Umpolung Addition of Aldehydes to Aryl Imines

Article abstract of DOI:10.1002/anie.201610578

One of the classical ways to synthesize amines involves the coupling of carbonyl compounds and imines, either through enolate chemistry or acyl-based carbanion equivalents. We herein report an alternative strategy that is based on the use of aldehydes as alkyl carbanion equivalents in a reductive coupling with aryl imines. A wide array of secondary amines can be synthesized in moderate to high yields. This reaction is mediated by hydrazine and catalyzed by ruthenium(II) complexes, and it tolerates various functional groups, such as esters, amides, and nitriles.

Full text of DOI:10.1002/anie.201610578

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201610578
German Edition: DOI: 10.1002/ange.201610578
Ruthenium Catalysis
Umpolung Addition of Aldehydes to Aryl Imines
Ning Chen+, Xi-Jie Dai+, Haining Wang+, and Chao-Jun Li*
Abstract: One of the classical ways to synthesize amines
involves the coupling of carbonyl compounds and imines,
either through enolate chemistry or acyl-based carbanion
equivalents. We herein report an alternative strategy that is
based on the use of aldehydes as alkyl carbanion equivalents in
a reductive coupling with aryl imines. A wide array of
secondary amines can be synthesized in moderate to high
yields. This reaction is mediated by hydrazine and catalyzed by
ruthenium(II) complexes, and it tolerates various functional
groups, such as esters, amides, and nitriles.
Amines are ubiquitous in natural products and bioactive
molecules. Organic nitrogen compounds constitute over 90%
of the 200 top-selling drugs, and feature in many name
reactions.[1,2] Over the past decades, tremendous efforts have
been devoted to the synthesis of a wide array of amines. In
particular, the direct nucleophilic addition of organometallic
reagents (e.g., Grignard reagents) to imines represents
a powerful synthetic method for such purposes.[3] Despite
the robustness of reactivity, most organometallic reagents are
typically prepared from stoichiometric amounts of the
corresponding metals and organic halides (Scheme 1a).
Another obvious drawback associated with this high reac-
tivity is the poor chemoselectivity, exemplified by low func-
tional group compatibility towards, among others, esters,
amides, and nitriles. Alternative strategies for amine synthesis
include the Mannich reaction via enolate formation[4] (Sche-
me 1b) as well as the umpolung addition of aldehydes to
imines, for example in benzoin-type condensations (Sche-
me 1c)[5,6] and pinacol-type couplings (Scheme 1d).[7,8] All of
these common alternatives feature oxygenated carbanions
derived from aldehydes.[9] Herein, we describe a novel
umpolung addition of aldehydes to aryl imines for efficient
amine synthesis, a mild process that is mediated by hydrazine
in the presence of a ruthenium(II) complex (Scheme 1e).
Very recently, we developed a ruthenium-catalyzed,
redox-based strategy for the direct deoxygenation of aliphatic
primary alcohols in complex organic molecules with great
efficiency and excellent selectivity.[10] According to our
Scheme 1. Classical strategies for amine synthesis. a) Addition of
organometallic reagents to imines. b–d) Addition of carbonyl-derived
oxygenated carbanions to imines. e) Addition of aldehyde-derived alkyl
carbanions to aryl imines.
proposed mechanism, the ruthenium(II)-coordinated hydra-
zone A (derived from a carbonyl compound) might react with
another carbonyl compound to form a new carbon–carbon
bond via a six-membered-ring transition state B (a Zimmer-
man–Traxler chair-like transition state; Scheme 2). This
hypothesis was lately proven to be synthetically viable,
providing rapid access to a broad range of secondary and
tertiary alcohols.[11] Encouraged by this proof-of-concept
discovery, we questioned whether imines could be involved
as alternative electrophilic partners in transition state C. If so,
the subsequent imine addition can be readily envisioned for
amine synthesis. However, the much lower reactivity of
imines combined with the potential complications arising
from the structural similarity of imines and hydrazones
rendered the development of such an addition reaction
a great challenge.
In our model study, N-benzylidene aniline (2a) was
chosen as the imine coupling partner while para-chloroben-
zaldehyde (1a) was used as the carbanion precursor to be able
to differentiate the nucleophilic partner from the electrophilic
counterpart. Our initial attempts indicated that four major
side products were generated over the course of the reaction,
namely hydrazinolysis (aniline and azine), hydrolysis (ben-
zaldehyde), and deoxygenated products (para-chlorotoluene;
[*] Dr. N. Chen,[+] X.-J. Dai,[+] Dr. H. Wang,[+] Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Centre for Green Chemistry
and Catalysis, McGill University
801 Sherbrooke St. W., Montreal, Quebec H3A 0B8 (Canada)
E-mail: cj.li@mcgill.ca
Dr. N. Chen[+]
Department of Organic Chemistry, Faculty of Science
Beijing University of Chemical Technology
Beijing (China)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201610578.
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absence of K3PO4 (entry 8). Intriguingly, whereas superior
reactivity was observed with K3PO4, phosphates and carbo-
nates bearing other alkali metal cations displayed no or little
reactivity (entries 9 and 10). Furthermore, cesium fluoride
turned out to be vital to increase the reaction efficiency
(entry 11). Finally, the removal of a chloride from the
ruthenium catalyst with silver triflate diminished the product
yield (entry 12).
With optimized reaction conditions in hand, we then
investigated the aldehyde scope (Scheme 3). To probe the
generality of the current reaction, a variety of aryl-, hetero-
aryl-, and alkyl-substituted aldehydes were tested as nucleo-
philic partners in the coupling with N-benzylidene aniline
(2a). In general, aromatic aldehydes showed good reactivity
in this reaction. Specifically, different halide substituents on
the arene only had a minor influence on the reactivity. In
comparison with benzaldehyde, similar yields were obtained
with chlorine or fluorine substituents at the para position
(Scheme 3, 3a and 3i vs. 3b). Compared to meta- and para-
substituted chlorobenzaldehyde, the ortho-substituted one
was the least reactive (3d vs. 3a and 3c). These results
indicate that the reaction is strongly influenced by steric
hindrance. Similar observations for steric bias were made with
para-, meta-, and ortho-tolualdehyde (3e–3g). Further studies
with para-substituted aldehydes showed that electronic
effects play an insignificant role in this reaction as substrates
Scheme 2. Mechanistic hypothesis for the imine addition. Inspired by
our proposed ruthenium complex A in the deoxygenation chemistry
and the six-membered-ring chair-like transition state (TS) B in carbonyl
addition, we surmised that a similar TS C could be invoked for the
synthesis of amines from imines.
see the side products in Table 1). Subsequent catalyst screen-
ing suggested that ruthenium(II) catalysts with spectator
ligands efficiently catalyzed the reaction, with [Ru(p-cyme-
ne)Cl2]2 (the least expensive one) providing the highest yield
(Table 1, entries 1–3). On the other hand, the evaluation of
various phosphine ligands showed that the reaction was
generally favored by electron-rich phosphines, such as 1,2-
bis(dimethylphosphino)ethane (dmpe) and tri(tert-butyl)-
phosphine (entries 5–7). It should be noted that the loading
of the phosphine ligand has a strong influence on the reaction
efficiency. Specifically, the yield was significantly lower when
the ligand-to-metal ratio was increased to 2:1 (entry 5). This
result implies that an excessive amount of phosphine ligand
might saturate the ruthenium catalyst, leaving no empty
coordination sites for the reactants. The base is also critical for
this reaction as the desired product was not detected in the
Table 1: Optimization of the reductive coupling of aldehydes with
imines.
Entry
Variation from the standard reaction conditions
3a [%][a]
1
2
3
4
5
6
7
8
9
–
83 (4)
27 (3)
75 (9)
9 (66)
45 (18)
76 (9)
39 (37)
0 (0)[b]
0 (0)[b]
13 (21)
21 (56)
73 (16)
[Ru(benzene)Cl2]2 as the catalyst
[Ru(cod)Cl2]n as the catalyst
without dmpe
dmpe (6 mol%)
tBu3P (1.5 mol%) instead of dmpe
dppe instead of dmpe
without K3PO4
Na3PO4 or Li3PO4 instead of K3PO4
Cs2CO3 instead of K3PO4
without CsF
10
11
12
with AgOTf (6 mol%)
[a] All yields were determined by 1H NMR analysis using trimethoxy-
benzene as an internal standard; the NMR yields of recovered unreacted
2a are given in parentheses. [b] Complete hydrazinolysis of 2a was
observed.
Scheme 3. Aldehyde scope. Reaction conditions: 2a (0.2 mmol),
1 (0.3 mmol, 1.5 equiv). Yields of isolated products are given. [a] The
hydrazones were separated by simple filtration prior to use.
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with either strongly electron-withdrawing (CF3, 3h; 3,4-
dichloro, 3l) or strongly electron-donating groups (dioxo,
3m) provided comparable yields. Hydrazones prepared from
benzaldehydes with phenyl, benzyloxy, or naphthyl substitu-
ents were poorly soluble in THF (1’j, 1’k, 1’n, and 1’o). In
these cases, the corresponding hydrazones were separated by
a simple filtration because of their facile precipitation. As
a result, the direct use of these solid hydrazones (1’) afforded
moderate yields of the corresponding amines (3j, 3k, 3n, and
3o). In cases where low yields were obtained, most of the
imine substrate 2a was recovered (3d, 3g, and 3n). The
couplings of heteroaromatic aldehydes, such as 2-furan-,
3-pyridine-, and 3-thiophenecarboxaldehyde, proceeded well
to give the corresponding products in good yields (3p–3r).
Finally, aliphatic aldehydes were also effective in this reaction
but the desired products were formed in lower yields owing to
competing elimination reactions (3s–3u).
Having established the scope of the reaction with respect
to the nucleophilic partner, we moved on to investigate the
suitability of various electrophilic imines (Scheme 4). A wide
range of substituted aromatic imines were coupled with para-
chlorobenzylidene hydrazine (1’a) or benzylidene hydrazine
(1’b) in moderate to good yields. We identified a mild
electronic influence on the reactivity upon varying the
aromatic substituent on the imine carbon atom. For example,
the yield dropped from 82% to 56% when an electron-
withdrawing fluoro substituent was replaced with an electron-
donating 1,3-dioxole substituent (4c and 4 f). This result may
be explained in terms of the decreased electrophilicity of the
corresponding imine. By contrast, a dramatic electronic
influence was observed for variations of the aromatic
substituent on the imine nitrogen atom. Compared with 4d,
4i, which features a para-methyl instead of a hydrogen
substituent, was formed in significantly lower yield. With
N-piperonylidene (para-tolyl)amine (2j), a very electron-rich
imine, the yield even dropped to only 10%. To our delight,
upon modifying the reaction conditions by adding hydrazone
1’a in five portions (with a 30 minute interval), the yield was
improved to 44% (4j). The yields also improved when
a chlorine substituent, as a weakly electron-withdrawing
group, was attached to the aromatic ring on the imine
nitrogen atom (4k–4m). We also found that the coupling of
an imine with a naphthalene-1-yl group at the nitrogen atom
(4n, 60%) is slightly more efficient than that of the
corresponding imine with the naphthalene-1-yl group at the
imine carbon atom (4h, 47%). These results confirmed that
the steric influence of substituents on the imine carbon atom
is stronger than that resulting from substituents on the
nitrogen atom. Notably, sensitive functional groups that are
incompatible with robust organometallic reagents, such as
esters, amides, and nitriles, remained untouched in this
process. Similarly, the poor reactivity of 4p is likely due to
the electron-donating nature of the acetamido group.
Scheme 4. Imine scope. Yields of isolated products are given. Reac-
tions conditions: 2a (0.2 mmol), 1a or 1b (0.3 mmol, 1.5 equiv).
[a] The hydrazone was added in five portions with 30 min intervals
(2.5 h in total). [b] The gram-scale reaction was performed using 2t
(4 mmol) and 1a (6 mmol) in the presence of [Ru(p-cymene)Cl2]2
(0.75 mol%) and dmpe (1.5 mol%).
2u) were examined in the current process, and all afforded the
corresponding products in good yields (Scheme 4, 4s–4u).
Unfortunately, aliphatic imines such as N-propylidene aniline,
N-benzylidene methanamine, and N-benzylidene benzyla-
mine, as well as ketimines such as N,1-diphenylethan-1-imine
were comparatively inert under the standard conditions.
Finally, this method was assessed on a larger scale.
Gratifyingly, 1.03 g of 4t were obtained from 0.92 g of imine
2t (4 mmol) at 608C, with only 0.75 mol% of Ru(p-cyme-
ne)Cl2]2 and 1.5 mol% of dmpe, which corresponds to a yield
of 72% (Scheme 4, 4t). To facilitate this scale-up manipu-
lation, a three-neck round-bottom flask with a condenser
equipped with a nitrogen balloon was used as an alternative
reaction vessel.
In summary, we have developed a method for the
umpolung addition of aldehydes to aryl imines that is
mediated by hydrazine in the presence of a ruthenium(II)
precatalyst and dmpe. This process features aldehyde-derived
alkyl carbanion equivalents, complementary to the oxygen-
ated carbanions used in traditional coupling reactions
between carbonyl compounds and aryl imines. Compared to
classical organometallic coupling reactions, this approach not
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Acknowledgements
This work was financially supported by the Canada Research
Chair (Tier 1) foundation, FQRNT (CCVC), NSERC, CFI,
and McGill University. We also thank the CSC (China
Scholarship Council) for a postdoctoral fellowship (N.C.).
We sincerely thank the group of Prof. Jiaxi Xu at the Beijing
University of Chemical Technology for providing the cis
imines (2s–2u).
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Conflict of interest
The authors declare no conflict of interest.
Keywords: aldehydes · hydrazine · imines · reductive addition ·
ruthenium catalysis
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Manuscript received: October 28, 2016
Final Article published: && &&, &&&&
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Communications
Ruthenium Catalysis
N. Chen, X.-J. Dai, H. Wang,
C.-J. Li*
&&&& — &&&&
Umpolung Addition of Aldehydes to Aryl
Imines
Hydrazine mediates the reductive cou-
pling of aldehydes and aryl imines in the
presence of a ruthenium(II) precatalyst
and a bidentate phosphine ligand. This
alternative approach to amine synthesis
involves aldehyde-derived alkyl carbanion
equivalents, enables the synthesis of
a wide array of secondary amines in
moderate to good yields, and tolerates
various functional groups.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!