Characterization and utility of N-unsubstituted imines synthesized from alkyl azides by ruthenium catalysis

Article abstract of DOI:10.1002/anie.201204483

Shine a light: A fluorescent light-induced synthetic method for the title compounds has been developed and the chemoselective nature of the reaction is highlighted by the observation of the cis/trans isomers of various N-unsubstituted imines. The synthetic utility of this method is demonstrated by the one-pot imine formation/asymmetric allylation sequence of benzyl azide catalyzed by 1. (Ipc=isopinocampheyl). Copyright

Full text of DOI:10.1002/anie.201204483

Angewandte
Chemie
DOI: 10.1002/anie.201204483
Synthetic Methodology
Characterization and Utility of N-Unsubstituted Imines Synthesized
from Alkyl Azides by Ruthenium Catalysis**
Jin Hee Lee, Sreya Gupta, Wook Jeong, Young Ho Rhee,* and Jaiwook Park*
Imines have been recognized as pivotal intermediates in
organic synthesis, particularly for the preparation of nitrogen-
containing bioactive natural products and derivatives.[1,2]
Compared with carbonyl groups, imines are more difficult
to handle because of their chemically labile nature. As a result
of this problem, the transformation into the amine products
usually employs imines possessing a substituent on the
nitrogen atom (N-substituted imines). However, from a syn-
thetic viewpoint this protocol necessitates removal of the
substituent to access the amine products [Eq. (1), Figure 1].
In this regard, the use of N-unsubstituted imines would be
ideal in that the elimination step is not necessary.
been proposed as an intermediate without isolation (or
detection) in most cases. For example, Chen and Brown,[5]
and Itsuno et al.[6] suggested that N-unsubstituted imines
could be formed from the N-trialkylsilyl imine precursors, but
the scope of this method is restricted to the preparation of
non-enolizable imines. In addition, N-unsubstituted imines
are not generally obtained as a stable entity in the conven-
tional reaction of carbonyl compounds with ammonia (only
limited examples such as ortho-hydroxyarylketimines are
known to be stable under these reaction conditions)[7]
.
Recently, Kobayashi and co-workers[8] and Thadani and co-
workers[9] reported the aminoallylation of carbonyl com-
pounds in one-pot, wherein the N-unsubstituted imines were
not detected, but proposed as plausible intermediates. The
use of excess ammonia in these cases poses a limitation in
terms of the scope of the nucleophiles that react with N-
unsubstituted imines. For example, the asymmetric allylation
of N-unsubstituted imines using this method showed only
poor enantioselectivity. In the meantime, N-metalloimines
generated from alkyl cyanides have been frequently used as
À
a surrogate for N-unsubstituted imines in C C bond forma-
tion reactions and reductions.[10–13] However, this method
requires highly reactive chemical reagents in stoichiometric
amounts. As illustrated by these few examples, developing
general synthetic methods for N-unsubstituted imines under
mild reaction conditions represents a formidable challenge,
and remains elusive in organic synthesis.
From a conceptual viewpoint, N-unsubstituted imines can
be potentially accessed from easily available alkyl azide
precursors with the removal of N2 and subsequent migration
of hydrogen [Eq. (2), Figure 1].[14] This method is particularly
attractive because the reaction can proceed under very mild
reaction conditions. In fact, stoichiometric formation of
a metal/imine complex based upon this concept has already
been reported.[15–18] However, attempts using photolytic[19] or
metal-catalyzed conditions[20] could not deliver the free N-
unsubstituted imines, presumably because of the instability
and the high reactivity of the imines. Recently, we reported
a simple synthesis of an isolable bridged diruthenium complex
1 and its utility under photolytic conditions for the racemi-
zation of secondary alcohols[21] and the chemoselective
hydrosilylation of aldehydes.[22] Herein, we report that N-
unsubstituted imines can be efficiently generated using 1 and
the structurally related ruthenium complex 2.[23,24] Remark-
ably, the mild reaction conditions used in this transformation
even allowed the observation of cis/trans isomers of the N-
unsubstituted imines by NMR spectra taken at room temper-
ature. Moreover, this new protocol enables various chemo-
selective transformations of N-unsubstituted imines.
Figure 1. N-unsubstituted imines: Basic concept.
Unlike N-substituted imines, however, the synthetic scope
of N-unsubstituted imines is still very limited. N-unsubsti-
tuted imines are known to be much less stable than the N-
substituted analogues. This feature is easily addressed by the
fact that only few N-unsubstituted imines have been success-
fully isolated or characterized.[3,4] In fact, such imines have
[*] J. H. Lee, S. Gupta, W. Jeong, Prof. Y. H. Rhee, Prof. J. Park
Department of Chemistry, POSTECH (Pohang University of Science
and Technology), Pohang, 790-784 (Korea)
E-mail: yhrhee@postech.ac.kr
pjw@postech.ac.kr
Homepage: http://oml.postech.ac.kr
[**] This work was supported by the National Research Foundation of
Korea (2012-007235) and by KOSEF through the EPB center (2012-
0000534).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204483.
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Our initial efforts focused on the synthesis of benzaldi-
mine (4) from benzyl azide (3)under ruthenium-catalyzed
photolytic conditions and unprecedented behavior of N-
unsubstituted aldimines was observed [Eq. (3), Figure 2]. In
Encouraged by these results, we explored the synthesis
and detection of other structurally diverse N-unsubstituted
imines. As shown in Equation (4), the outcome depended
upon the structure of the alkyl azide substrates. For example,
the secondary benzylic azide 5 was completely converted into
the ketimine 6 in greater than 90% yield (NMR) in the
presence of the ruthenium complex 2 (2 mol%). In this case,
1
the H NMR spectrum taken at room temperature showed
the presence of the cis/trans isomers in a 2.9:1 ratio (for the
spectral data and the assignment of cis/trans isomers, see the
Supporting Information). In addition, bis(benzylic) azide (7)
was completely consumed within 12 hours to give the
chromatographically stable N-unsubstituted diphenylketi-
mine 8 in 91% yield upon isolation. Unlike the benzylic
azides, the reaction of the aliphatic primary alkyl azide 9 was
considerably slow. Also, the yield of the aldimine products 10
as measured by 1H NMR spectroscopy was significantly lower
[a small triplet/doublet peak at about d = 8.00 ppm (J =
22 Hz, 4 Hz) is indicative of imine formation]. Interestingly,
an aldimine possessing a silyl ether at the neighboring carbon
atom (12) could be obtained from the azide precursor 11 in
82% yield [Eq. (5)]. In this case, the NMR spectrum showed
Figure 2. NMR spectrum of cis-4 and trans-4. THF=tetrahydrofuran.
the presence of 1 mol% of the catalyst 1 under a household
fluorescent light (30 W) in [D8]THF, the substrate was
completely consumed after 10 hours at room temperature.
Remarkably, a significant amount of benzaldimine (4; 93%
yield as determined by NMR analysis) was observed under
these mild reaction conditions with no undesired events as
previously reported in the literature (Figure 2).[25] In addition,
the 1H NMR spectrum of the crude reaction mixture showed
two distinct sets (each with two doublets) of peaks for the
imino hydrogen in approximately a 5:1 ratio. Based upon the
coupling constant (J = 16 Hz), the major set of peaks was
assigned to cis-4 (Figure 2). The minor set has a significantly
larger coupling constant (J = 25 Hz) and were therefore
assigned to trans-4. Notably, 4 as prepared under these
neutral conditions was quite stable. No significant decom-
position was seen in the [D8]THF solution, even after one day
at room temperature. This observation is in sharp contrast to
the previous reports which described only cis-4 as a very
unstable species.[3] Lowering the temperature somewhat
increased the relative ratio of cis-4. On the basis of the
relative integration of the peaks in the NMR spectrum of the
crude reaction mixture, the DG value between two geo-
metrical isomers in [D8]THF was determined to be about
1 kcalmolÀ1.[26] It should be also noted that both the
ruthenium catalyst and fluorescent light were required for
the imine formation. The catalytic reaction in the dark as well
as the photolytic reaction without 1 showed no conversion.
that the major species exists as the trans isomer. To addition-
ally verify imine formation, we pursued in situ capture of the
imine product with triethylborane under the photolytic
conditions. As shown in Equation (6), generation of the
1
borane imine adduct 13 was indeed observed by H NMR
spectroscopy (the characteristic doublet peak at d = 9.41 ppm
was assigned to the imino hydrogen atom). This analysis is
again in good agreement with previous reports on the
characterization data obtained for the borane imine complex
13,[5] and thus unambiguously confirms formation of N-
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unsubstituted imines from benzyl azide. Notably, even the
borane complex of the aliphatic N-unsubstituted aldimine 14
could be obtained from 9 in high yield [Eq (7); the character-
istic doublet peak at d = 8.87 ppm was assigned to the imino
hydrogen atom).
was also successful when 2 was employed. In addition to the
simple allylation discussed above, the one-pot reaction of
azides also showed excellent substrate-controlled diastereo-
selectivity. For example, the azide 21 gave the amine 22 in
86% yield with 87:13 syn selectivity [Eq. (8); TBDMS = tert-
Having established the chemoselective access to various
N-unsubstituted imines, we then explored the synthetic utility
of these compounds. On the basis of the facile formation of
the triethylborane adduct shown in Equations (6) and (7), the
one-pot imine formation/allylation sequence was first
explored using the commercially available 15 (1.5 equiv) as
the allylating agent (Scheme 1). To our delight, the prelimi-
butyldimethylsilyl]. In addition, the cyclohexyl azide 23 gave
the allylated product 24 in 80% yield as a single diastereomer
[Eq (9)]. These examples demonstrate the potential synthetic
utility of the reaction as the substrates are easily accessed
from the corresponding epoxides[27] (for detailed procedures
on the synthesis of the substrates, see the Supporting
Information). As demonstrated by the efficient preparation
of 25 and 26, the reaction also showed an excellent level of
reagent-controlled diastereoselectivity [Eqs. (10) and (11);
Pin = pinacol].
Scheme 1. Examples of the imine formation/allylation sequence.
nary reaction of benzyl azide under the ruthenium-catalyzed
photolytic conditions gave the aromatic allylic amine 16 in
83% yield upon isolation when the catalyst 1 (1 mol%) was
employed. In addition, the aliphatic homoallylic amine 17 was
obtained in comparable yield (85%). The unique chemo-
selectivity of the proposed reaction is highlighted by the
formation of the amine 18, which possesses an ester group, in
91% yield. Notably, the scope of the reaction was successfully
expanded to the synthesis of the allylated a-amino ester 19,
which could not be easily accessed by the previous studies
which relied on the use of excess ammonia or strong reducing
agents. In this case, the reaction with 1 was slow, but use of 2
(1 mol%) significantly improved the reactivity, thus produc-
ing 19 in 73% yield. Synthesis of the tertiary carbinylamine 20
Finally, it should be emphasized that the mild reaction
conditions enabled the asymmetric allylation of the in situ
generated 4 using the chiral allylboronate species.[28,29] For
example, employing the (À)-(Ipc)2B at À788C in the presence
of 2.5 mol% of 2 gave the product (S)-16 in 87% yield with
89% ee [Eq. (12); Ipc = isopinocampheyl].
We then explored the reaction of N-unsubstituted imines
with heteroatom nucleophiles. As shown in Equation (13), we
discovered that various N-unsubstituted imines generated
from the azide precursors react with primary amines to give
N-substituted imines in near-quantitative yields with no need
for additives. Notably, enolizable N-unsubstituted aldimines
proved efficient for this transformation, as indicated by the
high yield for the synthesis of imines 29 and 30. In addition,
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Ru-H species B[30] may be involved as a catalytically active
species for the conversion of azides into N-unsubstituted
imines. In addition, the use of fluorescent light is needed only
for the generation of B.
On the basis of this information, a plausible reaction
sequence can be suggested (Scheme 2). The photogenerated
the water-sensitive trimethoxysilane 31 also gave the corre-
sponding imine 32 in high yield [Eq. (14)].
Scheme 2. Proposed mechanism for the imine formation.
As discussed above, the chemoselective generation of the
N-unsubstituted imine species seems to be the key event in
the proposed reaction. Additional studies provided insights
into the mechanism of formation of the N-unsubstituted
imines. Treatment of the benzyl azide 3 with a stoichiometric
amount of 1 generated the Ru-H species B and benzonitrile
[Eq. (15)]. Moreover, the isolated Ru-H species B effectively
ruthenium complex A attacks the azide to generate the Ru-H
species B and the benzonitrile, presumably by way of the
formation of the imido complex C. Upon losing a CO
ligand,[31] B is converted into the coordinatively unsaturated
species D. The high reactivity of this ruthenium complex
facilitates the conversion of azides into imines. The resulting
imine species might be weakly coordinating to the ruthenium
center. The dissociation of the imine from the ruthenium
complex could be promoted by the subsequent reaction with
amine nucleophiles or allylboranes.
In summary, we developed a novel ruthenium catalyst
system which enabled generation of various N-unsubstituted
imines under mild reaction conditions. As demonstrated by
the observation of geometrical isomers of the enolizable N-
unsubstituted imines, chemoselective preparation of structur-
ally well-defined N-unsubstituted imines was of crucial
importance. It is clear that the protocol introduced here
opens up new possibilities in ideal amine synthesis. Expanding
the synthetic scope of N-unsubstituted imines is now in
progress.
Received: June 9, 2012
Revised: July 23, 2012
Published online: September 28, 2012
catalyzed the formation of the N-substituted imine 27 from
benzyl azide [Eq. (16)]. Notably, the fluorescent light was not
necessary in this case. This result strongly suggests that the
Keywords: allylation · azides · imines · photochemistry ·
.
ruthenium
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