Direct catalytic asymmetric mannich-type reaction of benzyl isocyanide: Stereoselective synthesis of 1,2-diarylethylenediamines

Article abstract of DOI:10.1002/ejoc.201500336

A direct catalytic asymmetric Mannich-type reaction of benzyl isocyanide using a Cu^I catalyst and N-(diphenylthiophosphinoyl)imines was developed. The simultaneous activation strategy by soft-soft interaction was the key to promote the reaction using a weakly acidic pronucleophile, benzyl isocyanide. The spontaneous cyclization of the Mannich adduct afforded the corresponding enantioenriched imidazolines, which could be precursors for a variety of 1,2-diarylethylenediamines. Enantioenriched 4,5-diarylimidazolines were directly accessed by catalytic asymmetric C-C bond-forming reaction of benzyl isocyanide and N-(thiophosphinoyl)aldimines. The imidazolines were readily transformed into enantioenriched 1,2-diarylethylenediamines.

Full text of DOI:10.1002/ejoc.201500336

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500336
Direct Catalytic Asymmetric Mannich-Type Reaction of Benzyl Isocyanide:
Stereoselective Synthesis of 1,2-Diarylethylenediamines
Keiji Tamura,[a] Naoya Kumagai,*[a] and Masakatsu Shibasaki*[a,b]
Keywords: Isocyanides / Asymmetric catalysis / Chiral diamines / Mannich reaction / Imidazoline
A direct catalytic asymmetric Mannich-type reaction of
benzyl isocyanide using a CuI catalyst and N-(diphenylthio-
benzyl isocyanide. The spontaneous cyclization of the
Mannich adduct afforded the corresponding enantioenriched
phosphinoyl)imines was developed. The simultaneous acti- imidazolines, which could be precursors for a variety of 1,2-
vation strategy by soft–soft interaction was the key to pro-
mote the reaction using a weakly acidic pronucleophile,
diarylethylenediamines.
basesweregenerallyidentical,sothatonlyC2-symmetric1,2-di-
arylethylenediamines were accessible.[4] Non-C2-symmetric
1,2-diarylethylenediamine motifs are found in biologically
active compounds, and stereoselective synthesis of this class
of compounds is in high demand.[5] For utility as chiral li-
gands in enantioselective catalysis, differential steric/elec-
tronic modifications of the two aryl groups allow for a more
Introduction
Optically pure 1,2-diarylethylenediamines have been in
widespread use as chiral ligands for a range of catalytic
asymmetric reactions.[1] Given the growing demand for a
variety of 1,2-diarylethylenediamines, several synthetic ap-
proaches have been reported to date.[2] The use of enantio-
enriched hydrobenzoins as starting materials, oxygen ana-
logues of 1,2-diarylethylenediamines, has been a commonly
exploited method because of the reliable procedures to
access optically active hydrobenzoins [Scheme 1a (i)].[2a]
Spirocyclic diimines were shown to be feasible precursors
for 1,2-diarylethylenediamines through a reduction/resolu-
tion sequence [Scheme 1a (ii)].[1a] However, these methods
require lengthy transformations, expensive starting materi-
als, and arduous chiral resolution, leading to the fact that
the range of commercially available 1,2-diarylethylenedi-
amines remains limited. In 2008, Chin et al. reported a ge-
neral synthetic method for 1,2-diarylethylenediamines uti-
lizing the aza-Cope rearrangement [Scheme 1a (iii)].[2b]
Commercially available (R,R)-1,2-bis(2-hydroxyphenyl)-1,2-
diaminoethane was used as a pivotal unit to form the corre-
sponding Schiff bases with various aldehydes, which under-
went diaza-Cope rearrangement in a diastereoselective
manner, to provide a range of chiral 1,2-diarylethylenedi-
amines. However, this procedure includes chirality introduc-
tion and carbon–carbon bond formation in separate steps,
rendering the process less efficient in terms of step econ-
omy.[3] Furthermore, the two aromatic groups of the Schiff
[a] Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
E-mail: nkumagai@bikaken.or.jp
mshibasa@bikaken.or.jp
http://www.bikaken.or.jp/research/group/shibasaki/shibasaki-
lab/index_e.html
[b] JST, ACT-C,
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500336.
Scheme 1. Synthetic methods for 1,2-diarylethylenediamines.
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K. Tamura, N. Kumagai, M. Shibasaki
SHORT COMMUNICATION
flexible design of ligand architecture bearing the 1,2-diaryl- could be barely transformed into 1,2-diarylethylenedi-
ethylenediamine motif.
amines.[7] In spite of the extensive research devoted to this
In this context, we anticipated that a direct catalytic type of reaction, the employment of benzylic isocyanides as
enantioselective Mannich-type reaction of benzylic isocyan- pronucleophiles in the Mannich-type reaction has been
ides would enable expeditious access to both C2- and non- much less explored, probably because of the lower acidity
C2-symmetric 1,2-diarylethylenediamines [Scheme 1a (iv)]. of the α-proton [Scheme 1b (ii)].[8] On the basis of our ex-
The direct catalytic asymmetric Mannich-type reaction of tensive studies on catalytic asymmetric addition of low-re-
isocyanides has recently emerged as a powerful tool to active nitrile-based pronucleophiles,[9] we envisioned that a
furnish enantioenriched imidazolines, which can be trans- catalyst design based on cooperative catalysis[10] would
formed into 1,2-diamines by hydrolysis [Scheme 1b (i)].[6] overcome the intrinsic low reactivity of benzylic isocyan-
Although several catalytic protocols have been developed, ides. Herein, we report the direct catalytic asymmetric
the scope of isocyanides was limited to fairly acidic isocyan- Mannich-type reaction of benzyl isocyanide and N-[di-
ides, e.g., α-isocyano esters, and the resulting imidazolines phenylthiophosphinoyl (thioDpp)]imines as soft Lewis-
Table 1. Initial screening.[a]
[a] Benzyl isocyanide (1) was added to the mixture of Lewis acid and ligand, followed by the addition of imine 2a. [b] MesCu represents
mesitylcopper. Tetrakis(acetonitrile) complex of CuPF6 was used. [c] Combined yield of both diastereomers after silica gel column
chromatography. [d] dr and ee were determined by 1H NMR analysis and chiral-stationary-phase HPLC analysis, respectively. [e] 10 mol-
% of mesitylcopper and 5 mol-% of (R,Rp)-Ph-Taniaphos were used. [f] Inverse addition was applied [imine 2a was added prior to benzyl
isocyanide (1)].
2
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Stereoselective Synthesis of 1,2-Diarylethylenediamines
basic electrophiles, which could be simultaneously activated the enantioselectivity,[14] which prompted us to attempt a
by a soft Lewis acid. The resulting enantioenriched imid- reaction with mesitylcopper and (R,Rp)-Ph-Taniaphos in a
azolines were transformed into both C2- and non-C2-sym- ratio of 2:1, affording 3a in comparable yield with constant
metric 1,2-diarylethylenediamines.
and marginally improved enantioselectivity (Entry 10).[15]
The addition of 2a to a mixture of mesitylcopper and
(R,Rp)-Ph-Taniaphos prior to 1 (for Entries 1–10, 1 was
added prior to 2a) had a beneficial effect to improve further
Results and Discussion
From our study of the soft Lewis acid/hard Brønsted the diastereo- and enantioselectivity, furnishing the imid-
base cooperative catalytic system,[10b] we anticipated that a azoline 3a in 84% yield with a diastereomeric ratio of 3:1
soft Lewis acid would activate the isocyanide functionality and 78% ee for trans (Entry 11).[16] A plausible reaction
to facilitate deprotonation of benzyl isocyanide (1) by a mechanism is delineated in Figure 1. Initially, a chiral
mild Brønsted base. For the subsequent enantioselective (R,Rp)-Ph-Taniaphos/CuI complex was formed to activate 1
addition to imines, imines bearing a soft Lewis-basic func- in an end-on coordination mode (complex 4), and sub-
tionality would have a better opportunity to be assembled sequent deprotonation led to the formation of a CuI com-
with the activated nucleophile in a chiral environment of a plex 5 bearing a nucleophilically active α-C-bound benzyl
chirally decorated Lewis acid catalyst.
isocyanide with liberation of mesitylene.[17] The coordina-
On the basis of this assumption, N-thioDpp-imine[11,12] tion of N-thioDpp-imine 2 to the complex 5 induced C–C
2a derived from benzaldehyde was selected as an electro- bond formation in the near proximity of the chiral environ-
phile (Table 1). In the initial screening of chiral ligands, ment of (R,Rp)-Ph-Taniaphos (complex 6). Thus-formed in-
mesitylcopper was used as a conjugated soft Lewis acidic/ termediate 7 quickly cyclized to give C-bound CuI–imid-
Brønsted basic catalyst component (vide infra; Figure 1).[13] azoline complex 8, which functioned as the soft Lewis acid/
A series of archetypical chiral bis(phosphine) ligands was hard Brønsted base cooperative catalyst and subsequent
tested with an equimolar amount of mesitylcopper (En- proton exchange with 1 completed the catalytic cycle. We
tries 1–8). In general, trans-imidazolines 3a were preferen- also tested cationic CuI and AgI salts as soft Lewis acids in
tially produced with low enantioselectivity (Entries 1–7) ex- combination with additional Brønsted base (Entries 12–15).
cept for the reaction with (R,Rp)-Ph-Taniaphos, which af- A binary catalyst comprising [Cu(CH3CN)4]PF6/KOtBu
forded trans-3a with promising enantioselectivity (56% ee) promoted the catalytic generation of the α-isocyano carb-
(Entry 8). Lowering the reaction temperature (–40 °C) with anion from 1 and subsequent reaction with 2 at room tem-
the extended reaction time slightly improved enantio- perature to give imidazoline 3a with slightly higher dia-
selectivity (Entry 9). The reaction with a two-fold excess of stereoselectivity (Entry 12). A further attempt to improve
(R,Rp)-Ph-Taniaphos with respect to mesitylcopper eroded stereoselectivity at a lower reaction temperature resulted in
Figure 1. Plausible pathways.
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K. Tamura, N. Kumagai, M. Shibasaki
SHORT COMMUNICATION
Scheme 2. Attempts at reactions with other imines.
failure (Entry 13). The reaction with AgI salts instead of
[Cu(CH3CN)4]PF6 significantly decreased the enantio-
selectivity of trans-3a (Entries 14 and 15). The basic catalyst
lacking a soft Lewis acid barely promoted the reaction, sug-
gesting that cooperative catalysis was essential for this reac-
tion (Entry 16). Under the optimized reaction conditions
(Entry 11), the reaction using analogous N-(diphenyl-
phosphinoyl)imine 9,[18] lacking the soft Lewis-basic func-
tionality, produced the corresponding imidazoline 10 in low
conversion as well as low diastereoselectivity, which implied
that C–C bond formation proceeded with noncoordinated
imine 9 (Scheme 2).[19] The reactions of other commonly
used activated imines, e.g., N-Boc, N-p-Ns, and N-(2-pyr-
idinesulfonyl)imines 11–13, respectively, resulted in a com-
plicated mixture or the recovery of the substrates, which
indicated that the simultaneous activation of benzyl iso-
cyanide (1) and N-thioDpp-imine 2 by a soft–soft inter-
action was the key to promote the reaction.
Table 2. Substrate scope of N-thioDpp-imines 2.[a]
Table 2 summarizes the substrate scope of the reaction.
Imines bearing electron-donating substituents on the aro-
matic ring showed similar yields and stereoselectivities as 2a
(Entries 2–4). On the other hand, imines bearing electron-
withdrawing substituents generally gave lower yields and
stereoselectivities, presumably due to partial decomposition
during the reaction (Entries 5–9).[20] An imine derived from
2-naphthaldehyde gave moderate diastereoselectivity and
enantioselectivity (Entry 10). Imines derived from hetero-
aromatic aldehydes were also applicable to these reaction
conditions, providing similar reaction outcomes (Entries 11
and 12).[21] Although the diastereomeric ratio remained low,
the present catalytic protocol could be applied to the reac-
tion with N-thioDpp-ketimine 14, affording the corre-
sponding imidazoline 15 with 76% ee (Equation 1).
[a] Isolated yield (combined yields of trans and cis isomers) is
noted; drs and ees were determined by H NMR analysis and chi-
ral-stationary-phase HPLC analysis, respectively.
1
The thioDpp group on the nitrogen atom of product 3
was easily removed by treatment with aqueous HClO4 at
4
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Stereoselective Synthesis of 1,2-Diarylethylenediamines
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yield (Scheme 3). The following basic hydrolysis of 16a with
saturated aqueous Ba(OH)2 at 80 °C furnished 1,2-diphen-
ylethylenediamine (17a) in 93% yield.[22] The enantiopurity
of 16a and 17a remained unchanged under these transfor-
mations;[23] trans-3f (m-Br) and trans-3i (p-F) were also sub-
jected to the two-step hydrolytic conditions to afford 1,2-
diarylethylenediamines 17f and 17i, respectively, demon-
strating the versatile synthesis of non-C2-symmetric 1,2-di-
arylethylenediamines.
[2]
[3]
[4]
P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
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ment approach. Electron-deficient p-nitrobenzaldehyde gave a
five-membered aminal intermediate to enable the stepwise for-
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[6]
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[7]
Scheme 3. Demonstration of the synthesis of enantioenriched 1,2-
diarylethylenediamines. Reagents and conditions: (a) 60% HClO4
aq., EtOH, 65 °C, 18–24 h; (b) satd. Ba(OH)2 aq., 80 °C, 23 h;
(c) satd. Ba(OH)2 aq., 65 °C, 24 h.
Conclusions
A direct catalytic asymmetric Mannich-type reaction of
benzyl isocyanide and N-thioDpp-imines was developed.
The simultaneous activation strategy was the key to activate
the less acidic benzyl isocyanide and promote the subse-
quent C–C bond-forming reaction. Although the diastereo-
and enantioselectivity remained unsatisfactory, the expedi-
tious approach to 1,2-diarylethylenediamine by a single-
step construction of a C–C bond and two stereogenic cen-
ters is noteworthy. Further improvement in stereoselectivity
to devise a general and reliable protocol for optically pure
1,2-diarylethylenediamine is currently under way.
[8]
Only racemic reactions have been developed: a) R. S. Bon, C.
Hong, M. J. Bouma, R. F. Schmitz, F. J. J. de Kanter, M. Lutz,
A. L. Spek, R. V. A. Orru, Org. Lett. 2003, 5, 3759; b) N. El-
ders, R. F. Schmitz, F. J. J. de Kanter, E. Ruijter, M. B. Groen,
R. V. A. Orru, J. Org. Chem. 2007, 72, 6135; c) M. A. Honey,
Y. Yamashita, S. Kobayashi, Chem. Commun. 2014, 50, 3288.
a) Y. Kawato, N. Kumagai, M. Shibasaki, Chem. Commun.
2013, 49, 11227; b) D. Sureshkumar, V. Ganesh, N. Kumagai,
M. Shibasaki, Chem. Eur. J. 2014, 20, 15723.
Recent reviews on cooperative catalysis: Lewis acid/Brønsted
base: a) M. Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102,
2187; b) N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed.
2011, 50, 4760; Angew. Chem. 2011, 123, 4856; Lewis acid/
Lewis base: c) M. Kanai, N. Kato, E. Ichikawa, M. Shibasaki,
Synlett 2005, 1491; d) D. H. Paull, C. J. Abraham, M. T.
Scerba, E. Alden-Danforth, T. Lectka, Acc. Chem. Res. 2008,
41, 655–663. Lewis acid/Brønsted acid and Lewis acid/Lewis
acid: e) H. Yamamoto, K. Futatsugi, Angew. Chem. Int. Ed.
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oto, K. Futatsugi, in Acid Catalysis in Modern Organic Synthe-
sis (Eds.: H. Yamamoto, K. Ishihara), Wiley-VCH, Weinheim,
2008.
[9]
Acknowledgments
[10]
This work was financially supported by JST, ACT-C, and
KAKENHI (no. 25713002) from JSPS.
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SHORT COMMUNICATION
[11]
[16] Although the association/dissociation of 1 and 2 was in rapid
equilibrium, prior addition of 2 might have a beneficial effect
on partly avoiding oversaturation of the Cu complex by 1. Slow
addition of 1 gave a similar reaction outcome.
[17] Intermolecular deprotonation by the other complex 4 might be
involved.
Synthesis of N-thioDpp-imines: a) X. Xu, C. Wang, Z. Zhou,
Z. Zeng, X. Ma, G. Zhao, C. Tang, Lett. Org. Chem. 2006, 3,
640; b) X. Xu, C. Wang, Z. Zhou, Z. Zeng, X. Ma, G. Zhao,
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10338. See also ref.[9a]
[12]
[18] For a review, see: S. M. Weinreb, R. K. Orr, Synthesis 2005,
1205.
[19] 10 was very prone to decomposition, and enantioselectivity was
not determined.
[20] Indeed, the reaction with an imine having a strongly electron-
withdrawing m-NO2 substituent gave no product because of
decomposition of the imine.
[21] For the determination of the absolute configuration, see the
Supporting Information.
[22] When the reaction was conducted by using 50% KOH aq. at
100 °C as described in ref.[7e], the diamine was obtained in ca.
60% yield with a slight reduction in enantiopurity (from 73%
to 69%).
[13] a) T. Tsuda, T. Yazawa, K. Watanabe, T. Fujii, T. Saeg, J. Org.
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[14] The reaction with 5 mol-% of mesitylcopper and 10 mol-% of
(R,Rp)-Ph-Taniaphos under otherwise identical conditions gave
3a in 88% yield, trans/cis = 61:39, 48% ee (trans), 49% ee (cis).
[15] The slight positive effect of the ratio of mesitylcopper/ligand
might be relevant to the highly coordinative nature of 1. A
speculative discussion is provided in the Supporting Infor-
mation.
[23] See the Supporting Information.
Received: March 12, 2015
Published Online: ᭿
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Stereoselective Synthesis of 1,2-Diarylethylenediamines
Diamine Synthesis
K. Tamura, N. Kumagai,*
M. Shibasaki* ................................... 1–7
Direct Catalytic Asymmetric Mannich-
Type Reaction of Benzyl Isocyanide:
Stereoselective Synthesis of 1,2-Diaryl-
ethylenediamines
Enantioenriched
4,5-diarylimidazolines
aldimines. The imidazolines were readily
transformed into enantioenriched 1,2-di-
arylethylenediamines.
were directly accessed by catalytic asym-
metric C–C bond-forming reaction of
benzyl isocyanide and N-(thiophosphinoyl)-
Keywords: Isocyanides
/
Asymmetric
catalysis / Chiral diamines / Mannich reac-
tion / Imidazoline
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