Imino ene-type reaction of enamines with N-sulfonylimines and application to diastereoselective synthesis of N-sulfonyl-1,3-diamines

Article abstract of DOI:10.1016/j.tetlet.2014.05.123

Enamines react rapidly with N-sulfonylimines to afford imino ene-type adducts. The reaction proceeds even at -78 °C in the presence of acetic acid and shows high diastereoselectivity. Acid hydrolysis of imino ene-type products affords β-amino ketones, and

Full text of DOI:10.1016/j.tetlet.2014.05.123

Accepted Manuscript
Imino ene-type reaction of enamines with N-sulfonylimines and application to
diastereoselective synthesis of N-sulfonyl-1,3-diamines
Mai Ito, Takeru Kashiwagi, Shunsuke Kotani, Makoto Nakajima, Masaharu
Sugiura
PII:
S0040-4039(14)00956-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.123
TETL 44714
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
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15 March 2014
26 May 2014
30 May 2014
Please cite this article as: Ito, M., Kashiwagi, T., Kotani, S., Nakajima, M., Sugiura, M., Imino ene-type reaction of
enamines with N-sulfonylimines and application to diastereoselective synthesis of N-sulfonyl-1,3-diamines,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.123
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Imino ene-type reaction of enamines with N-
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diamines
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R'O2S
NH
O
SO2R'
H
2
N
+
Hydrolysis
1
R
R
R'O2S
R
1,2-anti
Mai Ito, Takeru Kashiwagi, Shunsuke Kotani,
Makoto Nakajima, and Masaharu Sugiura*
NH
N
R'O2S
N
NH
N
3
H
2
H
Graduate School of Pharmaceutical Sciences, Kumamoto
University, and Priority Organization for Innovation and
Excellence, Kumamoto University,
1
R
Reduction
Imino ene-type
reaction
1,2-anti-2,3-syn

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Imino ene-type reaction of enamines with N-sulfonylimines and application to
diastereoselective synthesis of N-sulfonyl-1,3-diamines
Mai Ito,a Takeru Kashiwagi,a Shunsuke Kotani,a,b Makoto Nakajima,a Masaharu Sugiuraa,
a
Graduate School of Pharmaceutical Sciences, Kumamoto University.
Priority Organization for Innovation and Excellence, Kumamoto University.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Enamines react rapidly with N-sulfonylimines to afford imino ene-type adducts. The reaction
proceeds even at –78 °C in the presence of acetic acid and shows high diastereoselectivity.
Acid hydrolysis of imino ene-type products affords -amino ketones, and reduction with
NaBH3CN furnishes N-sulfonyl-1,3-diamines with high diastereoselectivities. The
stereochemistry of these transformations is considered based on transition state models.
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Diamines
Enamine
Imino ene-type reaction
One-pot reaction
Enamines are powerful enolate equivalents in organic
synthesis and are widely utilized in alkylations, acylations, and
Michael additions.1 However, reactions of enamines with imines
are limited. In 1969, Nomura et al. reported that
cyclohexanones/morpholine-derived enamines slowly reacted
with benzaldehyde/aniline-derived imines in methanol to afford
imino ene-type adducts in low yields.2,3 Later, they also found
other transformations via [2+2] cycloaddition between enamines
and N-arylimines in acetic acid.4 In 1975, Marchetti et al.
revealed that 2-phenyl-3H-indol-3-one reacted reversibly with
cyclohexanone-derived enamines to afford imino ene-type
products.5 They proposed a synchronous mechanism to explain
the position of the double bond of the enamine products.
Recently, Dixon et al. reported chiral biphenol-catalyzed
enantioselective Mannich-type reaction of N-Boc-imines with
aryl methyl ketones-derived enamines.6
(Scheme 1, the third equation). This communication reports these
findings.
HSiCl3
SO2R'
R'O2S
R
N
N
NH
N
3
HMPA catalyst
+
2
1
R
H
Domino C–C bond
formation/reduction
1,2-anti-2,3-anti-3
1
2
(Previous Work)
R'O2S
NH
O
Imino
ene-type
reaction
2
Hydrolysis
1
R
R'O2S
5
(This Work)
NH
N
R
R'O2S
NH
N
3
2
4
1
R
We have more recently found that a domino reaction of N-
sulfonylimines 1, enamines 2, and trichlorosilane in the presence
of HMPA as a Lewis base catalyst provides N-sulfonyl-1,3-
Reduction
1,2-anti-2,3-syn-3
diamines
3 with high 1,2-anti-2,3-anti diastereoselectivity
Scheme 1. Imino ene-type reaction of N-sulfonylimines 1 and
enamines 2 and transformations of imino ene-type products 4.
(Scheme 1, the first equation).7 In the course of this study, we
unexpectedly found that imines 1 and enamines 2, in the absence
of trichlorosilane and the catalyst, underwent a rapid imino ene-
type reaction to afford enamines 4. Acid hydrolysis of 4 afforded
1,2-anti--amino ketones 5 (Scheme 1, the second equation).
Meanwhile, reduction of 4 with NaBH3CN afforded 1,2-anti-2,3-
syn-N-sulfonyldiamines 3 with a stereochemistry that differed
from that observed in the domino reaction with trichlorosilane7
Initially, we monitored the reaction of benzaldehyde-derived
N-tosylimine 1a and cyclohexanone/piperidine-derived enamine
2a by 1H-NMR spectroscopy (Eq 1). After the addition of
enamine 2a to a solution of imine 1a in CD2Cl2 at 0 °C, the
instant generation of imino ene-type adduct 4aa was observed
with good diastereoselectivity (anti/syn = 88/12).8 According to
Mayr’s reactivity scale, the second order kinetic constant (k20 °C
)
———
 Corresponding authors. Tel.: +81-96-371-4395; fax: +81-96-362-7692; e-mail address: msugiura@kumamoto-u.ac.jp (M. Sugiura).

2
Tetrahedron Letters
for C–C bond formation between imine 1a and enamine 2a can
be estimated to be 32.1 Lmol–1s–1 (>99% conversion within 10 s
at 20 °C).9 Representative 1H-NMR data of anti-4aa are shown in
Eq 1. The broad peak at 9.28 ppm was assigned to the amide
proton bound intramolecularly to the piperidino nitrogen, as it
disappeared quickly upon addition of CD3OD. Interestingly, this
deuteration experiment revealed that the H4 olefin proton was
also gradually substituted by deuterium.8,10
Meanwhile, the reaction of imine 1a with acetophenone-
derived enamine 2b, bearing no allylic proton, proceeded rapidly
to afford enamine 4ab (Scheme 3).8 This result supports the
stepwise mechanism via a zwitterionic intermediate (Scheme 2)
rather than a concerted mechanism.
Because enamine 2a alone was not deuterated by CD3OD, we
speculated that the tosylamide group intramolecularly delivered
the deuterium atom to the 4-position. Scheme 2 illustrates the
proposed reaction mechanism. Nucleophilic addition of 2a to 1a
affords a zwitterionic intermediate ZI, and the amide anion
abstracts the hydrogen at the 4-position intramolecularly to afford
imino ene-type product 4aa. Upon addition of CD3OD, the amide
hydrogen of 4aa is quickly exchanged with a deuterium to afford
N-D-4aa, which then delivers the deuterium atom to the 4-
position, forming deuterated zwitterionic intermediate ZI-d.
Because the amide anion of ZI-d cannot abstract the trans proton
at the 4-position, the retro-imino ene-type reaction of ZI-d may
proceed to generate deuterated enamine 2a-d, which then reacts
again with imine 1a from the side anti to the deuterium atom to
afford the deuterated product ent-4aa-d.
Scheme 3. The reaction of imine 1a and enamine 2b.
Having these mechanistic insights in mind, imino ene-type
reactions between various N-sulfonylimines 1 with enamine 2a
were investigated (Table 1). To evaluate the reaction efficiency,
imino ene-type products 4 were converted to -amino ketones 5
by hydrolysis using aqueous acetic acid. The reaction of imine 1a
with enamine 2a proceeded even at −78 °C and showed an
improved anti selectivity (anti/syn = 94/6), although the reaction
time was extended to 21 h (entry 1). Addition of acetic acid (1
equiv) effectively shortened the reaction time (3 h) without
decreasing the diastereoselectivity (entry 2). This additive was
also effective for the reaction of other imines with enamine 2a
(entries 3–9). N-Mesylimine 1b required a longer reaction time (6
h), but provided somewhat higher selectivity than 1a (entry 3).
With slight modifications of the reaction temperature and/or time
according to their electronic and steric nature, aromatic N-
tosylimines 1c–g afforded the corresponding -amino ketones in
high yields and diastereoselectivities (entries 4–8). Whereas
cinnamaldehyde-derived N-tosylimine 1h exhibited
a low
diastereoselectivity (entry 9), cyclohexanecarboxaldehyde- and
3-phenylpropanal-derived imines 1i and 1j provided high anti
selectivities (entries 10 and 11). Acetic acid was not added in the
latter cases to suppress the decomposition of imines 1i and 1j
with the acid. These results indicate that the bulkier the R group
of imine 1 is, the higher the diastereoselectivity is.
Scheme 2. Assumed mechanism for imino ene-type reaction
and deuterium incorporation.
Table 1. Imino ene-type reactions between various N-
sulfonylimines 1 and enamines 2a
To prove the reversibility assumed above, N-mesylimine 1b
was added to the product 4aa prepared in CDCl3, and the reaction
was monitored by 1H-NMR analysis (Eq 2).8 Rapid generation of
the corresponding N-mesylimine adduct 4ba was observed, and
the 4aa to 4ba ratio was almost constant after 4 h.11 These
observations clearly support the reversibility of the process.
Entry
1b,c
2
R (1)
Ph (1a)
5
Yield (%)
anti/syn
94/6
95/5
96/4
97/3
5aa
5aa
5ba
5ca
82
89
96
90
Ph (1a)
3d
Ph (1b)e
p-O2NC6H4 (1c)
4f

3
5g
p-MeOC6H4 (1d)
2-naphthyl (1e)
1-naphthyl (1f)
2-furyl (1g)
(E)-PhCH=CH (1h)
cyclohexyl (1i)
Ph(CH2)2 (1j)
5da
5ea
5fa
5ga
5ha
5ia
97
95
82
91
67
50
76
93/7
97/3
>99/1
93/7
66/34
99/1
99/1
6
7f,g
8
9
10b,g
11b,g
5ja
a
Unless otherwise noted, the reaction of an imine 1 (0.5 mmol) and enamine
2a (1.2 equiv) was conducted in the presence of AcOH (1 equiv) at –78 °C
for 3 h. The reaction mixture was then quenched by treatment with aqueous
acetic acid at rt.
b Without acetic acid.
c For 21 h.
d For 6 h.
e N-Mesylimine (1b) was used instead of 1a.
f For 24 h.
g At –45 °C.
At low temperature, the imino ene-type reaction would not be
under equilibrium but kinetically controlled, because the
diastereomeric ratio of 4aa, generated from 1a and 2a at 0 °C
(anti/syn = 88/12), was not changed after standing at –78 °C for 3
h with acetic acid (1.0 equiv). Thus, the stereochemistry can be
rationalized as shown in Scheme 4. The acetic acid protonates
and activates the imine. The enamine adds to the resulting
iminium ion via transition states TS1 or TS2. TS1 would
presumably be more stable than TS2 because of the lower steric
repulsion of the R group, resulting in the anti iminium ion
intermediate. Then deprotonation by the acetate anion would
furnish the anti imino ene-type product. When the R group is as
bulky as 1-naphthyl, TS1 becomes exclusive (Table 1, entry 7).
On the other hand, TS2, leading to the syn product, becomes
competitive when the R group is as small as PhCH=CH, thus
lowering the selectivity (Table 1, entry 9).
Scheme 5. The reaction of imine 1a and various enamines 2.
To utilize the enamine moiety of the imino ene products 4,
reduction to the N-sulfonyl-1,3-diamines was next
3
investigated.12,13 It turned out that 4aa prepared in situ from 1a
and 2a could be reduced by treatment with acetic acid (9 equiv)
and NaBH3CN14 (2 equiv) at –45 °C to afford 1,2-anti-2,3-syn-N-
sulfonyl-1,3-diamine 3aa with high diastereoselectivity (Table 2,
entry 1).15 Notably, the stereochemical outcome differs from that
of the domino reaction using trichlorosilane reported
previously.7,16 With a slight modification of the amount of
reductant and/or the reaction temperature, the reaction of other
aromatic imines 1b–e, 1g, 1i, and 1j also furnished the
corresponding 1,2-anti-2,3-syn-N-sulfonyldiamines 3 with high
yields and diastereoselectivities (entries 2–8). It should be noted
that the observed diastereoselectivity in the C–C bond formation
was retained under the reduction conditions (Tables 1 and 2).
Table 2. Synthesis of N-sulfonyl-1,3-diamines 3 from various
N-tosylimines 1 and enamine 2aa
Entry
1c
R (1)
3
Yield (%)
Drb
Ph (1a)
3aa
3ba
3ca
3da
3ea
3ga
3ia
3ja
93
92
90
87
97
84
80
75
95/5
96/4
96/4
96/4
97/3
94/6
93/7
99/1
2c
Ph (1b)d
3e
p-O2NC6H4 (1c)
p-MeOC6H4 (1d)
2-naphthyl (1e)
2-furyl (1g)
cyclohexyl (1i)
Ph(CH2)2 (1j)
Scheme 4. Transition state models for the imino ene-type
reaction in the presence of acetic acid.
4c
5c,f
6e,f
7
The scope and limitation of enamines were next examined for
the reaction with imine 1a (Scheme 5). Cyclohexenylamines 2a,
2c, and 2d provided high diastereoselectivities, whereas
cyclopentenylamine 2e showed a lower selectivity. TS2 in
Scheme 4 would become more competitive in the case of 2e,
because the cyclopentenyl group interferes less with the R group
than the cyclohexenyl group.
8c
a
Unless otherwise noted, the reaction of an imine 1 (0.5 mmol) and enamine
2a (1.2 equiv) was conducted under the conditions shown in Table 1. Acetic
acid (9 equiv) and sodium cyanoborohydride (2 or 3 equiv) in methanol were
successively added, and the reaction mixture was stirred at –45 °C for 1 h
before workup.
b
Dr = 1,2-anti-2,3-syn-isomer/1,2-syn-2,3-syn-isomer. The other isomers
were not observed. See ref 15.
c With NaBH3CN (2 equiv).
d N-Mesylimine (1b) was used instead of 1a.
e With NaBH3CN (3 equiv).
f At 0 °C for the reduction step.
The scope and limitation of enamines in the N-sulfonyl-1,3-
diamine synthesis using imine 1a were also examined (Scheme
6). Although enamine 2b provided a low diastereoselectivity,
enamines 2a, 2c, 2d, and 2e exhibited high diastereoselectivities,
as observed in the C–C bond formation/hydrolysis (Schemes 5
and 6)

4
Tetrahedron Letters
4.
(a) Nomura, Y.; Tomoda, S.; Takeuchi, Y. Chem. Lett. 1972, 79–82.
(b) Nomura, Y.; Kimura, M.; Shibata, T.; Takeuchi, Y.; Tomoda, S.
Bull. Chem. Soc. Jpn. 1982, 55, 3343–3344.
5.
Berti, C.; Greci, L.; Marchetti, L. Gazz. Chim. Ital. 1975, 105, 993–
999. See also p. 2018–2019 of ref. 1d.
6.
7.
Tillman, A. L.; Dixon, D. J. Org. Biomol. Chem. 2007, 5, 606–609.
Kashiwagi, T.; Kotani, S.; Nakajima, M.; Sugiura, M. Tetrahedron
Lett. 2014, 55, 1924–1926. For -amino alcohol synthesis using
aldehydes instead of imines, see: Kashiwagi, T.; Kotani, S.; Sugiura,
M.; Nakajima, M. Tetrahedron 2011, 67, 531–539.
8.
9.
For NMR spectra, see the Supplementary Material.
(a) Appel, R.; Mayr, H. J. Am. Chem. Soc. 2011, 133, 8240–8251. (b)
Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. Eur. J. 2003, 9,
2209–2218. For a review: (c) Mayr, H.; Ofial, A. R. J. Phys. Org.
Chem. 2008, 21, 584–595.
10.
The deuterium exchange of the H2 proton was also observed,
indicating transient generation of the 2,3-enamine. See NMR spectra
in the Supplementary Material.
11.
12.
The reversibility was also confirmed by other control experiments,
see the Supplementary Material.
For 1,3-diamines in chiral auxiliaries or catalysts, see: (a) Blaser, H.-
U. Chem. Rev. 1992, 92, 935–952. (b) Ozaki, S.; Mimura, H.;
Yasuhara, N.; Masui, M.; Yamagata, Y.; Tomita, K.; Collins, T. J. J.
Scheme 6. N-Sulfonyl-1,3-diamine synthesis from imine 1a
and various enamines 2.
The stereochemistry of the reduction can be rationalized by
assuming an axial attack of NaBH3CN on the iminium ion
intermediate (Figure 1).16 Because of the allylic strain between
the piperidine ring, the tosylamide side chain locates in the axial
position and hinders the equatorial attack of the reductant. The
cycloalkane moiety should be important to fix the conformation
of the iminium ion intermediate, because the reaction of enamine
2b resulted in a low selectivity (Scheme 6).
Chem. Soc., Perkin Trans.
2 1990, 353–360. (c) Pini, D.;
Mastantuono, A.; Uccello-Barretta, G.; Iuliano, A.; Salvadori, P.
Tetrahedron 1993, 49, 9613–9624. (d) Ogino, K.; Tamiya, H.;
Kimura, Y.; Azuma, H.; Tagaki, W. J. Chem. Soc., Perkin Trans. 2
1996, 979–984. (e) Reddy, P. V. G.; Tabassum, S.; Blanrue, A.;
Wilhelm, R. Chem. Commun. 2009, 5910–5912. (f) Sohtome, Y.;
Shin, B.; Horitsugi, N.; Takagi, R.; Noguchi, K.; Nagasawa, K.
Angew. Chem. Int. Ed. 2010, 49, 7299–7303. (g) Wang, W.-H.; Abe,
T.; Wang, X.-B.; Kodama, K.; Hirose, T.; Zhang, G.-Y. Tetrahedron:
Asymmetry 2010, 21, 2925–2933. (h) Zhang, H.; Liao, Y.-H.; Yuan,
W.-C.; Zhang, X.-M. Eur. J. Org. Chem. 2010, 3215–3218. (i) Wang,
W.-H.; Wang, X.-B.; Kodama, K.; Hirose, T.; Zhang, G.-Y.
Tetrahedron 2010, 66, 4970–4976. (j) Murtinho, D.; Serra, M. E. S.;
Rocha Gonsalves, A. M. d'A. Tetrahedron: Asymmetry 2010, 21, 62–
68. (k) Yao, Q. J.; Judeh, Z. M. A. Tetrahedron 2011, 67, 4086–4092.
(l) Kodama, K.; Sugawara, K.; Hirose, T. Chem. Eur. J. 2011, 17,
13584–13592. (m) Hirose, T.; Sugawara, K.; Kodama, K. J. Org.
Chem. 2011, 76, 5413–5428. (n) Groselj, U.; Ricko, S.; Svete, J.;
Stanovnik, B. Chirality 2012, 24, 412–419. (o) Csillag, K.; Szakonyi,
Z.; Fulop, F. Tetrahedron: Asymmetry 2013, 24, 553–561. (p)
Mayans, E.; Gargallo, A.; Alvarez-Larena, A.; Illa, O.; Ortuno, R. M.
Eur. J. Org. Chem. 2013, 1425–1433.
For other synthetic methods for 1,3-diamines, see: (a) Merla, B.;
Arend, M.; Risch, N. Synlett 1997, 177–178. (b) Kaiser, A.; Balbi, M.
Tetrahedron: Asymmetry 1999, 10, 1001–1014. (c) Merla, B.; Risch,
N. Synthesis 2002, 1365–1372. (d) Hou, X.-L.; Luo, Y.-M.; Yuan, K.;
Dai, L.-X. J. Chem. Soc. Perkin Trans. 1 2002, 1487–1490. (e)
Chauveau, A.; Martens, T.; Bonin, M.; Micouin, L.; Husson, H.-P.
Synthesis 2002, 1885–1890. (f) Matsubara, R.; Nakamura, Y.;
Kobayashi, S. Angew. Chem. Int. Ed. 2004, 43, 1679–1681. (g) Lanter,
J. C.; Chen, H.; Zhang, X.; Sui, Z. Org. Lett. 2005, 7, 5905–5907. (h)
Zhao, C.-H.; Liu, L.; Wang, D.; Chen, Y.-J. Eur. J. Org. Chem. 2006,
2977–2986. (i) Terada, M.; Machioka, K.; Sorimachi, K. Angew.
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2897–2904.
Fig 1. Assumed transition state.
In summary, we have demonstrated that N-sulfonylimines and
enamines undergo an imino ene-type reaction smoothly with a
high diastereoselectivity. Hydrolysis and reduction of the imino
ene products afforded 1,2-anti--amino ketones and 1,2-anti-2,3-
syn-N-sulfonyldiamines, respectively, without decreasing the
high diastereoselectivities. Asymmetric catalysis and the
extension of this method to reactions with various electrophiles
other than imines are currently under investigation.
13.
Acknowledgments
This work was partially supported by a Grant-in-Aid for
scientific research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
Supplementary Material
14.
15.
Supplementary data associated with this article can be found
in the online version at...
The relative configurations of both the major and second major
diastereomers of 3aa were unambiguously determined by X-ray
crystallography to be 1,2-anti-2,3-syn (Figure, left) and 1,2-syn-2,3-
syn (Figure, right), respectively. CCDC 991772 (1,2-anti-2,3-syn-
3aa) and CCDC 991773 (1,2-syn-2,3-syn-3aa) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
References and notes
1.
For leading references, see: (a) Stork, G.; Terrell, R.; Szmuszkovicz,
J. J. Am. Chem. Soc. 1954, 76, 2029–2030. (b) Stork, G.; Landesman,
H. K. J. Am. Chem. Soc. 1956, 78, 5128–5129. (c) Stork, G.;
Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am.
Chem. Soc. 1963, 85, 207–222. For a review, see: (d) Hickmott, P. W.
Tetrahedron 1982, 38, 1975–2050.
2.
3.
Tomoda, S.; Takeuchi, Y.; Nomura, Y. Tetrahedron Lett. 1969, 10,
3549–3552.
For a review on imino ene reaction, see: Borzilleri, R. M.; Weinreb,
S. M. Synthesis 1995, 347–360.

5
product 4aa is not the predominant intermediate for the domino
reaction using trichlorosilane (ref. 7). In this domino reaction, the
silane tethering to the tosylamide side chain would reduce the
iminium ion intermediate to afford the 1,2-anti-2,3-anti-N-sulfonyl-
diamine as shown below.
16.
The addition of trichlorosilane to imino ene-type product 4aa (in
CH2Cl2 at 0 °C for 1 h) afforded 1,2-anti-2,3-anti-N-sulfonyldiamine
3aa in low yield (26%). Higher yield (68%) was obtained when
enamine 2a was added to a solution of imine 1a and trichlorosilane
under the same conditions. Therefore, we believe that imino ene-type