Titanium-mediated cross-coupling reactions of imines with ketones or aldehydes: An efficient route for the synthesis of 1,2-amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2012.07.020

The cross-coupling reactions of imines with ketones using Ti(O ⁱPr)₄/c-C₅H₉MgCl reagent lead to 1,2-amino alcohols after hydrolysis. The coupling reactions with aldehydes could also afford 1,2-amino alcohols, however, in some cases, aziridines were obtained as major products in a stereoselective manner.

Full text of DOI:10.1016/j.tetlet.2012.07.020

Tetrahedron Letters 53 (2012) 5084–5087
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Titanium-mediated cross-coupling reactions of imines with ketones or
aldehydes: an efficient route for the synthesis of 1,2-amino alcohols
⇑
Guoqin Fan, Yuanhong Liu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
The cross-coupling reactions of imines with ketones using Ti(OiPr)4/c-C5H9MgCl reagent lead to 1,2-
amino alcohols after hydrolysis. The coupling reactions with aldehydes could also afford 1,2-amino alco-
hols, however, in some cases, aziridines were obtained as major products in a stereoselective manner.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 20 April 2012
Revised 28 June 2012
Accepted 6 July 2012
Available online 20 July 2012
Keywords:
Titanium-imine complex
Azatitanacyclopropane
Coupling
Ketones and aldehydes
1,2-Amino alcohol
Group 4 metallacyclic compounds, such as titana- or zirconacy-
cles, are attractive intermediates in organic synthesis, which have
received considerable attention during the past several decades.1
These metallacycles can be easily prepared by the reductive cou-
pling of unsaturated compounds such as alkynes, alkenes, nitriles,
ketones etc. on a low-valent metal equivalent. They are relatively
stable under certain reaction conditions, however, upon treatment
with suitable electrophiles, they can display diverse reactivities
leading to a wide range of selective transformation reactions.2
Although much progress has been achieved in this chemistry, most
of the studies concentrated on the metallacycles synthesized via
coupling reactions of two unsaturated molecules in which at least
one of the component is alkyne or alkene. There are only limited
reports for the preparation of heterometallacycles via coupling
metallacyclic products.3 Taguchi and co-workers also described
Cp2ZrBu2-mediated coupling reactions of chiral aldimines with
aldehydes.4 However, these reactions either require the tedious
multi-step synthesis or restricted to special substituted imines.
In contrast, titanium-imine complex prepared via activation of imi-
nes with Ti(OiPr)4/iPrMgCl system do not lead to the expected cou-
pling products with aldehydes,6 and there is also no report for
titanium-mediated coupling reactions of imines with ketones, to
the best of our knowledge. Recently, we have developed a series
of reactions on utilization of low-valent titanium reagents,7 includ-
ing selective coupling of 1,3-butadiynes with aldehydes using
Ti(OiPr)4/n-BuLi reagent7a and titanium-mediated cis-[3]cumu-
lenes formation in the presence of Lewis acid.7b These results
prompted us to examine the synthetic route for the formation of
heterometallacycles. We now report an efficient imine/ketone or
aldehyde coupling reactions using Ti(OiPr)4/c-C5H9MgCl reagent.
We began our investigation of titanium-mediated coupling
reactions of imines with ketones. It occurred to us that to achieve
the desired coupling reactions, the proper choice of the Grignard
reagent for producing the low valent TiII-equivalent is very impor-
tant. After a lot of efforts, we found that Ti-imine complex 2 (can be
elucidated as azatitanacyclopropane) generated by reactions of
imine with Ti(OiPr)4/c-C5H9MgCl8 at À30 °C could couple with
ketones smoothly (Scheme of Table 1). The procedure is operation-
ally convenient: To a solution of imine 1a and 1.3 equiv of Ti(OiPr)4
in Et2O at À30 °C was added 2.6 equiv of c-C5H9MgCl, the mixture
was stirred at the same temperature for 1.5 h. Quenching the mix-
ture at this stage by D2O followed by aqueous workup afforded the
reduction product PhCH(D)NHPh in 98% yield with a deuterium
reactions of two heteroatom-substituted
p-systems such as alde-
hydes, ketones, nitriles, imines, and so on. For example, cross-cou-
pling reactions of imines and aldehydes can be achieved via
reactions of carbonyl compounds with a metal complex of imi-
nes.3,4 These reactions could provide a useful route for the synthe-
sis of 1,2-amino alcohol derivatives, which are widely used as
important building blocks for the synthesis of biologically active
targets, and as ligands for asymmetric synthesis.5 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 aldehydes in a diastereoselective fashion to give
⇑
Corresponding author. Tel.: +86 21 54925135; fax: +86 21 64166128.
E-mail address: yhliu@mail.sioc.ac.cn (Y. Liu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.020

G. Fan, Y. Liu / Tetrahedron Letters 53 (2012) 5084–5087
5085
Table 1
Titanium-mediated coupling reactions of imines with ketones
O
1.3 equiv Ti(OiPr)4
2.6 equiv c-C5H9MgCl
R1
R2
R1
R1HN
R2
OH
R3
R4
N
N
R3
-30 oC to rt, 2 h
R4
(iPrO)2Ti
-30 oC, 1.5 h,
in Et2O
R2
1
2
3
Entry
1
Imine
Ketone
Product
Yielda (%)
Ph
O
OH
Me
Ph
PhHN
Ph
N
3a
88 (2:1)
Ph
Me
Ph
1a
(
)
O
O
O
OH
PhHN
2
3
4
1a
1a
1a
3b
3c
3d
82 (4.3:1)
80
Ph
Ph
Ph
Ph
Ph
OH
Ph
Ph
PhHN
Ph
Ph
OH
PhHN
Ph
80 (3:1)
Ph
Ph
Ph
O
OH
PhHN
Ph
5
1a
3e
62 (1.6:1)
Me
Ph
Me
OH
Ph
O
PhHN
6
7
1a
1a
nPr
nPr
OH
Me
tBu
3f
79
Ph
O
PhHN
3g
83b
Me
Ph
O
OH
PhHN
8
1a
3h
47
Ph
Ph
O
O
OH
Ph
Ph
PhHN
p-OMeC6H4
N
Ph
Ph
Ph
9
3i
3j
81
74
p-OMeC6H4
1b
p-OMeC6H4
OH
Ph
Ph
(p-OMeC6H4)HN
N
10
Ph
O
Ph
Ph
1c
OH
(1-naphthyl)HN
nPr
nPr
N
N
Ph
11
3k
64
Ph
Ph
Ph
1d
nBu
(nBu)HN
Ph
O
OH
nPr
nPr
12
13
3l
71
61
1e
CH3
O
OH
Ph
Ph
MeHN
Ph
N
3m
Ph
Ph
1f
a
Isolated yields. 1.2 equiv of ketone were used. Diastereomeric ratios are shown in the parentheses, which were determined by 1H NMR.
3g was obtained as a single diastereomer, the stereochemistry was not defined yet.
b
incorporation of 96%. The results strongly indicated the formation
of azatitanacyclopropane 2a. Addition of acetophenone instead of
hydrolysis followed by warming up to room temperature provided,
after aqueous workup, the 1,2-amino alcohol 3a in 88% yield as a
mixture of two diastereomers (Table 1, entry 1). With the opti-
mized reaction conditions in hand, we next examined the reaction
scope with respect to various imines and ketones. As shown in
Table 1, the reactions worked well with aryl or dialkyl ketones.
Aryl ketones substituted with alkyl, aryl, alkenyl, or alkynyl groups
were all compatible for coupling reactions, furnishing the
corresponding products in generally good yields (entries 1–5, 9–
10, and 13). The functionalities of cyclopropyl, alkenyl, and alkynyl
moieties were well tolerated during the reaction. Sterically
demanding ketones such as benzophenone and 3,3-dimethylb-
utan-2-one also coupled with imines to afford the desired products
in 61–83% yields (entries 3, 7, 9–10, and 13). As for imines, N-aryl

5086
G. Fan, Y. Liu / Tetrahedron Letters 53 (2012) 5084–5087
i) Ti(OiPr)4/
OMe
Ph
Ph
c-C5H9MgCl,
OH
Ph
in Et2O, -30 o
C
H2N
Ph
OH
Ph
Ph
NH
H2, Pd(OH)2
N
MeO
ii) benzophenone,
-30 oC to rt
AcOH/CH2Cl2/MeOH,
30 oC, overnight
Ph
3n
Ph
Ph
4
(R)- , 66%
(S)-1g
, 55%
ee 100%
[α ]D20 +246.4 (c 1.0, CHCl3)
lit.10[α ]D20 +248.0 (c 1.0, CHCl3)
Scheme 1. Chiral induction via coupling reaction of chiral aldimine with ketone.
Table 2
Titanium-mediated coupling reactions of imines with aldehydes
O
R1
N
R1
R1HN
R2
OH
R3
R3
-30 oC to rt, 2 h
H
N
(iPrO)2Ti
+
R3
R2
R2
2
3
4
Entry
1b
Imine
Aldehyde
Product
Yielda
Ph
O
PhHN
OH
N
Ph
H
S
Ph
61% (9.1:1)
S
3o
PhHN
1a
Ph
O
OH
p-OMeC6H4
N
2b
p-ClC6H4
72% (6.7:1)
59% (2.4:1)
p-OMeC6H4
H
p-ClC6H4
1h
3p
OH
O
PhHN
Ph
3b
1a
Ph
H
3q
Ph
O
Ph
N
PhHN
Ph
3r,d 18% (33:1)
OH
Ph
Ph
H
4c
5c
6b
1a
+
Ph
Ph
5a, 53%
O
O
Ph
N
p-ClC6H4
o-BrC6H4
H
H
1a
1a
p-ClC6H4
, 60%
Ph
5b
Ph
N
PhHN
OH
o-BrC6H4
+
Ph
3s
o-BrC6H4
, 41%
Ph
5c
, 9%
O
p-OMeC6H4
p-OMeC6H4
HN
Ph
OH
N
p-ClC6H4
H
+
7b
1c
p-ClC6H4
p-ClC6H4
Ph
3t, 11%
5d, 32%
a
b
c
Isolated yields. Diastereomeric ratios are shown in the parentheses, which were determined by 1H NMR.
1.2 equiv of aldehyde were used.
1.0 equiv of aldehyde was used.
d
Stereochemistry of the major isomer of 3r is shown as indicated.
and N-alkyl imines all could be used in this reaction, showing a
broad range of imine substrates.
Interestingly, the coupling reaction of the chiral imine (S)-
1g4,8c9 with benzophenone gave the product 3n in 55% yield as a
single diastereomer (Scheme 1). The stereochemistry of 3n was
determined by conversion of 3n into the corresponding free 1,2-
amino alcohol 4 by removal of the –CH(Ph)CH2OMe group. The
optically pure (R)-410 was obtained in 66% yield with 100% ee.
Next, we proceeded to examine the reactions with aldehydes.
It was found that the reactions of imines with electron-rich aryl
aldehydes such as 2-thiophenecarboxaldehyde and 4-methoxy-
benzaldehyde afforded the 1,2-amino alcohols 3o and 3p in 61%

G. Fan, Y. Liu / Tetrahedron Letters 53 (2012) 5084–5087
5087
O
Ph
N
Ti(OiPr)4
c-C5H9MgCl
Ph
Ph
Ph
Ph
Ph
Ph
N
iPrOMgCl
N
Ph
H
(iPrO)2Ti
(iPrO)2Ti
coupling
ring
O
Ph
iPrOMgCl
2
opening
6
2a
, major isomer
Ph
Ph
N
ClMgN
Ph
Ph
ClMgN
Ph
Ph
Ph
O
Ti(OiPr)2
OiPr
Ph
O=Ti(OiPr)2
+
O
(iPrO)3Ti
iPrOMgCl
7
8
5a
Scheme 2. Possible reaction mechanism for the formation of cis-aziridines.
and 72% yields, respectively, with good diastereoselectivity
(Table 2, entries 1 and 2). The reaction with cinnamaldehyde also
afforded amino alcohol 3q as a major product, however, with
lower stereoselectivity (entry 3). Interestingly, the use of
benzaldehyde resulted in the formation of aziridine 5a as a major
product, along with 18% of amino alcohol 3r (entry 4). The stereo-
chemistry of the major isomer of 3r is anti with respect to two
phenyl groups by comparing the NMR spectra with that of a
known compound.11 However, the stereochemistry of aziridine
5a was found to be cis as confirmed by X-ray crystal analysis,12
indicating that the configuration of hydroxyl-bearing carbon
was inversed during the cyclization process. When electron-poor
aryl aldehydes such as p-chloro- or o-bromobenzaldehydes were
employed as coupling partners, aziridines 5b–5d were also ob-
tained as major products as a single diastereomer (entries 5–7).
The cis-stereochemistry of 5b was also verified by X-ray crystal
analysis.12 The configurations of 5c–5d were deduced from that
of 5a and 5b.
References and notes
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Chem. Res. 2011, 44, 541; (d) Wolan, A.; Six, Y. Tetrahedron 2010, 66, 15; (e)
Wolan, A.; Six, Y. Tetrahedron 2010, 66, 3097; (f) Sato, F.; Urabe, H.; Okamoto, S.
Chem. Rev. 2000, 100, 2835.
2. For recent papers, see: For Ti: (a) Song, Z.; Hsieh, Y.; Kanno, K.; Nakajima, K.;
Takahashi, T. Organometallics 2011, 30, 844; (b) Yatsumonji, Y.; Sugita, T.;
Tsubouchi, A.; Takeda, T. Org. Lett. 2010, 12, 1968; (c) Hanamoto, T.; Yamada, K.
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129, 15112; (g) Takahashi, T.; Song, Z.; Sato, K.; Kuzuba, Y.; Nakajima, K.;
Kanno, K. J. Am. Chem. Soc. 2007, 129, 11678; (h) Ryan, J.; Micalizio, G. C. J. Am.
Chem. Soc. 2006, 128, 2764; (i) Takahashi, T.; Kuzuba, Y.; Kong, F.; Nakajima, K.;
Xi, Z. J. Am. Chem. Soc. 2005, 127, 17188; (j) Urabe, H.; Mitsui, K.; Ohta, S.; Sato,
F. J. Am. Chem. Soc. 2003, 125, 6074; For Zr: (k) Fu, X.; Yu, S.; Fan, G.; Liu, Y.; Li, Y.
Organometallics 2012, 31, 531; (l) Zhao, J.; Zhang, S.; Zhang, W.; Xi, Z.
Organometallics 2011, 30, 3464; (m) Zhang, S.; Zhao, J.; Zhang, W.; Xi, Z. Org.
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H.; Zhou, L.; Kanno, K.; Guo, Q.; Shen, B.; Takahashi, T. Org. Lett. 2009, 11, 3318;
(u) Ni, Y.; Nakajima, K.; Kanno, K.; Takahashi, T. Org. Lett. 2009, 11, 3702; (v) Fu,
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Although the detailed mechanism for the formation of
aziridines is not clear yet, we tentatively propose the following
pathway (Scheme 2): Insertion of a carbonyl group to azatitana-
cyclopentane 2a affords hetero-substituted titanacycle 6. As indi-
cated by hydrolysis results, the two phenyl groups in 6 orient
trans in the major isomer in order to avoid the steric hindrance.
i
Ring-opening of 6 by PrOMgCl produced by reactions of Ti(OiPr)4
and c-C5H9MgCl occurs to deliver a linear complex 7.13 Attack of
nitrogen nucleophile to the adjacent carbon from the backside of
the oxygen leaving group provides the ring-closure product cis-
aziridine 5a.
4. Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33, 4469.
5. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835;
(b)Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds., 1st ed.; Springer: Berlin, 1999.
In conclusion, we have developed an efficient method for the
cross coupling reactions of imines with ketones or aldehydes using
Ti(OiPr)4/c-C5H9MgCl reagent. The present methodology is conve-
nient and practical for the synthesis of 1,2-amino alcohols. In addi-
tion, the coupling reactions with benzaldehyde or electron-poor
aryl aldehydes afford aziridines as major products in a stereoselec-
tive manner. Further studies on the scope and limitations of this
method are currently in progress.
6. Gao, Y.; Yoshida, Y.; Sato, F. Synlett 1997, 1353.
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12. See Supplementary data
Supplementary data
13. For ligand exchange reactions of titanium complexes with lithium or sodium
alkoxides, see Ref. 8b,c.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
020.