Catalytic imine-imine cross-coupling reactions

Article abstract of DOI:10.1039/c4cc06156j

We report here efficient catalytic imine-imine cross-coupling reactions based on an umpolung strategy; an imine bearing a 9-fluorenyl moiety on its nitrogen atom, which acted as a nucleophile, reacted with another imine to afford an imine-imine cross-coupling adduct in high yield. Furthermore, a chiral guanidine acted as a chiral catalyst for these coupling reactions, and optically active 1,2-diamines were obtained in high yields with high enantioselectivities. This journal is

Full text of DOI:10.1039/c4cc06156j

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Catalytic imine–imine cross-coupling reactions†
Masatoshi Matsumoto,‡ Masashi Harada,‡ Yasuhiro Yamashita and Shu Kobayashi*
¯
Cite this: Chem. Commun., 2014,
50, 13041
Received 6th August 2014,
Accepted 29th August 2014
DOI: 10.1039/c4cc06156j
www.rsc.org/chemcomm
We report here efficient catalytic imine–imine cross-coupling reac-
tions based on an umpolung strategy; an imine bearing a 9-fluorenyl
moiety on its nitrogen atom, which acted as a nucleophile, reacted
with another imine to afford an imine–imine cross-coupling adduct in
high yield. Furthermore, a chiral guanidine acted as a chiral catalyst for
these coupling reactions, and optically active 1,2-diamines were
obtained in high yields with high enantioselectivities.
1,2-Diamine structures are often observed in many biologically
important compounds, such as the anti-influenza agent, oseltamivir
and anticancer agents, cisplatin derivatives, etc.1,2 Imine–imine
coupling reactions potentially provide the best route to
1,2-diamines because imines are easily prepared from the corre-
sponding carbonyl precursors; however, in spite of many efforts,
imine–imine cross-coupling reactions have been found to be very
difficult. Indeed, almost all previous imine–imine coupling
reactions relied on radical-mediated reactions and generally
provided homo-coupling products.3–14 In the literature, only
Fig. 1 Important 1,2-diamine structures and imine–imine coupling strategies
for 1,2-diamine synthesis. (a) The traditional strategy for imine–imine coupling
reactions using stoichiometric amounts of metal compounds to afford
symmetrical 1,2-diamines. (b) Our strategy for imine–imine cross-coupling
reactions affording unsymmetrical 1,2-diamines.
To develop imine–imine cross-coupling reactions, we planned to
two imine–imine cross-coupling reactions have been reported. use an umpolung strategy.18 An imine usually acts as an electrophile,
One is a radical-mediated reaction, in which 2 equivalents of but if an imine could act as a nucleophile, it would react with
Zn–Cu, 2.2 equivalents of BF3ÁOEt2 and 1 equivalent of MeSiCl3 another imine that acts as an electrophile, and a nucleophile–
were used and some homo-coupling products were obtained as electrophile coupling might be possible. For this purpose, we
side products.15 Including this, all previous radical-mediated focused on an imine bearing a 9-fluorenyl moiety on its nitrogen
reactions required more than stoichiometric amounts of metal atom (fluorenyl imine), previously known as an electrophile.19–22 We
reductants or promoters (lanthanide,3–6 Al,7 Ti,8,9 Zr,10 In,11 thought that the hydrogen atom at the dibenzylic position of the
Zn–Cu,12,15 Mn,13 Li,14 etc.,16 Fig. 1a), and thus large quantities fluorenyl imine was relatively acidic and that deprotonation of this
of metal waste were formed after the reactions. In the other hydrogen atom would be possible by a weak base. If deprotonation
reaction an in situ generated titanium–imine17 complex reacted occurred, then a nucleophilic anion species would be formed, which
with another imine to afford a cross-coupling adduct, where also could then react with an electrophilic imine, and thus an imine–
more than one equivalent of organometallic species were imine cross-coupling might be realized (Fig. 1b). We have already
required. To the best of our knowledge, no catalytic imine–imine reported that effective activation of an aminoalkane by using a
cross-coupling reaction has been reported.
9-fluorenylidene substituent as a protecting and activating
group was successfully carried out in the presence of a catalytic
amount of a base.23–26 In this system, the carbanion smoothly
formed at the a-positions of the fluorenylideneamino groups
via 14p electron stabilization27 and catalytically reacted with
imines to afford 1,2-diamine derivatives in high yields with
high stereoselectivities. Based on these findings, we envisioned
Department of Chemistry, School of Science, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
† Electronic supplementary information (ESI) available: Supplementary tables
and schemes (Tables S1, S2, Schemes S1, S2), experimental details, and physical
data of obtained products. See DOI: 10.1039/c4cc06156j
‡ These authors contributed equally to this work.
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Table 1 Catalytic imine–imine cross-coupling reactions
that if similar nucleophilic carbanion species were formed by
deprotonation of N-9-fluorenyl imines, they might react with
imines to realize imine–imine cross-coupling reactions.
We conducted the reaction of N-fluorenyl imine 2a derived from
benzaldehyde with imine 1a bearing a diphenylphosphinyl (DPP)
substituent as an N-protecting group in the presence of a catalytic
amount of a base (Table S1, ESI†). In the presence of potassium tert-
butoxide (KOtBu) and 18-crown-6 ether, the reaction proceeded in
THF at room temperature to afford the desired cross-coupling
product in 60% yield with moderate diastereoselectivity. It should
be noted that the fluorenyl imine worked as a nucleophile and
reacted with another imine, and that no homo-coupling product was
produced. The effect of solvents was then examined. Diethyl ether
(Et2O) showed better selectivity but lower conversion was observed
due to low solubility of 1a. The reaction proceeded smoothly in a
mixed solvent of Et2O/CH2Cl2 (4/1) to afford the desired 1,2-diamine
compound in high yield with high syn selectivity (90% yield, syn/
anti = 99/1). It was also found that weaker Brønsted bases were
successfully employed in the coupling reaction, and among them,
potassium 2,2,2-trifluoroethoxide (KOCH2CF3) worked well and
higher syn selectivity (syn/anti = 499/1) was obtained with 97%
yield. While the desired cross-coupling product was obtained in
excellent yield, there were no homo-coupling products.
Entry R1
R2
Yielda (%) syn/antib
1
Ph (1a)
p-MeC6H4 (1b)
m-MeC6H4 (1c) Ph (2a)
o-MeC6H4 (1d) Ph (2a)
p-MeOC6H4 (1e) Ph (2a)
Ph (2a)
Ph (2a)
3aa
3ba
3ca
3da
3ea
3fa
97
99
97
91
90
99
499/o1
94/6
96/4
97/3
84/16
96/4
2c,d
3c, f
4c, f
5c, f
6c
p-BrC6H4 (1f)
Furfuryl (1g)
3-Py (1h)
Cy (1i)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
p-MeC6H4 (2b) 3ab 499
m-MeC6H4 (2c) 3ac 99
o-MeC6H4 (2d) 3ad 499
7
8
3ga 499
499/o1
3ha
3ia
3ja
93
99
92
91
99/1
9
90/10
97/3
10 f
iBu (1j)
11g,h,i nBu (1k)
3ka
499/o1
12
13
14
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
98/2
98/2
499/o1
499/o1
95/5
15
2-Naph (2e)
p-ClC6H4 (2f)
Furfuryl (2g)
3ae
3af
3ag
92
99
83
16e
17
96/4
18
2-Thienyl (2h) 3ah 499
97/3
93/7
85/15
90/10
499/o1
91/9
19 f
20e, f
21 f
22 f
23 j
nBu (2i)
iBu (2j)
3ai
3aj
3ak
3al
3am
3ij
81
79
82
78
83
81
92
Cy (2k)
tBu (2l)
COOEt (2m)
iBu (2j)
24g,k,h Cy (1i)
99/1
3/97
We then investigated the substrate scope of this imine–
imine cross-coupling reaction (Table 1). First, a variety of N-
DPP imines were investigated. Ortho to para substitution on the
25l
Ph (1a)
Ph (2a)
3aa
a
b
DPP = diphenylphosphinyl; Flu = fluorenyl. Isolated yield. Deter-
benzene ring by a methyl group did not have any significant mined by 1H NMR analysis. At À40 1C. For 24 h. At À20 1C.
c
d
e
f
KOtBu (5 mol%) and 18-crown-6 (5.5 mol%) were employed as catalysts.
effect on reactivities and selectivities, and high yields and high
g
h
i
In DMF. At 0 1C. KOtBu (5 mol%) and PhOH (5.5 mol%) were
j
syn selectivities were obtained (entries 2–4). Electronic effects of
the substituents were then examined. When N-DPP imine 1e the reaction was performed at 25 1C. KOtBu (10 mol%) and 18-crown-6
prepared from p-methoxybenzaldehyde was used, the diaster-
employed as catalysts. DBU (10 mol%) was used instead of KOCH2CF3.
k
l
(11 mol%) were employed as catalysts. In toluene at 20 1C.
eoselectivity decreased slightly (entry 5). Imine 1f bearing an
electron-withdrawing group was also found to be applicable to using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base catalyst
the reaction system (entry 6). N-DPP imines 1g and 1h prepared (entry 23). It is noted that a combination of aliphatic N-DPP imine
from heteroaromatic aldehydes were successfully employed 1i and aliphatic N-fluorenyl imine 2j in DMF at lower temperature
(entries 7 and 8). The imines prepared from aliphatic aldehydes successfully afforded the desired compound 3ij in 81% yield with
could also be employed in this coupling reaction. N-DPP imine excellent syn selectivity (syn/anti = 99/1, entry 24).
1i derived from cyclohexanecarboxyaldehyde reacted smoothly to
During the investigation of the substrate scope, it was
afford the desired product in high yield (entry 9). Imines 1j–1k surprisingly found that the reaction of 1a with 2a in toluene gave
derived from primary aliphatic aldehydes were also found to the opposite diastereomer with high selectivity (Table 1, entry 25).
react with N-fluorenyl imine 2a in moderate to high yields Thus, the diastereoselectivity dramatically changed from syn to anti
(entries 10 and 11). These results are remarkable because imines when the solvent Et2O–CH2Cl2 was replaced with toluene (Table 2,
derived from aliphatic aldehydes generally cause many side entries 1 and 2). We further examined the switch of diastereo-
reactions, and successful examples of even aliphatic imine– selectivity of other substrates. In the reactions with 4-chlorophenyl
imine homo-coupling reactions are very rare.
fluorenyl imine 2f, the same anti selectivity was obtained in both
Next, the scope of the N-fluorenyl imine was examined. As was Et2O–CH2Cl2 and toluene (entries 3 and 4), while the syn isomer was
the case when the DPP imines were investigated, the steric effect of obtained with high selectivity when the reaction was conducted in
the imine was not significant, and high yields and high syn Et2O–CH2Cl2 at À20 1C (entry 5). In the reactions with 4-methylphenyl
selectivities were observed (entries 12–15). When fluorenyl imine fluorenyl imine 2b, syn selectivity was obtained in both Et2O–CH2Cl2
2f bearing an electron-withdrawing substituent, Cl, was employed, and toluene (entries 6 and 7), although the selectivity in toluene was
high yield and high syn selectivity were obtained (entry 16). Imines moderate. In the case of imine 2n bearing a stronger electron-
2g and 2h derived from heteroaromatic aldehydes were also withdrawing substituent, 4-nitrophenyl fluorenyl imine, only anti-
successfully employed (entries 17 and 18). Aliphatic N-fluorenyl selectivity was obtained in both solvents (entries 8 and 9). On the
imines 2i–l were also examined, and good yields and high syn other hand, 3-chlorophenyl fluorenyl imine 2o gave a syn adduct in
selectivities were obtained (entries 19–22). N-Fluorenyl imine 2m Et2O–CH2Cl2 at 20 1C (entry 10). A substitution at the 3-position
derived from ethyl glyoxylate could be successfully employed by provided a less electronic influence on the selectivity. This interesting
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Table 2 Switch of diastereoselectivity
Entry R (2)
Conditions
3
Yielda (%) syn/antib
1
2
3
Ph (2a)
Ph (2a)
Et2O/CH2Cl2 (4/1) 3aa
97
92
92
95
99
499/1
3/97
Scheme 1 Substrate scope of asymmetric catalysis.
Toluene 3aa
Et2O/CH2Cl2 (4/1) 3af
Toluene 3af
Et2O/CH2Cl2 (4/1) 3af
p-ClC6H4 (2f)
p-ClC6H4 (2f)
p-ClC6H4 (2f)
p-MeC6H4 (2b) Et2O/CH2Cl2 (4/1) 3ab 499
p-MeC6H4 (2b) Toluene
3ab 495d
p-NO2C6H4 (2n) Et2O/CH2Cl2 (4/1) 3an
p-NO2C6H4 (2n) Toluene 3an
m-ClC6H4 (2o)
13/87
4/96
95/5
98/2
59/41
7/93
2/98
99/1
4
5c
6
7
8
9
10
70
90
Et2O/CH2Cl2 (4/1) 3ao 499
a
Isolated yield. b Determined by 1H NMR analysis. c At À20 1C. d NMR yield.
Scheme 2 Transformation of the coupling product to 3-amino-b-lactam.
phenomenon could be explained by a solvent effect and an
epimerization mechanism. DPP-imine 1a was attacked by fluor-
enyl imine 2 via deprotonation by a base catalyst to afford the
cross-coupling product 3 in a syn selective manner. When the
fluorenyl imine has an electron-withdrawing substituent on
the phenyl ring, further deprotonation at the a-hydrogen of the
product might occur (Scheme S1, ESI†). Moreover, it is noted
that the pKa value of the hydrogen may change in different
solvents and at different temperatures.
To verify if the epimerization did occur, a diastereomeric
mixture of the isolated product 3aa was treated in toluene
under the reaction conditions (Scheme S2, ESI†). After 18 h,
the diastereomer ratio changed dramatically, and the anti
product was obtained as a major compound. This result
indicated that the anti product was thermodynamically stable
and strongly supported the epimerization mechanism.
Further investigations on the epimerization were conducted
in toluene by using different bases (Table S2, ESI†). When the
reaction of 1a with 2a utilizing KOtBu and 18-crown-6 ether was
quenched in a shorter reaction time (0.5 h), ca. a 1 : 1 syn/anti
mixture of product 3aa was obtained (entry 2). Other weaker
bases could also support our hypothesis. When KOPh or DBU
was employed, the syn isomer was obtained with good to high
selectivities (entries 4 and 5). These results indicated that the
epimerization could be suppressed by using a weaker base.
The above experiments indicated that epimerization of the
fluorenylidene amino group by a base catalyst occurred during
the reaction process, and thermodynamically stable anti iso-
mers were obtained with high selectivities under the reaction
conditions. The epimerization was faster in toluene than in
Et2O–CH2Cl2, and was suppressed by using weak bases and
performing reactions at lower temperature.
on the N-fluorenyl group, an N-fluorenylglyoxylateimine was selected
as a model substrate. It was found that the reaction of N-Boc
protected imine 5 with N-fluorenyl imine 2p bearing a tert-butyl
ester proceeded in toluene at À60 1C for 18 h using a catalytic
amount of chiral guanidine 4 to afford the desired adduct in 90%
yield with excellent diastereo- and enantioselectivities (Scheme 1).29
The reaction was successfully applied to a concise synthesis
of 3-amino-b-lactam, a useful intermediate for the synthesis
of monobactams (Scheme 2).30 The coupling product 6 was
hydrolyzed under acidic conditions to afford the corresponding
a,b-diamino ester 8, which was further cyclized to afford the
desired 3-amino-b-lactam 9 in high yield.31
It was assumed that carbanion 10, which was formed from
N-fluorenyl imine 2a, reacted with DPP imines 1 or Boc imines
to afford cross-coupling products (Scheme 3). Since DPP imines
and Boc imines are much more reactive than N-fluorenyl imines
In the imine–imine coupling strategy, chiral modification of a
base catalyst might lead to a catalytic asymmetric coupling reaction.
However, no such examples, even in homo-coupling reactions, are
reported. We thought that chiral organobase species28 with aromatic
moieties could be promising catalysts for the formation of asym-
metric environments around these types of substrates via p–p
interactions. Because of the low pKa value of the active hydrogen
Scheme 3 Assumed reaction pathways.
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as electrophiles, no homo-coupling products were obtained. For- Peking University) is acknowledged for his contribution to a
mation of carbanion 10 was confirmed by 1H NMR analysis. part of this work.
N-Fluorenyl imine 2a was treated with a stoichiometric amount
of KN(SiMe3)2 at ambient temperature in THF-d8 to form carbanion
Notes and references
10. There are two key protons in 2a, observed by 1H NMR analysis,
´
´
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whose remaining proton was observed at d 8.54. These results
suggest that the anion of 10 is located on the fluorenyl group
stabilized by the 14p electron system. The deprotonation step was
2 P. J. De Clercq, Chem. Rev., 1997, 97, 1755–1792.
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1
very fast and no intermediate was observed by H NMR analysis.
We further conducted the deprotonation using other bases such as
KOCH2CF3, and KOtBu, and the same results were obtained.
Formation of 10 was also observed from aminoalkane 11 and a
base. Namely, 11 was treated with a base at ambient temperature in
THF-d8 to form the same carbanion 10. The formation of 10 was
also very fast and no intermediate was observed by 1H NMR
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selectivity is not clear at this stage and is under investigation.32
In conclusion, we have developed the first catalytic imine–imine
cross-coupling reaction, which proceeds under mild conditions to
afford 1,2-diamines in high yields with high diastereoselectivities.
Distinguishing features of this novel reaction are as follows: (1) only
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This work was partially supported by a Grant-in-Aid for
Science Research from the Japan Society for the Promotion of
Science (JSPS), the Global COE Program, The University of
Tokyo, MEXT, Japan, and the Japan Science Technology Agency
(JST). Mr. Zhiyao Zhou (a UTRIP (short stay) student from
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13044 | Chem. Commun., 2014, 50, 13041--13044
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