N-Bromosuccinimide initiated one-pot synthesis of imidazoline

Article abstract of DOI:10.1021/ol2006902

Chemical equations presented. A novel cationic Br initiated one-pot imidazoline synthesis has been developed using olefin, nitrile, amine, and N-bromosuccinimide. The olefinic substrates and the nitrile partners can be flexibly varied to achieve a range o

Full text of DOI:10.1021/ol2006902

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2448–2451
N-Bromosuccinimide Initiated One-Pot
Synthesis of Imidazoline
Ling Zhou, Jing Zhou, Chong Kiat Tan, Jie Chen, and Ying-Yeung Yeung*
Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543
chmyyy@nus.edu.sg
Received March 15, 2011
ABSTRACT
A novel cationic Br initiated one-pot imidazoline synthesis has been developed using olefin, nitrile, amine, and N-bromosuccinimide. The olefinic
substrates and the nitrile partners can be flexibly varied to achieve a range of imidazoline derivatives.
Nitrogen containing heterocyclic compounds are of great
interest in many areas.1 Important examples include ami-
dines and imidazolines; these compounds are the funda-
mental units of natural products,2 biologically active mol-
ecules,3 organocatalysts,4 and metal complexation ligands.5
In particular, imidazolines have attracted much attention
as they can easily be transformed into imidazoles which are
well-known scaffolds that appear in several highly signifi-
cant biomolecules.6 Moreover, imidazolines can be hydro-
lyzed to yield the 1,2-diamine which is often used for the
synthesis of organocatalysts and the metal complexation
ligands.7 Many research endeavors have been dedicated to
the development of efficient and environmentally benign
approaches to the synthesis of these compounds over the
past few decades.3,8 However, apart from long and ineffi-
cient synthetic sequences, potentially hazardous azide
reagents and/or metallic reagents are commonly used to
introduce the nitrogen functionalities in the literature
processes which hinder their application in the manufac-
turing sector.9
On the other hand, the Ritter-type reactions, which
involve anamine-captured nitronium intermediate, appear
to offer an attractive strategy for the construction of
imidazoline. To our surprise, sporadic cases have been
reported using this approach, the results returned show-
ing limited scope, low yielding reactions, and/or low
selectivity. In addition, a catalyst is usually required to
(1) (a) Kemp, J. E. In Comprehensive Organic Synthesis, Vol. 7; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; pp 469À513. (b)
Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Comprehensive
Heterocyclic Chemistry II, Vol. 1A; Padwa, A., Ed.; Pergamon Press:
Oxford, U.K., 1996, pp 1À60. (c) Rai, K. M. L.; Hassner, A. In
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(2) (a) Kumamoto, T. In Superbases for Organic Synthesis: Guani-
dines, Amidines, Phosphazenes and Related Organoctalysts; Ishikawa, I.,
Ed.; John Wiley & Sons Press: West Sussex, U.K., 2009; pp 295À313. (b)
Berlinck, R. G. S.; Burtoloso, A. C. B.; Kossuga, M. H. Nat. Prod. Rep.
2008, 25, 919–954. (c) Berlinck, R. G. S.; Kossuga, M. H. Nat. Prod. Rep.
2005, 22, 516–550. (d) Nagasawa, K.; Hashimoto, Y. Chem. Record
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4571–4624. (b) De Luca, L. Curr. Med. Chem. 2006, 13, 1–23.
(4) Ahmad, S. M.; Braddock, D. C.; Cansell, G.; Hermitage, S. A.;
Redmond, J. M.; White, A. J. P. Tetrahedron Lett. 2007, 48, 5948–5952.
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(6) (a) Haneda, S.; Okui, A.; Ueba, C.; Hayashi, M. Tetrahedron
2007, 63, 2414–2417. (b) Nicolaou, K. C.; Mathison, C. J. N.;
Montagnon, T. Angew. Chem., Int. Ed. 2003, 42, 4077–4082. (c)
Mohammadpoor-Baltork, I.; Zolfigol, M. A.; Abdollahi-Aibeik, M.
Synlett 2004, 2803–2805. (d) Ishihara, M.; Togo, H. Synlett 2006, 227–
230. (e) Huh, D. H.; Ryu, H.; Kim, Y. G. Tetrahedron 2004, 60, 9857–
9862. (f) Bellina, F.; Cauteruccio, S.; Fiore, A. D.; Marchetti, C.; Rossi,
R. Tetrahedron 2008, 64, 6060–6072.
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S.; Bisai, A.; Prasad, B. A. B.; Singh, V. K. J. Org. Chem. 2007, 72, 2133–
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r
10.1021/ol2006902
Published on Web 04/12/2011
2011 American Chemical Society

activate the halogen source (e.g., N-haloamide) to mediate
the electrophilic halogenation.10
Table 1. Synthesis of Amidine 1a Using Various Amides
In the course of our effort to develop electrophilic cas-
cades that use the brominating source, N-bromosuccini-
mide (NBS), we reported a novel one-pot electrophilic
aminoalkoxylation reaction that used an olefin, NBS, a
cyclic ether, and a sulphonamide (Scheme 1, eq 1).11 The
process was highly efficient and involved no additional
NBS activator. Several bioactive morpholine derivatives
were prepared efficiently using this electrophilic process.
The cascade sequence starts with a nucleophilic attack of
bromonium ion A by a cyclic ether to yield oxonium
intermediate B. Subsequent attack of B by a sulfonamide
gives the desired aminoether derivative C. We rationalized
that instead of a cyclic ether, a nitrile could be used which,
in principle, suggested that a halo-amidine derivative could
be prepared through a DfEfF sequence (Scheme 1, eq 2).
entrya
R
NXS
X
yielde (%)
1
Ts
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
I
92
90
60
61
90
81
91
83
87
90
24
26
2b
3c
4d
5
Ts
Ts
Ts
PhSO2
6
pMeOC6H4SO2
7
Ns
8
Ms
9
CCl3CO
CF3CO
Ts
10
11
12
Ts
Scheme 1. Bromonium Ion Promoted Electrophilic Cascades
a Reactions were carried out with cyclohexene (0.6 mmol), NXS (0.6
mmol), and RNH2 (0.5 mmol) in MeCN (3 mL) at 25 °C for 4 h. b 1.0 g
scale. c SnCl4 (0.2 mmol) was used. d Cu(OTf)2 (0.1 mmol) was used.
e Isolated yield.
in reaction yield (Table 1, entries 3À4).13 It is noteworthy
that the reaction is readily scalable without loss of effi-
ciency (Table 1, entry 2). In addition, the performance of
the reaction is not affected when the addition sequence is
changed. Compound 1a can be converted to imidazoline
2a (95% yield) simply by heating in MeCN at reflux for 2 h
(Scheme 2).
Thus, an initial experiment was performed using cyclo-
hexene, NBS, acetonitrile, and tosyl amide at 25 °C. As
expected, the corresponding bromoamidine 1a was ob-
tained in 92% yield (Table 1, entry 1).12 In addition totosyl
amide, other electron-deficient amides including PhSO2NH2,
p-MeOPhSO2NH2, NsNH2, MsNH2, CCl3CONH2, and
CF3CONH2 worked equally well (Table 1, entries 5À10).
On the other hand, dialkyl amines or electron-rich amides
such as acetamide were unable to offer any desired pro-
duct. In addition, other halogen sources such as N-chlor-
osuccinimide (NCS) or N-iodosuccinimide (NIS) were
found to be less reactive (Table 1, entries 11À12). Inter-
estingly, the addition of Lewis acids resulted in a decrease
Having proven the concept of this multicomponent
bromoamidine synthesis, we further expanded its scope
by varying the olefinic substrates (Table 2). In most cases,
Scheme 2. Synthesis of 2a
the corresponding imidazolines 2 were obtained as the sole
products, a result of intramolecular cyclization of the
bromoamidine 1.14 Interestingly, a ring-opening product
2f (87%) was obtained when R-pinene was used, probably
through a bromonium ion-initiated rearrangement (Scheme 3).
The structures of 1a, 2f, and 2m were confirmed by
(10) Sporadic reports related to this type of cascade: (a) Booker-
Milburn, K. I.; Guly, D. J.; Cox, B.; Procopiou, P. A. Org. Lett. 2003, 5,
3313–3315. (b) Abe, T.; Takeda, H.; Miwa, Y.; Yamada, K.; Yamada,
R.; Ishikura, M. Helv. Chim. Acta 2010, 93, 233–241. (c) Crookes, B.;
Seden, T. P.; Turner, R. W. J. Chem. Soc., Chem. Commun. 1968, 342.
(11) (a) Zhou, L.; Tan, C. K.; Zhou, J.; Yeung, Y.-Y. J. Am. Chem.
Soc. 2010, 132, 10245–10247. For recent examples of electrophilic Br
initiated cascades, see:(b) Snyder, S. A.; Treitler, D. S. Angew. Chem.,
Int. Ed. 2009, 48, 7899–7903. (c) Snyder, S. A.; Treitler, D. S.; Brucks,
A. P. J. Am. Chem. Soc. 2010, 132, 14303–14314. (d) Alcaide, B.;
Almendros, P.; Luna, A.; Torres, M. R. Adv. Synth. Catal. 2010, 352,
621–626.
(14) Representative procedure: To a solution of N-bromosuccini-
mide (107 mg, 0.6 mmol) and sulfonamide (0.5 mmol) in dry acetonitrile
(3 mL) in the dark was added olefin (0.6 mmol). After stirring for 4 h at
25 °C, the reaction was quenched with saturated Na2S2O3 (5 mL) and
NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 Â 15 mL).
The combined extracts were washed with brine (15 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography to yield the corresponding
product.
(12) The details appear in the Supporting Information.
(13) An acid catalyst or a highly electrophilic halogen source is
usually required to promote the cohalogenation. For a related Ritter-
type reaction, see: (a) Hassner, A.; Levy, L. A.; Gault, R. Tetrahedron
Lett. 1966, 7, 3119–3123. (b) Bellucci, G.; Bianchini, R.; Chiappe, C. J.
Org. Chem. 1991, 56, 3067–3073. (c) Yeung, Y.-Y.; Gao, X.; Corey, E. J.
J. Am. Chem. Soc. 2006, 128, 9644–9645.
Org. Lett., Vol. 13, No. 9, 2011
2449

Table 2. One-Pot Synthesis of Amidines and Imidazolines Using
Various Olefins
Scheme 3. Proposed Mechanism for the Formation of 2f
the Markovnikov-type products were isolated (Table 2,
entries 2À11); (2) high positional selectivity whereby the
more electron-rich olefins react more readily (Table 2,
entries 4 and 8); (3) high stereoselectivity which only leads
Scheme 4. Proposed Mechanisms for the Haloamidine Cycli-
zations of 1a and 1c
to the trans-bromoamidines from (E)-alkenes, and the cis-
imidazolines when (Z)-alkenes are used (Table 2, entries
1À4, 13, and 14);indeed, a trans-imidazoline was isolated
Table 3. Synthesis of Amidines Using Various Nitriles
entrya
R
product
yieldb (%)
1
2
3
4
5
Et
3a
3b
3c
3d
3e
88
73
81
86
53
nPr
iPr
CHdCH2
Ph
a Reactions were carried out with olefin (0.6 mmol), NBS (0.6 mmol),
and RNH2 (0.5 mmol) in MeCN (3 mL) at 25 °C for 4 h. The yields were
isolated yields. b 1.0 mmol of olefin was used. c The reaction time was 16
h. d Isolated yield.
a Reactions were carried out with cyclohexene (0.6 mmol), NBS (0.6
mmol), and TsNH2 (0.5 mmol) in RCN (1 mL) at 25 °C for 4 h. b Isolated
yield.
X-ray crystallographic studies.12 The general features of
this reaction include (1) high regioselectivity wherein only
as the sole product when a trans-olefin was used (Table 2,
entry 12); and (4) disubstituted olefinic substrates (Table 1,
2450
Org. Lett., Vol. 13, No. 9, 2011

entry 1; Table 2, entry 1) that provide the haloamidine
products while the trisubstituted olefinic substrates afford
the imidazoline products under the standard reaction
conditions; this can be attributed to a difference in the
conformation of the substrates (Scheme 4). Taking 1a and
1c as examples, for haloamidine 1a, the most stable con-
former is G with the two substituents in equatorial posi-
tions(Scheme4, eq1). G can be isomerized tothelessstable
conformer H in order to cyclize to imidazoline 2a. Alter-
natively, in the 1cf2c transformation (Scheme 4, eq 2), the
J/I ratio appears to be higher than the H/G ratio as the
steric stress of the methyl group in I is released in con-
formerJ(equatorialmethyl). Nevertheless, thedifficulty in
cyclization of 1a (comparing to 1c) could be overcome by
heating up the reaction mixture (cf. Scheme 2).
NBS, an amide, and a nitrile. A wide range of imidazo-
line derivatives can be synthesized using this methodol-
ogy. This type of reaction is highly practical in several
aspects: (1) all the reagents, especially the cascade
initiator NBS, are inexpensive and commercially avail-
able; (2) the reaction setup is very convenient, involving
a simple mixing of the components at room tempera-
ture, and a change in the addition sequence does not
affect its efficiency; and (3) the reaction is readily
scalable. Research toward the exploration of reactions
that are analogous to this methodology, as well as
the synthesis of bioactive imidazoline derivatives, is
underway.
Acknowledgment. We are thankful for the financial
support from the National University of Singapore (Grant
No. 143-000-428-112).
The scope of this amidine synthesis appears to be quite
broad not only with regards to the olefinic component but
also in terms of the nitrile partner. A variety of nitriles were
found to react with cyclohexene, NBS, and TsNH2 to yield
amidines 3aÀe in good yields (Table 3).
Supporting Information Available. Experimental pro-
cedures and additional information. This material is
available free of charge via the Internet at http://pubs.
acs.org.
In summary, we have developed a general and effi-
cient one-pot imidazoline synthesis that uses an olefin,
Org. Lett., Vol. 13, No. 9, 2011
2451