IMHB prevents N1 from readily
attaining the correct angle of approach for nucleophilic attack,
while N2 is now ideally positioned to react with the adjacent leav-
ing group-bearing C10 (Fig. 1); the prevalence of this conformation
was supported by DFT calculations (B3LYP/6-31+G⁄⁄). Similar
IMHBs have also been observed in bis-Boc protected aryl guani-
dines, and their effects upon reactivity and conformation are an
on-going subject of research within our group.16
Notably, under these conditions the major isomer 10a corre-
sponds to the product of nucleophilic attack by the Boc protected
nitrogen N2, while the minor isomer 11a is formed through attack
by the unprotected nitrogen N1 (numbering as per Fig. 1). This
It was speculated that the use of a much stronger base might
negate the influence of the IMHB upon the outcome of this reaction

4534
D. H. O’Donovan, I. Rozas / Tetrahedron Letters 53 (2012) 4532–4535
Table 2
Preparation of 2-aryl iminoimidazolidines 12 and 1-aryl-2-iminoimidazolidines 13 via the cyclization of (2-hydroxyethyl)guanidines 9
NR2
R1
HN
N
NBoc R
NH
R1
+
a,b
OH
N
N
N
H
N
H
R2
9
10 R2 = Boc
11 R2 = Boc
13 R2 = .HCl
12 R2 = .HCl
Entry
Product
R1
Base/solvent Step (a)
Yield (%) (10)
Yield (%) (11)
Ratio (10:11) step (a)
Yield (%) (12/13)
Overall yield (%)
1
2
3
4
5
6
12a
12b
12c
13a
13b
13c
H
Et3N/CH2Cl2
Et3N/CH2Cl2
Et3N/CH2Cl2
NaH/THF
NaH/THF
NaH/THF
64
66
61
13
22
49
24
19
21
52
61
30a
2.7:1
3.5:1
2.9:1
1:4
1:2.9
1.6:1
83
84
87
80
90
96
53
55
53
42
55
29
Me
Ph
H
Me
Ph
(a) Et3N/CH2Cl2 or NaH/THF, MsCl, 0 °C to rt, 0.5 h, 30– 66%. (b) 4 M HCl/1,4-dioxane, 55 °C, 3.5 h, 83–96%.
For entry 6, 11c was the intended product of step (a), but 10c remained as the major product of the reaction.
comparison with its epimer, indicating that the chiral centre does
not undergo racemization during this sequence of reactions (see
Supplementary data).
In summary, we have developed new and expedient methods
for the synthesis of 4-substituted aryl-2-iminoimidazolidines,
including a divergent strategy for the synthesis of 1-aryl and
2-aryl-2-iminoimidazolidines. The cyclization of (2-hydroxy-
ethyl)guanidines 9 also provides concise access to optically active
4-substituted derivatives, although the preparation of sterically
hindered 1-aryl-2-iminoimidazolidines may be more difficult to
control. The pharmacological activities of the product 2-iminoimi-
dazolidine hydrochloride salts are currently under investigation
and will be reported in subsequent publications.
Figure 1. Optimized DFT structure of 9a (B3LYP/6-31+G⁄⁄) with intramolecular
hydrogen bonding shown in red.17
through deprotonation of N1. In the event, carrying out the cycliza-
tion reaction with sodium hydride as the base typically led to an
inversion of the ratio of product isomers (Table 2, entry 4). Inter-
estingly, the use of the slightly weaker base NaHMDS afforded
47% of the 1-aryl isomer 10a and 31% of 11a. The reaction was also
attempted with the very strong base, lithium diisopropylamide,
however, using this reagent only led to a very poor conversion into
the 2-aryl isomer 11a and the majority of the starting material
underwent decomposition to a complex mixture of side-products
(TLC).
In the synthesis of 4-methyl-2-iminoimidazolidines 10b and
11b, the reactivity closely resembles that of unsubstituted species
10a and 11a. Using triethylamine in the cyclization reaction affor-
ded the 2-aryl isomer 10b as the major product, while switching to
sodium hydride provided a 61% yield of the 1-aryl isomer 11b
(Table 2). Nevertheless, the synthesis of 4-phenyl-2-iminoimidaz-
olidines proved less amenable to this type of control. In this in-
stance, using triethylamine provided a 61% yield of the expected
2-aryl isomer 10c, however, changing to sodium hydride afforded
only a 30% yield of the 1-aryl isomer 11c and 10c remained the ma-
jor product. This discrepancy might be attributable to the bulky
phenyl substituent preventing the approach of the unprotected
nitrogen N1, and, hence, attack by the less hindered nitrogen N2
remains preferred.
Acknowledgements
The authors are grateful to the IRCSET for financial support (D.
H. O’D.) and are indebted to Dr. John O’Brien for NMR studies. Com-
putations were performed on the IITAC cluster maintained by the
Trinity Center for High Performance Computing.
Supplementary data
Supplementary data (characterisation data and HPLC analysis of
the final hydrochloride salts) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.06.042.
References and notes
1. Nagle, P. S.; Quinn, S. J.; Kelly, J. M.; O’ Donovan, D. H.; Khan, A. R.; Rodriguez, F.;
Nguyen, B.; Wilson, W. D.; Rozas, I. Org. Biomol. Chem. 2010, 8, 5558.
2. Rodriguez, F.; Rozas, I.; Ortega, J. E.; Erdozain, A. M.; Meana, J. J.; Callado, L. F. J.
Med. Chem. 2009, 52, 601.
3. Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964.
4. Mulcahy, J. V.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 12630.
5. Yotsu-Yamashita, M.; Kim, Y. H.; Dudley, S. C., Jr.; Choudhary, G.; Pfahnl, A.;
Oshima, Y.; Daly, J. W. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 4346.
6. Dardonville, C.; Goya, P.; Rozas, I.; Alsasua, A.; Martín, I.; Borrego, J. Bioorg. Med.
Chem. 2000, 8, 1567.
7. Adcock, B.; Lawson, A. J. Chem. Soc. 1965, 474.
8. Huber, D.; Leclerc, G.; Ehrhardt, J. D.; Andermann, G. Tetrahedron Lett. 1987, 28,
6453.
9. Jeon, Y. T.; Luo, C.; Forray, C.; Vaysse, P. J-J.; Branchek, T. A.; Gluchowski, C.
Bioorg. Med. Chem. Lett. 1995, 5, 2255.
10. Greenhill, J. V.; Ismail, M. J.; Edwards, P. N.; Philip, N.; Taylor, P. J. J. Chem. Soc.
Perkin Trans. 2 1985, 1255.
The cyclization products were readily deprotected in good to
quantitative yields using 4 M HCl in 1,4-dioxane and the resulting
hydrochloride salts were generally obtained in >95% purity (HPLC).
The optical purity of the hydrochloride salt 13c was examined by
the preparation of the corresponding (S)-Mosher’s acid derivative,
which was confirmed to exist as a single diastereoisomer by
11. Johnson, T. B.; Nicolet, B. H. J. Am. Chem. Soc. 1973, 1911, 33.

D. H. O’Donovan, I. Rozas / Tetrahedron Letters 53 (2012) 4532–4535
4535
12. Hsu, F.-L.; Hamada, A.; Booher, M. E.; Patil, P. N.; Miller, D. D. J. Med. Chem.
1980, 23, 1232.
13. O’ Donovan, D. H.; Rozas, I. Tetrahedron Lett. 2011, 52, 4117.
14. For an example of this procedure, see: Feng, D.-Z.; Song, Y.-L.; Jiang, X.-H.; Peib,
G.; Longa, Y.-Q. Org. Biomol. Chem. 2007, 5, 2690.
15. Ghiviriga, I.; Elgendy, B. E. M.; Steel, P. J.; Katritzky, A. R. Org. Biomol. Chem.
2009, 7, 4110.
16. Kelly, B.; O’ Donovan, D. H.; O’ Brien, J.; Mccabe, T.; Blanco, F.; Rozas, I. J. Org.
Chem. 2011, 76, 9216.
17. Calculated using Gaussian 09 with the B3LYP functional and the 6-31+G (d,p)
basis set. Zero imaginary frequencies recorded. (a) Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;
Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.;
Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, J.; Hasegawa, M.; Ishida, T.; Nakajima, Y.;
Honda, O.; Kitao, R.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.;
Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,
S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J.
B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;
Fox, D. J. GAUSSIAN 09, Revision A.1; Gaussian Inc.: Wallingford CT, 2009; (b)
Goering, B. K.; Cornell University: Dissertation, 1995.