Visible light-induced intramolecular cyclization reactions of diamines: A new strategy to construct tetrahydroimidazoles

Article abstract of DOI:10.1039/c1cc12203g

A new and efficient synthesis of highly substituted tetrahydroimidazole derivatives by means of visible light-induced intramolecular cyclization reactions has been described. This photoredox catalytic reaction exhibited high diastereoselectivity and afforded the desired products in good yields.

Full text of DOI:10.1039/c1cc12203g

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COMMUNICATION
Visible light-induced intramolecular cyclization reactions of diamines:
a new strategy to construct tetrahydroimidazolesw
Jun Xuan, Ying Cheng, Jing An, Liang-Qiu Lu, Xiao-Xiao Zhang and Wen-Jing Xiao*
Received 17th April 2011, Accepted 9th June 2011
DOI: 10.1039/c1cc12203g
A new and efficient synthesis of highly substituted tetrahydro-
imidazole derivatives by means of visible light-induced intra-
molecular cyclization reactions has been described. This photoredox
catalytic reaction exhibited high diastereoselectivity and afforded
the desired products in good yields.
Recently, the use of the visible light to initiate organic reactions
has attracted much attention1 because of its natural abundance,
ease of use, non-toxicity and potential applications.2 For
instance, [2+2] or [3+2] cycloaddition reactions and a tin-free
Scheme 1 Visible light induced the asymmetric synthesis of tetra-
reductive dehalogenation reaction, which are initiated by
photoredox catalysts under visible light irradiation,3 have been
reported by the research groups of Yoon4 and Stephenson,5
hydroimidazole derivatives.
respectively. Moreover, the highly reactive iminium intermediate,
new route to highly substituted tetrahydroimidazoles in a stereo-
which can be generated from the oxidation of tertiary amines
selective manner is desirable.
through photoredox catalysis, has also been successfully used
As part of our ongoing programme on the development of
for further functionalization.6 Notably, MacMillan and
carbon- and heterocycle-oriented methodologies,11 we envisioned
co-workers disclosed an enantioselective alkylation of aldehydes
that the enantiomerically pure substrate I, which was derived
by merging photoredox catalysis with organocatalysis.7 These
from commercially available natural amino acids, could be
seminal investigations have shown the great potential of visible
oxidized to iminium intermediate III in the presence of photo-
light photocatalysis in synthetic chemistry. However, to our
redox catalysts and O2 under visible light irradiation. Followed
knowledge, visible light-induced asymmetric reactions are still rare.
by an intramolecular cyclization, the biologically important
On the other hand, the tetrahydroimidazole moiety is a common
tetrahydroimidazole IV could be diastereoselectively obtained
structural subunit present in various natural products, many
by the induction of the chirality of substrates (Scheme 1). In
of which display a wide range of biological activities.8 As a
this communication, we describe the preliminary results of
result, great efforts have been devoted to the development of a
this study.
straightforward access to optically active tetrahydroimidazoles.
Our initial study began with the reaction of the enantio-
An elegant method to prepare tetrahydroimidazoles is the
merically pure diamine 1a prepared from L-phenylananine in
condensation reaction of 1,2-diamine with aldehydes, although
the presence of 5.0 mol% Ru(bpy)3Cl2 with O2 under visible
in situ removal of water is needed to increase the reaction
efficiency.9 Very recently, the Wu group disclosed a concise
light irradiation. As highlighted in Table 1, the reaction media
had a significant effect on the reaction efficiency (Table 1,
synthesis of tetrahydroimidazoles through 1,3-dipolar cyclo-
entries 1–4). Some solvents, such as DMF and CH3CN, which
additions of azomethine ylides with fluorinated imines.10
were widely used in photoredox catalytic reactions,4,5 did not
Despite these advances, the development of a strategically
work well in this reaction (Table 1, entries 1 and 2). To our delight,
the proposed cyclization reaction underwent smoothly when it
was performed in ethanol or methanol albeit with fair diastereo-
Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry,
Central China Normal University, 152 Luoyu Road,
Wuhan, Hubei 430079, China. E-mail: wxiao@mail.ccnu.edu.cn;
Fax: +86 27 67862041; Tel: +86 27 67862041
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterisation data, including X-ray
crystal data for 2a. CCDC 818677. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c1cc12203g
selectivity (Table 1, entries 3 and 4). To further improve the
reaction efficiency, we then examined the influence of a base on
this process (Table 1, entries 5–10). Initial experiments revealed
that the use of tBuOK gave optimal results (93% yield and 4 : 1 dr,
Table 1, entry 10). Further optimization showed that the
catalyst loading could be decreased to 1.0 mol% without a signifi-
cant loss in the yield or diastereoselectivity (Table 1, entry 11).
c
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Chem. Commun., 2011, 47, 8337–8339 8337

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Table 1 Optimisation of reaction conditionsa
Table 3 Substrate scope: variation of substituent Ra
Entry
Solvent
Base
Time/h
Yieldb (%)
drc
1
2
3
4
5
6
7
8
DMF
CH3CN
EtOH
DBU
DBU
DBU
DBU
—
24
10
8
8
24
8
24
16
9
9
9
48
0
27
72
89
0
84
23
93
84
93
93
92
—
ndd
2 : 1
3 : 1
—
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
TMGg
Et3N
2 : 1
nd
K2CO3
NaOH
tBuOK
tBuOK
tBuOK
1 : 1
2.5 : 1
4 : 1
4 : 1
10 : 1
9
10
11e
12f
a
Unless otherwise specified, all reactions were carried out with 1a
(0.2 mmol), Ru(bpy)3Cl2 (5.0 mol%), base (5.0 equiv.) and O2 in the
b
solvent (4 mL) under visible light irradiation at RT. Isolated yield.
c
d
Determined by 1H NMR of crude products. nd = not determined.
a
All reactions were carried out with 1 (0.2 mmol), Ru(bpy)3Cl2
(1.0 mol%), tBuOK (5.0 equiv.) and O2 in MeOH (4 mL) under visible
e
f
1.0 mol% Ru(bpy)3Cl2 was used. After completion of reaction,
g
b
light irradiation at RT. Reaction time determined by TLC. DCM
c
DCM (1.0 mL) was added and stirring was continued for 48 h. TMG =
tetramethyl guanidine.
d
(1.0 mL) was added and stirring was continued until 48 h. Isolated
e
1
yield. Determined by H NMR.
Table 2 Substrate scope: substituents on Ar1 and Ar2 a
significant latitude in the steric demands of the diamine (1) was
possible (Ar1 = 4-MeOC6H4 and 2-MeOC6H4, respectively).
Attempts to carry out the reaction of the substrate with the
alkyl group instead of Ar1 or Ar2 failed owing to its lower
reactivity. Such problems remain to be further explored.
A variety of substituted 1,2-diamine derivatives can be
successfully employed in this photoredox-initiated reaction
(Table 3). For example, 1,2-diamines 1j and 1l prepared from
L-alanine and L-leucine could afford the corresponding
products 2j and 2l in high yields (92 and 94% yields, respectively)
and excellent diastereoselectivities (419 : 1). The substrates 1k
and 1m derived from L-valine and L-isoleucine generated
products 2k and 2m in 89 and 90% isolated yields, respectively,
but with relatively lower diastereoselectivities. Moreover, the
heteroatom-substituted diamine 1n was also tolerated in this
process and it gave the corresponding tetrahydroimidazole 2n in
45% yield with 3 : 1 dr.
Yieldc
Entry Ar1
Ar2
Product Timeb/h (%)
drd
10 : 1
419 : 1
419 : 1
419 : 1
419 : 1
8 : 1
1
2
3
4
5
6
7
8
9
C6H5
C6H5
4-MeC6H4 C6H5
4-MeOC6H4 C6H5
2-MeOC6H4 C6H5
2a
2b
2c
2d
2e
2f
48
48
48
48
72
48
48
48
72
92
93
90
92
92
92
94
91
94
4-ClC6H4
4-BrC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeC6H4 2g
4-MeOC6H4 2h
419 : 1
419 : 1
419 : 1
4-ClC6H4
2i
a
All reactions were carried out with 1a (0.2 mmol), Ru(bpy)3Cl2
(1.0 mol%), tBuOK (5.0 equiv.) and O2 in MeOH (4 mL) under visible
The structures and the absolute (2R,4S)-configuration of 2a
have been unambiguously established by X-ray diffraction
studies.12 Based on our experimental results, a stereochemical
course of this reaction was proposed as depicted in Scheme 2.
The addition of the nitrogen anion to the iminium ion from
b
light irradiation at RT. After completion of reaction, DCM (1.0 mL)
c
was added and stirring was continued for the indicated time. Isolated
yield. Determined by 1H NMR.
d
Notably, prolonging the reaction time dramatically increased
the diastereoselectivity of the reaction (Table 1, entry 12).
With the optimal reaction conditions in hand, the scope of
substrates was explored. This visible light-induced cyclization
reaction appeared to be quite tolerant with respect to structural
variation of both aryl groups (Table 2). Incorporation of methyl,
methoxyl, chloro and bromo substituents at the C(4)-position
in Ar1 or Ar2 revealed that electronic modification of aromatic
rings could be accomplished without a substantial loss of reaction
efficiency (Table 2, entries 2–9). As shown in entries 3 and 4,
Scheme 2 Proposed stereochemical pathways.
c
8338 Chem. Commun., 2011, 47, 8337–8339
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procedures under benign conditions and is completely atom-
economic in character.
We are grateful to the National Science Foundation of China
(21072069 and 21002036) and the National Basic Research
Program of China (2011CB808600) for support of this research.
Notes and references
1 For selected reviews of visible light photoexcition of an organo-
metallic complex to initiate organic reactions, see: (a) T. P. Yoon,
M. A. Ischay and J. Du, Nat. Chem., 2010, 2, 527; (b) J. M. R.
Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2011,
40, 102.
2 For a recent review of chemistry using visible light, see: X. Sala,
I. Romero, M. Rodriguze, E. Lluis and A. Llobet, Angew. Chem.,
Int. Ed., 2009, 48, 2842.
Scheme 3 Two pathways of the epimerization of the product.
its Re is much more favorable than that to its Si face due to the
steric repulsion. When the reaction time was prolonged,
product epi-2 could be converted into the thermodynamically
more stable cis form under the reaction conditions.
2+
3 For reviews of the photochemistry and photophysics of Ru(bpy)3
and related complexes, see: (a) K. Kalyanasundaram, Coord. Chem.
Rev., 1982, 46, 159; (b) A. Juris, V. Balzani, F. Barigelletti,
S. Campagna, P. Belser and A. V. Zelewsky, Coord. Chem. Rev.,
1988, 84, 85.
Two pathways were proposed to explain the epimerization.
In path A, epi-2 could isomerize to 2 through the iminium ion
intermediate with the assistance of MeOH or the ruthenium
catalyst (Scheme 3). Alternatively, excess tBuOK in the reaction
system might promote the epimerization through a deprotonation/
diastereoselective protonation sequence (path B). To gain some
insights into this process, a few control experiments were
carried out. Treatment of 2c (dr = 3 : 1) with MeOH/CH2Cl2
and Ru(bpy)3Cl2, respectively, for 48 h increased the dr to 9 : 1
in both cases, while the dr was dramatically improved to 13 : 1
4 (a) M. A. Ischay, M. E. Anzovino, J. Du and T. P. Yoon, J. Am.
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t
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that path B was more favorable although we could not rule out
path A at the current stage.
To demonstrate the preparative utility of this methodology,
the reaction of 1c (1.1 g) was performed on a 2.2 mmol scale in
the presence of 1 mol% of Ru(bpy)3Cl2 under our standard
conditions, affording cis-2c in 87% yield with 419 : 1 dr
(eqn (1)). Significantly, this method can be extended to the
synthesis of biologically important hexahydropyrimidine
derivatives in 61% yield (eqn (2)).13
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ð1Þ
ð2Þ
12 See ESIw for details.
In summary, we have developed an efficient synthesis of
highly substituted tetrahydroimidazole derivatives by means
of intramolecular cyclizations of diamines through a photoredox
catalysis strategy. The reaction itself features simple experimental
13 (a) S. Groszkowki, L. Korzycka and W. Bialasiewicz, Pol. J.
Pharmacol. Pharm., 1973, 25, 573 (Chem. Abstr., 1974,
80, 116181r); (b) K. Drandarov, A. Guggisberg and M. Hesse,
Helv. Chim. Acta, 1999, 82, 229.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8337–8339 8339