Titanium-mediated reductive cross-coupling reactions of imines with terminal alkynes: An efficient route for the synthesis of stereodefined allylic amines

Article abstract of DOI:10.3762/bjoc.9.69

Low-valency titanium species, generated in situ by using Ti(OiPr) ₄/2 c-C₅H₉ MgCl reagent, react with imines to give a titanium-imine complex that can couple with terminal alkynes to provide azatitanacyclopentenes with excellent regioselectivity. Stereo-defined allylic amines are obtained in good yields after hydrolysis or iodonolysis of the corresponding azatitanacyclopentenes. When ethynylcyclopropane is used as the coupling partner to react with imines in this reaction, the initially generated allylic amine undergoes an unexpected 1,3-amino migration on silica gel during the column chromatography.

Full text of DOI:10.3762/bjoc.9.69

Titanium-mediated reductive cross-coupling
reactions of imines with terminal alkynes:
An efficient route for the synthesis of
stereodefined allylic amines
Kebin Mao1,2, Guoqin Fan1, Yuanhong Liu*1,§, Shi Li1, Xu You1
and Dan Liu2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 621–627.
1State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, People’s Republic of China and
2College of Chemical Engineering, Shenyang University of Chemical
Technology, Shenyang 110142, People’s Republic of China
doi:10.3762/bjoc.9.69
Received: 25 December 2012
Accepted: 04 March 2013
Published: 27 March 2013
Email:
Associate Editor: K. Itami
Yuanhong Liu* - yhliu@mail.sioc.ac.cn
© 2013 Mao et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
§ Tel:+86-21-54925135; Fax: +86-21-64166128
Keywords:
allylic amine; azatitanacyclopentene; reductive cross-coupling;
regioselectivity; terminal alkyne; titanium-imine complex
Abstract
Low-valency titanium species, generated in situ by using Ti(OiPr)4/2 c-C5H9MgCl reagent, react with imines to give a titanium-
imine complex that can couple with terminal alkynes to provide azatitanacyclopentenes with excellent regioselectivity. Stereo-
defined allylic amines are obtained in good yields after hydrolysis or iodonolysis of the corresponding azatitanacyclopentenes.
When ethynylcyclopropane is used as the coupling partner to react with imines in this reaction, the initially generated allylic amine
undergoes an unexpected 1,3-amino migration on silica gel during the column chromatography.
Introduction
Allylic amines are fundamental three-carbon building blocks in Thus, allylic amines have been used for the synthesis of numer-
organic chemistry and their synthesis is an important industrial ous heterocycles and bioactive amines, such as α- and β-amino
and synthetic goal [1-4]. The two functionalities in the allylic acids [12-15], different alkaloids [16], aminoallylsilanes [17],
amine fragment, i.e., the nucleophilic amino group and the aminoepoxides [18], iodocyclocarbamates [19] and isoxazo-
alkene, can ideally participate in cycloaddition reactions [5,6], lines [20]. Although it has been reported that allylic amines can
condensation reactions [7], nucleophilic substitution reactions be synthesized by methods such as amination of allylic alco-
[8,9], radical reactions [10] and Pd-catalyzed reactions [11]. hols [21-24], direct allylic amination of simple alkenes [25-27],
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Beilstein J. Org. Chem. 2013, 9, 621–627.
Morita–Baylis–Hillman reaction [28], alkenylation of imines Ti(OiPr)4/2 c-C5H9MgCl reagent [40-42] leading to 1,2-amino
[29-32], etc., it is still a great challenge to synthesize allylic alcohols [39]. These results prompted us to study the cross-
amines with a stereodefined alkene moiety. The low-valency coupling of imines with terminal alkynes by using the
group 4 metal complexes (M = Ti or Zr) mediated reductive Ti(OiPr)4/2 c-C5H9MgCl reagent. In this paper, we describe the
cross-coupling of imines with alkynes is one of the useful detailed results of these reactions (Scheme 1).
methods to construct stereodefined allylic amines. For example,
Buchwald et al. reported that zirconocene-imine complexes,
generated by treating Cp2ZrMeCl with lithium dialkylamide
followed by elimination of methane from the resulting
zirconocene(methyl) amide complex, coupled with alkynes to
give geometrically pure allylic amines after hydrolysis [33].
They also developed an asymmetric variant of this reaction that
proceeded to give allylic amine products with ee’s up to 99% by
using chiral ansa-zirconocenes [34]. However, these reactions
required a tedious multistep procedure for the preparation of
zirconocene–imine complexes. In addition, the use of terminal
alkynes produced an inseparable mixture of two regioisomers in
some cases [33] or could not give the desired products [34].
Sato et al. reported that a divalent titanium reagent generated by
Scheme 1: Titanium-mediated cross-coupling of imines with terminal
alkynes.
the Ti(OiPr)4/2 iPrMgX system reacted with arylaldimines to
provide the corresponding (η2-imine)Ti(OiPr)2 complex that, in
turn, reacted with alkynes to give allylic amines after hydroly-
sis of the resulting azatitanacyclopentenes [35]. In this report, a Results and Discussion
terminal alkyne showed excellent regioselectivity and much Synthesis of allylic amines by reductive cross-coupling using
better reactivity than internal alkynes. But only one successful Ti(OiPr)4/2 c-C5H9MgCl. First, a typical example for the syn-
example using a terminal alkyne appeared in this report thesis of allylic amines by reductive cross-coupling reactions
(1-octyne). Sato’s group further applied this reaction for the using Ti(OiPr)4/2 c-C5H9MgCl reagent was studied by using
synthesis of optically active allylic amines with chiral imines imine 2a and 1-heptyne as model substrates (Scheme 2). Based
and terminal alkynes [36]. However, the imine substrates on our previous report [39], Ti-imine complex 3a was gener-
employed in their reactions were all N-alkyl substituted ones ated in situ by the reaction of imine 2a with 1.3 equiv of
[35,36]. Until now the scope and limitations for titanium-medi- Ti(OiPr)4/2 c-C5H9MgCl at −30 °C. It was found that Ti-imine
ated reductive cross-coupling reactions of imines with terminal complex 3a could smoothly couple with 1.5 equiv of 1-heptyne
alkynes have been far less studied.
to give allylic amine 5a in 77% NMR yield after hydrolysis of
the resulting azatitanacyclopentene complex 4a with saturated
Our group has developed a series of reactions using low- aqueous NaHCO3 solution. In this reaction, azatitanacyclo-
valency titanium reagents [37-39], including selective coupling pentene 4a, rather than its regioisomer 4a’, was formed prefer-
of 1,3-butadiynes with aldehydes using Ti(OiPr)4/2 n-BuLi entially, in which the pentyl group is situated adjacent to tita-
reagent [37] and titanium-mediated formation of cis-[3]cumu- nium (Scheme 3, reaction 1). Accordingly, the allylic amine 5a
lenes in the presence of a Lewis acid [38]. Very recently, we could be obtained after hydrolysis with excellent regioselec-
reported titanium mediated cross-coupling reactions of imines tivity. There was no apparent formation of the regioisomer 4a’
with ketones or aldehydes by the activation of imines with and allylic amine 5a’ in this reaction, which may be due to the
Scheme 2: Synthesis of allylic amine 5a by titanium-mediated coupling reaction of imine 2a with 1-heptyne.
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Scheme 3: The regiochemistry of titanium-mediated cross-coupling of imine with terminal alkyne.
strong steric repulsion between the phenyl and pentyl groups
during the coupling process (Scheme 3, reaction 2).
Reaction scope of various terminal alkynes and imines. With
the optimized reaction conditions in hand, we next investigated
the reaction scope by first performing the reaction of imine 2a
with various terminal alkynes as shown in Table 1. When the
terminal alkynes with n-hexyl or tert-butyl groups were used as
coupling partners to react with imine 2a, the corresponding
allylic amines 5b–c were obtained in 69–88% yields (Table 1,
entries 2 and 3). The (E)-configuration of allylic amines 5 was
confirmed by X-ray crystal analysis of 5c as shown in Figure 1
[43]. Terminal alkynes with chloro- or phenyl-functionalized
alkyl chains were both compatible with this coupling reaction,
furnishing the corresponding products 5d and 5e in 66% and
68% yields, respectively (Table 1, entries 4 and 5). Even
terminal alkynes with trimethylsilyl or 2-pyridyl functionalities
were tolerated well during the reaction to give allylic amines 5f
and 5g in 80% and 81% yields, respectively (Table 1, entries 6
Figure 1: X-ray crystal structure of compound 5c.
and 7).
A broad range of imine substrates were also examined for this (Table 2, entries 4–7). The results indicated that the electronic
reaction, as shown in Table 2. When the cross-coupling reac- nature of the C-aryl ring also had little influence on the product
tions of N-(p-bromophenyl)- or N-(p-methoxyphenyl)-substi- yields. The reaction of N-propyl-substituted imine 2g with
tuted imines 2b and 2c were employed with 2-ethynylpyridine 2-ethynylpyridine produced the corresponding allylic amine 5o
under the same conditions, the corresponding allylic amines 5h in 60% yield (Table 2, entry 8). In contrast to the results
and 5i were obtained in 84% and 80% yields, respectively (Ta- obtained by using Ti(OiPr)4/2 iPrMgX reagent [35], the
ble 2, entries 1 and 2). The results indicated that electron-poor coupling of imine 2g with 1-octyne could not afford the desired
or -rich aryl substituents on the nitrogen atom of imines 2 had coupling product in our system (Table 2, entry 9). The structure
little influence on the yields of products 5. The reaction of of allylic amines was also determined by X-ray crystal analyses
imine 2d, with a bulky N-(1-naphthyl) group, with t-Bu-substi- of compounds 5h and the acylated derivative (7) of 5l [43].
tuted alkyne also proceeded well to give allylic amine 5j in 67%
yield (Table 2, entry 3). C-(p-bromophenyl)- or C-(p-methoxy- Titanium-mediated reductive cross-coupling reaction of
phenyl)-substituted imines 2e and 2f reacted well with a series imines with ethynylcyclopropane. When ethynylcyclo-
of terminal alkynes, furnishing 5k–5n in 75–84% yields propane was used as the coupling partner of imines 2 in the tita-
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Table 1: Synthesis of various allylic amines by titanium-mediated coupling reactions of imine 2a with different terminal alkynes.
entry
1
terminal alkyne
product
yield (%) of 2aa
67
5a
5b
5c
5d
5e
5f
2
3
4
5
6
7
69
88
66
68
80
81
5g
aIsolated yields.
nium-mediated reaction, 1,3-amino group migration occurred azatitanacyclopropene 3e with 1.5 equiv of ethynylcyclo-
unexpectedly during the purification of the products by silica- propane at −30 °C for 3 h afforded, after silica-gel chromatogra-
gel chromatography (Scheme 4). For example, the reaction of phy, the amino-migration product of 1-cyclopropyl allylic
Scheme 4: Synthesis of allylic amines 5q and 6q.
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Table 2: Synthesis of various allylic amines by titanium-mediated coupling reactions of different imines with terminal alkynes.
entry
1
imine
terminal alkyne
time (h)a
product
yield (%)b
84
6
5h
5i
2b
2c
2d
2
3c
4
6
4
5
80
67
81
5j
5k
2e
2e
5
6
6
3
81
84
5l
2e
2f
5m
7
6
75
5n
8
9
6
3
60
–d
5o
5p
2g
2g
aReaction time for the second step. bIsolated yields. c1-Naph is 1-naphthyl. dThe desired product was not isolated.
amine 6q in 74% yield. The structure of 6q was confirmed isomerization may proceed via the formation of an allyl cationic
unambiguously by X-ray crystal analysis of its amide deriva- intermediate promoted by silica gel due to its weak Lewis
tive 8 ((E)-N-(3-(4-bromophenyl)-1-cyclopropylallyl)-3,5- acidity [44,45].
dinitro-N-phenylbenzamide) as shown in Figure 2 [43]. Careful
analysis of the crude reaction mixture before silica-gel purifica- Iodonolysis of azatitanacyclopentene. Furthermore, we found
tion revealed that the normal coupling product 5q was observed that iodinated allylic amine 9 could be obtained by iodonolysis
in 94% NMR yield. The result indicated that an isomerization of the azatitanacyclopentenes 4 (Scheme 5). For example, on
of 5q to 6q occurred during the silica-gel isolation process. This treatment of azatitanacyclopentene 4g with two equiv of iodine
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Acknowledegments
We thank the National Natural Science Foundation of China
(Grant No. 21072208, 21125210, 20821002), Chinese Academy
of Science, and the Major State Basic Research Development
Program (Grant No. 2011CB808700) for financial support.
Supporting Information
Supporting Information File 1
Experimental section and NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-69-S1.pdf]
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