Catalytic one-pot synthesis of cyclic amidines by virtue of tandem reactions involving intramolecular hydroamination under mild conditions

Article abstract of DOI:10.1021/ja064788i

A new synthetic methodology for the generation of cyclic amidines has been developed by the reaction of 1,n-aminoalkynes with electron-deficient azides using a ruthenium catalyst at ambient temperature. The reaction proceeds most likely via a tandem sequence of intramolecular hydroamination of aminoalkynes, cycloaddition of azides with the resulting enamines, and rearrangement of triazoline intermediates. It demonstrates, as the proof-of-principle, that an equilibria cascade sequence can be favorably driven by an irreversible step, thus enabling a facile one-pot synthetic route to deliver molecular complexity under unprecedented mild conditions without relying on the traditional linear approaches. Copyright

Full text of DOI:10.1021/ja064788i

Published on Web 09/01/2006
Catalytic One-Pot Synthesis of Cyclic Amidines by Virtue of Tandem
Reactions Involving Intramolecular Hydroamination under Mild Conditions
Sukbok Chang,* Minjae Lee, Doo Young Jung, Eun Jeong Yoo, Seung Hwan Cho, and Sun Kyu Han
Center for Molecular Design and Synthesis (CMDS), Department of Chemistry and School of Molecular Science
(BK21), Korea AdVanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea
Received July 6, 2006; E-mail: sbchang@kaist.ac.kr
Table 1. Scope of Azides in the Reaction with Aminoalkyne 7a
A range of multicomponent reactions, especially consisting of
multiple reversible steps, are often favorably driven by a certain
irreversible step to facilitate the whole transformation.1 For example,
release of stable molecules such as N2, CO, or CO2 can serve as a
driving force, thereby enabling the reactions to be carried out under
mild conditions. Recently, we have reported highly efficient Cu-
catalyzed three component reactions,2 in which terminal alkynes
and sulfonyl azides are coupled with amines, alcohols, and water
to give amidines, imidates, and amides, respectively. Although the
mechanistic details are not fully described yet, it is presumed to
proceed via a ketenimine intermediate, which has been also
proposed by Fokin et al.3
To expand the scope of these novel couplings, we envisioned
that the reaction of 1,n-aminoalkynes with sulfonyl azides could
provide cycloamidines,4 which are highly useful in medicinal and
coordination chemistry as well as materials science.5 When 1-(N-
benzyl)amino-4-pentyne (1) was treated with TsN3 (2), to our
surprise, 5-membered amidines were obtained as a mixture of 3
and 4 using CuI catalyst (eq 1). The outcome was unexpected in
that the intramolecular attack of amino group into the putative
tethered ketenimine (5) should lead to a six-membered amidine (6)
if it follows the same pathway as in the intermolecular version.
entry
R2
ratio (8/9)b
yield (%)c
1
(4-Me)C6H4SO2
(4-Me)C6H4SO2
MeSO2
2-PySO2
C6H5CO
(4-O2N)C6H4CO
(4-Me)C6H4CO
(PhO)2PO
PhCH2OCO
PhCH2
8.0:1
8.1:1
6.5:1
75
81
81
66
65
80
65
69
74
<5
2d
3
4
5
6
7
8
9
10
11:1
>25:1
>25:1
>25:1
>25:1
>25:1
a Azide (0.24 mmol) and 7 (0.2 mmol) in THF (2.0 mL). b 1H NMR
ratio of crude mixture. c Combined yield. d Et3N (1.2 equiv) was used.
benzoyl azides, irrespective of the electronic nature of the substit-
uents (entries 5-7). Additionally, phosphoryl- and benzyloxycar-
bonyl azide could be also employed as reacting counterparts (entries
8-9).8 However, relatively electron-rich azides such as alkyl or
aryl variants did not react (entry 10).
On the basis of the product distribution and precedents that
electron-deficient azides react with activated olefins including
enamines,9 a plausible pathway for the present reaction is depicted
in Scheme 1. The transformation is assumed to be initiated by the
intrahydroamination by the assistance of a metal catalyst.10 While
the emerging enamine exists as an isomeric mixture,11 the more
stable exo-methylene pyrrolidine adduct (10) is preferentially
cyclized with azides giving a spiro triazoline (11), which is then
rearranged to cycloamidine 3 upon release of diazomethane. In fact,
we were able to capture in situ CH2N2 from a reaction in the
presence of 4-phenylbenzoic acid.12
In the case of 1,5-aminoalkynes, endo-adduct 12 rather than its
exo-isomer reacts more readily with azides.11 Rearrangement of the
resultant triazoline (14) is postulated to lead to 8a upon the
migration of a Me group and release of N2.13 It is noteworthy that
the present reactions include a mild intramolecular hydroamination
as the most probable key pathway, which normally takes place under
much harsher conditions using late transition metal catalysts.14
We immediately found that several significant differences exist
between the inter- and intramolecular reactions. First, whereas only
a few copper salts, representatively CuI, perform the interreactions,
the intramolecular version could be catalyzed with a range of metal
species including Pd(II), Pt(II), Au(III), Ru(0, III) as well as Cu-
(I), although the catalytic activity and selectivity were dependent
on the metals employed.6 Among those, Ru3(CO)12 displayed
notably high efficiency in THF. Second, while sulfonyl azides were
the only efficiently viable substrates in the interreactions, a range
of electron-deficient azides readily participated in the intraversion
of amidine synthesis (Table 1).
When 1,5-aminoalkyne (7) was reacted with p-toluenesulfonyl
azide at ambient temperature, two cycloamidine products 8 and 9
(8.0:1) were produced in high yield by virtue of Ru3(CO)12 (entry
1).7 The yield was slightly improved by the presence of Et3N while
the selectivity was not significantly changed (entry 2). The reaction
proceeded smoothly with various sulfonyl azides (entries 3-4).
Noticeably, only one compound 8 having a R-methyl group was
produced exclusively in good yields when 7 was reacted with
The mechanistic interpretation gains credence by several experi-
ments in addition to the product distribution and capture of released
CH2N2. First, treatment of TsN3 with an independently prepared
cyclic enamines from 1-benzyl-2-pyrrolidinone using Tebbe reagent
9
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J. AM. CHEM. SOC. 2006, 128, 12366-12367
10.1021/ja064788i CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
6). Additionally, no significant stereo induction was observed when
a chiral azide was employed (entry 7). However, it should be
mentioned that the present one-pot reaction readily delivers
molecular complexity such as spirocyclic amidine or bicyclic
tetrahydroisoquinoline system (entries 8-9).
In the case of aminoalkyne 16 having a resident in the backbone,
3,4-syn-cycloamidine 17 was obtained as the sole product (eq 3).
Hence, the Me-group migration step proceeded with a perfect
diastereoselectivity.
Table 2. Ru-Catalyzed Synthesis of Cyclic Amidinesa
In conclusion, we have developed a new synthetic methodology
by bridging two reactions in a tandem manner. It demonstrates, as
the proof-of-principle, that equilibria tandem sequence can be
favorably driven by an irreversible step, thereby enabling a facile
one-pot synthetic route to deliver molecular complexity under
unprecedented mild conditions. It is anticipated that applications
of this concept would pave a new way to synthetically valuable
processes without relying on the traditional linear approaches.
Acknowledgment. Dedicated to Professor Sunggak Kim on the
occasion of his 60th birthday. This research was supported by KRF
Grant KRF-2005-015-C00248 and by the CMDS at KAIST.
Supporting Information Available: Data of 1H and 13C NMR
spectra of new compounds, and two CIF files. This material is available
free of charge via the Internet at http://pubs.acs.org.
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provided a mixture of cyclic amidines (the same products as in
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